HEMOGLOBINOPATHIES (haemoglobinopathia, singular; hemoglobin + grech, pathos suffering, disease; synonym hemoglobinosis) — group of the hereditary diseases caused by existence in erythrocytes of abnormal haemo globins or oppression of synthesis of polypeptide chains of normal haemo globins. Rank as G. as expressed patol, the states proceeding more often with hemolitic anemia (see) and numerous cases of a latent carriage of abnormal haemo globins or genes thalassemias (see).
After L. Polinga's works, H. A. Itano and sotr. (1949), devoted to hemoglobin S, and opening in the field of biochemical, geneticists G. began to consider as a kind of molecular pathology. In 1950 H. A. Itano and J. Neil described abnormal hemoglobin C, in 1951 H. A. Itano described abnormal hemoglobin D. In 1954 hemoglobin E at the same time, but independently from each other was described by Chernov, Minnikh and Chongcha-reonsuk (And. I. Chernoff, V. Minnich, S. Chongchareonsuk) and H. A. Itano, Bør-dzher, Sturgeon (W. R. Berger, P. Sturgeon). Hemoglobin G described Edington (G. M of Edington) and G. Lehmann in 1954. Also abnormal haemo globins of H, I, J, K, L, M, N, O, P, Q, etc. are known.
In the world contain apprx. 100 million people — carriers of abnormal haemo globins, however these figures should be considered, apparently, underestimated owing to imperfection of methods of identification of abnormal haemo globins and insufficient information about G.'s distribution in various areas of the globe.
In G.'s distribution such factors as belonging to certain racial and ethnic groups, frequency of marriages between blood relatives, population shift, incidence of tropical malaria matter. Variations in synthesis of hemoglobin occur preferential at residents of the countries of Southern Europe (the coast of the Mediterranean Sea), Africa and Asia or at natives of these countries, among the Black population of North and South America. G. are more widespread in a zone of a so-called malarial belt of the globe, i.e. tropical, and it is slightly less — in a subtropical zone. They meet and in some southern republics of the USSR (Azerbaijan, Tajikistan).
Crescent anomaly of erythrocytes is most widespread in tropical Africa, the countries of the Mediterranean, the Middle East, India. Believe that only in tropical Africa contain up to 40 million people — carriers of abnormal hemoglobin S. Not less frequent is, apparently, also the thalassemia. The carriage abnormal is more localized by hemoglobin C and E. Heterozygous carriers of abnormal hemoglobin C — more than 7 million in the Western Africa and apprx. 0,5 million among Blacks of the USA. In Southeast Asia (Indochina, Thailand, Burma, Indonesia, India, Bangladesh and yuzh. regions of China) carriers of abnormal hemoglobin E more than 30 million people. The main center of abnormal hemoglobin D is in Northwest India where the number of heterozygous carriers is defined in several million people. Isolated cases are described in North and Western Africa, Asia Minor and among the Black population there is USA. The centers (beta talassemias and sporadic cases of hemoglobinopathies of S, S, D, E and an alpha thalassemia are found among the population of Azerbaijan, Tajikistan and some Areas of Caucasus.
The etiology and a pathogeny
Anomaly of hemoglobin can result or qualitative changes of its primary structure and function, or quantitative reduction of synthesis of linear chains of a globin (see. Gemoglobin , genetics of hemoglobin). Over 250 abnormal haemo-globins are known; theoretically in a molecule of hemoglobin perhaps more than 4000 various point mutations [D. Beale, G. Lehmann, 1965] from which by means of modern methods can be differentiated with normal hemoglobin only apprx. 1500. This number included mutations like pure amino-acid substitutions, at the same time possible anomalies are not considered owing to deletions (see), splittings of polypeptide chains, etc.
G.'s emergence is caused by a mutation at the level of the structural or regulatory genes managing synthesis of polypeptide chains of a globin. Mutations at the level of structural genes are characteristic of true G.: drepanocytic anemia, With - D-, E-and M-hemoglobinopathies and diseases caused by existence of unstable haemo globins. Mutations at the level of regulatory genes are found at thalassemias, hemoglobinopathies of H and Bart.
At homozygous carriers of genes usually life expectancy of erythrocytes with patol, hemoglobin is shortened, and also the erythrogenesis is in certain cases broken. Heterozygous carriers of abnormal haemo globins, except haemo globins of H and Bart, options of M-hemoglobinopathies, and also carriers of unstable haemo globins in usual conditions of life are almost healthy people.
