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PubMed2001

Genetics of iron storage and hemochromatosis.

The regulation of total body iron is important to all organisms. In mammals, the iron content of the body is controlled almost entirely through regulation of absorption. The precise mechanism by which iron is absorbed and the manner in which the absorption is regulated is unknown, but a number of different proteins that are involved either in the transport process itself or its regulation have been identified. These include HFE, a class 1 HLA molecule involved in hereditary hemochromatosis, the divalent metal transporter (DMT-1), hephaestin, the transferrin receptor, and mobilferrin. Iron overload occurs in a number of hereditary disorders including atransferrinemia, aceruloplasminemia, X-linked hereditary sideroblastic anemia, thalassemia major, congenital dyserythropoietic anemia, and various red cell enzyme deficiencies. In Europeans, most cases of hereditary hemochromatosis are due to mutations of the HFE gene. There are two major mutations of this gene c.845G-->A (C282Y) and c.187C-->G (H63D). These mutations have extraordinarily high prevalence in northern Europe and approximately five in a thousand Europeans are homozygous for the 845A mutation. The penetrance of even the homozygous state for the 845A mutation is very low and that for the compound heterozygote 845A/187G, which is also associated with hemochromatosis, is even lower. The reason for the markedly variable penetrance that exists in this disorder remains unknown.

Child↗
PubMed2001

Hereditary hemochromatosis since discovery of the HFE gene.

BACKGROUND: Hereditary hemochromatosis is an inherited disorder of iron metabolism that is characterized by excessive iron deposition in major organs of the body. Chronic increased iron absorption leads to multiorgan dysfunction. Since the discovery of the gene responsible for the majority of cases, research has progressed rapidly to identify the gene product, the effects of mutations, and the implications for different populations. The protein product of the HFE gene is a transmembrane glycoprotein, termed HFE, that modulates iron uptake. Mutations in the HFE protein compromise its function and produce disease symptoms. Two mutations, C282Y and H63D, have been linked to the majority of disease cases. APPROACH: We reviewed the recent literature for the molecular basis of hereditary hemochromatosis. Genotypic information was combined with biochemical and clinical phenotypic information to achieve a better understanding of the disease mechanism. CONTENT: This review provides a comprehensive discussion of known mutations in the HFE gene and their phenotypic expression. Diagnostic criteria using molecular genetic techniques in conjunction with traditional biochemical tests are provided. Current methods and limitations of molecular testing are examined in detail. A strategy for population screening and an algorithm for diagnosis that incorporates molecular testing are presented. Treatment by therapeutic phlebotomy and the use of blood obtained from hemochromatosis patients are discussed. SUMMARY: Although the disease mechanism has not been completely elucidated, phenotypic and penetrance data are becoming available. Controversy still exists concerning the role of genetic testing in diagnosis and population screening.

Genetic Testing↗
PubMedDate not supplied

[Hereditary hemochromatosis].

Hereditary hemochromatosis is an inherited autosomal recessive disease, associated to a mutation in the recently described HFE gene, which is located on the short arm of chromosome 6. The product of this gene combines with the beta-2-microglobulin and the ferritin receptor, and regulates the iron absorption in the small intestine crypt cells. It is possible that the mutation may cause the increased iron uptake by the intestinal cells. The disease is very much common in men after the forties, and its expression is influenced by concomitant alcoholism, iron rich diet, oral and parenteral iron administration, menstrual blood loss or abnormal hemorrhages, blood donations, pregnancy, lactation, and iron malabsorption clinical conditions, like celiac disease. Many patients are asymptomatic, and the diagnosis may be suspected by hepatomegaly of unknown cause, abnormal iron metabolism tests, increased serum aminotransferase levels, diabetes mellitus, and anonymous arthropathy. Less commonly hereditary hemochromatosis presented by symptoms and signs of chronic liver disease, or by the classic triad described by Trousseau skin pigmentation, hepatomegaly and diabetes mellitus. The diagnosis is confirmed by the increased serum ferritin levels and transferrin saturation, and the stainable iron in hepatocytes, measured by scale devised by Scheuer et al, or the measurement of the hepatic iron. The C282Y mutation was found in 64 to 100% of patients; eventually, subjects with hepatic iron overload identical to hereditary hemochromatosis has no mutation, and homozygous for the C282Y mutation do not express iron overload. Iron is best and quickly removed by weekly or twice-weekly phlebotomy of 500 ml, containing approximately 250 mg iron. One to 3 years of weekly phlebotomy may be required to reduce stores to normal. As a guide to long-term maintenance therapy, is recommended phlebotomy every 3 months and the serum ferritin level should be maintained by less than 50 ng/ml.

