In Transfusion-Dependent Thalassemia Children, Increased Iron Overload is Associated with Lower Serum Alpha-Klotho, Which is Strongly Associated with Lower Total and Ionized Calcium Concentrations

Abstract

Background: Patients with transfusion-dependent thalassemia (TDT) show disorders in calcium metabolism. The α-Klotho protein is predominantly expressed in tissues that are involved in calcium homeostasis, and lowered levels are associated with bone disease. The aim of the study is to examine the associations between low α-Klotho status and calcium metabolism in relation to iron status in children with TDT. Methods: Calcium, α-Klotho, parathyroid hormone (PTH), calcyphosin, vitamin D3, phosphorous, fibroblast growth factor receptor 2 (FGFR2), as well as iron and erythron biomarkers were measured in 60 children with TDT and 30 healthy control children. Results: A meaningful part of TDT patients showed lowered α-Klotho levels, and those children also showed low serum total and ionized calcium concentrations. TDT patients showed increased PTH, FGFR2, and calcyphosin and lowered vitamin D3 as compared with healthy children. The α-Klotho levels were significantly correlated with total and ionized calcium (positively) and with iron overload and transfusions biomarkers (inversely). Partial Least Squares path analysis showed that 40.1% of the variance in serum total calcium could be explained by the regression on α-Klotho, vitamin D3 (both positively), and calcyphosin (inversely) and that the effects of the latter are mediated by iron overload and the number of blood transfusions. Conclusion: In conclusion, the iron overload in TDT and its consequences may induce lowered levels of α-Klotho which in turn may lead to lower calcium thereby explaining at least in part the effects of TDT on bone metabolism including spontaneous pathological fractures, osteoporosis, osteopenia, and skeletal deformities.