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Edouard Bardou-Jacquet,
Severine Cunat,
Marie-Pascale Beaumont-Epinette,
Caroline Kannengiesser,
Xavier Causse,
Sylvie Sauvion,
Bruno Pouliquen,
Yves Deugnier,
Veronique David, Olivier Loréal,
Patricia Aguilar-Martinez,
Pierre Brissot,
Anne-Marie Jouanolle
British Journal of Haematology 04/2013; · 4.94 Impact Factor
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ABSTRACT: Natural polyamines such as putrescine (Put), spermidine (Spd), and spermine (Spm), which are present in the human diet in large amounts, associated with their active transporter, are assumed to play a role in non-heme iron uptake and iron bioavailability from nutrients. Enterocytes and hepatocytes play pivotal roles in the regulation of body iron homeostasis. In this study, we report the effects of natural polyamines on iron transport in the Caco-2 cell line. In enterocyte-like Caco-2 cells, polyamines did not significantly modulate the transepithelial iron flux across the cell monolayer cultured on permeable membranes. In contrast, Spd, Spm, and to a lesser extent, Put were shown to activate Caco-2 cell iron uptake and to induce an increase in the ferritin level. This iron co-transport in enterocytes, which involved an interaction between iron and polyamine then cell uptake of the polyamine-iron complexes by the polyamine transport system, was more pronounced in proliferating than in differentiated Caco-2 cells. Moreover, it was observed at physiological concentrations of both polyamines and iron. It could thus play a role in the rapid renewal of enterocytes. These data suggest the involvement of polyamines as components of the pool of transferrin-independent iron-chelating vectors. Further investigations are needed to demonstrate their biological relevance in physiological situations.
Molecular and Cellular Biochemistry 03/2013; · 2.06 Impact Factor
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ABSTRACT: Genetic haemochromatosis is a hereditary disease characterised by tissue iron overload. In Caucasians it is most often due to homozygous C282Y HFE gene mutation, but other genes may be involved. Without treatment by venesections, patients can develop life-threatening visceral damage such as liver cirrhosis and carcinoma, diabetes or heart failure. This treatment has been remarkably successful in preventing these complications, but patients survive with other symptoms of the disease susceptible to impair, sometimes seriously, their quality of life. This is the case of arthropathy and osteoporosis complicating haemochromatosis. In this chapter, focus has been placed on the rheumatological complications of genetic haemochromatosis.
Best practice & research. Clinical rheumatology 10/2011; 25(5):649-64. · 2.90 Impact Factor
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Edouard Bardou-Jacquet,
Marie-Laure Island,
Anne-Marie Jouanolle,
Lénaïck Détivaud,
Nadia Fatih,
Martine Ropert,
Eolia Brissot,
Annick Mosser,
Hervé Maisonneuve,
Pierre Brissot, Olivier Loréal
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ABSTRACT: DMT1 is a transmembrane iron transporter involved in iron duodenal absorption and cellular iron uptake. Mutations in the human SLC11A2 gene coding DMT1 lead to microcytic anemia and hepatic iron overload, with unexpectedly low levels of plasma ferritin in the presence of iron stores.
We report a patient with a similar phenotype due to two mutations in the SLC11A2 gene, the known p.Gly212Val (G212V) mutation and a novel one, p.Asn491Ser (N491S). To assess the expression of DMT1 in human liver, we studied the expression of the four DMT1 mRNA isoforms by real-time quantitative PCR in control human liver samples. We also studied the effect of G212V and N491S DMT1 mutations on RNA splicing in blood leukocytes and cellular trafficking of dsRed2-tagged-DMT1 protein in the human hepatic cell line HuH7.
Our results showed that i) only the isoforms 1B-IRE and 1B-nonIRE were significantly expressed in human liver; ii) the G212V mutation did not seem to affect mRNA splicing and the N491S mutation induced a splicing alteration leading to a truncated protein, which seemed quantitatively of low relevance; and iii) the N491S mutation, in contrast to the G212V mutation, led to abnormal protein trafficking.
Our data confirm the major role of DMT1 in the maintenance of iron homeostasis in humans and demonstrate that the N491S mutation, through its deleterious effect on protein trafficking, contributes together with the G212V mutation to the development of anemia and hepatic iron overload.
