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Close concepts: macrocytic anemia, disturbance of maturing of a cellular kernel, pernicious anemia, B12 vitamin - scarce anemia, foliyevodefitsitny anemia, refractory macrocytic anemia (Di Guglielmo's syndrome).
Distinguishing characters of megaloblastny anemia is detection of big erythrocytes, macrocytes in a circulator bed and megaloblasts in marrow. From the point of view of a pathophysiology, the combination of these factors reflects disturbances of synthesis of deoxyribonucleic acid (DNA), reduplication of chromosomes and cell division. Pathological changes are found in all bodies having the high level of cell renewal. For example, at patients with deficit of folic acid or B12 vitamin, two basic reasons of megaloblastny anemia, the megaloblastny changes taking a mucous membrane of a stomach and intestines, a cervical epithelium and marrow are found. As the system of a hemopoiesis is by the nature system with a high exchange of cells, it is most sensitive to any disturbances of synthesis of DNA. The system of a hemopoiesis is also most available to research of megaloblastny changes. Creation of automatic counters of cells considerably simplified diagnosis, allowed to perform precision measurement of volume of the circulating erythrocytes and to receive quantitative criteria of a macrocytosis, gave the chance to the practical doctor to conduct routine researches for the purpose of early diagnosis of megaloblastny anemia.
Detection of disturbance of a hemogenesis at megaloblastny anemia stimulated more than 100 flyings ago a number of the researches which led to opening of many important stages of synthesis of DNA.
One of outstanding achievements of this research work was discovery of vitamins — folic acid and B12 vitamin. On the basis of Whipple of supervision made in 1925 that the liver stimulates a hemogenesis Minot and Murphy carried out the experiment noted by the Nobel Prize in which showed efficiency of hepatic therapy of patients with pernicious anemia. Soon after this Castle studied a role of an internal factor, the transport protein cosecreted by covering cells of a stomach which is necessary for acceleration of absorption of an outside factor (B12 vitamin) which is contained in a liver. In the subsequent Hoidgkin allocated an outside factor which structure was studied by means of a new technique of X-ray diffraction. This work was also conferred the Nobel Prize.
Fig. Recyclings and interrelation of folic acid and B12 vitamin; an explanation in the text.
Still before completely purified vitamin B12, Wills was received and its employees found the second factor which is contained in the raw extract of a liver which cured macrocytic anemia at Indians, but was inefficient at patients with pernicious anemia. Later this factor was allocated from leaves of vegetables, and after definition of a chemical structure received the name of folic or pteroilglyutaminovy acid. Further development of the knowledge concerning a role of these substances (folic acid and B12 vitamin) in synthesis of DNA led to new opening. As shown in fig., both folic acid, and B12 vitamin take part basically to stages of a purine and pirimidinovy metabolism, and. transformations of a deoksiuridilat into thymidylate which happen in the course of synthesis of DNA [4, 5]. Now two active forms of V1a vitamin are known. Deoksiadenozil BJ2 a kongenor participates in L-metilmalonil SOA isomerization while metil-V the kongenor acts as the donator of methyl radicals at transformation gomo-Cys in Met. The subsequent reaction is closely connected with an intracellular metabolism of folic acid. N-5-metiltetragidrofoliyevaya acid act as the donator of methyl radicals for B12 vitamin and an end product of this reaction, tetrahydrofolic acid, is substrate for many important metabolic processes, including transformation of Ser into Gly, a purine and pirimidinovy metabolism and synthesis of thymidylate.
Functions of B12 vitamin and folic acid are in difficult interrelation. At insufficient receipt of any of these substances there is a disturbance of all process of synthesis of DNA. For example, deficit of folic acid in food leads N-5-metiltetragidrofoliyevoy acids to decline in the ability to give methyl radicals for connection with B12 vitamin that is followed by reduction of synthesis of Met and providing a metabolism of folic acid with tetrahydrofolic acid of all subsequent stages. At disturbance of formation of 5,10-methyltetrahydrofolic acid normal synthesis of thymidylate is impossible. Therefore, disturbance of synthesis of DNA is a natural outcome of deficit of folic acid. In case of deficit of B12 vitamin owing to impossibility of transfer of methyl radicals from methyltetrahydrofolic acid to B12 vitamin transformation of N-5-methyltetrahydro-folic acid into tetrahydrofolic acid is blocked. The folic acid arriving with food is acquired in the form of methyltetrahydrofolic acid and those stages of synthesis of DNA for which tetrahydrofolic acid is necessary lack for the necessary substance. The same outcome, as at a lack of folic acid: general disturbance of synthesis of DNA.
Primary and secondary disturbances of synthesis of DNA result also from reception of some medicines which influence or stages of a metabolism of folic acid, or directly inhibit synthesis of DNA. For example, the chemotherapeutic drugs inhibiting a degidrofolatreduktaza interrupt a normal intracellular cycle of an exchange of folic acid and lead to a megaloblastoz. As a result of braking of transformation of degidrofoliyevy acid into tetrahydrofolic acid there is impossible a recycle of folic acid and its participation in thymidylate synthesis. Drugs which influence a metabolism of purine and a pyrimidine and also a timidilatsintetaza can cause megaloblastny anemia too. Some substances directly influence formation of DNA. At last, morphological changes, characteristic of megaloblastny anemia, are observed at patients with inborn disturbances of a metabolism of folic acid and B12 vitamin and at malignant new growths at which there are acquired disturbances of synthesis of DNA and cell fission.