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PubMed1978

Histocompatibility antigens as markers of abnormal iron metabolism in idiopathic hemochromatosis.

To determine the frequency of HLA histocompatibility antigens in persons with idiopathic hemochromatosis and their usefulness as genetic markers of the disease, HLA typing for the A, B and C loci was carried out. HLA-A3 was found in 61% of 18 unrelated individuals with idiopathic hemochromatosis compared with 25% of 253 randomly chosen control subjects (P less than 0.001), and HLA-B7 was found in 50% and 22% respectively (P less than 0.025). Eighty-six members of seven families with idiopathic hemochromatosis were screened for abnormalities in iron metabolism with tests for serum iron concentration, transferrin saturation, serum ferritin concentration and iron content of the hepatocytes. Of the 14 persons selected for liver biopsy because of abnormalities detected by these tests, 8 had increased amounts of stainable iron in the hepatocytes. Body iron overload was subsequently demonstrated in six of the seven, who had undergone repeated phlebotomy. In sibships having one member with hemochromatosis, only 1 of 22 members had two haplotypes in common with the proband, whereas in sibships having more than 1 member with the disease 4 of 5 affected members had two haplotypes in common. HLA typing in families with hemochromatosis may provide a means of identifying persons at risk of acquiring the disease.

Epitopes↗
PubMed1997

Screening of patients with iron overload to identify hemochromatosis and porphyria cutanea tarda.

OBJECTIVE: To assess the importance of iron overload as a risk factor for porphyria cutanea tarda (PCT). DESIGN: Prospective study during a 4-month period. SETTING: Departments of emergency care, gastroenterology, and dermatology in a tertiary referral center. PATIENTS: Patients were deemed eligible for inclusion in the study if serum ferritin levels were greater than 500 micrograms/L (normal range: females, < 125 micrograms/L; males, < 325 micrograms/L). MAIN OUTCOME MEASURES: Porphyrin excretion profiles were analyzed on all patients included in the study, where clinically relevant. A diagnosis of PCT was confirmed biochemically in all cases. The HLA typing was then performed on newly diagnosed cases of PCT. RESULTS: Of 4127 patients tested, 240 patients with an elevated serum ferritin level were identified, of whom 74 had an elevated serum ferritin level of more than 500 micrograms/L. Of the latter group, 17.5% had hemochromatosis and 6.7% had PCT. The incidence of PCT in the hemochromatosis group was 23%; HLA typing revealed the presence of at least 1 of the hemochromatosis markers. CONCLUSIONS: A high serum ferritin level in the absence of evident cause should prompt investigation for both hemochromatosis and PCT. The HLA heterozygosity for hemochromatosis in some patients with PCT may be a cause of hepatic siderosis.

Adult↗
PubMed2003

AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis.

The majority of Caucasian patients with hemochromatosis are homozygous for C282Y mutation of the HFE gene. In contrast to its high prevalence in Caucasians, hemochromatosis is a rare disorder in Japan. This may be due to the low prevalence of the C282Y mutation of the HFE gene in Japanese. Recent reports suggest that the mutations of transferrin receptor 2 (TfR2) gene may be involved in non-HFE hemochromatosis. Therefore, we investigated the TfR2 gene of 6 sporadic and 5 familiar cases of Japanese hemochromatosis. Three siblings in one family were found to be homozygous for an AVAQ 594-597 deletion. All three had severe iron deposits in the hepatocytes and bile ducts, but none was affected by diabetes mellitus. This mutation was not detected in 100 control individuals. Further study was undertaken to investigate whether the large deletion of the TfR2 gene is the mutation responsible for some of the Japanese hemochromatosis cases.

Journal Article↗
PubMed2001

Hemochromatosis and iron therapy of Restless Legs Syndrome.

Restless legs syndrome (RLS) occurs in some persons with iron deficiency, and some persons with RLS benefit from oral iron therapy. Approximately one in 200 persons of northern European ancestry have hemochromatosis attributable to inheritance of two common mutations of the hemochromatosis-associated HFE gene on chromosome 6. We evaluated and treated a 46-year-old man with RLS who was diagnosed as having hemochromatosis after he developed new symptoms associated with taking iron therapy for RLS. He had transferrin saturation 88%, serum ferritin 658 ng/ml, and C282Y homozygosity. Therapeutic phlebotomy of one unit of blood (450-500 ml) weekly (total 24 units) relieved his non-RLS symptoms, caused RLS symptoms to occur more frequently, and was associated with transient fatigue and mild dependent edema. His sister, who also has RLS, was subsequently diagnosed as having hemochromatosis. We conclude that serum transferrin saturation and ferritin levels should be measured before initiation of iron therapy of RLS. Patients with a history of iron deficiency or low serum iron parameters should undergo evaluation for iron deficiency; patients who have histories suggestive of hemochromatosis or iron overload or elevated pre-treatment transferrin saturation or serum ferritin levels should undergo evaluation to determine the cause of these abnormalities before they are treated with iron. In all persons with RLS treated with oral iron, serum iron parameters should be re-measured once or twice yearly during therapy.

