Hepcidin and β-thalassemia major

Nemeth, Elizabeta

doi:10.1182/blood-2013-05-502617

Cited by 36 publications

(35 citation statements)

References 8 publications

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“…Along with the changes in hematological parameters, alterations in iron status in our TM patient was consistent with the data published on large cohorts of TM patients 10,18,19 . She showed normal sFe, but significant hyperferritinemia (ferritin level of 2872 μg/L, Table 3).…”

Section: Iron Status and Hepcidinsupporting

confidence: 78%

“…Imbalances in iron metabolism (including hepcidin levels) and their interconnection with defective erythropoiesis have been widely studied in β-thalassemia (intermedia and major) (ref. 10 ), congenital dyserythropoietic anemia 11 , pyruvate kinase deficiency 12 and DiamondBlackfan anemia 13 . In this study, we investigated the relationship between iron metabolism and erythropoietic activity in pediatric patients with erythrocyte membrane defects and thalassemia traits.…”

Section: Hepcidin and Iron Metabolismmentioning

confidence: 99%

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Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits

Sulovska¹,

Holub²,

Zidova³

et al. 2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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a Background and Aims. Erythropoiesis is closely related to iron metabolism in a balanced homeostasis. Analyses of diverse erythroid and iron metabolism disorders have shown that disrupted erythropoiesis negatively affects iron homeostasis and vice versa. The aim of this study was to characterize the relationship between erythropoietic activity and iron homeostasis in pediatric patients with erythrocyte membrane defects and thalassemia traits. Methods. Selected markers of erythropoietic activity (erythropoietin, soluble transferrin receptor -sTfR and growth differentiation factor 15) and iron status parameters (serum iron, ferritin and hepcidin) were evaluated in pediatric patients with erythrocyte membrane defects and thalassemia traits. Results. The patients with erythrocyte membrane defects and thalassemia traits had altered iron homeostasis due to disturbed erythropoiesis. In comparison with healthy controls, they had a normal to low hepcidin/ferritin ratio and concomitantly elevated sTfR. Conclusion. The findings suggest that pediatric patients with erythrocyte membrane defects and thalassemia traits are more susceptible to iron overload than the general population and that the (hepcidin/ferritin)/sTfR ratio can be used to monitor any worsening of the disease.

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Section: Iron Status and Hepcidinsupporting

confidence: 78%

Section: Hepcidin and Iron Metabolismmentioning

confidence: 99%

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits

Sulovska¹,

Holub²,

Zidova³

et al. 2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Remarkably, hepcidin levels also increased and reduced iron and transferrin saturation were found, which was independent of GDF15 expression. This is significant since GDF15 has been suspected of being the culprit in downregulating hepcidin in thalassemia, leading to iron overload [70]. The role of GDF11 in these beneficial effects was elucidated by a series of elegant molecular studies which were initially based on results of gene expression studies in the fetal livers of mice with thalassemia major.…”

Section: Activin Receptor Ligand Trapsmentioning

confidence: 99%

Thalassemia 2016: Modern medicine battles an ancient disease

Rund

2015

American J Hematol

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Thalassemia was first clinically described nearly a century ago and treatment of this widespread genetic disease has greatly advanced during this period. DNA‐based diagnosis elucidated the molecular basis of the disease and clarified the variable clinical picture. It also paved the way for modern methods of carrier identification and prevention via DNA‐based prenatal diagnosis. Every aspect of supportive care, including safer blood supply, more regular transfusions, specific monitoring of iron overload, parenteral and oral chelation, and other therapies, has prolonged life and improved the quality of life of these patients. Significant advances have also been made in allogenic bone marrow transplantation, the only curative therapy. Recently, there has been a rejuvenated interest in studying thalassemia at the basic science level, leading to the discovery of previously unknown mechanisms leading to anemia and enabling the development of novel therapies. These will potentially improve the treatment of, and possibly cure the disease. Pathways involving activin receptors, heat shock proteins, JAK2 inhibitors and macrophage targeted therapy, among others, are being studied or are currently in clinical trials for treating thalassemia. Novel types of genetic therapies are in use or under investigation. In addition to the challenges of treating each individual patient, the longer survival of thalassemia patients has raised considerations regarding worldwide control of thalassemia, since prevention is not universally implemented. This review will trace a number of the original medical milestones of thalassemia diagnosis and treatment, as well as some of the most recent developments which may lead to innovative therapeutic modalities. Am. J. Hematol. 91:15–21, 2016. © 2015 Wiley Periodicals, Inc.