Adult↗
PubMed2004

Correlation between iron status and genetic hemochromatosis (codon C282Y) in a large German population.

BACKGROUND: Genetic hemochromatosis leads to iron overload in many tissues and may lead to liver cirrhosis and hepatocellular carcinoma. Early diagnosis and therapy are crucial. Since 80-100% of hemochromatosis patients of European origin are homozygous for a cysteine to tyrosine exchange in the HFE gene at codon 282, genetic screening might be useful. Representative population studies are needed to evaluate the phenotype of people heterozygous and homozygous for the C282Y mutation. OBJECTIVE: To determine the correlation between parameters of iron metabolism and the hemochromatosis genotype in a large population-based study. METHODS: A representative population-based survey, the Diabetomobil study, analyzed 5,083 German probands. Serum transferrin saturation and ferritin levels were determined, and the C282Y mutation of the HFE gene was analyzed by restriction fragment length polymorphism-polymerase chain reaction analysis. RESULTS: Nine of 373 probands with a transferrin saturation > 55% (2.4%) and none of 264 randomly selected probands with a transferrin saturation < or = 55% (0%) were homozygous for the C282Y mutation. Three of the nine homozygous probands had ferritin values less than 250 micrograms/L. The frequency of the heterozygous genotype was 8.8%, and the percentage of heterozygous probands increased with increasing levels of transferrin saturation. CONCLUSION: We propose a population screening strategy with an initial transferrin saturation test, followed by genotyping for the C282Y mutation if the transferrin saturation is above 55%, regardless of the ferritin level. Heterozygous individuals with higher transferrin saturation values may be protected against iron loss but may also be more susceptible for certain liver diseases, depending on the simultaneous prevalence of other diseases.

Adult↗
PubMed2004

[Hereditary hemochromatosis: molecular diagnosis and effect of treatment].

Hereditary hemochromatosis is a genetic disorder, inherited as an autosomal recessive trait, characterized by iron overload. A single mutation (C282Y) in the HFE gene is found in more than 90% of these patients. We report the case of a 50-year-old man, with clinical symptoms of hemochromatosis, who was found to be homozygous for the C282Y mutation. We present the results of therapeutic phlebotomy after one year of the treatment. Genetic tests were performed on the patient's close relatives and revealed that his son was also homozygous for the C282Y mutation. Early phlebotomy could prevent iron deposition and organ damage in this patient. Genetic determining of the HFE mutations is a useful noninvasive method of diagnosing hereditary hemochromatosis.

Adult↗
PubMedDate not supplied

HFE genotyping demonstrates a significant incidence of hemochromatosis in undifferentiated arthritis.

OBJECTIVE: Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated to be 1 in 10, while up to 1 in 200 is affected by the disease. Arthropathy is one early clinical manifestation of this disease, but the articular features are often misdiagnosed. In this study the two frequent mutations of the HLA-linked hemochromatosis gene (HFE) were investigated in a rheumatology clinic population. METHODS: Two hundred and six consecutive patients (mean age 57.7 years; 38 male/168 female) attending a rheumatology clinic over a period of 14 months were screened for HFE mutations (C282Y and H63D). All standard diagnostic procedures were used to identify the aetiology of the arthropathy. Mutations were evaluated by separation on PAGE of digested PCR amplificates of DNA (by SnapI and Bcl-I, for C282Y and H63D, respectively) obtained from PBMCs. RESULTS: The C282Y and H63D allele frequencies were 4.5 and 12.8 in patients with rheumatic diseases. Five patients were homozygote for H63D (2.4%), and one for C282Y (0.5%). Five patients were compound heterozygous (2.4%). The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis was 12.9 and exceeded that of healthy subjects (p = 0.01). CONCLUSIONS: Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin, to allow early diagnosis of hemochromatosis.

Adult↗
PubMedDate not supplied

Genetic hemochromatosis update.