Blood Cells Molecules and Diseases 08/2011; 47(4):243-8. · 2.35 Impact Factor
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ABSTRACT: Iron disorders of genetic origin are mainly composed of iron overload diseases, the most frequent being HFE-related hemochromatosis. Hepcidin deficiency underlies iron overload in HFE-hemochromatosis as well as in several other genetic iron excess disorders, such as hemojuvelin or hepcidin-related hemochromatosis and transferrin receptor 2-related hemochromatosis. Deficiency of ferroportin, the only known cellular protein iron exporter, produces iron overload in the typical form of ferroportin disease. By contrast, genetically enhanced hepcidin production, as observed in matriptase-2 deficiency, generates iron-refractory iron deficiency anemia. Diagnosis of these iron storage disorders is usually established noninvasively through combined biochemical, imaging and genetic approaches. Moreover, improved knowledge of the molecular mechanisms accounting for the variations of iron stores opens the way of novel therapeutic approaches aiming to restore normal iron homeostasis. In this review, we will summarize recent findings about these various genetic entities that have been identified owing to an exemplary interplay between clinicians and basic scientists.
Trends in Molecular Medicine 08/2011; 17(12):707-13. · 10.35 Impact Factor
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ABSTRACT: Besides transferrin iron, which represents the normal form of circulating iron, non-transferrin bound iron (NTBI) has been identified in the plasma of patients with various pathological conditions in which transferrin saturation is significantly elevated. SCOPE OF THE REVIEW: To show that: i) NTBI is present not only during chronic iron overload disorders (hemochromatosis, transfusional iron overload) but also in miscellaneous diseases which are not primarily iron overloaded conditions; ii) this iron species represents a potentially toxic iron form due to its high propensity to induce reactive oxygen species and is responsible for cellular damage not only at the plasma membrane level but also towards different intracellular organelles; iii) the NTBI concept may be expanded to include intracytosolic iron forms which are not linked to ferritin, the major storage protein which exerts, at the cellular level, the same type of protective effect towards the intracellular environment as transferrin in the plasma.
Plasma NTBI and especially labile plasma iron determinations represent a new important biological tool since elimination of this toxic iron species is a major therapeutic goal.
The NTBI approach represents an important mechanistic concept for explaining cellular iron excess and toxicity and provides new important biochemical diagnostic tools. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.
Biochimica et Biophysica Acta 08/2011; 1820(3):403-10. · 4.66 Impact Factor
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ABSTRACT: Hepcidin regulates plasma iron bioavailability and subsequently iron availability for erythropoiesis. rHuEPO has been reported to decrease hepcidin expression in case of repeated subcutaneous injections. Thus, hepcidin level measurement could be a candidate marker for detection of rHuEPO abuse. However, when used for doping, rHuEPO can be injected intravenously and the scheme of injection is unknown. Our aim was to evaluate the early effects of a single intravenous rHuEPO injection on serum hepcidin levels. Fourteen male healthy volunteers received one intravenous injection of 50 U/Kg of rHuEPO during a placebo-controlled, randomized, double-blind, cross-over study. Serum hepcidin, quantified by a competitive ELISA method and iron parameters was then evaluated for 24 h. Serum levels of hepcidin were significantly increased 4 h after rHuEPO injection when compared with placebo injection (78.3 ± 55.5 vs. 57.5 ± 34.6 ng/ml, respectively; +36%, p < 0.05), whereas iron and transferrin saturation dramatically decreased 12 h after rHuEPO injection when compared with placebo injection (9.2 ± 3.5 vs. 15.8 ± 4.2 μg/l, respectively; -42%, p < 0.05 and 14.8 ± 5.0 vs. 26.3 ± 6.4%, respectively; -44%, p < 0.05). In addition, 12 and 24 h after rHuEPO injection serum hepcidin levels were lower compared with placebo injection (41.6 ± 27.4 vs. 56.6 ± 28.1 ng/ml after 12 h; -27%, p < 0.05 and 26.0 ± 29.6 vs. 81.2 ± 29.4 ng/ml after 24 h; -68%, p < 0.05). Intravenous injection of recombinant EPO induces a precocious and transient increase of serum hepcidin leading to a transient decrease of iron bioavailability. The transitory increase and dynamics of its concentration make difficult the practical use of hepcidin to detect rHuEPO doping.
