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PubMed2003

Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and co-inducibility during iron overload.

In contrast to the human genome, the mouse genome contains two HEPC genes encoding hepcidin, a key regulator of iron homeostasis. Here we report a comparative analysis of sequence, genomic structure, expression and iron regulation of mouse HEPC genes. The predicted processed 25 amino acid hepcidin 2 peptide share 68% identity with hepcidin 1 with perfect conservation of eight cysteine residues. Both HEPC1 and HEPC2 genes have similar genomic organization and have probably arisen from a recent duplication of chromosome 7 region, including the HEPC ancestral gene and a part of the adjacent USF2 gene. Insertion of a retroviral intracisternal A-particle element was found upstream of the HEPC1 gene. Both genes are highly expressed in the liver and to a much lesser extent in the heart. In contrast to HEPC1, a high amount of HEPC2 transcripts was detected in the pancreas. Expression of both genes was increased in the liver during carbonyl-iron and iron-dextran overload. Overall our data suggest that both HEPC1 and HEPC2 genes are involved in iron metabolism regulation but could exhibit different activities and/or play distinct roles.

Amino Acid Sequence↗
PubMed1994

Arterial connective tissue alterations in thalassemia major: a biochemical study of a case with severe iron overload.

A biochemical analysis of glycosaminoglycans and collagen was performed in arteries of a 15-year old teenager who died of beta thalassemia major. The patient presented the severe clinical complications resulting from hemochromatosis, which was evidenced at autopsy and by histological examination. The arteries under study comprised the thoracic and abdominal aortas and the iliac and pulmonary arteries, which were compared with the same arteries from normal individuals. Data on total glycosaminoglycan and total collagen, including the determination of the relative contents of the different glycosaminoglycans, suggest an as yet undescribed fibrotic process in the thalassemic arteries. Also altered were the proportions of the disaccharides making up chondroitin sulfate and heparan sulfate. A reduction in the molecular weight of arterial heparan sulfate, presumably with free radical involvement, was also detected. These changes in the extracellular matrix may be ascribed to the presence of large amounts of iron in the tissue, and as such they should be expected in other disorders with chronic iron overload.

Adolescent↗
PubMed1981

Liposome-encapsulated desferrioxamine in experimental iron overload.

We have encapsulated desferrioxamine (DF) in multilamellar liposomes (ML) and unilamellar liposomes (UL). Liposomes were prepared either with or without a glycolipid, i..e. galactocerebroside (GC). The average diameter of ML was 0.5 microgram, and that of UL was 0.08 microgram. Less tha 5% of DF leaked out from the liposomes after incubation in mouse plasma for 6 h. 59Fe-ferritin and 59Fe-labelled heat damaged erythrocytes (59Fe-DRBC) were administered to normal and hypertransfused mice as models of iron overload. Ferritin was used to label liver parenchymal cells and DRBC to label the Kupffer cells of the liver. A single injection of ML or UL with or without galactocerebroside into normal and hypertransfused mice enhanced from 3- to 15-fold the urinary excretion of radioiron from 59Fe-ferritin and from 59Fe-DRBC injected mice. For both the normal and hypertransfused mice, liposomes containing GC removed more 59Fe radioactivity from mice receiving 59Fe-DRBC. Thus GAC-liposomes may have a higher affinity for parenchymal cells of the liver, whereas liposomes without the glycolipid may have a higher uptake by the Kupffer cells.

Animals↗
PubMedDate not supplied

Nitric oxide and iron: effect of iron overload on nitric oxide production in endotoxemia.