Hereditary Hemochromatosis is an autosomal recessive disease, characterized by chronic iron overload. It is mainly due to mutations of the HFE-1 gene. In the large majority of patients, the substitution of tyrosine for cysteine at amino acid 282 (C282Y) is found at the homozygous state. Since the HFE-1 hemochromatosis identification, several other entities of iron overload have been individualized. In the present article, the frequency, penetrance and pathophysiology of HFE-1 hemochromatosis as well as various clinical presentations resulting from different mutations affecting different proteins involved in iron metabolism are described.

Adult↗
PubMed2006

[Molecular basis of hereditary hemochromatosis].

Hereditary hemochromatosis (HH) is a genetic metabolic disease characterized by increased intestinal iron absorption and progressive iron loading in the cells of various organs. Human body iron homeostasis involves a number of complicated processes, some of which are not identified yet. Genetic analysis of patients affected by HH recently led to the discovery of many novel proteins and mechanisms that can influence the uptake, transport, storage, and excretion of iron. It also showed that hemochromatosis is a very complex disease and that the type of mutation can influence its clinical manifestation. This review presents the current knowledge about the mechanisms of iron metabolism and describes the types of hereditary hemochromatosis and the mutations which induce the disease.

Animals↗
PubMedDate not supplied

Role of hemochromatosis genes in chronic hepatitis C.

PURPOSE: Hereditary hemochromatosis is commonly associated with iron overload and hepatitis C virus (HCV). Association between hemochromatosis C282Y or H63D mutation has been observed, although not uniformly, and iron overload is also commonly found in chronic HCV hepatitis. This study explored the contribution of genetic hemochromatosis to iron accumulation in hepatitis C. DESIGN: Review of current literature. RESULTS: The prevalence of increased serum iron stores in patients with HCV infection is 28% (patients having an elevated ferritin or transferrin saturation). Patients with elevated serum iron markers have more active chronic hepatitis with more liver fibrosis. In the opinion of the experts HFE mutations are not associated with a high hepatic iron content. No relation was detected between hepatic iron stores and HFE gene mutation. Significant iron deposition in the liver was uncommon and overall the quantity of iron that was detectable histologically and biochemically was unrelated to the grade and stage of HCV related liver injury. The mechanism by which liver iron accumulates in patients is unclear. CONCLUSIONS: Carriage of HFE mutations does not have a role in the accumulation of iron or the liver disease in HCV. These findings do not support a role for iron depletion in patients with chronic HCV infection, including these with elevated serum studies.

Aspartic Acid↗
PubMed1997

HLA-H and associated proteins in patients with hemochromatosis.

BACKGROUND: The 845A(C282Y) mutation in the HLA-H gene accounts for most cases of hereditary hemochromatosis in patients who are of European origin. Some lack this mutation, however, and it is not present in Asian patients. Thus, other mutations either in HLA-H or associated proteins may be present in such patients. HLA-H associates with beta-2-microglobulin. Calreticulin associates with class 1 HLA proteins and appears to be identical with mobilferrin, a putative iron transport protein. These two proteins are therefore candidates for mutations in patients with hemochromatosis. MATERIALS AND METHODS: We have sequenced the coding region and parts of introns of the HLA-H gene, the beta-2-microglobulin gene, and the calreticulin (mobilferrin) gene of 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the 845A(C282Y) mutation. The number of chromosomes at risk studied were 18 for HLA-H, 14 for beta-2-microglobulin and 10 for calreticulin. RESULTS: We detected 3 new intronic polymorphisms in the HLA-H gene, each a point mutation. Some differences from published sequences of beta-2-microglobulin and calreticulin were documented, but these were uniformly present in all samples. CONCLUSIONS: The lack of additional mutations in the HLA-H gene is remarkable, and we speculate that the C282Y mutation may be a gain-of-function change.

Asia↗
PubMed1998

Mutation analysis of the HLA-H gene in French hemochromatosis patients, and genetic counseling in families.

Mutation analysis of the HLA-H gene in French hemochromatosis patients and genetic counseling in families: Genotype analysis of 61 hemochromatosis patients living in France and 126 controls confirms that the disease is strongly associated with homozygosity for the mutation C282Y of the HLA-H gene: in our sample 67.2% patients, and none of the controls, carry two copies of the C282Y mutation; the frequency of the C282Y allele in a control population is 3.97%. A second variant (H63D) at the HLA-H gene is somehow more enriched (8.2%) in patient chromosomes that do not carry the C282Y mutation. The C282Y mutation was used in 10 hemochromatosis families for genetic counseling.

