Iron Chelators for Thalassaemia

Hershko, Chaim; Konijn, Abraham M.; Link, Gabriela

doi:10.1046/j.1365-2141.1998.00726.x

Cited by 142 publications

(108 citation statements)

References 65 publications

(64 reference statements)

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“…Furthermore, all her other endocrinological problems, that is, diabetes mellitus, primary hypothyroidism and secondary gonadal insufficiency, still needed treatment. This accords with previous findings in b-TM, that these endocrine abnormalities are likely to be irreversible (2). In addition, the timing of the development of NYHA functional class IV fits well with a previous case report showing that about 3 months after GH withdrawal cardiac functional indices worsened in a GH-deficient patient (26).…”

Section: Discussionsupporting

confidence: 80%

“…Iron accumulation is a consequence of blood transfusions as well as increased iron absorption caused by erythopoietic activity. Posttransfusion iron accumulation is a constant threat to these patients, and the most serious damage of iron overload appears in the liver, endocrine organs and myocardium (2). Pathological findings in the heart include dilated, thickened ventricular walls with particularly heavy iron deposits in the ventricles, epicardium and papillary muscles.…”

Section: Introductionmentioning

confidence: 99%

“…Growth retardation, delayed puberty, hypothyroidism, hypoparathyroidism and diabetes mellitus are all well-established complications of transfusional siderosis (6). Because diabetes mellitus and hypothyroidism appear when most endocrine cells are destroyed and replaced by fibrosis, these complications are rarely reversible (2).…”

Section: Introductionmentioning

confidence: 99%

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Is growth hormone deficiency contributing to heart failure in patients with beta-thalassemia major?

Erfurth

Holmer²,

Nilsson

et al. 2004

European Journal of Endocrinology

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A 21-year-old woman with b-thalassemia major (b-TM) and GH deficiency developed end-stage heart failure, New York Heart Association (NYHA) functional class IV, within 3 months after withdrawal of recombinant human growth hormone (GH). A myocardial biopsy excluded myocarditis and showed moderate iron deposit in the heart. Before her admission, intensified treatments with digoxin, angiotensin-converting enzyme inhibitor, diuretics and extra chelation therapy (desferrioxamine (DFO)) had not improved her progressive heart failure. At admission, GH was reinstituted together with intensified treatment of cardiac drugs and low doses of DFO, and her heart failure reversed. Four months later, NYHA functional class II was reached and within 1 year her cardiac function was normalised. We suggest that GH deficiency due to iron-induced damage to the hypothalamic -pituitary axis can contribute to heart failure in adult patients with b-TM. European Journal of Endocrinology 151 161-166

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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Is growth hormone deficiency contributing to heart failure in patients with beta-thalassemia major?

Erfurth

Holmer²,

Nilsson

et al. 2004

European Journal of Endocrinology

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“…Because raising levels of iron may overwhelm the iron binding capacity of transferrin, resulting in the appearance of non-transferrin bound iron (42), which is capable of catalyzing the formation of the hydroxyl radicals (through the Fenton and Haber-Weiss reactions) (43), it has been suggested that irondependent induction of reactive oxygen species (ROS) may modulate the transcription of these genes (36,44). The possibility of iron-dependent oxidative damage to elastic fibers has also been suggested, but not proven (30).…”

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confidence: 99%

Fluctuations of Intracellular Iron Modulate Elastin Production

Bunda

Kaviani

Hinek

2005

Journal of Biological Chemistry

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Production of insoluble elastin, the major component of elastic fibers, can be modulated by numerous intrinsic and exogenous factors. Because patients with hemolytic disorders characterized with fluctuations in iron concentration demonstrate defective elastic fibers, we speculated that iron might also modulate elastogenesis. In the present report we demonstrate that treatment of cultured human skin fibroblasts with low concentration of iron 2-20 M (ferric ammonium citrate) induced a significant increase in the synthesis of tropoelastin and deposition of insoluble elastin. Northern blot and realtime reverse transcription-PCR analysis revealed that treatment with 20 M iron led to an increase of ϳ3-fold in elastin mRNA levels. Because treatment with an intracellular iron chelator, desferrioxamine, caused a significant decrease in elastin mRNA level and consequent inhibition of elastin deposition, we conclude that iron facilitates elastin gene expression. Our experimental evidence also demonstrates the existence of an opposite effect, in which higher, but not cytotoxic concentrations of iron (100 -400 M) induced the production of intracellular reactive oxygen species that coincided with a significant decrease in elastin message stability and the disappearance of iron-dependent stimulatory effect on elastogenesis. This stimulatory elastogenic effect was reversed, however, in cultures simultaneously treated with high iron concentration (200 M) and the intracellular hydroxyl radical scavenger, dimethylthiourea. Thus, presented data, for the first time, demonstrate the existence of two opposite iron-dependent mechanisms that may affect the steady state of elastin message. We speculate that extreme fluctuations in intracellular iron levels result in impaired elastic fiber production as observed in hemolytic diseases.Mature elastic fibers and laminae provide extensibility and elastic recoil to vascular walls and ligaments and form a connective tissue framework of lungs, elastic cartilage, and skin (1, 2). They are complex structures made of polymeric (insoluble) elastin and 12-nm microfibrils that consist of several glycoproteins, e.g. fibrillins, fibulins, and microfibril-associated glycoproteins (3-6). Elastic fiber formation (elastogenesis) is a complex process involving several intracellular and extracellular events. Cells (fibroblasts, endothelial cells, chondroblasts, or vascular smooth muscle cells) must first synthesize and secrete numerous glycoproteins to form a microfibrillar scaffold upon which tropoelastin, the precursor peptides, are properly assembled and covalently cross-linked by lysyl oxidase into a resilient polymer, insoluble elastin (7-10). Production of elastin reaches its highest levels in the third trimester of the fetal life and steadily decreases during early postnatal development (11,12). In undisturbed tissues, elastic fibers may last over the entire human lifespan (13,14).The net deposition of elastin appears to be controlled on both the transcriptional level (tropoelastin mRNA message express...

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“…Desferrioxamine is a pharmacological agent, which is currently used for the treatment of thalassaemia, neuroblastoma and Alzheimer's disease. [33][34][35][36] This suggests the possibility of augmenting the hypoxia response or of extending the therapeutic range of the hypoxia-signalling pathway beyond tissues that are pathologically typified by hypoxia. A typical scenario for example would be if erythropoietin were the therapeutic gene under control of a hypoxia responsive promoter.…”

Section: Discussionmentioning

confidence: 99%