Iron Overload Cardiomyopathy in Clinical Practice
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 20 Linguagem: Inglês
10.1161/circulationaha.111.050773
ISSN1524-4539
AutoresDimitrios Th. Kremastinos, Dimitrios Farmakis,
Tópico(s)Trace Elements in Health
ResumoHomeCirculationVol. 124, No. 20Iron Overload Cardiomyopathy in Clinical Practice Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIron Overload Cardiomyopathy in Clinical Practice Dimitrios T. Kremastinos and Dimitrios Farmakis Dimitrios T. KremastinosDimitrios T. Kremastinos From the Second Department of Cardiology, Attikon University Hospital, Athens, Greece. and Dimitrios FarmakisDimitrios Farmakis From the Second Department of Cardiology, Attikon University Hospital, Athens, Greece. Originally published15 Nov 2011https://doi.org/10.1161/CIRCULATIONAHA.111.050773Circulation. 2011;124:2253–2263IntroductionThe cardiomyopathies are heart muscle diseases of primary or secondary origin. Primary cardiomyopathies are often of unknown cause, hence their treatment is limited to general heart failure management. In secondary cardiomyopathies, in contrast, the identification of the underlying cause allows for a more specific, hence effective, approach that, when applied early, may prevent the development of heart failure.The term iron overload cardiomyopathy (IOC) recently has been introduced to describe a secondary form of cardiomyopathy resulting from the accumulation of iron in the myocardium mainly because of genetically determined disorders of iron metabolism or multiple transfusions.1,2 This condition, although previously overlooked, has lately attracted the attention of investigators because iron overload is, on one hand, a frequently encountered condition, especially in association with certain hematologic conditions, and on the other hand, its accurate identification and effective management have now become possible.IOC has been recently described as a dilated cardiomyopathy, characterized by left ventricular (LV) remodeling with chamber dilatation and reduced LV ejection fraction (LVEF).1 However, primary hemochromatosis, a genetically determined condition leading to iron overload, is classically categorized as an infiltrative cause of restrictive cardiomyopathy.3 Moreover, secondary hemochromatosis may lead to severe diastolic LV dysfunction in the early stages of the disease, before LVEF is affected.4,5 In the present review, we describe the forms, pathophysiology, and phenotypic expression of IOC, focusing on ventricular geometry and function and describing the early diastolic abnormalities that lead ultimately to heart muscle dysfunction and heart failure. The clinical implications of the condition are also discussed.Iron OverloadIron overload is the accumulation of excess body iron in different organs as a result of increased intestinal absorption, parenteral administration, or increased dietary intake.6 Besides being a crucial component of hemoglobin with a key role in erythropoiesis, oxygen transportation and storage, iron also has further important functions as part of several enzymatic systems and metabolic processes.7 Thus, iron deficiency results in impairment of functional status even in the absence of anemia, whereas iron repletion therapy is beneficial regardless of the presence of anemia.8 Iron homeostasis is therefore essential, and is regulated by a complex system that involves iron absorption, transportation, and storage with the participation of several regulatory proteins.9 Those proteins include ferritin, which serves for the intracellular iron storage; ferroportin, which is responsible for the release of stored iron from duodenal epithelial cells and macrophages in the form of ferrous iron (Fe2+); hepcidin, which regulates the release of ferrous iron from duodenal cells and macrophages by acting on ferroportin; ceruloplasmin, which oxidizes ferrous iron to ferric iron (Fe3+) before its transportation; transferrin, the transporter of ferric iron in the circulation; and other less understood ones (Figure 1).7,9Download figureDownload PowerPointFigure 1. A schematic presentation of the role of the main proteins involved in iron metabolism (see text for details).However, iron is a double-facet element, and a derangement of iron homeostasis leading to excessive iron intake and storage is deleterious to several tissues. The heart, along with the liver and the endocrine glands, is the main organ affected by excess iron accumulation, and thus iron-loading conditions are primarily manifested as cardiac dysfunction and failure, liver dysfunction and cirrhosis, and endocrine abnormalities including hypothyroidism, hypogonadism, and diabetes mellitus, as well.6,9The term iron overload cardiomyopathy describes the different forms of cardiac dysfunction secondary to myocardial iron deposition.1,9 Besides being a major cause of morbidity, IOC accounts for one third of deaths in