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Hereditary hemochromatosis (HH) is a genetic iron overload disease, in the majority of cases associated with homozygosity for the C282Y mutation of the HFE gene. In spite of this genetic homogeneity, there is a great clinical heterogeneity among HH patients. Low CD8(+) lymphocyte numbers have been associated with a more severe expression of iron overload in HH patients, and in experimental models of iron overload. HH patients present low serum transferrin levels. Transferrin is an indispensable resource for lymphopoiesis. Lymphocyte homeostasis follows general ecology rules of population dynamics that involve competition for limiting resources. In the present study, we questioned whether transferrin levels could be associated with the anomalies seen previously in lymphocyte subset numbers in HH patients. Transferrin levels, total and subset T lymphocyte counts were done in 426 apparently healthy subjects genotyped for HFE. All HFE C282Y carriers presented significantly lower serum transferrin levels than the wild type group, a difference that could not be explained solely by the degree of iron overload. Significant differences were also seen in transferrin levels between males and females, with females presenting higher average serum Transferrin levels. In the population of subjects with Transferrin levels lower than 248 mg/dl, a positive correlation was seen between the peripheral CD8(+) lymphocyte numbers and serum transferrin levels (R(2) = 2.41; r = 0.16; P = 0.018). To test the possible limiting resource effect of transferrin, the correlation between transferrin levels and CD8(+) lymphocyte numbers was scrutinized in 34 HH patients, homozygous for the C282Y mutation. In the homozygous males, where the lowest average transferrin levels were seen, another highly significant correlation was observed between Transferrin levels and CD8(+) numbers. This correlation points to a possible role of transferrin as a limiting resource for MHC class I dependent lymphocyte proliferation, an effect that was not observed in C282Y homozygous female patients.
Blood Cells Mol Dis
PMID:Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8(+) T lymphocyte numbers. 1614 24

The mechanism of excessive iron storage in patients with hereditary hemochromatosis caused by mutations of the HFE gene seems to be a failure to up-regulate hepcidin in the face of increased body iron. Since the cytokines IL-1 and IL-6 stimulate hepcidin transcription in the absence of HFE, chronic inflammatory states might counteract the effect of HFE mutations. We measured the pre-phlebotomy plasma levels of C reactive protein (CRP) and of interleukin 6 (IL-6) in homozygotes for the C282Y mutation of HFE. There was no difference in these levels in subjects with high iron stores than in those with low iron stores, suggesting that the phenotypic differences between such homozygotes is not appreciably affected by ongoing chronic inflammation.
Blood Cells Mol Dis
PMID:Chronic inflammation does not appear to modify the homozygous hereditary hemochromatosis phenotype. 1615 80

Hereditary hemochromatosis is a common disorder of iron metabolism most frequently associated with mutations in the HFE gene. Hereditary hemochromatosis may be caused by other genetic mutations including those in the SLC40A1 gene. This report describes the clinical and laboratory findings of two Spanish families with autosomal dominant iron overload associated with previously unrecognized Ferroportin 1 mutations (p.R88T and p.I180T). The phenotype of iron overload in the patients carrying these mutations could correspond to the group of clinical mutations that lose their iron export function.
Blood Cells Mol Dis
PMID:Autosomal dominant hereditary hemochromatosis associated with two novel Ferroportin 1 mutations in Spain. 1625 44

Hereditary hemochromatosis is one of the most frequent genetic disorders in Europeans, but its prevalence in Poland is still unknown. The aim of the study was an initial assessment of the prevalence of C282Y and H62D HFE gene mutations and their influence on the course of chronic hepatitis C. Forty-one patients were admitted to the Department of Infectious Diseases, Medical University of Gdansk in 2000-2004 because of chronic liver diseases with accompanying disturbances in iron metabolism. Genetic tests for the C282Y and H63D mutations were performed by PCR and restriction fragment length polymorphism (PCR-RFLP) analysis. The HFE gene mutations were confirmed in 24 of 41 (59%) cases with symptoms of chronic liver disease and iron overload, significantly more frequently in HCV-negative patients (12/14 vs. 12/27; chi2=8.28; p=0.05). The C282Y and H63D HFE gene mutations were detected in 16 of 41 (39%) and 9 of 41 (22%) cases, respectively. HCV-negative patients were C282Y carriers significantly more frequently than HCV-positive patients [9/14 vs. 2/27 C282Y homozygotes; 2/14 vs. 3/27 C282Y heterozygotes (p<0.0001)]. The carrier state of the H63D HFE gene mutation was not significantly more frequent in HCV-positive than HCV-negative patients. HCV infection seems to be a negative predictive marker of HFE gene mutations in patients with iron overload. The relationship of H63D HFE gene mutations with chronic hepatitis C and the possible influence of HCV infection on iron metabolism needs further analysis.
Int J Mol Med 2005 Dec
PMID:HFE gene mutations in Polish patients with disturbances of iron metabolism: an initial assessment. 1627 99

