THALASSEMIA (Greek thalassa sea + haima blood; synonym: erythroblastic anemia, targetoid and cellular anemia, family mikrotsitemichesky anemia, hemolitic Mediterranean anemia, hereditary leptocytosis) — group of the hereditary hemolitic anemias which are characterized by disturbance in various extent of synthesis of globinovy chains of hemoglobin and also hemolysis, a hypochromia and inefficient erythrocyto-poezom.
T. carry to «quantitative» to hemoglobinopathies (see), at to-rykh it is reduced, sometimes completely there is no synthesis of the globinovy chains which are molecular composition of normal hemoglobin of the person (see Hemoglobin); at the same time the structure of chains is not changed.
In view of big genetic heterogeneity of T. (the major thalassemic genes (3 °, r +, of, 6 | 3, etc.), causing its wide wedge, polymorphism, sometimes for designation of various forms T. use the term «thalassemic syndromes». In classification of T., based on results of biochemical and genetic researches, allocate the following forms: I. Alpha Talas - semiya (and - a thalassemia): 1) a heterozygous carriage of a «mute» gene (a-th2), 2) a heterozygous carriage of a manifest gene (a-thi), 3) a hemoglobinopathy of N, 4) a homozygous a-thalassemia (an edema of a fruit with Hb Bart’s). II. Beta talassemnya (beta talassemia): 1) a heterozygous beta talassemia, including a carriage of «mute» P-th of a gene, 2) a homozygous beta talassemia (anemia Sacks) — r °-the II P+ - thalassemias, 3) a heterozygous bbeta-thalassemia (F-thalassemia), 4) a homozygous bbeta-thalassemia (F-thalassemia) — br °-and br + - a thalassemia. III. The thalassemia connected with structural disturbances of hemoglobin: 1) Eroge-gemoglobinopatiya, 2) hemoglobinopathy of Constant Spring (CS).
For the first time T. (obviously, a homozygous beta talassemia) it was described Sacks and Li (Th. Century of Cooley, R. of Lee) in 1925 Ital. researchers of Riyet-ti (F. Rietti, 1925), Greppp (E. Grep-pi, 1928), etc. reported to Mikeli (F. Micheli, 1935) about the easy forms of this disease which afterwards appeared heterozygous. Ka-minopetros (1938) and Uintrob (M. M. of Wintrobe, 1940) established to J. Caminopetros hereditary character of a thalassemia. In 1965 J. D. Heywood and sotr. Uitroll and Klegg (D. J. Weatherall, J. Century of Clegg) existence in reticulocytes of patients R - Talas - semiyey the partial or full block of synthesis r-polipvptidnykh chains of a globin of in vitro was shown. The alpha thalassemia is described in 1955 Rigasom and the Gutta (D. A. Rigas, A. Gouttas) independently from each other.
T. it is widespread in the basic in the countries located on the coast of the Mediterranean and Black seas. Due to the population shift genes of T. were brought to America and other parts of the world. In distribution of T. the significant role is played by ecological and ethnic factors, kinship marriages, incidence of malaria in this area (now and in without having given - ¡Ñл1))))))). The most high frequency (to 30%) a heterozygous nosshchgelstvo of a beta talassemia is revealed in ital. population (the Southern Sardinia). In the nek-ry regions of Greece (island Rhodes) the beta talassemia meets the frequency up to 20% of all T., are considerably widespread also and - and bbeta-thalassemias. T. it is widespread also in the countries of Southeast Asia. Abnormal genes in various combinations, including with structural hemoglobinopathies, lead to emergence of St. 60 various forms T.
In the territory of the USSR detailed studying of distribution R - Talas - semii is carried out in the nek-ry republics of Transcaucasia and Central Asia.
Family cases of a beta talassemia are described also among nationalities of Dagestan, in Kazakhstan, Moldova, Mordovian by the ASSR, and also in Penza and some other the areas of RSFSR located in the European part. The alpha thalassemia (in particular, a hemoglobinopathy of N) is revealed in the Azerbaijani, Georgian, Armenian, Tajik, Uzbek and Russian families.
Etiology and pathogeny
Etiol. a factor at T. mutations of regulatory globinovy genes, deletions are (see) nek-ry structural genes, their inefficient transcription (see), synthesis abnormally unstable, or nonfunctioning, template-RNA. Considerable heterogeneity of the mutations leading to thalassemic syndromes is proved. At T. mode of inheritance code inantny.