hereditary hemochromatosis, especially in young male patients3; it is the leading cause of mortality in thalassemia major10; and it is also a major cause of death in other conditions associated with secondary iron overload.11Pathogenesis and FormsIron overload may be either primary or secondary (Table 1). The primary form of iron overload is termed hereditary or primary hemochromatosis, an autosomal disorder resulting from mutations in genes encoding proteins involved in iron metabolism.12 Iron overload in this condition results from the increased intestinal iron absorption and a further derangement of iron metabolism. Four types are currently identified according to the implicated gene mutation. Type 1 results from mutations of the HFE gene on chromosome 6, and it corresponds to classical hereditary hemochromatosis. Type 2 is associated with mutations of the HJV gene on chromosome 1 that encodes hemojuvelin (subtype 1A) or in the HAMP gene on chromosome 19 that encodes hepcidin (subtype 2B). Type 3 results from mutations of the TfR2 gene on chromosome 7 encoding transferrin receptor 2. Finally, type 4 is caused by mutations of the SLC40A1 gene on chromosome 2 that encodes ferroportin. All mutations are inherited by the autosomal recessive type, with the exception of type 4, which is inherited as an autosomal dominant condition. Types 1, 3, and 4 are manifested in adulthood and usually during the fourth or fifth decade of life, whereas type 2, also called juvenile hemochromatosis, is clinically expressed much earlier, in the second or third decade, and its phenotype is much more severe.12 The typical clinical triad of hereditary hemochromatosis is cirrhosis, bronze skin, and diabetes mellitus, but the phenotype of the disorder is extremely variable and depends on several interfering genetic and other factors, particularly in HFE-related hemochromatosis (type 1). In types 1 and 3, hepatic involvement predominates, whereas in type 2, endocrine and cardiac complications are more pronounced, and heart failure is a frequent cause of death before the age of 30 years.12Table 1. Main Conditions Leading to Iron OverloadPrimary iron overload Hereditary hemochromatosis Type I: HFE-related Type II: Juvenile Subtype A: HJV-related Subtype B: HAMP-related Type III: TfR2-related Type IV: Ferroportin-relatedSecondary iron overload Hereditary anemias Hemoglobinopathies Thalassemia Sickle cell disease Diamond–Blackfan anemia Congenital dyserythropoiesis anemia Sideroblastic anemia Acquired anemias Myelodysplastic syndromes Myelofibrosis Aplastic anemia Leukemias Myeloproliferative disorders Stem cell transplantation Chronic kidney disease Other conditions Chronic liver disease Friedreich ataxia Aceruloplasminemia Congenital atransferrinemia Increased dietary intakeSecondary iron overload is mainly caused by the considerably high parenteral iron administration, and is primarily observed in association with transfusion-dependent hereditary or acquired anemias, such as inherited hemoglobinopathies, myelodysplastic syndromes (MDS), myelofibrosis, aplastic anemia, sideroblastic anemia, and Blackfan-Diamond anemia.11 Regarding inherited hemoglobinopathies, which are the most common single-gene disorders in humans, all thalassemia major patients and ≈20% of those with sickle cell disease are transfusion-dependent.13,14 On the other hand, the effective management of MDS and other acquired hematologic conditions with novel agents has improved patients' survival, increasing at the same time the need for supportive care with blood transfusions.15 Thus, the majority of MDS patients are currently chronically transfused, and it has been calculated that about half of patients who receive 75 to 100 U of transfused blood develop clinically significant myocardial iron overload.13,16 Other conditions associated with secondary iron overload include chronic liver diseases such as alcoholic cirrhosis, Friedreich ataxia, porphyria cutanea tarda, intravenous iron therapy in end-stage renal disease, extreme dietary intake, and some rare disorders affecting iron metabolism, such as congenital atransferrinemia or aceruloplasminemia.1,2Pathogenetic MechanismsIn hereditary hemochromatosis, mutations of genes encoding crucial proteins involved in iron metabolism lead to an inappropriately high duodenal iron absorption compared with the total body iron content.12 In secondary hemochromatosis, iron overload results primarily from repetitive blood transfusions that saturate the reticuloendothelial system cells with iron, which then spills out to other parenchymal cells.17,18 During iron overload, transferrin, the carrier of iron in the circulation, which is normally ≈30% saturated, becomes fully saturated, and the toxic non–transferrin-bound iron species appear in the circulation.14 It should be stressed that the cellular uptake of non–transferrin-bound iron is not controlled by the negative feedback