Amino Acid Substitution↗
PubMed1998

Prevalence of the C282Y mutation in Brittany: penetrance of genetic hemochromatosis?

Hemochromatosis (GH) is an inborn error of iron metabolism, characterized by progressive iron loading that, if untreated, causes high morbidity and death. The gene responsible for the disease (HFE), located 4.5 megabases telomeric to the HLA-A locus, encodes a protein homologous to class I MHC molecules. A main mutation, C282Y, has been identified within the gene. Although hemochromatosis is considered as the most frequent inherited disease in the populations of Northern European origin, its prevalence in Brittany had not been evaluated yet. In this issue we report the C282Y mutation frequency in a cohort of 1000 newborns from maternity hospitals of the four breton départements. The homozygote frequency was 5/1000 and heterozygote frequency was 12%; such high frequencies raise the question of the penetrance of the disease and the relevance of systematic genotypic screening for hemochromatosis.

Alleles↗
PubMed1979

The triad of hemochromatosis, hepatoma and erythrocytosis.

The triad of hemochromatosis, hepatoma and erythrocytosis is a rare combination. Hemochromatosis is often not recognized until the patient presents with the symptoms of hepatocellular carcinoma and erythrocytosis, and the development of erythrocytosis is an important clue to the under-lying hepatoma. The high serum iron concentration and the high saturation of the iron-binding protein, as well as the typical bone marrow hemosiderin pattern, are important aids in the recognition of hemochromatosis. To date, all patients with this triad have been elderly males. The clinical course is usually one of rapid deterioration and death. The seven previously reported cases have been reviewed and the relationship of the erythrocytosis to the increased production of erythropoietin is discussed.

Aged↗
PubMed1992

Human leukocyte antigen typing of siblings in hereditary hemochromatosis: a cost approach.

To assess the clinical value of human leukocyte antigen typing in the diagnosis and management of hereditary hemochromatosis, 105 siblings of 35 proband cases of hemochromatosis were retrospectively analyzed to study whether the exclusion of human leukocyte antigen typing would have adversely affected management. All siblings and probands had already been tested for human leukocyte antigen-A and human leukocyte antigen-B typing, serum ferritin and transferrin saturation. The median age of siblings was 55 yr (range = 11 to 82). Siblings were categorized according to putative genotype (homozygote, heterozygote and normal) using human leukocyte antigen typing. Phenotypic expression of hemochromatosis was considered to be iron overload as indicated by an elevated ferritin (male = greater than 350 micrograms/L, female = greater than 200 micrograms/L) and/or transferrin saturation (greater than 55%). Six of 37 homozygotes had a normal ferritin and transferrin saturation, with five of these patients under 32 yr old. No putative heterozygotes with both an abnormal ferritin and transferrin saturation were seen, although 12 of 48 (25%) heterozygotes had either an elevated ferritin or transferrin saturation. Twenty of 20 normal siblings had a normal ferritin and transferrin saturation. To assess the cost of screening with and without human leukocyte antigen typing, a cost model simulation was used that compared the costs of both methods in a hypothetical family (proband, homozygote, heterozygote and normal sibling).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Association between heterozygous alpha 1-antitrypsin deficiency and genetic hemochromatosis.

Primary hemochromatosis is a genetically determined autosomal recessive disorder characterized by the excessive accumulation of body iron, most of which is deposited in the parenchymal cells of various organs. alpha 1-Antitrypsin deficiency is characterized among others by defective secretion of alpha 1-antitrypsin from liver cells. Whereas the risk of cirrhosis is increased in homozygous patients (PI ZZ) and possible in heterozygous patients (non-PI MM) as well, a greater risk for hepatocellular carcinoma has been suggested only in homozygous patients. Because these two metabolic disorders are relatively common, it has been difficult to determine whether they are associated with each other. In this study, we tried to determine the relationship between these two disorders using the case material seen at the University of Pittsburgh during a 7-yr period. We studied 15 patients with genetic hemochromatosis. alpha 1-Antitrypsin quantitation and phenotyping were performed in each case using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds ratio and chi 2 tests were used to measure the relative risk and significance of association, respectively. Eleven patients (73%) were found to be PI M and four (27%) were identified as being heterozygotes: three (20%) were PI MZ, and one (7%) was PI MS. The prevalence of the PI MS phenotype was similar to that in the general population (7% vs. 6.4%; NS). The PI MZ phenotype, however, was statistically more common in patients with hemochromatosis than in the general population (20% vs. 2.2%; p less than 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases.