Pathogeny of T. it is various, however deficit of the main fraction of hemoglobin — HbA (Ai) is the cornerstone of each form. At the same time the main disturbing factors are surplus and - or p-chains of hemoglobin and an overload of cells of an erythroidal sprout and internals iron that leads to damage of membranes of erythroidal cells, an inefficient erythrocytopoiesis (see the Hemopoiesis) and to a hemosiderosis (see). At homozygous R-talasse-mii owing to the increased destruction of abnormal erythrocytes and hron. hypoxias there is an expressed erythroidal hyperplasia of marrow with characteristic changes of a skeleton, emergence of the extramedullary centers of a hemopoiesis (see). At heterozygous forms of a beta talassemia these phenomena are less expressed.
The reason of the anemia developing at the majority and - thalassemias, is deficit of products and - glo-bpnovykh chains that leads to decrease in content of normal hemoglobin, first of all NYA. Are broken products of erythroidal cells in marrow and saturation by their hemoglobin that is shown in the form of characteristic of all T. a microcythemia, a giiokhromiya and decrease in the erythrocyte indexes reflecting degree of a gemoglobiniza-tion.
At deficit of alpha-chains of hemoglobin in blood of newborns Hb Bart’s collects (ua), an is later (including at adults) — NN (R4). Homozygous and - the thalassemia is characterized by total or partial absence of normal hemoglobin and existence of 70 — 100% of N Bart's, to-ry is not capable to transfer oxygen. Carriers homozygous and - thalassemias are impractical — the fruit perishes vnutriutrobno at the phenomena of an edema. At one of manifest forms and - thalassemias (a hemoglobinopathy of N) in erythrocytes during the coloring diamond cresylic blue are found inclusions of NN, in the functional relation defective. It treats unstable pigments of blood, easily is exposed to oxidation and is besieged in process of cell aging. Anemia at a hemoglobinopathy of N, in addition to hemolysis, can be caused by deficit of iron or an intercurrent infection. The considerable number of patients has an additional fraction of hemoglobin — Hb Constant Spring.
At severe forms of T. (usually homozygous or double heterozygous states — on a gene of T. and to a gene of one of abnormal haemo globins) the changes characteristic of hereditary hron are observed. hemolitic anemias — a hyperplasia of red marrow, expansion of marrowy spaces, thinning of compact substance of a bone (sometimes meet patol. fractures of bones), the centers of an extramedullary hemopoiesis, expressed spleno-and a hepatomegalia (see. Hemolitic anemia).
A clinical picture
Among beta talassemias depending on a wedge, pictures distinguish big, intermediate, small and minimum forms.
The big beta talassemia (anemia Sacks) is characterized by the increased maintenance of HbF (50% and more from the general maintenance of N) or NA2. NA2 and HbF are in some cases at the same time increased (in this regard the big beta talassemia is subdivided into A2-, F-and A2G - Talas - semiyu).
The often biggest beta talassemia comes to light aged from 2 up to 8 years. The growth inhibition, increase in a stomach owing to a gepatosplenomegaliya, deformation of a skull (a «tower» skull, the «Mongoloid» person) as a result of change in the pre-natal period of the person and a calvaria caused by osteoporosis are characteristic; icteric coloring of skin and visible mucous membranes are noted; fever. The factor complicating disease is development of a secondary hypersplenism (see the Spleen). In the expressed cases are observed a myocardial dystrophy (see) with heart failure (see) and a pericardis (see). From blood symptoms of heavy hypochromia anemia come to light (a color indicator apprx. 0,5, decrease in a hemoglobin content to 20 — 50 g1l), edges it begins to be shown at the end of the first year of life. The quantity of erythrocytes is reduced to 1 — 2 million, are sharply expressed them morfol. changes (anizo-and poikilocytosis, poly-chromatophilia, hypochromia, fragmentation, shizotsitoz, existence of targetoid erythrocytes, basphilic stippling, normoblastoz). Targetoid erythrocytes characteristic of all types of T., have the increased osmotic resistance. Decrease in average volume of erythrocytes and average content of hemoglobin in one erythrocyte is usually noted. In the scanning supermicroscope the large number of erythrocytes with the changed configuration — a drop - and bell-shaped, etc. is observed. Are characteristic a leukopenia with a lymphocytosis of other sprouts of blood, a neutrophylic leukocytosis with shift to the left at hemolitic crises, a pancytopenia at a hypersplenism. During hemolitic crises (see) and after a splenectomy (see) the quantity of normoblasts sharply increases in blood, the high reticulocytosis inadequate to extent of hemolysis comes to light. In a blood plasma the content of iron (gipersidere-miya) is increased, in urine the pigment dipyrrol is found. Signs of hemolysis are increase in content of not conjugated bilirubin, and also an urobilinuria and increase in content of stercobilin in Calais.