Excessive body iron or iron overload occurs under conditions such as primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis), which are reaching epidemic levels worldwide. Primary hemochromatosis is the most common genetic disorder with an allele frequency greater than 10% in individuals of European ancestry, while hemosiderosis is less common but associated with a much higher morbidity and mortality. Iron overload leads to iron deposition in many tissues especially the liver, brain, heart and endocrine tissues. Elevated cardiac iron leads to diastolic dysfunction, arrhythmias and dilated cardiomyopathy, and is the primary determinant of survival in patients with secondary iron overload as well as a leading cause of morbidity and mortality in primary hemochromatosis patients. In addition, iron-induced cardiac injury plays a role in acute iron toxicosis (iron poisoning), myocardial ischemia-reperfusion injury, Friedreich ataxia and neurodegenerative diseases. Patients with iron overload also routinely suffer from a range of endocrinopathies, including diabetes mellitus and anterior pituitary dysfunction. Despite clear connections between elevated iron and clinical disease, iron transport remains poorly understood. While low-capacity divalent metal and transferrin-bound transporters are critical under normal physiological conditions, L-type Ca2+ channels (LTCC) are high-capacity pathways of ferrous iron (Fe2+) uptake into cardiomyocytes especially under iron overload conditions. Fe2+ uptake through L-type Ca2+ channels may also be crucial in other excitable cells such as pancreatic beta cells, anterior pituitary cells and neurons. Consequently, LTCC blockers represent a potential new therapy to reduce the toxic effects of excess iron.
J Mol Med (Berl) 2006 May
PMID:Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. 1660 32

Hereditary hemochromatosis (HH) is a clinically heterogeneous disease. Among other factors, the individual immunological profile of CD8+ T-lymphocytes has been described to influence the severity of iron overload, with low numbers being negatively correlated with the total amount of body iron stored. With the objective of testing the modifier effect of the individual CD8+ T-lymphocyte profile on the levels of iron stores with age in HH, we reviewed the clinical and immunological data from a group of well-characterized C282Y homozygous HH subjects, regularly followed-up for a period of 20 years. A total of 70 subjects were analyzed. Sixty-four were adults (> or = 18 years): 42 males (mean age 47 +/- 14; range 22-75 years) and 22 females (mean age 46 +/- 14; range 19-65 years). Six were younger than 18 years, 5 males (mean age 9 +/- 4; range 5-14 years) and 1 female (15 years). The characterization of subjects included measurements, at diagnosis, of the iron parameters, transferrin saturation (TfSat) and serum ferritin, quantification of total body iron stores (TBIS) removed by phlebotomies, presence of associated clinical manifestations, and the T-cell immunophenotype (CD4+ and CD8+ T-lymphocytes) determined by flow cytometry. In general, statistically significant lower values of TfSat (67 +/- 17% vs. 89 +/- 14%, P = 0.0006) and ferritin levels (58 +/- 9 vs. 949 +/- 233 ng/ml, P = 0.02) were found in the young subjects in comparison to adults. After the age of 18, however, no further effect of age was significantly found on the biochemical iron parameters either in males or females. A modifier effect of the individual CD8+ T-lymphocyte profile on the association between iron stores and age was demonstrated by multiple regression analysis, where a significant correlation between TBIS and age was found only in males with low (< or = 0.41 x 10(6)/ml) CD8+ T-cell numbers (R2 = 0.43, P < 0.0001). In conclusion, in the present population of C282Y homozygous subjects, the CD8+ T-lymphocyte profile could be considered a modifier of the iron overload with increasing age in males, with low numbers predicting a severe outcome.
Blood Cells Mol Dis
PMID:The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: an update of clinical and immunological data from 70 C282Y homozygous subjects. 1676 69

