**4. Pathophysiology of β-thalassemia**

**3. Genotype phenotype relationship in β-thalassemia**

which there is marked or mild reduction in production of β-chain [5].

of the β0

**3.1. Genetic modifiers**

*3.1.1. Primary modifiers*

of β-globin.

(HbF) in adult life.

*3.1.2. Secondary modifiers*

β-thalassemia [8].

carrier state [11].

[9].

**2.** The coinheritance of α-thalassemia.

Mutations causing thalassemia can affect any step in the pathway of globin gene expression. The most common forms arise from mutations that derange splicing of the mRNA precursors or prematurely terminate translation of the mRNA. The resulting phenotype reflect the effects

116 Epidemiology of Communicable and Non-Communicable Diseases - Attributes of Lifestyle and Nature on Humankind

Several modifier genes have been identified which are able to influence the severity of βthalassemia, so at phenotypic level β-thalassemias are considered multigenic diseases. Improved understanding of the influence of modifier genes involved in modulating the complex pathophysiology of β-thalassemia may allow prediction of disease phenotype [6].

Primary genetic modifiers in homozygous β-thalassemia include genetic variants able to reduce the globin chain imbalance, therefore resulting in a milder form of thalassemia.

**1.** The presence of silent or mild β-thalassemia alleles associated with a high residual output

**3.** Genetic determinants able to sustain a continuous production of gamma globin chains

The clinical phenotype of homozygous β-thalassemia may also be modified by the coinheri-

**1.** TA7 polymorphism in the promoter region of the uridine diphosphate-glucuronosyl

**2.** Apolipoprotein Eε4 allele seems to be a genetic risk factor for left ventricular failure in

**3.** Genes involved in iron (i.e., C282Y and H63D HFE gene mutations) and bone metabolism

**4.** Glutathione-S-transferase M1 gene polymorphism has been associated with an increased

**5.** Excess functional α-globin genes (α gene triplication or quadruplicating) in heterozygous β-thalassemia may lead to thalassemia intermedia phenotype instead of the asymptomatic

transferase gene is associated with cholelitiasis in thalassemic patients [7].

risk of cardiac iron overload in patients with thalassemia major [10].

tance of other genetic variants mapping outside the globin clusters.

, B++ thalassemia in

thalassemia in which there is no B-globin gene production and B+

The basic defect in β-thalassemia is a reduced or absent production of β-globin chains with relative excess of α-chains. Because α- and non-α chains pair with each other at a ratio close to 1:1 to form normal Hb, the excess unmatched α chains accumulate in the cell as an unstable product, leading to cell destruction in the bone marrow and in the extramedullary sites. This process is referred to as ineffective erythropoiesis (IE) and is the hallmark of β-thalassemia [12].

**Figure 1.** Pathophysiology of β-thalassemia.

The excess α-chains may, in minor amounts, combine with residual β- (in β+ -thalassemia) and γ-chains (whose synthesis persists usually in small quantity after birth), undergo proteolysis, or in large part become associated with the erythroid precursors with deleterious effects on erythroid maturation and survival. Also excess α-chain precipitation in the red cell membrane causes structural and functional alterations with changes in deformability, stability, and red cell hydration [12].

Alterations of erythroid precursors result in an enhanced rate of apoptosis, which is a programmed cell death. Apoptosis could contribute significantly to ineffective erythropoiesis and occurs primarily at the polychromatophilic erythroblast stage. The ineffective erythropoiesis (IE) and anemia have several consequences producing the clinical picture of the disease. The first response to anemia is an increased production of erythropoietin, causing a marked erythroid hyperplasia, which may range between 25 and 30 times normal. Anemia may produce cardiac enlargement and sometimes severe cardiac failure [12].

Increased erythropoietin synthesis may stimulate the formation of extramedullary erythropoietic tissue, primarily in the thorax and paraspinal region. Marrow expansion also results in characteristic deformities of the skull and face, as well as osteopenia [13].

High levels of iron, closely associated with denatured hemoglobin, have been found in the membrane of β-thalassemic red cells [14].

Severe IE, chronic anemia, and hypoxia also cause increased gastrointestinal (GI) tract iron absorption. This is combined with increased iron from the breakdown of RBCs and the increased iron introduced into the circulation by the transfusions necessary to treat thalassemia, plus inadequate excretory pathways lead to progressive deposition of iron in tissues and hemosiderosis occurs [13].

Free iron species, such as labile plasma iron as well as labile iron pool in the RBCs accumulate when transferrin saturation exceeds 70%. These free iron species generate reactive oxygen species with eventual tissue damage, organ dysfunction, and death (**Figure 1**) [13].