Arbeitsphysiologie 08/2011; 112(4):1391-7. · 2.15 Impact Factor
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Caroline Le Lan,
Annick Mosser,
Martine Ropert,
Lénaïck Detivaud,
Véronique Loustaud-Ratti,
Denis Vital-Durand,
Laurent Roget,
Edouard Bardou-Jacquet,
Bruno Turlin,
Véronique David, Olivier Loréal,
Yves Deugnier,
Pierre Brissot,
Anne-Marie Jouanolle
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ABSTRACT: Ferroportin disease is characterized by iron overload. It has an autosomal-dominant pattern of inheritance and has been associated with mutations in the SLC40A1 gene, which encodes the cellular iron exporter ferroportin. Since the first description in 2001, about 30 mutations have been reported; the heterogeneity of ferroportin disease phenotypes has led to the hypothesis that the nature of the mutation affects the function of the protein in different ways. We studied genotypes and phenotypes of a large cohort of patients with ferroportin disease.
We studied clinical, biochemical, imaging, histologic, and genetic data from 70 affected subjects from 33 families with 19 mutations.
We found that ferroportin disease, at the time of diagnosis, has limited consequences in the absence of cofactors. Data indicated that transferrin saturation, which correlated with fibrosis and levels of alanine aminotransferase, might be a marker of disease severity. Although the study was performed in a large number of families, we observed incomplete penetrance and no correlation between genotypes and phenotypes.
Members of families with ferroportin disease should be screened for biochemical parameters of iron metabolism as well as genotype to detect silent mutations that might cause disease with acquired or genetic cofactors. Patients should be followed up long term to identify potential complications of the disease.
Gastroenterology 12/2010; 140(4):1199-1207.e1-2. · 11.68 Impact Factor
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ABSTRACT: Alcoholism increases the risk of cirrhosis and/or hepatocellular carcinoma development. Iron, like ethanol, modulates the cell growth. However, the relationship between alcohol and iron toward hepatocyte proliferation has not been clearly elucidated. The purpose of this study was to evaluate, in the human HepaRG cell line model, the impact of ethanol on hepatocyte proliferation in relation to modulations of iron metabolism and the protective effect of iron metabolism manipulation by chelators in alcohol liver diseases.
The human hepatoma HepaRG cell line model was used. Cell viability was determined by measuring succinate dehydrogenase activity, total protein level by the Bradford method. DNA synthesis was evaluated by [(3)H]-methyl thymidine incorporation. Cytotoxicity was studied by release of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT) in culture medium and apoptosis by measuring caspase 3/7 activity. Gene expression was analyzed by RT-qPCR. Total iron, soluble transferrin receptor, and ferritin levels were, respectively, measured by colorimetrical, immuno-nephelometrical, and immuno-turbidimetrical methods. Intracellular iron uptake and accumulation was examined by radionuclide (55)Fe (III) measurement and Perls staining.
Results showed that ethanol decreased all the parameters associated with HepaRG cell proliferation (cell viability, total protein levels, and DNA synthesis) in a dose- and time-dependent manner. This effect was accompanied by cytotoxicity and apoptosis as evaluated by a significant increase in extracellular enzymes (LDH, AST, ALT) and caspase 3/7 activity, respectively. Ethanol exposure was accompanied by an increased cellular iron uptake, together with increased expression of genes involved in iron transport and storage such as l-ferritin, Divalent Metal transporter 1, transferrin, transferrin receptor 1, and ceruloplasmin. Ethanol impact was intensified by iron-citrate and decreased by iron chelators when added to the culture medium.
The results indicated that (i) ethanol-induced iron metabolism dysfunction could be one of the underlying mechanisms of ethanol antiproliferative effect and (ii) exogenous iron may accentuate ethanol hepatoxicity. These data suggest that iron metabolism manipulation by chelators may be a useful therapeutic approach in alcohol-related liver diseases.
Alcoholism Clinical and Experimental Research 12/2010; 35(3):408-19. · 3.34 Impact Factor
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ABSTRACT: To quantify hepatic and splenic iron load, which is a critical issue for iron overload disease diagnosis. MRI is useful to noninvasively determine liver iron concentration, but not proven to be adequate for robust evaluation of splenic iron load. We evaluated the usefulness of MRI-derived parameters to determine splenic iron concentration in mice.
A mouse model of experimental iron load was used. Multi-echo spin-echo images of liver and spleen were acquired at 4.7 Tesla. The parameters were tested at all echoes with and without an external reference. Splenic and hepatic iron concentrations were determined using biochemical assay as the gold standard.