The amount of iron within the cell is carefully regulated in order to provide an adequate level of micronutrient while preventing its accumulation and toxicity. Iron excess is believed to generate oxidative stress, understood as an increase in the steady-state concentration of oxygen radical intermediates. Nitric oxide (NO) is an inorganic free-radical gaseous molecule which has been shown over the last decade to play an unprecedented variety of roles in biological systems. The effect of nitrogen reactive species may explain the iron sequestration pattern that characterizes macrophages under inflammatory conditions. From a patho-physiological viewpoint, further studies are required to assess the usefulness of this mechanism to minimize formation and release of free radicals in diseased tissues. However, contrary to the deleterious effects of the reactive nitrogen oxide species formed from either NO/O(2) and NO/O(2)(-), it has been pointed out that NO shows antioxidant properties. A number of studies have described the complex relationships between iron and NO, but controversy remains as to the influence and significance of iron on inflammatory NO production. To explore the initial steps of the effects triggered by LPS administration in the presence of excess iron, male Wistar rats were treated with: lipopolysaccharide from Escherichia coli (serotype 0127:B8) (LPS); iron-dextran; or iron-dextran plus LPS and liver samples were taken after 6 h. EPR spectra of NO-Hb in the venous blood were determined at 77 K. Iron-dextran administered to rats intraperitoneally resulted predominantly in iron uptake by the liver Kupffer cells and led to an increased NO level in blood in the presence of LPS. Further studies will be required to assess the complex role of the Kupffer cells on iNOS induction and NO production.

Animals↗
PubMed2006

PCTH: a novel orally active chelator for the treatment of iron overload disease.

Our laboratories have prepared a novel class of iron (Fe) chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. This article will review the iron chelation efficacy of this series of chelators, both in cell culture and in animal models. Several PCIH analogs were shown to be effective at inducing iron mobilization and preventing iron uptake from the iron-transport protein, transferrin. Moreover, several of these ligands were effective at permeating the mitochondrion and inducing iron release. Studies in mice demonstrated that the PCIH analog, PCTH, was orally active and well tolerated by mice at doses ranging from 50 to 100 mg kg(-1), twice daily (b.d.). A dose-dependent increase in fecal 59Fe excretion was observed in the PCTH-treated group. This level of iron excretion was similar to that found for the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIH) and deferiprone (L1). The PCIH group of ligands clearly has the potential for the treatment of beta-thalassemia (thal) and Friedreich's Ataxia (FA).

Administration, Oral↗
PubMed2003

Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload.

BACKGROUND: Hereditary hemochromatosis is a recessive disorder characterized by iron accumulation in parenchymal cells, followed by organ damage and failure. The disorder is mainly attributable to the C282Y and H63D mutations in the HFE gene, but additional mutations in the HFE, transferrin receptor 2 (TfR2), and hepcidin genes have been reported. The copresence of mutations in different genes may explain the phenotypic heterogeneity of the disorder and its variable penetrance. METHODS: We used denaturing HPLC (DHPLC) for rapid DNA scanning of the HFE (exons 2, 3, and 4), hepcidin, and TfR2 (exons 2, 4 and 6) genes in a cohort of 657 individuals with altered indicators of iron status. RESULTS: DHPLC identification of C282Y and H63D HFE alleles was in perfect agreement with the restriction endonuclease assay. Fourteen DNA samples were heterozygous for the HFE S65C mutation. In addition, we found novel mutations: two in HFE (R66C in exon 2 and R224G in exon 4), one in the hepcidin gene (G71D), and one in TfR2 (V22I), plus several intronic or silent substitutions. Six of the seven individuals with hepcidin or TfR2 coding mutations carried also HFE C282Y or S65C mutations. CONCLUSION: DHPLC is an efficient method for mutational screening for the genes involved in hereditary hemochromatosis and for the study of their copresence.

Antimicrobial Cationic Peptides↗
PubMed1994

Biological markers of oxidative stress induced by ethanol and iron overload in rat.

Studies on rats treated for 15 months with ethanol (10%, w/v, solution in drinking water) revealed that the stimulation of hepatic cytochrome P-450 monooxygenases activity was accompanied by enhanced microsomal malondialdehyde formation, a lipid peroxidation index and a decreased level of the antioxidant, alpha-tocopherol. The other components of the prooxidant/antioxidant system, diene conjugates and catalase, glutathione peroxidase and superoxide dismutase activities were unaffected. Oxidative stress in blood was shown by a significant decrease in the alpha-tocopherol level whereas lipid peroxidation and antioxidant enzyme activity remained unchanged. The prooxidative effect of ethanol was catalytically promoted by an iron overload (Fe-saccharate, 100 mg Fe3+/kg body wt. intraperitoneally, 2, 5 and 7 day before test) to simulate the effect of alcoholic hemochromatosis. Thus, the level of malondialdehyde and alpha-tocopherol in the serum may be recommended as biological markers of ethanol-provoked oxidative stress, which is especially useful in the evaluation of the combined effect of ethanol and other chemicals that affect the redistribution of active iron complexes.