G.'s most is inherited according to Mendel's laws on the codominant autosomal type which is not linked to a floor.
Classification of hemoglobinopathies
Classification of hemoglobinopathies [according to E. R. Huehns in Yu. N. Tokarev's modification] it is created on the basis of results of special biochemical, and genetic researches.
I., the molecules of hemoglobin («qualitative» G.) caused by anomaly of primary structure: 1) drepanocytic disease, its options (S-hemoglobinopathies: S-thalassemia, SD, SC, etc.); 2) The Lepore-hemoglobinopathy arising owing to splitting of parts beta and delta chains of a globin; 3) Homozygous (With - D-and E-); 4) M-hemoglobinopathies; 5), caused by existence of unstable haemo globins (the haemo globins unstable to influence of oxidizers, heating, etc.); 6) Asymptomatic (G-hemoglobinopathies, etc.).
II., caused by disturbance of synthesis of polypeptide chains of haemo-globins («quantitative» G., or thalassemias): 1), the α-chains of a globin (the alpha thalassemia and diseases caused by existence of haemo globins of H and Bart) caused by disturbance of synthesis; 2), caused by disturbance of synthesis β and δ-chains of a globin (a β-thalassemia, β,δ-талассемия); 3) an asymptomatic hereditary persistirovaniye of fetalis hemoglobin, i.e. genetically caused increased hemoglobin content of F at adults.
III. The mixed group — double heterozygous states on a gene of a thalassemia and a gene of one of «qualitative» G.
the Clinical picture
the Clinical picture differs in the expressed polymorphism. For drepanocytic anemia (see) and thalassemias (see) development of heavy hemolitic anemia is characteristic. G.' famous now number clinically is not shown; options of hemoglobin at them are unusual (family) rather, than pathological.
The Lepore-hemoglobinopathy is clinically similar to a thalassemia.
The homozygous hemoglobinopathy of C (CC) is characterized by slight hemolitic anemia with the splenomegaly moderated by jaundice and a bilirubinemia, a normoblastny hyperplasia of marrow. In peripheral blood a set of targetoid cells and expressed morfol. changes of erythrocytes (anizo-and a poikilocytosis, a polychromatophilia), abnormal hemoglobin C makes St. 90%, normal hemoglobin A is absent, the hemoglobin content of F within norm or is a little increased (5 — 7%). Hemolitic crises with anemia arise more often at pregnant women.
The homozygous hemoglobinopathy of D (DD) proceeds asymptomatically. In isolated cases availability of abnormal hemoglobin D (DD) can be shown by slight anemia, a microspherocytosis of erythrocytes, increase in osmotic resistance, shortening of life expectancy of erythrocytes.
The homozygous hemoglobinopathy of E (EE) on a clinical current is very similar to a homozygous hemoglobinopathy
of S. U of patients with M-hemoglobinopathies conducting a wedge, a sign is inborn cyanosis owing to the raised metgemoglobinoobrazovaniye (see. Methemoglobinemia ).
Are characteristic of the majority of the options G. caused by existence of unstable haemo globins hron, not spherocytic hemolitic anemia with periodic release of dark urine (owing to existence of dipirrol in it) and the expressed polymorphism a wedge, manifestations — from asymptomatic to severe forms.
In smears of peripheral blood — a hypochromia and morfol, changes of erythrocytes — anizo-and a poikilocytosis, a mishenevidnost, existence of little bodies of Heinz and basphilic stippling (see. Erythrocytes ). Hemolysis of intracellular type happens preferential in a spleen that is clinically expressed by a splenomegaly. Other signs (a reticulocytosis, increase in an indirect bilirubin, etc.) are not specific., caused by unstable haemo globins, it is necessary to differentiate with hemolitic and hypochromia anemias of other etiology and first of all about iron scarce anemias. In diagnosis of the last tests on thermolability of hemoglobin [J. V. Dacie et al., 1964], detection of little bodies of Heinz, identification in urine of dipirrol are valuable. Intensity of an autogemoliz is increased, it decreases at addition to in vitro blood of glucose [the I type of hemolysis according to J. G. Selwyn and Deysi]. The electrophoresis of hemoglobin not always allows to reveal anomaly since some unstable haemo globins have normal (as at hemoglobin A) electrophoretic mobility.