The highly variable clinical phenotype observed in patients homozygous for the C282Y mutation of the hereditary hemochromatosis gene (HFE) is likely due to the influence of non-HFE modifier genes. The primary functional abnormality causing iron overload in hemochromatosis is hyper-absorption of dietary iron. We found that iron absorption in inbred mice varies in a strain-specific manner, as does the pattern of iron distribution to the liver and spleen. A/J mice absorbed approximately twice the amount of 59Fe delivered by gavage compared to the C57BL/6 strain. Genetic comparisons between A/J and C57BL/6 were facilitated by the availability of consomic chromosome substitution strains (CSS). Each CSS has an individual chromosome pair from A/J on an otherwise C57BL/6J background. We found that iron absorption and iron content in liver and in spleen were continuous variables suggesting that each trait is under multigenic control. No trait co-segregated among the CSS. Chromosome 5 from A/J, however, imparted the highest iron absorption phenotype and multiple CSS had absorption levels equivalent to A/J. Chromosomes 9 and X were associated with high spleen iron content. These data suggest that multiple genes contribute to the regulation of iron absorption and that individual organ iron phenotypes are independently regulated.
Blood Cells Mol Dis
PMID:Mapping genes responsible for strain-specific iron phenotypes in murine chromosome substitution strains. 1749 47

Classic hereditary hemochromatosis is an autosomal recessive disorder characterized by iron overload and sequence variants in the HFE gene. The HFE gene is located at 6p21.3 and contains 2 common single nucleotide polymorphisms (SNPs) C282Y and H63D, which are routinely tested for in the molecular diagnostics laboratory. In this study, we used DNA samples from 59 patients in which clinicians wanted to confirm or rule-out hereditary hemochromatosis that had been previously tested for the HFE SNPs using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and the ABI 7700 real time PCR assay with a MGB Eclipse ASR Probe system. The new assay used TAQman SNP Genotyping Assays, which were performed on the ABI 7500 FAST real time PCR platform. Allelic discrimination was determined during a postamplification plate read. Of the 59 samples genotyped, 7 were homozygous for C282Y, 6 were heterozygous for C282Y, 9 were homozygous for H63D, 10 were heterozygous for H63D, 6 were compound heterozygotes, and 20 were wild type. With the exception of one sample that was indeterminate by the TAQman SNP Genotyping Assay, all others showed 100% concordance between the 3 assays. The one indeterminate sample was heterozygous for C282Y by the PCR-RFLP and ABI 7700 real time PCR assays, but there was an insufficient quantity of DNA to perform the TAQman SNP Genotyping Assay. Our study suggests that the ABI 7500 FAST TAQman SNP Genotyping Assay is comparable with the PCR-RFLP and ABI 7700 real time PCR methods in detecting and characterizing these 2 HFE SNPs. Improved software and thermocycling capabilities have resulted in a very robust TAQman assay with the advantage of a much improved turn-around-time and throughput.
Diagn Mol Pathol 2007 Jun
PMID:Detection of the C282Y and H63D polymorphisms associated with hereditary hemochromatosis using the ABI 7500 fast real time PCR platform. 1752 82

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25-amino-acid peptide hepcidin is up-regulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it was considered the most common disease among Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and only its genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype. Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias. While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.
Blood Cells Mol Dis
PMID:Iron storage disease: facts, fiction and progress. 1754 May 89

Mutations in the SLC40A1 gene result in a dominant genetic disorder [ferroportin disease; hereditary hemochromatosis type (HH) IV], characterized by iron overload with two different clinical manifestations, normal transferrin saturation with macrophage iron accumulation (the most prevalent type) or high transferrin saturation with hepatocyte iron accumulation (classical hemochromatosis phenotype). In previous studies, the mutational analysis of SLC40A1 gene has been performed at the genomic DNA level by PCR amplification and direct sequencing of all coding regions and flanking intron-exon boundaries (usually in 9 PCR reactions). In this study, we analyzed the SLC40A1 gene at the mRNA level, in two RT-PCR reactions, followed by direct sequencing and/or NIRCA (non-isotopic RNase cleavage assay). This protocol turned out to be rapid, sensitive and reliable, facilitating the detection of the SLC40A1 gene mutations in two patients with hyperferritinemia, normal transferrin saturation and iron accumulation predominantly in macrophages and Kupffer cells. The first one displayed the well-described alteration V162 Delta and the second a novel mutation (R178G) that was further detected in two relatives in a pedigree analysis. The proposed procedure would facilitate the wide-range molecular analysis of the SLC40A1 gene, contributing to better understanding the pathogenesis of the ferroportin disease.
Blood Cells Mol Dis
PMID:Analysis of SLC40A1 gene at the mRNA level reveals rapidly the causative mutations in patients with hereditary hemochromatosis type IV. 1799 13


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