mechanism that regulates transferring bound iron uptake. This, in combination with the lack of an iron excretory mechanism, leads to intracellular iron accumulation. Uptake of iron from non–transferrin-bound iron species in hepatocytes, cardiac myocytes, and endocrine gland cells leads to tissue iron accumulation and, ultimately, the deleterious effects of iron overload.13 In thalassemia major patients, besides repetitive transfusions, there is also an increase in intestinal iron absorption because of inappropriate hepcidin suppression caused by the ineffective erythropoiesis.In the presence of iron overload, iron, in the form of ferrous iron (Fe2+), enters the myocytes through the voltage-dependent L-type calcium channels.19 Myocardial iron uptake is much slower in comparison with hepatic uptake, and thus myocardial iron overload develops at a later stage in comparison with hepatic iron overload.14 Iron deposition occurs initially in the ventricular myocardium and subsequently in the atrial myocardium and also affects the conducting system, but to a lesser extent compared with the working myocardium.14 The epicardial iron concentration is generally higher than the subendocardial one, but it was recently shown that there was no variation in iron deposition among the different LV segments in patients with severe IOC.20 Iron is stored in the myocytes in the form of ferritin, hemosiderin, and labile cellular iron (free iron), the latter being the most active one. Labile iron leads to the formation of reactive oxygen species via the Fenton reaction, which converts ferrous to ferric iron with the generation of the toxic hydroxyl radical. The cellular antioxidant properties are exceeded, resulting to peroxidation of membrane lipids, cellular proteins, and nucleic acids. At the same time, increased ferrous iron transportation through the L-type calcium channels also results in derangement of cardiomyocyte calcium transportation and impaired excitation-contraction coupling, which may in turn be involved in the development of the diastolic and systolic ventricular dysfunction seen in association with iron overload.2The end result of this process is the development of a cardiomyopathy characterized mainly by LV dysfunction.10,21 It should be noted that myocardial iron overload, although it holds a key role as a triggering factor in the development of IOC, is not the only mechanism involved. Early studies in thalassemia major showed that several indices of LV function had a poor correlation with the total number of blood units transfused. Those preliminary findings implied that IOC was rather a particular type of cardiomyopathy with complex pathophysiology and not a direct effect simply of iron infiltration.21,22 This concept was later confirmed, because a number of studies showed that, apart from iron, additional immunoinflammatory and genetic factors seemed to interfere in the pathogenesis of IOC, such as myocarditis, the HLA genotype, and the apolipoprotein E genotype.20–22 More specifically, myocarditis was identified as a cause of LV failure, whereas the HLA-DQA1*0501 allele and the apolipoprotein E e4 allele were both associated with an increased prevalence of adverse LV remodeling and reduced LVEF in patients with thalassemia major.23–25Besides direct myocardial injury, iron overload may also affect the heart indirectly through its effects on other organs. Thus, hepatic dysfunction, endocrinopathies (diabetes mellitus, hypothyroidism, hypoparathyroidism), and immune deficiency resulting from iron overload may contribute to the pathophysiology of IOC.26,27 The pathophysiology of IOC is summarized in Figure 2.Download figureDownload PowerPointFigure 2. Pathohysiology of iron overload cardiomyopathy. Dotted lines indicate not well-defined mechanisms; double line, indirect effects.Phenotypic ExpressionIn general, IOC is far more frequent in the secondary forms of iron overload than in primary hemochromatosis. Two phenotypes of IOC have been identified: the dilated phenotype, characterized by a process of LV remodeling leading to chamber dilatation and reduced LVEF, and the restrictive phenotype, characterized by diastolic LV dysfunction with restrictive filling, preserved LVEF, pulmonary hypertension, and subsequent right ventricular dilatation.10 Those 2 phenotypes are followed by several other manifestations including conduction system abnormalities, tachyarrhythmias, and perimyocarditis.1,23,28In the early stages of the disease, myocardial iron overload is expressed as diastolic LV dysfunction. Spirito et al4 studied 32 young thalassemia major patients with preserved LVEF; transmitral Doppler flow velocities revealed a restrictive LV filling pattern in 50% of those patients. To overcome the potential confounding effects of age, a larger trial in 88 thalassemia major patients with preserved LVEF recruited both adolescents and adults and evaluated both transmitral