Complications — trophic ulcers (see), cirrhosis are inherent in a big beta talassemia (see), cirrhosis of a pancreas (sometimes with symptoms of a diabetes mellitus) owing to development in internals of a hemosiderosis (see), to-ry becomes especially expressed as a result of repeated transfusions. The delay of puberty, signs of polyglandular insufficiency are characteristic (see) and urate diathesis (see), patol. fractures of bones. Resilience is lowered owing to inferiority of function T - and V-lymphocytes, development of pneumonia and sepsis is possible.
The intermediate form of a beta talassemia is characterized by more high-quality current, than a big beta talassemia. Symptoms of a disease are shown at later age and are expressed to a lesser extent. Anemia moderate (hemoglobin of 70 — 100 g! l at quantity of erythrocytes 2 500 000 — 3 000 000). Are expressed morfol. changes of erythrocytes. The splenomegaly in some cases is combined with a hepatomegalia. Changes of cardiovascular system and a growth inhibition at this form T. are not characteristic. Outward of patients is almost not changed. The main complications are the hypersplenism and defeat of bone system. Genetically this group of patients is various. Treat her, except heterozygous carriers on the beta talassemia sick with nek-ry homozygous forms, a hemoglobinopathy of N, and also various compounds, including sick with a hemoglobinosis of SF (see the Sickemia).
The small beta talassemia is characterized by slight hypochromia anemia and morfol. changes of erythrocytes; osmotic resistance of erythrocytes is usually increased, the level of serumal iron is normal or is slightly increased.
The minimum beta talassemia (Silvestroni's syndrome — Byanko) proceeds asymptomatically and it is found accidentally at a biokhimiko-gene-ticheskom a research of families with a gene of a beta talassemia. The hemoglobin content and quantity of erythrocytes at such patients are normal. The small hyperglobulia against the background of characteristic morfol is sometimes noted. changes of erythrocytes. Osmotic resistance of erythrocytes is increased or normal; the average content of hemoglobin in one erythrocyte can be reduced.
Degree of inefficiency of an erythro-cytopoiesis at all heterozygous forms of a beta talassemia (intermediate, small and minimum) usually small. At intercurrent diseases and pregnancy the course of a disease can become complicated considerably. Heterozygous forms of a beta talassemia are characterized by increase in maintenance of NA2 (on average 5,1%, but is not higher than 10%); along with it approximately at 20 — 50% of carriers of a gene increase in HbF is noted small (to 10%).
δβ-талассемия proceeds it is good-quality. At heterozygous carriers δβ-талассемия differs in the normal maintenance of NA2 and raised — HbF (to 20%); at homozygous HbF carriers can make up to 100% at total absence of other fractions of hemoglobin — NA and NA2 (so-called br a °-thalassemia). In erythrocytes of HbF it is distributed unevenly.
At so-called mute options of a heterozygous thalassemia of changes from gemoglobinovy fractions it is not noted though a wedge, symptoms of a disease and morfol. changes of erythrocytes can be observed. Such heterozygous carriers reveal at inspection of families, in to-rykh sick T are found. varying severity.
From alpha thalassemias its heterozygous form — a hemoglobinopathy of N has a wedge, signs; it represents hron. moderately severe hemolitic anemia. The splenomegaly at it is noted in 80% of cases, changes in bone system approximately at 1/3 patients, the liver at 70% of patients is increased, the hemosiderosis of internals is absent.