The current study was undertaken to assess whether fibrosis could regress under venesection therapy in patients with C282Y homozygous genetic hemochromatosis. The 36 patients studied were recruited from a subfile of our database consisting of 125 C282Y homozygotes with either severe fibrosis or cirrhosis (F3 or F4 fibrosis stage, respectively, according to the METAVIR grading system). The second liver biopsy was performed for management of liver cancer, extrahepatic surgery, or assessment of liver fibrosis. All paired biopsies were reviewed by two pathologists without knowledge of clinical data. Among the 13 patients who had F3 fibrosis on their initial liver biopsy, 3 had F0, 6 had F1, and 2 had F2 on their second liver biopsy. Among the 23 patients with cirrhosis on their initial liver biopsy, 1 had F0, 4 had F1, 3 had F2, and 2 had F3 on their second liver biopsy. When defining regression of fibrosis as a decrease of at least 2 METAVIR units, fibrosis regressed in 9 of 13 (69%) F3 and in 8 of 23 (35%) F4. When the ratio of gammaglobulins (g/L) to (platelets [n/mm(3)] x prothrombin activity [%]) was greater than 7.5, fibrosis never regressed. In conclusion, these data extend the concept of regression of fibrosis to patients with treated genetic hemochromatosis and suggest that some simple biochemical tests would be predictive of further regression of fibrosis as a result of venesection therapy. If confirmed on larger series, this could modify the ultrasound screening policy of hepatocellular carcinoma in genetic hemochromatosis.

Adolescent↗
PubMed1996

Localization of the hemochromatosis disease gene: linkage disequilibrium analysis using an American patient collection.

The genetic basis of idiopathic hemochromatosis, a common disorder of iron metabolism, has remained an enigma for over two decades. In an attempt to refine the chromosomal localization of this gene, we have conducted a linkage disequilibrium mapping study utilizing a large group of unrelated American patients. The 12 microsatellites used as genetic markers in this analysis include a series of recently described polymorphic dinucleotide (D6S1558, D6S1545 and D6S1554) and tetranucleotide (D6S1016 and D6S1281) repeats which map between D6S105 and D6S299. Haplotype reconstructions indicate that a core genotype, composed of D6S464 allele 3/D6S1260 allele 4/D6S1558 allele 5, exists on a majority of disease chromosomes. Stringent statistical measures of marker-disease disequilibrium suggest that only associations with D6S1260 are significant and furthermore, aid in the assignment of refined centromeric and telomeric limits for the likely location of the hemochromatosis gene. In summary, the genetic data presented in this report predict that the hemochromatosis locus resides between D6S464 and D6S1558, most likely very close to marker D6S1260. Because a single yeast artificial chromosome clone contains all three of the above loci, a thorough search for coding sequences in this region is likely to identify the gene mutated in this common disorder.

Chromosome Mapping↗
PubMedDate not supplied

Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics.

Hereditary hemochromatosis is classically inherited as a recessive trait but is genetically heterogeneous. Mutations in the HFE and the TFR2 genes account for about 80% of patients and a third locus on chromosome 1q is responsible for juvenile hemochromatosis. We describe here the clinical and biological characteristics of autosomal dominant form of iron overload due to the N144H mutation of the SLC11A3 gene. Clinical signs of iron overload in patients include joint pains, cardiomyopathies, liver fibrosis and hormonal disorders including diabetes mellitus. The main and most common clinical symptoms in this family were joint complaints and early signs of arthrosis. Serum ferritin levels in iron overloaded subjects varied from 31 to 2179 ng/ml and the transferrin saturation from 13 to 88.6%. The iron overload is moderate compared to patients with type 1 hemochromatosis but the deferoxamine test was normal in all patients. The disease in this family segregated as a dominant trait. None of the patients was homozygous or compound heterozygous for any known mutation in the HFE or TFR2 genes. The disease in this family represents a non-classical form of iron overload caused by the N144H mutation in the SLC11A3 gene. The reports of other distinct mutations in SLC11A3 suggest that this gene may be of interest for further etiologic research.

Adult↗