What is the etiopathogenesis of thalassemia major in children?

Etiopathogenesis of Thalassemia Major in Children

Thalassemia major is caused by severe reduction or complete absence of β-globin chain production due to mutations in the β-globin gene (HBB), resulting in profound anemia that becomes life-threatening by 1-2 years of age as fetal hemoglobin levels decline. 1

Genetic Basis

• Thalassemia major is an autosomal recessive genetic disorder caused by mutations in the β-globin gene (HBB) located on chromosome 11 2, 3
• The condition results from homozygosity or compound heterozygosity for β-thalassemia mutations, leading to severe reduction or complete absence of functional β-globin chain synthesis 1, 4
• The severity is determined by whether the mutation causes β+ (reduced production) or β0 (absent production) phenotypes 1

Molecular Pathophysiology

Primary Defect: Globin Chain Imbalance

• The fundamental pathophysiologic mechanism is an excess of α-globin chains relative to β-globin chains, which cannot form stable hemoglobin tetramers 1, 2
• Normal adult hemoglobin (HbA) is a heterotetramer requiring two α-globin and two β-globin chains; when β-globin is absent or severely reduced, unpaired α-chains accumulate 2, 3
• These unpaired α-globin chains precipitate within red blood cell precursors, causing membrane damage and premature cell death 3, 4

Ineffective Erythropoiesis

• The accumulation of unpaired α-globin chains leads to ineffective erythropoiesis—the bone marrow produces red blood cells that are destroyed before reaching circulation 1, 4
• This results in profound anemia despite compensatory expansion of erythroid precursors in the bone marrow 2, 4
• Hemolysis of the few red cells that do reach circulation further contributes to the severe anemia 3, 4

Clinical Manifestation Timeline

• Infants are healthy at birth because fetal hemoglobin (HbF, composed of α2γ2 chains) does not require β-globin chains 2, 5
• Symptoms emerge at approximately 1-2 years of age as fetal hemoglobin production declines and the switch to adult hemoglobin (requiring β-chains) occurs 1
• Without treatment, the profound anemia becomes life-threatening, historically causing death by age 10 years from cardiac complications 6

Secondary Pathophysiologic Consequences

Transfusion-Dependent Iron Overload

• Each unit of transfused blood contains approximately 200-250 mg of elemental iron, and humans lack physiological mechanisms for iron excretion 1
• Mildly increased gastrointestinal iron absorption occurs due to hepcidin suppression, further contributing to total body iron accumulation 1
• Iron deposition in organs generates reactive oxygen species (ROS) causing oxidative damage to hepatic, endocrine, cardiac, and vascular systems 4
• Cardiac iron loading becomes the leading cause of death, accounting for approximately 70% of mortality in transfusion-dependent patients 6

Hemodynamic Alterations

• Chronic anemia causes compensatory hemodynamic changes including increased cardiac index, elevated heart rate and stroke volume, lower systolic blood pressure, and decreased systemic vascular resistance 7
• These chronic volume overload states contribute to cardiac complications independent of iron toxicity 7

Phenotypic Variability

• The clinical severity is largely determined by the degree of globin chain imbalance 2, 3
• Factors modifying phenotype include the specific β-globin mutations, coinheritance of α-thalassemia (which reduces α-chain excess), and the ability to maintain elevated fetal hemoglobin production 5
• Some patients with severe β-thalassemia genotypes may have milder phenotypes if they produce high levels of fetal hemoglobin, which can partially compensate for absent β-globin 5

Diagnostic Criteria

• Thalassemia major is characterized by the requirement for more than 8 transfusion events per year in adults over 16 years of age 1
• Lifelong regular red blood cell transfusions are mandatory for survival 6
• Lifelong iron chelation therapy is required to prevent or reverse iron-related organ damage 1, 6