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

*Nadia Maria Sposi*

#### **Abstract**

In β-thalassemia, the erythropoietic process is markedly altered, and the lack or reduced synthesis of β-globin chains induces an excess of free α-globin chains within the erythroid cells. Aggregation, denaturation, and degradation of these chains lead to the formation of insoluble precipitates causing damage to the red blood cell membrane. One of the major consequences in this genetic disorder is iron overload due to ineffective erythropoiesis and premature hemolysis in the plasma and in major organs such as heart, liver, and endocrine glands. The chapter describes the etiology of iron accumulation, the role of hepcidin in regulating increased iron absorption, and the pathophysiology resulting from excess of "free iron" and discusses new ways to decrease the iron overload and to neutralize its deleterious effects in the tissues other than iron chelation.

**Keywords:** oxidative stress, iron overload, β-thalassemia

### **1. Introduction**

β-thalassemias are a group of hereditary blood disorders characterized by the reduced or absent synthesis of β-globin chains representing one of the most common autosomal recessive disorders worldwide. It is prevalent in the Mediterranean countries, the Middle East, and Southeast Asia, as well as countries along the Americas, coincidental with the occurrence of malaria. Carriers of β-thalassemia genes are considered relatively protected against malaria parasite. At present, because of vast population migration and intermarriage between different ethnic groups, β-thalassemia is also common in North and South America, Northern Europa, Australia, and the Caribbean. As a consequence of the reduced or absent synthesis of β-globin chains, there is an excess on α-globin chains that are instable and precipitate in red blood cell precursors causing abnormal cell maturation and their premature destruction in the bone marrow (ineffective erythropoiesis). 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. They are inherited in a multitude of genetic combinations responsible for clinical manifestations extremely diverse, spanning a broad spectrum from the transfusion-dependent state of thalassemia major (TM) to the asymptomatic state of heterozygous carriers for β<sup>0</sup> or β<sup>+</sup> (thalassemia trait). β-thalassemia intermedia requires only periodic blood transfusion,

while β-thalassemia minor does not require a specific treatment. One of the major consequences in this genetic disorder is iron overload due to multiple blood transfusions, ineffective erythropoiesis, and premature hemolysis in the plasma. Cardiomyopathy is the most common cause of death in transfusion-dependent thalassemia patients as a consequence of iron overloading. Thanks to the significant improvement in therapy, patients with β-thalassemia may reach an advanced age. This is associated with clinical symptoms that are the consequence of the disease itself and the treatment modalities. The aim of this chapter is that to give a complete picture of current knowledge on the etiology of iron accumulation, the role of hepcidin in regulating increased iron absorption, and the pathophysiology resulting from excess of "free iron." 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. [1–5]).
