Mechanisms of plasma non‐transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients

Abstract

Summary In transfusional iron overload, extra-hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non-transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond-Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin-iron utilization (DBA).

Clinical and methodological factors affecting non-transferrin-bound iron values using a novel fluorescent bead assay

“…NTBI appears when iron influx into the plasma compartment exceeds iron efflux, for example, with iron overload, ineffective erythropoiesis, or decreased transferrin iron clearance in erythroid hypoplasia 5 . NTBI is considered the main conduit of hepatic6, 7, 8 and extra-hepatic9, 10, 11, 12 iron loading of tissues, under hemosiderotic conditions.…”

Non-transferrin-bound iron is associated with biomarkers of oxidative stress, inflammation and endothelial dysfunction in type 2 diabetes

“…Standard biomarkers for iron status such as ferritin and soluble transferrin receptor concentrations do not necessarily provide an accurate A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 4 monitor of NTBI levels. In some cases changes in NTBI levels do follow changes in the levels of the standard biomarkers (Goto et al 2013), but in others this is not so (Porter et al 2014). Such findings have led to the suggestion that NTBI should be included as a valid independent biomarker of the potential adverse effects of iron in disease states Jacob 2004, Taher et al 2009).…”

Combined treatment of 3-hydroxypyridine-4-one derivatives and green tea extract to induce hepcidin expression in iron-overloaded β-thalassemic mice

“…Apparently, toxic forms of iron known as non-transferrin bound iron (NTBI), labile plasma iron and labile iron pools (LIP) are detectable in these patients [2,3]. Effective iron chelators are required to remove this iron to prevent oxidative damage in the vital organs, particularly the heart and liver.…”

“…The regulations result in a retention of iron within the cells and a reduction of iron in the plasma [19][20][21]. Recently, NTBI and hepcidin have been proposed to be novel reliable markers for iron metabolism, especially, iron overload condition [2,22,23]. Urinary and serum hepcidin levels are decreased in β-thalassemia, which exacerbates the condition leading to further iron overload [24].…”

“…Urinary and serum hepcidin levels are decreased in β-thalassemia, which exacerbates the condition leading to further iron overload [24]. Expression of hepcidin in patients with iron overload such as β-thalassemia and myelodysplatic syndromes may be suppressed by the growth differentiation factor 15, the twisted gastrulation factor 1, the bone morphogenetic protein-binding endothelial cell precursor-derived regulator and/or the erythroferrone [2,[25][26][27][28].…”