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“…During transfusion intervals, hemoglobin levels gradually decrease and ineffective erythropoiesis increases. Increased erythropoietic activity reduces hepcidin and increases iron absorption, exacerbating the iron overload (71).…”

Section: Hepcidin and Iron Regulation In β-Thalassemiamentioning

confidence: 99%

Iron regulation by hepcidin

Zhao

Zhang²,

Enns³

2013

J. Clin. Invest.

195

158

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Discovery and function of hepcidin in iron homeostasisHepcidin is a key peptide hormone that regulates iron homeostasis in chordates. Hepcidin was initially characterized as an antimicrobial peptide in a mass spectrometry-based search for cysteine-rich defensin-like peptides in blood (1) and in urine (2). However, both groups showed that hepcidin displays only a weak antimicrobial activity. Further, unlike defensins, which vary in sequence among species, hepcidin is highly conserved from zebrafish to humans. Shortly after hepcidin was described, subtractive hybridization studies comparing the livers of normal and iron overloaded mice established a connection between iron loading and increased hepcidin mRNA (3, 4). The fundamental insight into hepcidin's role in iron homeostasis came in 2004 with the discovery that hepcidin acts to lower iron in the blood by binding to and downregulating the iron transporter, ferroportin (FPN1) (5). FPN1 is the only known transporter that is responsible for the efflux of iron from cells. Downregulation of FPN1 by hepcidin in splenic and hepatic macrophages decreases the ability of macrophages to export recycled iron from senescent rbcs, which constitute the primary source of iron in the plasma. In addition, a high concentration of hepcidin in the blood decreases the transport of iron out of intestinal epithelial cells, further limiting iron in the blood. Control of hepcidin expressionHepcidin is synthesized, processed to an active form, and secreted predominantly by hepatocytes (6, 7). The expression of hepcidin is mediated through the bone morphogenetic protein (BMP) and JAK2/STAT3 signaling pathways (Figure 1). Under nonpathological conditions, iron levels in the body upregulate hepcidin expression. Although the underlying mechanisms are poorly understood, recent studies have documented the essential roles of hemojuvelin (HJV), hereditary hemochromatosis protein (HFE), transferrin receptor 2 (TfR2), and matriptase-2 (MT2, encoded by the gene TMPRSS6) in the process of hepcidin regulation in humans and animal models as well as of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).Intact BMP signaling is essential for hepcidin expression. The canonical BMP-signaling pathway is initiated upon BMP binding to a BMP receptor complex on the cell surface, which activates the receptor kinase to phosphorylate the cytoplasmic proteins SMAD1, SMAD5, and SMAD8. These phosphorylated, receptor-regulated SMADs then form transcription factor complexes with SMAD4, consisting of receptor-regulated SMADs and SMAD4, that translocate into the nucleus to induce the transcription of target genes such as hepcidin (18). In mice, liver-specific disruption of SMAD4 or the BMP receptors ALK2 or ALK3 markedly decreased hepcidin expression, resulting in iron overload (15,19).BMP6. At least 20 BMPs are expressed in mammals. In vitro studies reveal that BMP2, -4, -5, -6, -7, and -9 can robustly induce BMP signaling and markedly increase hepcidin expres...

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Hepcidin and β-thalassemia major

Cited by 36 publications

References 8 publications

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits

Thalassemia 2016: Modern medicine battles an ancient disease

Iron regulation by hepcidin

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