and pulmonary vein diastolic Doppler indices.5 Restrictive LV filling was also encountered in this cohort, but with a much lower prevalence (8%). Moreover, all patients with restrictive LV filling had advanced age and highly elevated serum ferritin concentration. Similar findings were subsequently reported by other investigators.29 More recent trials using natriuretic peptides revealed the presence of elevated LV filling pressures and diastolic LV dysfunction in the early stages of the disease.30,31If the cause of iron overload persists and no proper iron chelation therapy is initiated, the majority of patients with IOC develop LV remodeling that ultimately leads to LV dilatation and reduced LVEF, the so-called dilated phenotype of IOC.10,32 In a minority of cases (<10%) characterized by severe iron overload, restrictive LV dysfunction leads, in advanced age, to the development of pulmonary hypertension, right ventricular dilatation, and right-sided heart failure without LV anatomic remodeling and with preserved LVEF, even at the final stages, the so-called restrictive phenotype.5,32 Whether a patient follows the dilated or the restrictive pathway seems to be crucially dependent on the interaction between the main disease and the additional immunoinflammatory and molecular factors discussed above.23–25 The interference of some of those factors, such as myocarditis, leads to the dilated phenotype, which is believed to be multifactorial in pathophysiology.10,32Cardiovascular magnetic resonance imaging (CMR) with T2* relaxometry made possible the quantitative assessment of iron load and confirmed the close correlation between LVEF and myocardial iron deposition. In the seminal study by Anderson et al,33 in 106 thalassemia major patients, LVEF declined progressively as iron burden increased, whereas it remained within normal range in the absence of detectable myocardial iron. Those findings were subsequently confirmed in larger patient populations.34,35 Moreover, CMR also revealed evidence of myocardial fibrosis and scars in thalassemia major patients with iron overload,36 although the finding was later questioned by other investigators.37It should be noted that LV diastolic dysfunction and reduced LVEF may both be masked by an anemia-induced high-output state in patients with hemoglobinopathies and other hematologic conditions.38 Thus, a pseudonormalized pattern is frequently encountered in transmitral inflow,10 which may be unmasked by studying pulmonary vein flow pattern or mitral annulus motion by tissue Doppler imaging. On the other hand, it has been proposed that a higher cutoff value for LVEF should be applied in those patients.39Right ventricular function may be impaired by LV dysfunction and pulmonary hypertension.10 In addition, a form of right ventricular cardiomyopathy was previously reported in a small group of thalassemia major patients with congestive heart failure.40 More recently, a retrospective analysis of CMR data in 319 thalassemia major patients showed that right ventricular ejection fraction declined progressively with the increase of myocardial iron load, following a pattern similar to that of LVEF.41Clinical ImplicationsCurrent Impact and Physicians' AwarenessThe mutations leading to hereditary hemochromatosis are not rare, especially among white populations.11 However, the clinical impact of hereditary hemochromatosis on the cardiovascular system is generally limited, and, although IOC may account for a significant percentage of deaths in patients with the juvenile-onset forms, noncardiac complications and mortality usually predominate in the adult-onset forms.11 In contrast, secondary iron overload has a much greater clinical impact, because it is related to a significantly higher iron-loading rate, and its prevalence has a tendency to rise.11 On one hand, the growing usage of bone marrow transplantation and stem cell therapies and the improved survival of patients with hematologic malignancies or MDS increase the need for repetitive blood transfusions.1,11 On the other hand, the hemoglobinopathies are the most common monogenic disorders in humans, and, although traditionally confined to specific geographical regions, they have currently expanded to a global distribution because of financial immigration and ethnic globalization.10 Moreover, the survival of patients with hemoglobinopathy currently tends to reach that of the healthy population by virtue of modern therapy.42,43 However, IOC has generally been overlooked both by physicians and the medical literature. Given that IOC has a rising clinical impact, bears some distinct clinical features, and requires a particular diagnostic and therapeutic approach, cardiovascular care providers should be aware of this entity.Diagnosis and ScreeningThe initial evaluation and follow-up plan for patients with IOC or at risk for IOC is presented in Figure 3. History taking, physical