Journal Article↗
PubMed1998

Mutation analysis of the HFE gene associated with hereditary hemochromatosis in African Americans.

Homozygosity for the mutation Cys282Tyr in the HFE gene has recently been identified as a cause of hereditary hemochromatosis, a disorder resulting in the inappropriate absorption of iron. Approximately 10% of Caucasians are heterozygous for this mutation; however, the gene frequency in African Americans is unknown. A study of a control population of African Americans was performed to determine the frequency of the Cys282Tyr and His63Asp alleles in this ethnic group. The carrier frequency for each mutant allele in our African American population was 3.0%. DNA studies of four African-American hemochromatosis patients did not identify any individuals with the Cys282Tyr allele. These findings suggest that if the Cys282Tyr mutation confers susceptibility to hemochromatosis in Caucasians (as suggested by recent studies) there is an alternative mechanism for hemochromatosis in the American black population.

Adult↗
PubMedDate not supplied

Nonexpressing homozygotes for C282Y hemochromatosis: minority or majority of cases?

Genetic testing for the C282Y mutation of the HFE gene has been a major advance in the diagnosis of hereditary hemochromatosis. In most studies, more than 90% of typical hemochromatosis patients are homozygous for the C282Y mutation. Large-scale population screening studies in predominantly Caucasian populations have demonstrated a high prevalence of C282Y homozygotes of approximately 1 in 300. Despite this high prevalence by genetic testing, the clinical diagnosis of hemochromatosis and mortality from the disease are much less common. One possibility is the presence of many undiagnosed cases with nonspecific symptoms, and deaths occurring that are attributed to liver disease, diabetes, and heart disease without the recognition of iron overload secondary to hemochromatosis. Another possibility is a high prevalence of nonexpressing homozygotes. In this review, the available data on nonexpressing C282Y homozygotes is collected including information on pathogenesis, environmental interactions, and implications for population screening using genetic testing.

Gene Expression↗
PubMed2004

[Arthropathy of hereditary hemochromatosis].

Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in populations of caucasian origin with a prevalence of 1 : 200-400 for homozygous patients. Currently, 4 types of HH are distinguished. The classical and most common form is type 1 hemochromatosis which is characterized by HFE gene mutations on chromosome 6. The disease results from an excessive iron absorption leading to multiple manifestations such as hepatomegaly, diabetes mellitus, cardiomyopathy, infertility, and hepatic fibrosis/cirrhosis if untreated. A distinct clinical feature of hemochromatosis is represented by involvement of the joints (arthropathy of hemochromatosis) which occurs frequently and often before iron overload is present. Severity of arthropathy usually does not correlate with the extent of iron overload. In contrast to most other manifestations, it is not improved by iron depletion but can be treated symptomatically. This review outlines clinical aspects as well as pathogenesis, diagnosis and therapy of the disease.

Arthritis↗
PubMed1997

A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations.

The gene whose alteration causes hereditary hemochromatosis (HFE according to the international nomenclature) was, more than 20 years ago, shown to map to 6p21.3. It has since escaped all efforts to identify it by positional cloning strategies. Quite recently, a gene named HLA-H was reported as being responsible for the disease. Two missense mutations, Cys282Tyr (C282Y) and His63Asp (H63D), were observed, but no proof was produced that the gene described is the hemochromatosis gene. To validate this gene as the actual site of the alteration causing hemochromatosis, we decided to look for the two mutations in 132 unrelated patients from Brittany. Our results indicate that more than 92% of these patients are homozygous for the C282Y mutation, and that all 264 chromosomes but 5 carry either mutation. These findings confirm the direct implication of HLA-H in hemochromatosis.

Chromosomes, Human, Pair 6↗
PubMed2006

Revisiting hereditary hemochromatosis: current concepts and progress.

Originally regarded as a rare affliction notable for its distinctive evolution to "bronze diabetes," hereditary hemochromatosis is now recognized as the most common genetic disorder in populations of European ancestry. Recent advances in our understanding of iron metabolism, the identification of the gene responsible for hemochromatosis, and large epidemiologic studies have changed the diagnostic approach toward patients with hereditary hemochromatosis and other forms of iron overload. This article reviews the pathophysiology, epidemiology, clinical features, diagnostic testing, and management of hemochromatosis for the primary care provider.

Diagnosis, Differential↗
PubMed2004

Hemochromatosis mutations are not linked to dilated cardiomyopathy in Israeli patients.

