Iron dysregulation in beta-thalassemia

Abstract

Iron deficiency anemia and iron overload conditions affect more than one billion people worldwide. Iron homeostasis involves the regulation of cells that export iron into the plasma and cells that utilize or store iron. The cellular iron balance in humans is primarily mediated by the hepcidin-ferroportin axis. Ferroportin is the sole cellular iron export protein, and its expression is regulated transcriptionally, post-transcriptionally and post-translationally. Hepcidin, a hormone produced by liver cells, post-translationally regulates ferroportin expression on iron exporting cells by binding with ferroportin and promoting its internalization by endocytosis and subsequent degradation by lysosomes. Dysregulation of iron homeostasis leading to iron deposition in vital organs is the main cause of death in beta-thalassemia patients. Beta-thalassemia patients show marked hepcidin suppression, ineffective erythropoiesis, anemia and iron overload. Beta-thalassemia is common in the Mediterranean region, Southeast Asia and the Indian subcontinent, and the focus of this review is to provide an update on the factors mediating hepcidin related iron dysregulation in beta-thalassemia disease. Understanding this process may pave the way for new treatments to ameliorate iron overloading and improve the long term prognosis of these patients.

Oxidative Stress and Iron Overload in β-Thalassemia: An Overview

“…Living organisms have thus developed many proteins to carry iron in biological fluids and transport it through cellular membranes and to store it in a non-toxic and easily mobilizable form [2,[6][7][8]. Iron is bound to transferrin in the plasma, but the iron overload in β-thalassemia patients saturates the ability of the transferrin iron transport system, leading to nontransferrin bound iron (NTBI) and labile plasma iron (LPI) starting to circulate in plasma and subsequently becoming deposited inside the susceptible cells [9,10]. Rather than using the transferrin receptor, NTBI enters cells by nontransferrin pathways [1,11].…”

Increased Iron in Pediatric β-Thalassaemia Major Associates with CD3+, Not γδ Lymphocytes

“…Red blood cell contained almost 85% of total body iron [2]. Early degradation of this cells is the principal pathogenesis of β-thalassaemia major.…”

A new UROD mutation in childhood porphyria cutanea tarda after allogeneic stem cell transplantation for β‐thalassemia major

“…Heterozygous UROD deficiency does not cause symptoms in the absence of additional acquired risk factors. In β‐thalassemia major, hemoglobin synthesis causes severe anemia, extramedullary hematopoesis, and iron overload . Transfusion is the standard of care and aggravates iron overload.…”

“…PCT was triggered by severe iron overload. Iron excess results in a labile plasma and cytoplasmatic iron pool, which shows toxic redox activity . Mechanisms promoting UROD deficiency include increased synthesis of delta‐aminolevulinic acid, uroporphyrinogen oxidation to porphyrins, and promoting the synthesis of an UROD inhibitor within the hepatocytes .…”