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      Iron Overload and Chelation Therapy in Non-Transfusion Dependent Thalassemia

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          Abstract

          Iron overload (IOL) due to increased intestinal iron absorption constitutes a major clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), which is a cumulative process with advancing age. Current models for iron metabolism in patients with NTDT suggest that suppression of serum hepcidin leads to an increase in iron absorption and subsequent release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The consequences of IOL in patients with NTDT are multiple and multifactorial. Accurate and reliable methods of diagnosis and monitoring of body iron levels are essential, and the method of choice for measuring iron accumulation will depend on the patient’s needs and on the available facilities. Iron chelation therapy (ICT) remains the backbone of NTDT management and is one of the most effective and practical ways of decreasing morbidity and mortality. The aim of this review is to describe the mechanism of IOL in NTDT, and the clinical complications that can develop as a result, in addition to the current and future therapeutic options available for the management of IOL in NTDT.

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          Hepcidin and iron regulation, 10 years later.

          Tomas Ganz (2011)
          Under evolutionary pressure to counter the toxicity of iron and to maintain adequate iron supply for hemoglobin synthesis and essential metabolic functions, humans and other vertebrates have effective mechanisms to conserve iron and to regulate its concentration, storage, and distribution in tissues. The iron-regulatory hormone hepcidin, first described 10 years ago, and its receptor and iron channel ferroportin control the dietary absorption, storage, and tissue distribution of iron. Hepcidin causes ferroportin internalization and degradation, thereby decreasing iron transfer into blood plasma from the duodenum, from macrophages involved in recycling senescent erythrocytes, and from iron-storing hepatocytes. Hepcidin is feedback regulated by iron concentrations in plasma and the liver and by erythropoietic demand for iron. Genetic malfunctions affecting the hepcidin-ferroportin axis are a main cause of iron overload disorders but can also cause iron-restricted anemias. Modulation of hepcidin and ferroportin expression during infection and inflammation couples iron metabolism to host defense and decreases iron availability to invading pathogens. This response also restricts the iron supply to erythropoietic precursors and may cause or contribute to the anemia associated with infections and inflammatory disorders.
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            Non-transfusion-dependent thalassemias.

            Stefano Rivella, Elliott Vichinsky, Eliezer A Rachmilewitz … (2013)
            Non-transfusion-dependent thalassemias include a variety of phenotypes that, unlike patients with beta (β)-thalassemia major, do not require regular transfusion therapy for survival. The most commonly investigated forms are β-thalassemia intermedia, hemoglobin E/β-thalassemia, and α-thalassemia intermedia (hemoglobin H disease). However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis and peripheral hemolysis, the hallmarks of disease process, lead to a variety of subsequent pathophysiologies including iron overload and hypercoagulability that ultimately lead to a number of serious clinical morbidities. Thus, prompt and accurate diagnosis of non-transfusion-dependent thalassemia is essential to ensure early intervention. Although several management options are currently available, the need to develop more novel therapeutics is justified by recent advances in our understanding of the mechanisms of disease. Such efforts require wide international collaboration, especially since non-transfusion-dependent thalassemias are no longer bound to low- and middle-income countries but have spread to large multiethnic cities in Europe and the Americas due to continued migration.
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              Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells.

              Toshihiko Tanno, Prashanth Porayette, Orapan Sripichai … (2009)
              In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 20 December 2017
                Publication date Collection: December 2017
                Volume: 18
                Issue: 12
                Electronic Location Identifier: 2778
                Affiliations
                [1 ]Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; rib05@ 123456mail.aub.edu (R.B.-F.); joseph.sleiman.22@ 123456gmail.com (J.S.)
                [2 ]Faculty of Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; aab42@ 123456mail.aub.edu (A.-H.B.); bfc01@ 123456mail.aub.edu (B.C.)
                [3 ]Department of Medicine, Ca’Granda Foundation IRCCS, University of Milan, 20122 Milan, Italy; maria.cappellini@ 123456unimi.it
                [4 ]Department of Clinical Science and Community, University of Milan, 20122 Milan, Italy
                Author notes
                [* ]Correspondence: ataher@ 123456aub.edu.lb ; Tel.: +961-1-350-000; Fax: +961-1-370-814
                Article
                Publisher ID: ijms-18-02778
                DOI: 10.3390/ijms18122778
                PMC ID: 5751376
                PubMed ID: 29261151
                SO-VID: 22318266-777b-43e8-b7a7-7ca96623b2dd
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 23 November 2017
                Date accepted : 20 December 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: non-transfusion dependent thalassemia,iron overload,iron chelation therapy,serum ferritin,liver iron concentration
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: non-transfusion dependent thalassemia, iron overload, iron chelation therapy, serum ferritin, liver iron concentration

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