Our results show that (i) use of an internal or external reference is essential; (ii) optimal echo times were TE = 19.5 ms and TE = 32.5 ms for the liver and spleen, respectively; (iii) in the liver, the relationship between biochemical and MRI iron concentration determinations is logarithmic; (iv) in the spleen, the best relationship is an inverse function.
A single spin-echo sequence allows robust estimation of hepatic and splenic iron content. Parameters classically used for hepatic iron concentration cannot be applied to splenic iron determination, which requires both the specific sequence and the adapted fitting function.
Journal of Magnetic Resonance Imaging 09/2010; 32(3):639-46. · 2.70 Impact Factor
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ABSTRACT: Genetic iron overload has long been confined to the picture of classical hemochromatosis related to the HFE C282Y mutation (type 1 hemochromatosis). C282Y homozygosity affects approximately three people out of 1000 of the Caucasian population, representing one of the most frequent genetic predispositions. It has, however, rapidly become clear that the HFE C282Y mutation is not the sole culprit in genetic iron overload. Several novel mutations in HFE and other genes have been discovered and related to various entities, which are now known as types 2, 3 and 4 hemochromatosis. These diseases are far less frequent than the classical type 1 hemochromatosis but, by contrast, are not limited to the Caucasian population. Molecular diagnosis obviously plays a key role in the diagnostic strategy. In the future, it will undoubtedly enable not only identification of new diagnostic markers, but also provide potential molecular targets for pathophysiologically based innovative therapeutic approaches.
Expert Review of Molecular Diagnostics 09/2010; 10(6):755-63. · 4.86 Impact Factor
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ABSTRACT: Venesection has been proposed as a treatment for hepatic iron overload in a number of chronic liver disorders that are not primarily linked to mutations in iron metabolism genes. Our aim was to analyse the impact of venesection on iron mobilisation in a mouse model of secondary iron overload. C57Bl/6 mice were given oral iron supplementation with or without phlebotomy between day 0 (D0) and D22, and the results were compared to controls without iron overload. We studied serum and tissue iron parameters, mRNA levels of hepcidin1, ferroportin, and transferrin receptor 1, and protein levels of ferroportin in the liver and spleen. On D0, animals with iron overload displayed elevations in iron parameters and hepatic hepcidin1 mRNA. By D22, in the absence of phlebotomies, splenic iron had increased, but transferrin saturation had decreased. This was associated with high hepatic hepcidin1 mRNA, suggesting that iron bioavailability decreased due to splenic iron sequestration through ferroportin protein downregulation. After 22days with phlebotomy treatments, control mice displayed splenic iron mobilisation that compensated for the iron lost due to phlebotomy. In contrast, phlebotomy treatments in mice with iron overload caused anaemia due to inadequate iron mobilisation. In conclusion, our model of secondary iron overload led to decreased plasma iron associated with an increase in hepcidin expression and subsequent restriction of iron export from the spleen. Our data support the importance of managing hepcidin levels before starting venesection therapy in patients with secondary iron overload that are eligible for phlebotomy.
Biochimica et Biophysica Acta 03/2010; 1802(3):339-46. · 4.66 Impact Factor
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ABSTRACT: During the inflammatory process, hepcidin overexpression favours the development of anaemia of chronic diseases which represents the second most common form of anaemia worldwide. The identification of therapeutic agents decreasing hepcidin expression is therefore an important goal. The aim of this study was to target the STAT3 signalling involved in the development of increased hepcidin expression related to chronic inflammation. In a co-culture model associating mouse hepatocytes and rat liver epithelial cells, the mRNA levels of hepcidin1, albumin, aldolase B, Cyp3a4, Stat3, Smad4 and iron regulatory genes were measured by real-time PCR. STAT3 and phosphorylated SMAD1/5/8 proteins were analysed by Western blot. At variance of hepatocyte pure culture, co-culture provided high levels of hepcidin1 mRNA, reaching 400% of the freshly isolated hepatocyte values after 6 days of culture. Hepcidin expression was associated with the maintenance of hepatocyte phenotype, STAT3 phosphorylation and functional BMP/SMAD pathway. Stat3 siRNAs inhibited the hepcidin1 mRNA expression. STAT3 inhibitors, including curcumin, AG490 and a peptide (PpYLKTK), reduced hepcidin1 mRNA expression even when cells were additionally exposed to IL-6. Hepcidin1 mRNA was expressed at high levels by hepatocytes in the co-culture model, and STAT3 pathway activation was controlled through STAT3 inhibitors. Such inhibitors could be useful to prevent anaemia related to hepcidin overexpression during chronic inflammation.
