Beta thalassemia

Beta-thalassemia is a heterogeneous group of diseases, characterized by a decrease or lack of synthesis of beta-globin chains. Depending on the severity of the condition, 3 forms of beta-thalassemia are isolated: large, intermediate and small. The severity of clinical manifestations is directly proportional to the degree of imbalance of the globin chains. Depending on the degree of decrease in the synthesis of beta-globin chains, the following are isolated:

• beta ⁰ -talassemia (beta ⁰ -tal), at which the synthesis of beta-globin chains is completely absent;
• beta ⁺ -talassemia (beta ⁺ -tal), at which the synthesis of beta-globin chains is preserved.

Beta-Thalassemia is the most common form of thalassemia due to a decrease in beta-chain production.

This gene is common among representatives of ethnic groups living in the Mediterranean basin, especially in Italy, Greece and the Mediterranean islands, as well as in Turkey, India and South-East Asia. From 3 to 8% of Americans of Italian or Greek origin and 0.5% of Americans of Negroid origin are carriers of the Beta-Thalassemni gene. Individual sporadic cases are found in all areas of the globe, they are spontaneously occurring mutations or are brought from areas with a high frequency of the beta-thalassemia gene. A number of regions of Azerbaijan and Georgia are endemic in thalassemia. Like the sickle cell gene, the thalassemia gene combines with increased resistance to malaria, which may explain the geographical nature of the prevalence of this disease.

Causes of beta-thalassemia

Beta-thalassemia is caused by a number of mutations in the beta-globin locus on chromosome 11, which violate the synthesis of the beta-globin chain. More than 100 mutations, leading to blockade of different stages of gene expression, including transcription, mRNA processing and translation, are described. Promoter mutations that limit mRNA transcription and mutations that disrupt mRNA splicing generally reduce beta chain synthesis (beta ⁺ -talassemia), while nonsense mutations in the coding zone causing a premature stopping of the synthesis of beta-globin chains result in a complete their absence (beta ⁰ -talassemia).

Pathogenesis of beta-thalassemia

The pathogenesis of beta-thalassemia is associated both with the inability to synthesize an adequate amount of normal hemoglobin, and with the presence of relatively insoluble α-chain tetramers, which are formed due to an inadequate number of beta chains. Due to inadequate synthesis of hemoglobin, hypochromic microcytic anemia arises, and as a result of unbalanced accumulation of α-globin chains α ₄ -tetramers are formed which precipitate in developing and mature red blood cells. Cells of the reticuloendothelial system remove intracellular hemoglobin precipitates from erythrocytes, which leads to damage to the latter, shortening their lifespan and destroying erythrocaryocytes in the bone marrow, and reticulocytes and red blood cells in peripheral blood in the spleen, and development of hemolysis. At beta ^0- galassemia in erythrocytes, there is an excessive accumulation of fetal hemoglobin (HbF, OC ₂ Y ₂ ). Some patients also show an increase in HbA ₂ (a ₂ 5 ₂ ). HbF has an increased affinity for oxygen, resulting in increased tissue hypoxia, disrupted the growth and development of the child. Hemolysis leads to severe erythroid hyperplasia and a significant expansion of the volume of hematopoiesis zones, which in turn causes abnormalities in the skeleton. Inefficient erythropoiesis (destruction of erythrocaryocytes in the bone marrow) induces an increased absorption of iron, so even in patients with thalassemia who have not received blood transfusion, abnormal iron overload can develop.

Small form of beta-thalassemia

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

Hematologic characteristics also include:

• microcytosis;
• hypochromia;
• anisopyokilocytosis with target and basophilic peripheral blood erythrocytes;
• a slight expansion of the erythroid germ in the bone marrow.

The increase in spleen develops rarely and is usually not very pronounced.

