Hereditary hemolytic anemia, related to the violation of enzyme activity of erythrocytes
In the early forties of the last century appeared in the literature describing individual cases of hereditary hemolytic anemia, not having basic, characteristic (it was thought at the time) This feature disease - microspherocytosis. These became known as anemia nesferotsitarnyh. The main criteria is the lack of change in the forms of red blood cells, slight tendency to increase in the diameter of erythrocytes, of normal or increased osmotic resistance, No effect is the effect of splenectomy or incomplete, recessive inheritance.
It was subsequently found, that much of the so-called hereditary hemolytic anemias nesferotsitarnyh enzymes associated pathology erythrocytes. In other patients in this group, especially in individuals, in which the red blood cells at a special color were identified inclusion - calf Heinz, then various options have been found abnormal hemoglobin unstable.
Etiology and pathogenesis
Lack of erythrocyte enzyme activity may lead to disruption of ATP production in these, what, in turn, It leads to disruption of the ionic composition of red blood cells and shortening the duration of their lives. In other cases, violation of enzyme activity leads to a lack of red blood cells ability to resist the effects on them of oxidants, resulting in the oxidation of hemoglobin and the formation of peroxides of unsaturated fatty acids of the membrane of red blood cells and severe destruction of red blood cells. Besides, cause increased red blood cell hemolysis may be a violation of enzyme activity, involved in the metabolism of ATP.
Currently it is known for more than 20 reactions in metabolism erythrocytes, blockade which reduces their life expectancy.
The collapse of glucose in erythrocytes It carried out mainly by glycolysis. One glucose molecule is cleaved into two molecules of lactic acid (lactate) without the use of molecular oxygen. The metabolism of the red blood cells, in contrast to the metabolism of most other tissues have tricarboxylic acids (Krebs) and oxidative phosphorylation, in which glucose is broken down to carbon dioxide and water. In other tissues 95 % energy in form of ATP produced in the citric acid cycle and only 5 % Energy gives glycolysis. The erythrocytes only source of energy is glycolysis.
The process of glycolysis is a series of consecutive reactions. Under the influence of air is formed hexokinase glucose - glucose-6-phosphate.
With geksafosfoizomerazy formed phosphoric ester fructose - fructose-6-phosphate, and then involving 6-phosphofructokinase - diphosphoric ester fructose - fructose 1,6-bisphosphate.
For the conversion of glucose to fructose 1,6-bisphosphate requires two molecules of ATP, but no ATP in this step is not synthesized. Under the influence of the enzyme aldolase fructose 1,6-bisphosphate is cleaved into two molecules of triose phosphate. Formed dioksiatsetonfosfat and glyceraldehyde-3-phosphate. With the participation of the formation of triose phosphate isomerase, glyceraldehyde 3-phosphate from dioksiatsetonfosfata. Glyceraldehyde-3-phosphate is oxidized, and in the presence of inorganic phosphate synthesized 1.3-difosfoglicerinovaâ acid. This catalyzes the reaction gliceral′degidfosfatdegidrogenaza.
The next step is education 3- fosfoglicerinovoj acid using fosfogliceratkinazy enzyme and ATP. The second molecule of ATP is synthesized during the formation of Pyruvate from fosfoenolpiruvata under the influence of Pyruvate. Thus, spent two ATP molecules, and formed four, because each molecule of glucose arise two molecules of pyruvic acid. This is a small amount of energy ensures that normal Ionic balance erythrocyte.
Glycolysis is finished by recovering pyruvate to lactate, that permeates through the membrane of erythrocytes and burns in the tricarboxylic acid cycle in other tissues. In erythrocytes in contrast to other tissues during Glycolysis is produced in large quantities 2.3-difosfoglicerinovaâ acid, linking with β-globin gene circuits required for the impact of oxygen tissues as a result of lowering the affinity of hemoglobin for oxygen.
The second way the breakup of glucose in erythrocytes is the pentose phosphate cycle, in the course of which 34.4 formed restored form Coenzyme NADP, needed to restore glutathione. Recycled glutathione in red blood cell is basic stuff, vozdestviû opposes oxidants. Active hydrogen sulfgidrilna groups of glutathione is used for neutralizing peroxides, from the membrane and violate its integrity,
Currently describes the hereditary Glycolysis enzyme activity violations — hexokinase, geksofosfatizomerazy fosfofruktokinazy, triozofosfatizomerazy, gliceral′degidfosfatdegidrogenazy, 2,3-difosfogliceromutazy, 3-fosfogliceratkinazy, pyruvate.
All these violations are very rare. Even a deficiency of Pyruvate, occurring much more frequently, than the rest, described in a little more than 200 cases.
Among violations of pentozofosfatnogo enzyme activity cycle the most important activity deficit glukozo-6-fosfatdegidrogenaza. This defect of erythrocytes is the most common hereditary abnormality. Much less lack of activity 6-fosfoglûkonatdegidrogenazy.
From violations of the enzymes glutathione system Describes the deficit synthase reductase and Glutathione peroxidase.
A number of enzymatic defects in nucleotide metabolism system: adenilatkinazy, ATPase and pyrimidine-5-nukleotidnukleozidazy. These violations are extremely rare.
In the pathogenesis of anemia, associated with a deficiency of the enzyme activity of Glycolysis, the main role is played by violation power generation, as a result of which changes the Ionic composition of erythrocytes, shortened life expectancy. The destruction of red blood cells is mainly wärmetauscher macrophages spleen and liver.