examination, standard ECG, and chest x-ray should all be part of patients' initial evaluation and of their regular cardiac follow-up and screening. The latter is generally performed annually unless cardiac abnormalities or cardiac siderosis are present. History taking may reveal a known or suspected condition causing iron overload, such as hemoglobinopathies, MDS, or other transfusion-dependent hereditary or acquired anemias or hereditary hemochromatosis or other rare disorders of iron metabolism. A wide spectrum of cardiac symptoms, indicative of left- or right-sided heart failure or rhythm disorders, may be present, along with other symptoms related to the underlying disease or iron-induced extracardiac organ damage (hepatic dysfunction, diabetes mellitus, hypogonadism, other endocrine disorders, arthritis). Physical examination may reveal signs of left- or right-sided heart failure, along with findings related to the underlying cause of iron overload or iron-induced injury. Typical skin pigmentation is seen usually in association with moderate to severe iron overload and is practically the only specific sign of iron overload.Download figureDownload PowerPointFigure 3. A proposed algorithm for the diagnostic evaluation and follow-up of patients with known or suspected iron overload cardiomyopathy or at risk for iron overload cardiomyopathy.Basic laboratory investigation includes serum ferritin and transferrin saturation for the diagnosis of iron overload, along with a full blood count, hemoglobin electrophoresis, liver function tests, endocrine tests (diabetes mellitus, thyroid, gonads, etc) to assess the underlying disorder causing iron overload and the potential consequences of iron on organ function.17,44 Genetic testing may be needed for the diagnosis or confirmation of hereditary disorders and mainly of hemoglobinopathies (mutations mainly of the β-globin gene cluster) or hereditary hemochromatosis (mutations of HFE, HJV, HAMP, TfR2, or SLC40A1 genes).12Standard resting ECG allows the identification of supraventricular and ventricular arrhythmias and conduction system abnormalities, which are part of IOC clinical phenotype,28,45 although serious arrhythmias are usually prevented in patients following modern therapy. Nonspecific repolarization abnormalities may also be seen in association with intensive chelation therapy.46 Chest x-ray may reveal cardiomegaly due to LV enlargement in patients with the dilated phenotype of IOC, signs of pulmonary congestion in cases with left-sided heart failure, or left atrial or right ventricular enlargement with or without signs of pulmonary hypertension in those with the restrictive phenotype.Echocardiography is the main modality used in screening patients with iron-loading conditions for heart disease as part of their initial and regular follow-up evaluation.10 Left and right ventricular systolic and diastolic function abnormalities, and pericardial and valvular involvement, as well, may easily be detected. Impaired diastolic LV function featuring pseudonormalized or restrictive filling pattern, with or without left atrial enlargement constitute early findings.4,5,22,29,38,47,48 Advanced-stage disease is characterized by left and right cardiac chamber dilatation and reduced LVEF (the dilated phenotype) or, alternatively, by restrictive LV filling with left atrial and right ventricular dilatation, increased pulmonary artery pressure, and preserved LVEF (the restrictive phenotype).23,40,47,48 High cardiac output with chamber dilatation, eccentric LV hypertrophy, and normal or increased LVEF may also be seen.47,48 Although echocardiography identifies the consequences of iron on myocardial structure and function, it does not accurately predict myocardial iron content. However, it provides a simple means for the screening of asymptomatic patients and the follow-up of patients with known pathology.10Although sophisticated imaging methods such as strain and strain rate may identify subtle LV dysfunction,49 this may not be possible for the imaging techniques used in the everyday clinical practice. The amino-terminal pro-B-type natriuretic peptide may serve as an early index of diastolic LV dysfunction in patients with iron overload.10 Indeed, it was shown that amino-terminal pro-B-type natriuretic peptide might be elevated in thalassemia major patients with preserved LVEF before conventional Doppler indices of diastolic function became abnormal30 or when Doppler and tissue Doppler values were inconclusive.31CMR-derived T2* relaxation time is currently the mainstay for the quantitative assessment of cardiac iron deposition.11 Introduced a decade ago,33 this modality has revolutionized the clinical management of patients with hemoglobinopathies and other iron overload conditions, because it allows the accurate diagnosis and quantification of myocardial and hepatic iron deposition and hence the tailoring and monitoring of iron