Level of serumal iron is more often reduced. Content of the general hemoglobin varies from 50 to 130 g! l. Rather large number of erythrocytes is combined with a low indicator of a hematocrit owing to reduction of average volume of cells. Quantitative erythrocyte indexes are considerably reduced. Are characteristic typical for T. morfol. changes of erythrocytes. Degree of a reticulocytosis varies. In the majority of erythrocytes characteristic inclusions of NN are found. At an electrophoresis of hemoglobin (pH 9,0) the NN fraction migrating ahead NYA comes to light byst-rodvigayushchayasya. The maintenance of NN at pH 6,5 makes from 10 to 30%. Sometimes also Hb Bart’s comes to light (within 4 — 7%). NN is unstable and functionally defective. Anemia at this form T. becomes aggravated at intercurrent infections and reception of drugs oxidizers (streptocides, etc.).
The homozygous alpha thalassemia (an edema of a fruit with Hb Bart’s) is shown by death of a fruit. In the USSR this disease is not revealed.
Diagnosis establish on the basis a wedge, pictures, rentgenol. researches (small sites of osteoporosis along with sites of a hypertrophy of bones of a skull — a so-called symptom of a brush or a hedgehog, and also cross striation of both tubular, and flat bones are characteristic of a big beta talassemia) and all complex gematol. and biochemical. researches in combination with the family and genetic analysis — definition of the general hemoglobin, quantity of erythrocytes and reticulocytes, an indicator of a hematocrit, calculation of quantitative erythrocyte indexes, definition of osmotic resistance of erythrocytes, their morphology in a blood smear, identification of erythrocyte inclusions at their supravital coloring, definition of alkali-proof hemoglobin biochemical and cytochemical by methods, an electrophoresis of hemoglobin on an acetate cellulose film (pH 9,0 and 6,5) and in other environments with the subsequent quantitative definition of gemoglobinovy fractions, a research of biosynthesis of polypeptide chains of in vitro hemoglobin by means of marked radioactive amino acids.
Differential diagnosis is carried out with other forms of the hereditary and acquired hemolitic anemias (a microspherocytosis, structural hemoglobinopathies, etc.). Heterozygous hypochromia forms T. most often it is necessary to differentiate with an iron deficiency anemia (see) since identical signs — a hypochromia and a microcythemia are characteristic of both states.
At a big beta talassemia of a hemotransfusion (transfusion of whole blood or erythroweight) give only temporary effect, besides, at them danger of a hemosiderosis increases. Efficiency (extension of life of the patient) of the hyper transfusion mode using erythroweight or the defrozen erythrocytes is proved (for the purpose of maintenance of hemoglobin of the patient at the level of 100 — 120 g! k) and simultaneous long introduction of a helator of iron — desferal. At treatment of hemolitic crises small doses of glucocorticoid hormones are shown. Patients with an intermediate form T. only occasionally need hemotransfusions. Splenectomy at a big beta talassemia, in nek-ry cases of intermediate T. and at a hemoglobinopathy of N it is shown to children 5 years in the presence of a big spleen with signs of sequestration in it of erythrocytes, the expressed hypersplenism are more senior and at the increased need for hemotransfusions. At all manifest forms T. (big, intermediate and small) drugs of folic acid, and also vitamins of group B are shown.
Asymptomatic carriers of genes of T. do not need treatment.
Forecast at big T. adverse since patients perish at children's age from heart failure owing to a hemosiderosis of a myocardium; at other forms the forecast favorable.
Prevention. Copper-to-genetic consultation is necessary for the prevention of marriages between heterozygous carriers of genes of a thalassemia and the recommendation of failure from posterity.
See also Anemia .
Bibliography: The major hemoglobinopathies, under the editorship of O. K. Gavrilov and Yu. N. Tokarev, M., 1979; And d e l with about L. I N. Hypochromia anemias, M., 1981; Hereditary anemias and hemoglobinopathies, under the editorship of Yu. N. Tokarev, etc., M., 1983; T about-karev Yu. N. Problem of heterogeneity of hemoglobinopathies, Klin, medical, t. 59, No. 11, page 19, 1981; Anderson W.F. and. lake of Fourth Cooley's anemia symposium, N. Y., 1980; Bunn H. F., F o r g e t B. G. a. R a n n e at H. M. Human hemoglobins, Philadelphia, 1977; W e a t h e r a 1 1 D. J. ampere-second of 1 e g g J. B. The thalassaemia syndromes, Oxford a. o., 1980.
BB. H. Tokarev.