Beta-thalassemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2]
Overview
Beta-Thalassemia is an inherited disorder in hemoglobulin production due to a variety of genetic mutations in the gene responsible for Beta-globin production (HBB gene, on chromosome 11). The effects of beta-thalassemia on red blood cell morphology and function are significantly detrimental. Beta-Thalassemia contributes to abnormal hemoglobin and red blood cells (RBCs) that have impaired function in efficient oxygen delivery to different body tissues, which is called the state of anemia. As mutated genes are passed down, the shortage of functional red blood cells begins affecting the body from early infancy, and the lifelong persistence of insufficiency in beta-globin production results in chronic anemia. Hepatosplenomegaly, delayed developmental milestones, jaundice, bone problems, and different infections might happen in early infancy.
Pathophysiology
Beta-globin is an indispensable component of hemoglobin that is functioning alongside the alpha chain. In normal individuals, hemoglobin has two alpha-globin chains and two beta-globin chains (α2β2). In beta-thalassemia, the mutated gene of HBB is affecting the encoded beta-globin chains. The pattern of these impaired genes can cause different pathologic conditions as shown in the table below:
| Type of Beta Thalassemia | Hemoglobin Chain Composition (genotype) | Severity |
|---|---|---|
| β thalassemia minor | α2β+/α2β+ or α2β+/α2β0 | Mild |
| β thalassemia major | α2β0/α2β0 | Sever |
| Thalassemia intermedia | Variable (can be similar to Major variant or may have some residual beta globin production) | Variable (milder than the Major variant but more severe than Beta Thalassemia Minor) |
Then a cascade of events would contribute to ineffective erythropoiesis and reduced hemoglobin production or impaired hemoglobin stability, hemolysis, and increased erythropoietin production (the hormone secreted by the kidney in response to low oxygen levels). Most other pathologic manifestations happen due to iron overload following the transfusions needed for the treatment [1].
- Hemolysis may happen due to the destruction of ineffective RBCs in the bone marrow, spleen, and blood, causing various consequences as well as hepatosplenomegaly.
- Extramedullary hematopoiesis might happen following the expansion of the bone marrow due to an increased need for erythropoiesis and increased erythropoietin production.
- Biliary lithiasis or gallstones would frequently happen due to products of hemolysis, excess iron, and liver damage.
- Endocrine disturbances might happen due to chronic anemia and low oxygen levels in the blood and iron overload; followed by changes in the normal pattern of secretion of various hormones as well as:
- Growth hormone: It causes delayed growth and development.
- Hypothalamic-pituitary-gonadal axis hormones: It causes hypogonadism.
- Thyroid stimulating hormone: It causes hypothyroidism.
- Parathyroid hormone (PTH): It causes parathyroid dysfunction.
- Adrenal hormones dysfunction.
Genetics
The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished:
- Nondeletion forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most commonly, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
- Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobin syndromes.
The severity of the disease depends on the nature of the mutation.
- Mutations are characterized as (βo) if they prevent any formation of β chains.
- Mutations are characterized as (β+) if they allow some β chain formation to occur.
- Alleles without a mutation that reduces function is characterized as (β). (Note that the "+" in β+ is relative to βo, not β.)
In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.