AIMS: Hemochromatosis is a condition in which iron loading impairs the function of many organs, including the heart. Congestive heart failure with left ventricular dilatation is commonly found in patients with hemochromatosis. Two missense mutations (C282Y and H63D) have been shown to be responsible for the majority of cases of hemochromatosis. METHODS AND RESULTS: We examined 156 patients with congestive heart failure due to dilated cardiomyopathy. Details were recorded of clinical and echocardiographic parameters. DNA was extracted from peripheral blood and checked for the presence of the C282Y and H63D mutations by a commercially available single nucleotide primer extension assay. A control group of 98 healthy blood donors was also checked for the presence of these mutations. Of the 157 patients, 42 (26.75%) had at least one mutation. Five (3.65%) were homozygotic for the H63D mutation and 37 (23.6%) were heterozygotic for the H63D mutation. The C282Y mutation was not present. In a control population of 98 healthy blood donors, 27 (27.6%) were heterozygous for the H63D population and none had the C282Y mutation (no significant difference between the patients with cardiomyopathy and the healthy blood donors, chi(2) test 0.754). There was a non-significant trend to a difference in the prevalence of homozygotic H63D between the cardiomyopathy patients and the healthy blood donors (3.18% vs. 0%, P=0.076, chi(2) test). There was no statistically significant difference between the cardiomyopathy patients with and without the mutations in terms of age, gender, hemoglobin, iron, transferrin, ferritin, presence of diabetes mellitus, hypertension and previous coronary artery bypass grafting. CONCLUSION: In our population of patients with dilated cardiomyopathy, there was no evidence for hemochromatosis being an important etiology.

Aged↗
PubMed2005

Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin gene.

Hemochromatosis is a genetically heterogeneous condition. Mutations in the recently described hemojuvelin gene were found in patients with juvenile hemochromatosis, who usually manifest clinical signs of iron overload, including cardiomyopathy and hypogonadism, in their teens and early 20s. In this report, we describe three Japanese patients who showed typical clinical and hepatic histological damage compatible with hemochromatosis at around 50 years of age. Genetic analyses showed that all three patients carried mutations in the hemojuvelin gene. The first patient was homozygous for a novel mutation (745G > C [D249H]), and the second and third patients from the same family were homozygous for another novel mutation (934C > T [Q312X]). No mutations in their HFE, hepcidin, transferrin receptor 2, or ferroportin genes were found. One patient had chronic infection with Helicobacter pylori. The age at initial presentation of hemojuvelin-hemochromatosis occurs over a wider range than previously described.

Age of Onset↗
PubMed2000

[Hereditary hemochromatosis].

INTRODUCTION: Hereditary hemochromatosis is a fairly common disease in the Caucasian population, with a prevalence estimated at between 1.5 to 3/1,000 inhabitants. Over the past few years, its symptomatology has altered; at present, its clinical aspect with diabetes mellitus, cirrhosis, and darker skin pigmentation only constitutes 10% of new cases of this disease. CURRENT KNOWLEDGE AND KEY POINTS: In 1996, the discovery of the C282Y mutation in the HFE gene radically altered the diagnostic approach to hereditary hemochromatosis. At present, any patient admitted with an isolated case of asthenia, or with arthralgia or hypertransaminasemia should be examined via transferrin-saturation testing: if the transferrin saturation coefficient is > 45%, then the presence of the C282Y mutation should be investigated to confirm the diagnosis of hemochromatosis. A liver biopsy is no longer necessary to establish the diagnosis, but this is still useful in cases of possible cirrhosis, which is the main risk factor for hepatocellular carcinoma. Phlebotomy remains the sole recommended treatment, and should be undertaken in a case-specific manner. Family screening should be carried out for all first-degree relatives for every new case that is diagnosed. FUTURE PROSPECTS AND PROJECTS: The discovery of the HFE gene has permitted hereditary hemochromatosis to be easily differentiated from other forms of hepatic iron overload including a new syndrome, dysmotabolic hepatosiderosis. Casos of homozygotic C282Y without hepatic iron overload have been described, but the clinical outcome of some of these cases requires further study, and adds to the controversy on whether systematic population screening should be made available.

Amino Acid Substitution↗
PubMed2003

When and how should we screen for hereditary hemochromatosis?

Hemochromatosis is the clinical expression of iron overload and occurs as hereditary and secondary variants. In hereditary hemochromatosis, an inborn error in iron metabolism results in excess absorption of dietary iron, which gradually accumulates in the liver, pancreas, and heart. The most common form of hereditary hemochromatosis is related to homozygosity for the C282Y mutation in the HFE gene. Early diagnosis is essential because hereditary hemochromatosis is common, severe, and treatable. Early manifestations consist of asthenia, arthralgia, and serum transferrin saturation elevation. The C282Y mutation should be looked for to confirm the diagnosis in the patient and family members. Measurement of serum transferrin saturation followed by genetic testing in individuals with values above 45% is a reasonable screening strategy.

