The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major.

First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, Athens 11527, Greece.
Haematologica (Impact Factor: 5.94). 07/2006; 91(6):809-12.
Source: PubMed

ABSTRACT Hepcidin production is homeostatically regulated by iron stores, anemia and hypoxia. We evaluated the effect of iron overload and of ineffective erythropoeisis on hepcidin expression in patients with thalassemia major. Liver hepcidin mRNA levels correlated with hemoglobin concentration and inversely correlated with serum transferrin receptor, erythropoietin and non-transferrin-bound iron. They did not correlate with indices of iron load. Urinary hepcidin levels were disproportionably suppressed in regards to iron burden. We conclude that hepcidin expression is regulated mainly by increased erythropoietic activity rather than by iron load and that hepcidin plays a central regulatory role in iron circulation and iron toxicity in patients with thalassemia.

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    ABSTRACT: The thalassemia syndromes (α- and β-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α- or β-globin chain production results in impaired red blood cell synthesis, anemia and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis and dysfunctional iron metabolism have not been investigated in both α-thalassemia carriers (ATC) and β-thalassemia carriers (BTC). Here we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changings in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferrin and (hepcidin/ferritin)/sTfR are respectively increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis.This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 10/2014; · 2.41 Impact Factor
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    ABSTRACT: Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in Hbb(th3/+) mice with thalassemia intermedia, where it contributes to the suppression of hepcidin and the systemic iron overload characteristic of this disease.
    Nature Genetics 06/2014; 10(1038):2996. · 29.65 Impact Factor
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    ABSTRACT: This study aims to evaluate the serum prohepcidin level in β-thalassemia patients, to clarify its relation with serum level of ferritin and to assess the possible role of null polymorphisms of glutathione Stransferase genes, GSTM1 and GSTT1, for susceptibility to β-thalassemia and myocardial siderosis. The serum level of pro-hepcidin was assessed in 31 patients [16 children (52 %) and 15 young adults (48 %)] with β- thalassemia and nine healthy individuals [four children (44 %) and five young adults (56 %)] applying ELISA method. Genotyping for the null polymorphisms of GSTM1 and GSTT1 was performed successfully by multiplex PCR in 17 patients and in 40 healthy individuals, which were enrolled in the case–control study for assessment of the role of these polymorphisms as risk factors for β-thalassemia. The mean serum level of pro-hepcidin in patients did not differ significantly (159.12±70.12 ng/ml) from that in controls (144.64±53.30 ng/ml). We found a significant positive correlation with the serum ferritin (R= 0.371, p=0.039). In addition, there was an association between the serum pro-hepcidin and the type of chelating therapy. The frequency of GSTT1 null genotypes was significantly higher in patients than in controls (0.29 vs. 0.07, p=0.025). We observed tendencies for a higher serum ferritin and lower value of ejection fraction of the left ventricle (EFLV) of the patients carrying GSTT1 null genotypes than those with non-null GSTT1 genotypes. The serum levels of pro-hepcidin is not the most precise markers of iron overload and organ dysfunction, but it could be considered as a relatively good alternative of the serumferritin as an index of iron stores. In addition, we suggest that GSTT1 null genotype could be considered as a predisposing factor for β- thalassemia, myocardial siderosis, and dysfunction in patients with this disease.

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