Pathophysiology and treatment of patients with beta-thalassemia – an update

Abstract

Thalassemia (thal) is an autosomal recessive, hereditary, chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of α-globin chains (α-thal) or β-globin chains (β-thal) that compose the major adult hemoglobin (α 2β 2). It is caused by one or more mutations in the corresponding genes. The unpaired globin chains are unstable; they precipitate intracellularly, resulting in hemolysis, premature destruction of red blood cell [RBC] precursors in the bone marrow, and a short life-span of mature RBCs in the circulation. The state of anemia is treated by frequent RBC transfusions. This therapy results in the accumulation of iron (iron overload), a condition that is exacerbated by the breakdown products of hemoglobin (heme and iron) and the increased iron uptake for the chronic accelerated, but ineffective, RBC production. Iron catalyzes the generation of reactive oxygen species, which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system. Herein, we review recent findings regarding the pathophysiology underlying the major symptoms of β-thal and potential therapeutic modalities for the amelioration of its complications, as well as new modalities that may provide a cure for the disease.

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

“…Iron homeostasis depends on a coordinated regulation of molecules involved in the import of this element and those exporting it out of the cells. In particular, the iron status reflects the balance among iron uptake from the diet, its storage and mobilization, and its utilization [1]. Normally, 1-2 mg of iron is absorbed from the diet per day, with an equivalent amount lost by the turnover of gastrointestinal tract epithelial cells.…”

“…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]. Long-term uptake and accumulation of NTBI and LIP, its redox active component, lead to increate levels of storage iron and labile cellular iron [12].…”

“…Deferoxamine was the first iron chelator to be used clinically and is given by a slow, continuous, subcutaneous, overnight infusion through a portable pump. Its side effects are minimal, but its mode of administration results in low compliance [1]. Deferasirox presents several side effects [1,2].…”

“…Red blood cells that survive to reach the peripheral circulation are prematurely destroyed in the spleen. The break down products of Hb, heme, and iron catalyze chemical reactions that generate free radicals, including reactive oxygen species (ROS), which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system [1]. More than 300 different point mutations cause β-thalassemia.…”

“…It will also be explored whether there are ways to decrease the iron overload and to neutralize its deleterious effects in the tissues other than iron chelation (for an extensive revision, see Refs. [1][2][3][4][5]).…”