the Diagnosis is made on the basis of clinical and laboratory signs of an increased hemolysis (see). Identification morfol, changes of erythrocytes matters. The diagnosis is confirmed by data of an electrophoresis of hemoglobin (at structural G.: S, C, D, E, etc.), breakdown on alkaline stability of erythrocytes (at suspicion on availability of hemoglobin F), on stability of haemo-globins (at suspicion on existence of unstable haemo globins)
sick G.' Treatment generally symptomatic, and the choice of a method depends on a degree of activity and a stage of development (crisis, remission) of a disease. Methods of therapy of hereditary hemolitic anemias,> however with the amendments and additions caused by features of this kind of abnormal hemoglobin can be applied (changes in exchange of iron, existence at some patients of a hemolitic syndrome with signs of a hypersplenism). At G. in the period of crisis the bed rest, a diet, protein-rich and vitamins is necessary; hemotransfusions (the packed red cells is preferable) appoint lower than 8 — 9 g of % at concentration of hemoglobin. Introduction to an organism of the drugs connecting and excreting iron (desferal, etc.), is reasonable for prevention of a hemosiderosis.
Questions of treatment of the hemolitic anemias caused by unstable haemo globins are insufficiently studied. Steroid hormones are effective sometimes. Indications to a splenectomy are a refrakternost to usual methods of therapy, a severe disease with the expressed hemolysis, signs of a hypersplenism and sequestration of erythrocytes preferential in a spleen. During remission sick G. are subject dispensary nablyudy a niya with sanitation of the infectious centers and to timely treatment of intercurrent infections. Overseeing by patients shall be doubled at pregnancy, in stressful situations (surgery, etc.).
Forecast depends on G.'s type and the clinical course of a disease.
medicogenetic consultations with the purpose of the prevention of marriages between heterozygous carriers of genes of abnormal haemo-globins or for the purpose of the prevention (Are necessary at the consent of parents) the births of the sick child. According to WHO recommendations in areas, endemic on abnormal haemo globins, specialized clinics (clinics) with medicogenetic consultations shall be created. Such centers in the USSR are created at institutes of hematology and hemotransfusion (Moscow, Baku, Tashkent, Tbilisi).
Hemoglobinopathies at children proceed hard, especially homozygous forms — drepanocytic anemia, a big thalassemia. Are diagnosed since six-months age, i.e. during replacement of hemoglobin F with hemoglobin A.
Physical development of sick G. of children is slowed down. Their outward caused by change of bones and increase in a stomach at the expense of a gepatosplenomegaliya is characteristic.
the Children sick with drepanocytic anemia need hemotransfusions at reduction of level of hemoglobin lower than 8 — 9 g of %. The patient with a thalassemia pour a packed red cells even at insignificant reduction of a hemoglobin content.
Sick G. children are subject to dispensary observation of the hematologist, planned immunization, to them preventively enter gamma-globulin y appoint drugs folic to - you for the prevention of its deficit in an organism. In treatment (and prevention of crises) G. at children the awareness of parents on G.'s nature and their contact with the doctor is of great importance.
Without due care and treatment most of sick children perishes at the age of 2 — 5 years. Especially hard G. at their combination to disturbances of food proceed (proteinaceous and caloric insufficiency, the Kwasiorkor, etc.) and accession of intercurrent infections (measles, pneumonia, acute respiratory diseases).
Bibliography: Alekseev G. A. and Tokarev Yu. N. Hemoglobinopathies, M., 1969; Efroimson V. P. Immunogenetics, page 161, M., 1971; Beale D. Lehmann H. Abnormal haemoglobins and the genetic code, Nature (Lond.), v. 207, p. 259, 1965; Hutchison H. E. An introduction to the haemoglobinopathies and the methods used for their recognition, L., 1967; J o n x i s J. H. P. a. Huis-m a n T. H. J. A laboratory manual on abnormal haemoglobins, Oxford, 1968; Lehmann H. Huntsman R. G. Man's haemoglobins, Philadelphia, 1974; Necheles T. F., Allen D. M. a. Finkel H. E. Clinical disorders of hemoglobin, structure and synthesis, N. Y., 1969; Treatment of haemoglobinopathies and allied disorders, techn. rep. ser. No. 509, Geneva, WHO, 1972.
BB. H. Tokarev.