Animals↗
PubMed1990

Oysters, iron overload and Vibrio vulnificus septicaemia.

A case of Vibrio vulnificus septicaemia complicated by cutaneous leg ulceration is described. A 74 year old man with haemochromatosis and sideroblastic anaemia developed an acute febrile illness with cutaneous manifestations 24 hours after ingesting raw oysters. The presence of blistering should be considered an important clue to the diagnosis of Vibrio vulnificus septicaemia, and this can facilitate prompt effective antimicrobial therapy. Clinicians should be aware of this infection because of its high case fatality rate, especially in patients with iron overload states.

Aged↗
PubMed2006

A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload.

BACKGROUND: It has been recently demonstrated that CD8+ T-lymphocyte numbers are genetically transmitted in association with the MHC class I region. The present study was designed with the objective of narrowing the region associated with the setting of CD8+ T-lymphocyte numbers in a population of C282Y homozygous hemochromatosis subjects, in whom a high prevalence of abnormally low CD8+ T-lymphocyte counts has been described. METHODS: The study includes 43 C282Y homozygous subjects fully characterized both phenotypically and genotypically. Clinical characterization includes measurements of iron parameters at diagnosis (transferrin saturation and serum ferritin), total body iron stores and T-cell immunophenotyping determined by flow cytometry. Genetic characterization includes HLA class I alleles (A, B and C) and four additional microsatellite markers (D6S265, D6S2222, D6S105 and D6S2239) spanning 5 Megabases in the 6p21.3 region. RESULTS: Eighty-two extended C282Y carrying haplotypes were defined. Single-locus analysis revealed that the HLA-A region was associated with CD8+ T-cell numbers. Multivariate analysis showed that the combinations of the most common HLA-A alleles (HLA-A*03, -A*02 and -A*01) were associated with significantly lower numbers of CD8+ T-lymphocytes (0.30 +/- 0.14 x 106/ml), in comparison with subjects carrying only one copy of those alleles (0.46 +/- 0.19 x 106/ml) and subjects without any copy of those alleles (0.79 +/- 0.15 x 106/ml;p = 0.0001). No differences were observed in CD8+ T-cell counts among control subjects carrying the same combinations of HLA-A alleles (0.47 +/- 0.14; 0.45 +/- 0.21 and 0.41 +/- 0.17 x 106/ml, respectively), therefore not supporting a direct effect of HLA specificity but rather an indirect association with a locus close to HLA-A. Multivariate analysis showed that the combination of the most common HLA-A alleles also have an impact on the clinical expression of HH in terms of iron stores, in males(p = 0.0009). CONCLUSION: The present study provides evidence supporting an inextricable link between extended HLA haplotypes, CD8+ T-lymphocyte numbers and severity of iron overload in hereditary hemochromatosis(HH). It gives additional information to better define a candidate region involved in the regulation of CD8+ T-lymphocyte numbers. A new evolutionary hypothesis concerning the inheritance of the phenotype of low CD8+ T-lymphocyte numbers associated with particular ancestral HLA haplotypes carrying the C282Y mutation and its implication on the clinical heterogeneity of HH is discussed.

Adult↗
PubMed2004

Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload.

Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron 1 gene (SMN1). SMN is involved in various processes including the formation of the spliceosome, pre-mRNA splicing and transcription. To know whether SMN has an essential role in all mammalian cell types or an as yet unknown specific function in the neuromuscular system, deletion of murine Smn exon 7, the most frequent mutation found among SMA patients, has been restricted to liver. Homozygous mutation results in severe impairment of liver development associated with iron overload and lack of regeneration leading to dramatic liver atrophy and late embryonic lethality of mutant mice. These data strongly suggest an ubiquitous and essential role of full-length SMN protein in various mammalian cell types. In SMA patients, the residual amount of SMN allows normal function of various organs except motor neurons. However, data from mouse and human suggest that other tissues might be involved in severe form of SMA or during prolonged disease course which reinforce the need of therapeutic approaches targeted to all tissues. In addition, liver function of patients should be carefully investigated and followed up before and during therapeutic trials.