If there is a violation of pentozofosfatnogo enzyme activity cycle, Glutathione system destruction of red blood cells is associated with the oxidation of perekisnym membrane and most commonly occurs when the effects of oxidants (drugs), usually in sossoudistom line. Sometimes, when these violations occur intracellular enzymatic destruction of red blood cells, indistinguishable clinical picture of hemolysis with anemia, associated with a deficiency of enzymes of glycolysis.
The clinical manifestations of hemolytic anemia with a deficit of glycolytic enzymes
The clinical manifestations of hemolytic anemia deficiency of enzymes of glycolysis can be different - from heavy to asymptomatic. Most clinical manifestations impossible to distinguish one from another enzyme deficits.
Most patients have mild severe hemolytic anemia with a constant decrease in hemoglobin to 5,59-6,83 mmol / l (90-110 G / l) and periodic hemolytic crisis on this background when infection or pregnancy. In some patients, hemoglobin never decreases and the disease manifests itself only a small ikterichnost sclera. Much less a marked jaundice.
Spleen is increased in most patients, sometimes largely. Normal spleen size not exclude the presence of hemolytic anemia, related to the violation of enzyme activity. In some patients the liver increases.
Individual cases of hereditary deficiency described activity glyukozofosfatizomerazy, triosephosphate isomerase accompanied by severe hemolytic anemia. At deficiency of phosphofructokinase activity, hexokinase, 3-phosphoglycerate for hemolytic anemia is usually not serious. When the activity of pyruvate kinase deficiency, 2,3-difosfogliceromutazy, glitseraldegidrofosfatdegidrogenazy along with the absence of clinical manifestations can be observed very severe enzymatic deficiency of red blood cells.
Perhaps a combination of enzyme activity of erythrocyte deficit with other hereditary lesions, eg myasthenic syndrome, related to the violation of enzyme activity, involved in the breakdown of muscle glycogen, with ichthyosis, etc.. At deficiency of activity of hexokinase, triosephosphate isomerase addition anemia observed lejko- and thrombocytopenia.
With a deficit of activity of glucose-6-phosphate dehydrogenase, 6-fosfoglûkonatdegidrogenazy, Glutathione reductase was observed most often acute hemolytic anemia, associated with taking drugs. This enzyme deficiency may lead to permanent and clinical picture of hemolytic anemia, not distinguished by its manifestations and Hematological indicators of hemolytic anemia, associated with a deficiency of the enzyme activity of Glycolysis. While there are želtušnost′, splenomegaly, constant mild anemia.
A characteristic feature of the activity deficit pyrimidine-5-nukleotidazy is pronounced Basophilic punktaciâ erythrocytes with non-severe anaemia. The spleen is enlarged slightly.
Laboratory indicators of hemolytic anemia at deficiency of the enzymes of Glycolysis
Blood picture depends on the clinical manifestations of disease. Hemoglobin and erythrocytes may be normal, Sometimes there has been a pronounced anemia (HB 2.48-3.72 mmol/l, or 40-60 g/l). Color index close to unity, the average concentration of hemoglobin in erythrocytes is approaching normal.
Morphology of erythrocytes may be different — from out of focus before makrocitoza mikrosferocitoza express. Are often found expressed anizocitoz, poikilocytosis were, polihromaziâ erythrocytes. While many forms of anemia is determined by the mišenevidnost′ of red blood cells, Sometimes there is Basophilic punktaciâ. With a deficit of 3-fosfoglicerokinazy activity detected red blood cells with wavy edge and šilovidnymi art, Jolly corpuscles, at deficiency of Pyruvate activity — heterogeneous erythrocytes. The most characteristic makrocity, popalaûtsâ single mikrosferocity, has a penchant for flattening of the cells, sometimes identify erythrocytes with Scalloped edges or in the form of tutovoj berries. With a deficit of gliceral′degidrofosfatdegidrogenazy activity indicated a pronounced makroditoz erythrocytes.
The number of white blood cells and platelets the majority of patients have normal. Only in rare cases described the combination of enzymatic defect of erythrocytes, leukocytes and platelets. ESR usually normal.
For all forms of hemolytic anemia, flowing with constant hemolysis, characterized by irritation of red bone marrow germ, some degree of increase in the number of reticulocytes.
When collected in most cases detected bone marrow hyperplasia by increasing the number of èritrokariocitov, reducing the amount of fat (yellow) bone marrow.
Osmotic resistance of erythrocytes can be different even if the same defect of erythrocytes.
Differential diagnosis of hemolytic anemia at deficiency of the enzymes of Glycolysis
Previously given value test autogemoliza. Anticipated, that in cases, when glucose corrigiruet hemolysis in vitro, defect in enzymes of Glycolysis is excluded while in those cases, when glucose has no effect, deficiency of Pyruvate or other activity of the enzymes of Glycolysis is very probable. However, studies have shown the relative value of this method. Autogemoliza results depend on it at this particular point, symptoms of pathological process in a particular patient, and many other factors.
Among the laboratory tests, with an indicative value, but to distinguish a group of diseases, It should be noted the emergence of Taurus Gejnca after incubation of erythrocytes with β-acstilfenilgidrozinom. Taurus Gejnca easily formed in violation of pentozofosfatnogo enzyme activity cycle and Glutathione systems, as well as if there are some forms of unstable hemoglobin.
Clinical and hematologic manifestations of the disease to some extent depend on the level of the lesion, So how important is not only a violation of education ATP as a result of a defect, but then, What intermediate product accumulates depending on localization of hereditary enzymatic defect. Is set and the heterogeneity of enzymatic disorders in the same defect localization. Just like gemoglobinopatiâh, different amino acid substitution in the enzyme molecule red blood cells may cause various changes in enzyme function, Hence the differences in clinical manifestations of disease.