Journal of Molecular Medicine 02/2010; 88(5):477-86. · 4.67 Impact Factor
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ABSTRACT: Two oral chelators, CP20 (deferiprone) and ICL670 (deferasirox), have been synthesized for the purpose of treating iron overload diseases, especially thalassemias. Given their antiproliferative effects resulting from the essential role played by iron in cell processes, such compounds might also be useful as anticancer agents. In the present study, we tested the impact of these two iron chelators on iron metabolism, in the HepaRG cell line which allowed us to study proliferating and differentiated hepatocytes. ICL670 uptake was greater than the CP20 uptake. The iron depletion induced by ICL670 in differentiated cells increased soluble transferrin receptor expression, decreased intracellular ferritin expression, inhibited (55)Fe (III) uptake, and reduced the hepatocyte concentration of the labile iron pool. In contrast, CP20 induced an unexpected slight increase in intracellular ferritin, which was amplified by iron-treated chelator exposure. CP20 also promoted Fe(III) uptake in differentiated HepaRG cells, thus leading to an increase of both the labile pool and storage forms of iron evaluated by calcein fluorescence and Perls staining, respectively. In acellular conditions, compared to CP20, iron removing ability from the calcein-Fe(III) complex was 40 times higher for ICL670. On the whole, biological responses of HepaRG cells to ICL670 treatment were characteristic of expected iron depletion. In contrast, the effects of CP20 suggest the potential involvement of this compound in the iron uptake from the external medium into the hepatocytes from the HepaRG cell line, therefore acting like a siderophore in this cell model.
Biology of Metals 12/2009; 23(2):231-45. · 3.17 Impact Factor
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Blood 10/2009; 114(11):2360-1. · 9.90 Impact Factor
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Marie-Bérengère Troadec,
Fabrice Lainé,
Vincent Daniel,
Pierre Rochcongar,
Martine Ropert,
Florian Cabillic,
Michèle Perrin,
Jeff Morcet, Olivier Loréal,
Gordana Olbina,
Mark Westerman,
Elizabeta Nemeth,
Tomas Ganz,
Pierre Brissot
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ABSTRACT: Hepcidin and hemojuvelin (HJV) are two critical regulators of iron metabolism as indicated by the development of major iron overload associated to mutations in hepcidin and HJV genes. Hepcidin and HJV are highly expressed in liver and muscles, respectively. Intensive muscular exercise has been reported to modify serum iron parameters and to increase hepcidinuria. The present study aimed at evaluating the potential impact of low intensity muscle exercise on iron metabolism and on hepcidin, its key regulator. Fourteen normal volunteers underwent submaximal cycling-based exercise in a crossover design and various iron parameters, including serum and urinary hepcidin, were serially studied. The results demonstrated that submaximal ergocycle endurance exercise did not modulate hepcidin. This study also indicated that hepcidinuria did not show any daily variation whereas serum hepcidin did. The findings, by demonstrating that hepcidin concentrations are not influenced by submaximal cycling exercise, may have implications for hepcidin sampling in medical practice.
Arbeitsphysiologie 04/2009; 106(3):435-43. · 2.15 Impact Factor
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ABSTRACT: Low levels of hepcidin are responsible for the development of iron overload in p.Cys282Tyr HFE related hemochromatosis. Every genetic factor lowering the hepcidin gene expression could contribute to a more severe phenotype in HFE hemochromatosis. Based on this hypothesis, we identified a heterozygous nc.-153 C>T mutation in the hepcidin gene promoter sequence in a patient homozygous for the p.Cys282Tyr HFE mutation who presented massive iron overload, resisting to well conducted iron depletive treatment. Our results demonstrate that the nc.-153 C>T mutation, located within a BMP-RE (Bone Morphogenetic Protein-Responsive Element): i) decreases the transcriptional activity of the hepcidin promoter, ii) alters its IL-6 (Interleukin-6) total responsiveness, and iii) prevents the binding of the SMAD protein complex (1/5/8 and 4) to the BPM-RE. In conclusion, our results suggest that a mutation in the BMP-RE of hepcidin promoter may impact on human iron metabolism.