Animals↗
PubMed1999

Electron microscopic findings of the liver of a patient with Dubin-Johnson syndrome complicated by chronic hepatitis C and iron overload.

A patient was first found to have Dubin-Johnson syndrome and chronic hepatitis at the age of 25 years. Two years later, he underwent gastrectomy because of massive bleeding from duodenal ulcer, followed by posttransfusion self-limited biochemical liver damage. Twenty-five years later, his jaundice worsened to a serum bilirubin level of 10 mg/dl. The test for circulating hepatitis C virus RNA was highly positive, and liver histology showed cirrhosis with brown pigment granules in small numbers of hepatocytes. Some pigment granules were positive for histochemical iron stain. Ultrastructural study on the liver showed (1) the presence of iron-specific X-ray-positive pigment granules, and (2) large numbers of myelin-like bodies throughout the hepatocyte cytoplasm. Histologically advanced hepatic lesions of hepatitis C virus infection and posttransfu-sion iron overload may exacerbate bilirubin transport dysfunction of the syndrome.

Journal Article↗
PubMed2005

Total blood lymphocyte counts in hemochromatosis probands with HFE C282Y homozygosity: relationship to severity of iron overload and HLA-A and -B alleles and haplotypes.

BACKGROUND: It has been reported that some persons with hemochromatosis have low total blood lymphocyte counts, but the reason for this is unknown. METHODS: We measured total blood lymphocyte counts using an automated blood cell counter in 146 hemochromatosis probands (88 men, 58 women) with HFE C282Y homozygosity who were diagnosed in medical care. Univariate and multivariate analyses of total blood lymphocyte counts were evaluated using these variables: sex; age, transferrin saturation, and serum ferritin concentration at diagnosis; units of blood removed by phlebotomy to achieve iron depletion; and human leukocyte antigen (HLA)-A and -B alleles and haplotypes. RESULTS: The mean age at diagnosis was 49 +/- 14 years (range 18 - 80 years) in men and 50 +/- 13 years (range 22-88 years) in women. The correlations of total blood lymphocyte counts with sex, age, transferrin saturation, and serum ferritin concentration at diagnosis, and units of blood removed by phlebotomy to achieve iron depletion were not significant at the 0.05 level. Univariate analyses revealed significant associations between total blood lymphocyte counts and presence of the HLA-A*01, -B*08, and -B*14 alleles, and the A*01-B*08 haplotype. Presence of the A*01 allele, B*08 allele, or A*01-B*08 haplotype were associated with a lower total blood lymphocyte count, whereas presence of the B*14 allele was associated with a greater total blood lymphocyte count. There was an inverse association of total blood lymphocyte count with units of phlebotomy to achieve iron depletion, serum ferritin concentration, and with presence of the A*01-B*08 haplotype. CONCLUSION: We conclude that there is a significant inverse relationship of total blood lymphocyte counts and severity of iron overload in hemochromatosis probands with HFE C282Y homozygosity. The presence of the HLA-A*01 allele or the -B*08 allele was also associated with significantly lower total blood lymphocyte counts, whereas presence of the -B*14 allele was associated with significantly higher total blood lymphocyte counts. In univariate and multivariate analyses, total blood lymphocyte counts were significantly lower in probands with the HLA-A*01-B*08 haplotype than in probands without this haplotype.

Journal Article↗
PubMed1990

Iron overload and bone disease in chronic dialysis patients.

Bone pathology was studied in 27 patients showing either iron or aluminium accumulation in bone. These patients belonged to a group of 120 unselected chronic haemodialysis patients in whom transiliac bone biopsies had been obtained. Group A consisted of 12 patients with bone iron deposits (positive Perls' staining at the calcified bone boundary, CBB) and only minimal aluminium accumulation (bone aluminium below 20 micrograms/g wet weight). Group B included 15 patients with pronounced aluminium accumulation (positive aluminium staining at the CBB and bone aluminium of 20 micrograms/g wet weight or more) and without significant bone iron deposition (negative Perls' staining at the CBB). Bone diseases were classified as early hyperparathyroidism, osteitis fibrosa, mixed disease, osteomalacia, adynamic bone disease or other bone condition using osteoid volume, relative osteoblastic activity (ROBA%), and the presence of fibrosis, as criteria. In group A, 5 of 12 patients showed adynamic bone disease, a fairly uncommon condition in the general population of non-parathyroidectomised dialysis patients. In fact, in a control group of 80 patients without iron and without aluminium overload, only five patients showed adynamic bone disease. In group B, 8 of 15 patients showed osteomalacia, and 2 of 15 presented with mixed disease, which is in agreement with the established relationship between bone aluminium accumulation and the occurrence of defective bone mineralisation. It is concluded that iron overload in dialysis patients is associated with an increased frequency of adynamic bone disease.