In the hemogram, hypochromic hyperregenerative anemia of varying severity is detected. In typical cases, before the correction of anemia with the help of blood transfusions hemoglobin level less than 50 g / l. In patients with intermediate thalassemia, the level of hemoglobin without hemotransfusin is maintained at 60-80 g / l. In the blood smear, there are pyrochromia of erythrocytes, microcytosis, as well as numerous fanciful forms of fragmented poikilocytes and target cells. In the peripheral blood, a large number of normocytes (nucleated cells) are found, especially after splenectomy.

Biochemically revealed indirect hyperbilirubinemia; increase serum iron levels in combination with a decrease in serum iron-binding capacity. The level of lactate dehydrogenase is increased, which reflects the inefficiency of 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 decline. The level of hemoglobin A ₂ is about 3%, however, the ratio of HbA ₂ to HbA significantly increases. In patients with small thalassemia, the HbF level was increased to 2-6%, the level of HbA ₂ increased to 3.4-7%, which is of diagnostic importance; some patients have a normal level of HbA ₂ and a HbF level of 15-20% (the so-called beta-thalassemia variant with a high level of fetal hemoglobin).

Large thalassemia (Cooley's anemia) is a homozygous beta allele (J-thalassemia, which occurs as severe progressive hemolytic anemia.) The manifestations of large thalassemia usually begin in the second half of the first year of life.The patient has severe pallor of the skin, jaundice, severe anemia (hemoglobin - 60-20 g / l, eritrotsity- to 2 × 10 ¹² / l) characteristic growth retardation and changes in the skeletal system, especially from the bones of the skull the skull there patients deformation, leading to the formation of "sick person a.. The cranial skull, the enlargement of the upper jaw, the distance of the eye sockets and the Mongoloid section of the eyes, the incisors of the incisors and canines with the violation of the occlusion.The radiographically the skull in the cranial sinus has a characteristic "hair-on-end" - a symptom of a "hairy skull" or " hedgehog ", the so-called acicular periosteasis.In the long tubular bones, the medullar cavities are enlarged, the cortical layer is thinned, and pathological fractures are frequent.

Early signs of major thalassemia are a significant increase in the spleen and liver, due to extramedullary hemopoiesis and hemosiderosis. With the development of hypersplenism against leukemia and thrombocytopenia, infectious complications are frequent, a secondary hemorrhagic syndrome develops.

In older children growth is delayed; due to endocrine disorders, they rarely have a period of puberty.

A serious complication of the disease is hemosiderosis. Hemosiderosis and jaundice on a background of pallor cause a greenish-brown skin tone. Hemosiderosis of the liver ends with 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; To the terminal state, there are often conditions such as pericarditis and congestive chronic heart failure.

In untreated patients or in patients to whom blood transfusions were performed only during periods of exacerbation of anemia and hemolysis and not often enough, hypertrophy of erythropoietic tissue localized both in the bone marrow and outside it occurs. The increase in the number of cells of the erythroid germ in the bone marrow is not the true hyperplasia of the germ, but the result of the accumulation of inferior erythroid elements. The increase in their number is due to a significant predominance of nucleated cells of the red sprout, and not due to their maturation and differentiation. There is an accumulation of forms that are not capable of differentiation, which are destroyed in the bone marrow, that is, ineffective erythropoiesis is largely noted. More widely under the inefficient erythropoiesis is understood not only the process of intraosteal lysis of nucleated erythroid cells, but also the release into the peripheral blood of functionally inferior erythrocytes, anemia, the absence of reticulocytosis.

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

Intermediate thalassemia (a combination of beta ⁰ and beta ⁺ mutations).

This term refers to patients in whom clinical manifestations of the disease are intermediate between large and small forms in the severity of the process, usually patients inherit two beta-thalassemic mutations: one weak and one heavy. Clinically, jaundice and moderate splenomegaly are noted, the level of hemoglobin is 70-80 g / l. The absence of severe anemia allows not resorting to permanent blood transfusions, however, transfusion therapy 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, in connection with which hemosiderosis can develop. Often there are indications for splenectomy.

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

[1], [2], [3], [4], [5], [6], [7], [8]