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: 5.81). 07/2006; 91(6):809-12.
Source: PubMed


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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Available from: George N. Papanikolaou
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    • "In the present work, hepcidin expression did not correlate with other iron overload markers such as ferritin and liver iron stores. Concomitant findings were reported in previous studies (Pratummo et al., 2014; Kattamis et al., 2006). This was to be expected, as it is known that regulation of iron balance according to iron stores breaks down in disorders with massive erythroid proliferation and ineffective erythropoiesis such in β-thalassemia major. "
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    ABSTRACT: Iron overload is the major cause of morbidity and mortality in transfusion dependent β-thalassemia major patients. There is a sophisticated balance of body iron metabolism of storage and transport which is regulated by several factors including the peptide hepcidin. Hepcidin is the main iron regulatory molecule; it is secreted mainly by the liver and other tissues including monocytes and lymphocytes. Expression of hepcidin in such cells is unclear and has been studied in few reports with controverted result. Peripheral expression of hepcidin was measured using quantitative real time PCR (qRT-PCR) in 50 β-thalassemia major patients, in addition to 20 healthy volunteers as a control group. Hepcidin levels in β-thalassemia major patients showed statistically significant decrease in comparison to the control group, and was correlated to cardiac iron stores (T2*). However, hepcidin level was not different among the patients according to the HCV status or whether splenectomized or not. In conclusion; peripheral expression of hepcidin, in iron overloaded β-thalassemia major patients, is a reflection of hepatic expression. It can be used as a molecular predictor for the severity of cardiac iron overload and can be used as a future target for therapy in β-thalassemia major patients.
    Full-text · Article · Mar 2015 · Gene
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    • "The latter result agrees with previously reported similar correlations: a positive correlation between serum hepcidin and ferritin in healthy controls (Ganz et al. 2008; Koliaraki et al. 2009) and in patients with chronic heart failure with anemia (Matsumoto et al. 2010). The observed negative correlation between the serum prohepcidin and hemoglobin in our group of patients with βthalassemia is in variance to the results reported by some other research groups (Kattamis et al. 2006; Camberlein et al. 2008). This controversy could be attributed to the fact that they analyzed hepcidin mRNA in the liver of patients with β-thalassemia, whereas we studied the serum prohepcidin levels. "
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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.
    Full-text · Dataset · Aug 2013
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    • "Signals which regulate hepcidin expression are hierarchically arranged. In diseases characterized by ineffective erythropoesis, like talassemias, dominance of the stimulus of erythropoietic demand over the inhibition by iron stores can cause iron overload (122). Studies have shown that regulation of hepcidin by erythropoiesis is probably mediated by bone marrow-derivated signal molecules: growth differentiation factor 15 (GDF15), twisted gastrulation protein homologe 1 (TWSG1) and hormone erytropoetin (123–125) Suppression of hepcidin in hypoxia is mediated by hypoxia inducible factors (HIF) (126,127). "
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    ABSTRACT: Iron metabolism has been intensively examined over the last decade and there are many new players in this field which are worth to be introduced. Since its discovery many studies confirmed role of liver hormone hepcidin as key regulator of iron metabolism and pointed out liver as the central organ of system iron homeostasis. Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of hepcidin expression. This liver hormone is negative regulator of iron metabolism that represses iron efflux from macrophages, hepatocytes and enterocytes by its binding to iron export protein ferroportin. Ferroportin degradation leads to cellular iron retention and decreased iron availability. At level of a cell IRE/IRP (iron responsive elements/iron responsive proteins) system allows tight regulation of iron assimilation that prevents an excess of free intracellular iron which could lead to oxidative stress and damage of DNA, proteins and lipid membranes by ROS (reactive oxygen species). At the same time IRE/IRP system provides sufficient iron in order to meet the metabolic needs. Recently a significant progress in understanding of iron metabolism has been made and new molecular participants have been characterized. Article gives an overview of the current understanding of iron metabolism: absorption, distribution, cellular uptake, release, and storage. We also discuss mechanisms underlying systemic and cellular iron regulation with emphasis on central regulatory hormone hepcidin.
    Full-text · Article · Oct 2012 · Biochemia Medica
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