Haematologica 04/2009; 94(5):720-4. · 6.42 Impact Factor
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ABSTRACT: The protective effect of pyoverdins Pa A and Pf, peptidic siderophores secreted respectively by Pseudomonas aeruginosa and fluorescens, was studied in primary cultures of human hepatocytes exposed to iron (50 or 100 μM of iron-citrate). AST, ALT and MDA releases were measured as indexes of cytotoxicity. In order to demonstrate that these chelators were able to decrease iron uptake or increase iron release from the hepatocytes, labelled cells were obtained by maintaining the cultures in the presence of 1 μM 55Fe ferric chloride plus 50 μM iron citrate. One day after iron treatment, an increase in AST, ALT and MDA release was observed with 50 or 100 μM of iron citrate; it appeared that the concentrations 50 and 100 μM of iron were highly toxic for human hepatocytes. In the presence of 50 or 100 μM of iron, the addition of 50 or 100 μM of Pa A or Pf was effective to inhibit the increase observed in the enzyme leakage and the MDA production resulting from iron exposure. In human hepatocytes cultured for 1 day in the presence of 1 μM 55Fe-50 μM iron citrate plus 50 or 100 μM Pa A or Pf, a net decrease of iron uptake by the cells was observed, as demonstrated by the low intracellular iron level. When the hepatocytes were cultured for 1 day in the presence of 1 μM 55Fe-50 μM iron citrate and then for a further day in the presence of 50 or 100 μM Pa A or Pf without additional iron, the chelators increased the extracellular iron level, indicating their iron release from the loaded cells; however, the effects of Pa A and Pf on iron release did not differ significantly. In conclusion, iron loading achieved by adding iron citrate to the culture medium is highly toxic for human hepatocytes. Pyoverdins Pa A and Pf are effective in protecting human hepatocytes against the toxic effect of iron by both decreasing the uptake of the metal and increasing its release from the loaded cells.
Liver International 12/2008; 17(2):70 - 75.
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ABSTRACT: Patients with type 1 (HFE-related) genetic hemochromatosis are usually excluded from blood donation on the basis that this disease may facilitate bacterial infections. The aim of the present study was to evaluate the serum antibacterial effect against Salmonella enterica Typhimurium LT2 in relation to iron status.
Serum samples were collected in 26 iron-overloaded (homozygous C282Y mutation) and 35 iron-depleted hemochromatosis patients and 33 healthy control subjects. The antibacterial activity of sera and iron parameters were tested for each patient.
Serum from normal controls had an antibacterial effect against Salmonella Typhimurium LT2. The antibacterial effect decreased from the 1:2 to the 1:8 dilution and was always significantly lower in the iron-overloaded group. In both control and iron-depleted patients, a positive correlation was found between the decrease of antibacterial effect and the increase of both serum iron and transferrin saturation.
These results (a) support the view that chronic iron overload decreases serum antibacterial effect against Salmonella enterica Typhimurium LT2, (b) favor the interest of including, besides serum ferritinemia, serum transferrin saturation levels as a further criterion for iron-depletive treatment efficacy, and (c) provide an argument for not discouraging the use of blood from iron-depleted hemochromatosis patients for transfusion.
The American Journal of Gastroenterology 09/2008; 103(10):2502-8. · 7.28 Impact Factor
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ABSTRACT: Iron overload diseases of genetic origin are an ever changing world, due to major advances in genetics and molecular biology. Five major categories are now established: HFE-related or type1 hemochromatosis, frequently found in Caucasians, and four rarer diseases which are type 2 (A and B) hemochromatosis (juvenile hemochromatosis), type 3 hemochromatosis (transferrin receptor 2 hemochromatosis), type 4 (A and B) hemochromatosis (ferroportin disease), and a(hypo)ceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to an impairment of hepcidin synthesis, account for the development of cellular excess in types 1, 2, 3, and 4B hemochromatosis whereas decreased cellular iron egress is involved in the main form of type 4A) hemochromatosis and in aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. The combination of magnetic resonance imaging (for diagnosing visceral iron overload) and of genetic testing has drastically reduced the need for liver biopsy. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases paves the road for innovative therapeutic approaches.
Blood Reviews 08/2008; 22(4):195-210. · 5.36 Impact Factor
