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Beta-thalassemia

 
, medical expert
Last reviewed: 04.07.2025
 
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Beta-thalassemia is a heterogeneous group of diseases characterized by a decrease or absence of synthesis of beta-globin chains. Depending on the severity of the condition, there are 3 forms of beta-thalassemia: major, intermediate and minor. The severity of clinical manifestations is directly proportional to the degree of imbalance of globin chains. Depending on the degree of decrease in the synthesis of beta-globin chains, there are:

  • beta 0 -thalassemia (beta 0 -thal), in which the synthesis of beta-globin chains is completely absent;
  • beta + -thalassemia (beta + -thal), in which the synthesis of beta-globin chains is preserved.

Beta thalassemia is the most common form of thalassemia and is caused by decreased production of beta chains.

The gene is common among ethnic groups living in the Mediterranean basin, especially Italy, Greece, and the Mediterranean islands, as well as Turkey, India, and Southeast Asia. Between 3% and 8% of Americans of Italian or Greek descent and 0.5% of Americans of Negroid descent carry the beta-thalassemia gene. Sporadic cases of the disease occur in all regions of the world; they are spontaneous mutations or were introduced from areas with a high frequency of the beta-thalassemia gene. Thalassemia is endemic in several areas of Azerbaijan and Georgia. Like the sickle cell gene, the thalassemia gene is associated with increased resistance to malaria, which may explain the geographic distribution of the disease.

Causes of Beta Thalassemia

Beta thalassemia is caused by a number of mutations in the beta globin locus on chromosome 11 that disrupt the synthesis of the beta globin chain. More than 100 mutations have been described, leading to blockade of various stages of gene expression, including transcription, mRNA processing, and translation. Promoter mutations that limit mRNA transcription and mutations that disrupt mRNA splicing usually reduce beta chain synthesis (beta + -thalassemia), while nonsense mutations in the coding region that cause premature termination of beta globin chain synthesis lead to their complete absence (beta 0 -thalassemia).

Pathogenesis of beta-thalassemia

The pathogenesis of beta-thalassemia is associated with both the inability to synthesize adequate amounts of normal hemoglobin and the presence of relatively insoluble α-chain tetramers that form due to an insufficient number of beta chains. Hypochromic microcytic anemia occurs as a result of inadequate hemoglobin synthesis, and unbalanced accumulation of α-globin chains results in the formation of α4 - tetramers that precipitate in developing and mature erythrocytes. Cells of the reticuloendothelial system remove intracellular hemoglobin precipitates from erythrocytes, which damages the latter, shortens their lifespan, and destroys erythrocytes in the bone marrow, and reticulocytes and erythrocytes of peripheral blood in the spleen, developing hemolysis. In beta 0 -galassemia, there is an excessive accumulation of fetal hemoglobin (HbF, OC2 Y 2 ) in erythrocytes. Some patients also have an increased content of HbA 2 (a 2 5 2 ). HbF has an increased affinity for oxygen, resulting in increased tissue hypoxia, and impaired growth and development of the child. Hemolysis leads to pronounced erythroid hyperplasia and a significant expansion of the volume of hematopoiesis zones, which in turn causes skeletal abnormalities. Ineffective erythropoiesis (destruction of erythrocytes in the bone marrow) induces increased absorption of iron, so even patients with thalassemia who have not received blood transfusions may develop pathological iron overload.

Beta thalassemia minor

It occurs as a result of a single beta-thalassemic mutation of only one chromosome from pair 11. In heterozygous patients, the disease is usually asymptomatic, the hemoglobin level corresponds to the lower limit of the norm or is slightly reduced. The MCV and MCH indices are reduced to a typical level of 60-70 fl (normal - 85-92 fl) and 20-25 pg (normal - 27-32 pg), respectively.

Hematological characteristics also include:

  • microcytosis;
  • hypochromia;
  • anisopoikilocytosis with target shape and basophilic puncturation of peripheral blood erythrocytes;
  • slight expansion of the erythroid line in the bone marrow.

Enlargement of the spleen develops rarely and is usually mild.

The hemogram reveals hypochromic hyperregenerative anemia of varying severity. In typical cases, the hemoglobin level is less than 50 g/l before the correction of anemia with blood transfusions. In patients with thalassemia intermedia, the hemoglobin level is maintained at 60-80 g/l without blood transfusions. The blood smear reveals erythrocyte pipochromia, microcytosis, and numerous bizarrely shaped fragmented poikilocytes and target cells. A large number of normocytes (nucleated cells) are found in the peripheral blood, especially after splenectomy.