Genetic Predisposition to Disease↗
PubMed2005

Hemochromatosis: genetic testing and clinical practice.

The availability of a facile treatment for hemochromatosis renders early diagnosis of iron overload syndromes mandatory, and in many instances genetic testing allows identification of individuals at risk of developing clinical disease before pathologic iron storage occurs. Numerous proteins implicated in iron homeostasis have recently come to light, and defects in the cognate genes are associated with iron storage. Although most adult patients with hereditary iron overload are homozygous for the C282Y mutation of the HFE gene, an increasing number with hereditary iron storage have an HFE genotype not characteristic of the disease. Heterozygosity for mutations in the gene encoding ferroportin 1 (FPN1) is probably the second most common genetic cause of hereditary iron storage in adults; here the primarily affected cell is the macrophage. Rare defects, including mutations in the transferrin receptor 2 (TFR2) gene, have also been identified in pedigrees affected with "non-HFE hemochromatosis." Homozygous mutations in the newly identified genes encoding hemojuvelin (HFE2) and hepcidin (HAMP) cause juvenile hemochromatosis. At the same time, heterozygosity for mutations in these genes can modify the clinical expression of iron storage in patients predisposed to iron storage in adult life. Hemochromatosis might thus be considered as a polygenic disease with strong environmental influences on its clinical expression. As our mechanistic understanding of iron pathophysiology improves, our desire to integrate clinical decision making with the results of laboratory tests and molecular analysis of human genes poses increasing challenges.

Adult↗
PubMed2004

Screening for hemochromatosis in Turkey.

In this study we screened 3060 consecutive blood donors for an unbound iron-binding capacity level of <28 microM and then performed HFE mutation analysis in these subjects. Sixty-five of the 75 subjects with a low initial unbound iron-binding capacity (all had normal ferritin levels) came back and only 5 (8%) had a low fasting unbound iron-binding capacity. Mutational analysis revealed H63D heterozygosity in two of five subjects. Four of five subjects had liver biopsy indication and none had increased liver iron. HFE genotyping of 60 subjects with a low initial but normal fasting unbound iron-binding capacity revealed heterozygote H63D in seven (11.6%). No allelic variant of position 282 or 63 was found in three previously diagnosed patients with hereditary hemochromatosis. In conclusion, full phenotypic expression of hereditary hemochromatosis is very rare in Turkey. The absence of HFE mutations in three patients with hereditary hemochromatosis suggests that hereditary hemochromatosis in Turkey occurs without common HFE mutations.

Adult↗
PubMed2003

Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis.

Hereditary hemochromatosis is a prevalent genetic disorder of iron hyperabsorption leading to hyperferremia, tissue iron deposition and complications including cirrhosis, hepatocarcinoma, cardiomyopathy and diabetes. Most individuals affected with hereditary hemochromatosis are homozygous with respect to a missense mutation that disrupts the conformation of HFE, an atypical HLA class I molecule (ref. 1; OMIM 235200). Mice lacking Hfe or producing a C282Y mutant Hfe protein develop hyperferremia and have high hepatic iron levels. In both humans and mice, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. It has been suggested that HFE modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells; however, this model is unproven and controversial. Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE. Although expression of mouse Hamp is normally greater during iron overload, Hfe-/- mice have inappropriately low expression of Hamp. We crossed Hfe-/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe-/- mice. This argues against the crypt programming model and suggests that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease.

Animals↗
PubMed2003

Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis.

Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption. Most cases arise from a founder mutation in HFE (845G-->A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with beta2-microglobulin. Mice homozygous with respect to a null allele of Hfe (Hfe-/-) or homozygous with respect to the orthologous 882G-->A mutation (Hfe(845A/845A)) develop iron overload that recapitulates hereditary hemochromatosis in humans, confirming that hereditary hemochromatosis arises from loss of HFE function. Much work has focused on an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells is thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (also called DMT1, DCT1 and NRAMP2) and SLC11A3 (also called IREG1, ferroportin and MTP1; ref. 3). Published data on the expression of these transporters in the duodenum of HFE-deficient mice and humans are contradictory. In this report, we used a custom microarray to assay changes in duodenal and hepatic gene expression in Hfe-deficient mice. We found unexpected alterations in the expression of Slc39a1 (mouse ortholog of SLC11A3) and Cybrd1, which encode key iron transport proteins, and Hamp (hepcidin antimicrobial peptide), a hepatic regulator of iron transport. We propose that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.

Animals↗
PubMed2003

Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.

Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.

Adolescent↗