chelation therapy. Actually, it is postulated that the currently observed survival improvement in thalassemia major is partly attributable to the introduction of CMR-T2* imaging into clinical practice.42 The T2* relaxation time is mainly affected by iron in the form of hemosiderin and not by ferritin or labile cellular iron, but because there is a continuous reflux between the 3 forms of stored iron, the technique accurately predicts tissue iron content.11 Measured in a full-thickness area of interest in the interventricular septum, T2* is highly representative of global myocardial iron.20 A value of 20 ms is considered to be the threshold for myocardial siderosis. It has been shown in thalassemia major patients that T2* values ≥20 ms, corresponding to lack of iron overload or benign iron load, are associated with normal cardiac function with a high negative predictive value.33 T2* values <20 ms, indicative of myocardial siderosis, have an inverse correlation with LVEF,33–35 whereas T2* values <10 ms, indicative of severe iron overload, are associated with an increased annual risk of the development of heart failure or arrhythmias50 (Figure 4). More specifically, in a prospective study of 652 patients with thalassemia major, the occurrence of heart failure within 1 year was 47%, 21%, and 0.2% in patients with T2* 10 ms, respectively (relative risk for T2* 10 ms, 270).50 Arrhythmias occurred in 19% of patients with T2* 10 ms.50 However, the widespread implementation of the technique is still limited by its restricted availability in several developing countries.Download figureDownload PowerPointFigure 4. Schematic presentation of the relationship between cardiac T2* values, cardiac tissue iron concentration, and risk for heart failure (1data extracted from Kirk et al50).The traditional predictor of iron overload, serum ferritin, increases linearly with the number of blood transfusions and is closely correlated with liver iron content.33,50 However, it is also an acute-phase protein that increases in several other conditions and is poorly correlated with myocardial iron load. Nevertheless, serum ferritin provides a simple means for the monitoring of iron chelation therapy. Liver iron concentration, on the other hand, requires an invasive procedure (liver biopsy) and is also poorly correlated with myocardial iron content.The diagnosis of IOC is made when evidence of heart disease, particularly diastolic LV dysfunction with restrictive filling or LV remodeling with chamber dilatation and reduced LVEF, coexists with iron overload (serum ferritin >300 ng/mL, transferrin saturation >55%) and cardiac siderosis (cardiac T2* 2500 ng/mL still indicates the presence of significant total body iron content with a high risk of heart disease.51 Besides identifying patients with established IOC, it is of utmost importance to also identify those at risk for developing IOC, namely patients with iron overload with or without cardiac siderosis, and those with conditions potentially causing iron overload, as well, because proper and timely therapy prevents the development of IOC.Download figureDownload PowerPointFigure 5. Diagnosis of iron overload cardiomyopathy based on the algorithm proposed in Figure 2. Diagnosis requires the presence of (1) iron overload (serum ferritin >300 ng/mL, transferrin saturation >55%), (2) cardiac siderosis (cardiac iron <20 ms), and (3) evidence of heart disease. LV indicates left ventricular; LVEF, left ventricular ejection fraction; RV, right ventricular.Prevention and TherapyAll 4 types of hereditary hemochromatosis respond to therapeutic phlebotomy.12 Phlebotomy is an easily applicable, safe, and inexpensive procedure that prevents the development of iron-induced organ damage and prolongs survival when initiated early, but it cannot reverse the established severe complications, including liver cirrhosis, insulin-dependent diabetes mellitus, hypogonadism, and destructive arthritis.12 It is generally applied in patients with hereditary hemochromatosis when serum ferritin exceeds 1000 ng/mL or in the presence of symptoms and consists of an induction phase with weekly removal of 1 to 2 blood units to reduce serum ferritin <50 ng/mL and transferrin saturation <30%, followed by a life-long maintenance phase aiming at serum ferritin <100 ng/mL and transferrin saturation <50% (Figure 6).12Download figureDownload PowerPointFigure 6. Management of iron chelation in patients with or at risk of iron overload cardiomyopathy. ACEi indicates angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.Since the introduction of the potent iron chelator deferoxamine in the 1970s, the management of secondary iron overload also became possible. The subsequent advances in the field of chelators have rendered iron overload efficiently treatable and IOC almost completely preventable. Three chelators are currently avai
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