Biochemically, indirect hyperbilirubinemia is detected; elevated serum iron levels are combined with decreased iron-binding capacity of the serum. Lactate dehydrogenase levels are elevated, reflecting ineffective erythropoiesis.

A characteristic biochemical feature is an increase in the level of fetal hemoglobin in erythrocytes. Its level exceeds 70% during the first years of life, but as the child grows, it begins to decrease. The level of hemoglobin A 2 is approximately 3%, but the ratio of HbA 2 to HbA increases significantly. In patients with thalassemia minor, the level of HbF is increased to 2 - 6%, the level of HbA 2 is increased to 3.4-7%, which is of diagnostic value; some patients have a normal level of HbA 2 and a level of HbF within 15-20% (the so-called variant of beta-thalassemia with a high level of fetal hemoglobin).

Thalassemia major (Cooley's anemia) is a homozygous form of beta allele (J-thalassemia, occurring as severe progressive hemolytic anemia. Manifestations of thalassemia major usually begin in the second half of the first year of life. The patient has pronounced pallor of the skin, jaundice, severe anemia (hemoglobin - 60-20 g / l, erythrocytes - up to 2 x 10 12 / l). Growth retardation and changes in the skeletal system, especially in the bones of the skull, are characteristic. Patients have a deformation of the skull, leading to the formation of the "face of a patient with Cooley's anemia" - a tower skull, an increase in the upper jaw, remoteness of the eye sockets and a Mongoloid cut of the eyes, protrusion of incisors and canines with a bite disorder. Radiographically, the skull in the area of the cranial sinuses has a characteristic "hair-on-end" appearance - "hairy skull" or "hedgehog" symptom, the so-called needle periostosis. In long tubular bones, the bone marrow cavities are expanded, the cortical layer is thinned, pathological fractures are frequent.

Early signs of thalassemia major are significant enlargement of the spleen and liver, which occurs due to extramedullary hematopoiesis and hemosiderosis. With the development of hypersplenism against the background of leukopenia and thrombocytopenia, infectious complications are frequent, and secondary hemorrhagic syndrome develops.

Older children experience growth retardation and rarely reach puberty due to endocrine disorders.

A serious complication of the disease is hemosiderosis. Hemosiderosis and jaundice against the background of pallor cause a greenish-brown tint of the skin. Hemosiderosis of the liver ends in fibrosis, which in combination with intercurrent infections leads to cirrhosis. Fibrosis of the pancreas is complicated by diabetes mellitus. Hemosiderosis of the myocardium causes the development of heart failure; such conditions as pericarditis and congestive chronic heart failure often lead to a terminal state.

In untreated patients or in patients who were transfused only during periods of exacerbation of anemia and hemolysis and not frequently enough, hypertrophy of erythropoietic tissue occurs, localized both in the bone marrow and outside it. An increase in the number of erythroid germ cells in the bone marrow is not a true hyperplasia of the germ, but a result of the accumulation of defective erythroid elements. Their increase in number occurs due to a significant predominance of nucleated cells of the red germ, and not due to their maturation and differentiation. There is an accumulation of forms incapable of differentiation, which are destroyed in the bone marrow, i.e., ineffective erythropoiesis is observed to a significant extent. More broadly, ineffective erythropoiesis is understood not only as the process of intramedullary lysis of nucleated erythroid cells, but also the release of functionally defective erythrocytes into the peripheral blood, anemia, and the absence of reticulocytosis.

Death of a patient dependent on constant blood transfusions usually occurs during the 2nd decade of life; only a few of them survive to the 3rd decade. According to survival, there are three degrees of severity of homozygous beta-thalassemia: severe, developing from the first months of a child's life and quickly ending in his death; chronic, the most common form of the disease, in which children survive to 5-8 years; mild, in which patients survive to adulthood.

Thalassemia intermedia (combination of beta 0 and beta + mutations).

This term refers to patients whose clinical manifestations of the disease occupy an intermediate position between major and minor forms in terms of severity; patients usually inherit two beta-thalassemia mutations: one weak and one severe. Jaundice and moderate splenomegaly are clinically observed; the hemoglobin level is 70-80 g/l. The absence of severe anemia allows one to avoid constant blood transfusions, but transfusion therapy in them can help prevent noticeable cosmetic defects and bone anomalies. Even without regular transfusions, large amounts of iron are retained in the body of these patients, which can lead to hemosiderosis. Splenectomy is often indicated.

Patients form a heterogeneous group: some have homozygous forms of the disease, others are heterozygous carriers of the thalassemia gene in combination with genes for other thalassemia variants (beta, 5, hemoglobin Lepore).

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