Aluminum↗
PubMed1996

Erythrocytapheresis can reduce iron overload and prevent the need for chelation therapy in chronically transfused pediatric patients.

PURPOSE: This research was undertaken to determine the advantages, complications, costs, and efficacy of erythrocytapheresis in young pediatric patients who receive chronic erythrocyte transfusion therapy. PATIENTS AND METHODS: We retrospectively analyzed data for 10 children who received erythrocytapheresis for an average of 16 months. Erythrocytapheresis was compared to simple transfusion therapy with respect to annual blood unit exposure, occurrence of alloimmunization, and costs. Serum ferritin levels were compared before and after the period of erythrocytapheresis. RESULTS: Erythrocytapheresis was well tolerated, even in children as young as 5 years or as small as 20 kg. It required a greater annual unit exposure than simple transfusions, but did not increase alloimmunization. Ferritin levels decreased significantly in children receiving concurrent deferoxamine, and decreased or stabilized in those not on chelation therapy. Children started on erythrocytapheresis soon after stroke have not developed iron overload. Although the costs of erythrocytapheresis exceed that of simple transfusion, the substantial costs of deferoxamine therapy should be considered; one child on erythrocytapheresis has been able to discontinue chelation therapy following normalization of his ferritin level. CONCLUSION: Erythrocytapheresis is a safe and effective method for young patients receiving chronic erythrocyte transfusions. Erythrocytapheresis can reduce total iron burden and may obviate the need for expensive chelation therapy.

Adolescent↗
PubMed1994

Pulmonary function abnormalities in thalassemia major and the role of iron overload.

To determine the predominant abnormality of pulmonary function in patients with thalassemia major (TM), we evaluated 29 patients with TM who were receiving hypertransfusion therapy and chelation with desferrioxamine (DFO), and who ranged in age from 6 to 40 yr (mean 19.8 +/- 8.5 yr). A reduction in the total lung capacity (TLC) was the most striking abnormality, found in 21 of 29 patients (79%). Fourteen of these patients (67%) had a moderate or severe reduction in TLC. Expiratory flow rates, FEV1, and FEF25-75 were decreased below predicted values in 48 and 17% of the patients, respectively, but no patients had pure obstructive disease. Significant hypoxemia (oxygen saturation of less than 95%) was observed in only one patient. There was a significant inverse correlation between TLC and patient age (p < 0.003), transfusional iron burden (p < 0.003) and DFO ratio (p < 0.024). Restrictive disease is the predominant abnormality of pulmonary function in TM, with a mixed restrictive-obstructive pattern in a small number of patients. The restrictive disease becomes more severe with increasing age, and the degree and duration of iron overload appear to be important in its pathogenesis. The role of DFO therapy in preventing the pulmonary complications associated with TM requires further study.

Adolescent↗
PubMed1986

Progressive dysfunction of monocytes associated with iron overload and age in patients with thalassemia major.

We evaluated phagocytic and lytic activities of peripheral blood monocytes (PBMo) from patients with thalassemia major (ThP) using C pseudotropicalis as the target. PBMo from ThP showed decreased lytic activity (P less than .001), whereas the phagocytic activity did not differ from that of the controls. Significant inverse correlations were found between lytic activity of PBMo and age of patients (r2 = .47; P less than .01) and also between lytic activity and serum ferritin levels (r2 = .65; P less than .001). No association was found between lytic activity and other variables (blood transfusion regimens, therapy with desferrioxamine, liver damage, and the presence of sHBAg). Splenectomy showed no positive effect on PBMo functions from ThP. Our results suggest that PBMo from ThP have an intracellular defect in their microbicidal mechanisms associated with iron overload. This cell dysfunction could be responsible, at least in part, for the increased susceptibility to infections reported in ThP.

Adolescent↗