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Anemia due to a change in the activity of erythrocyte enzymes
Glucose is the main source of energy for red blood cells. After penetration into the red blood cell, it undergoes metabolism along the path of anaerobic glycolysis (Embden-Meyerhof cycle) or along the path of the pentose cycle (hexose monophosphate cycle). Hereditary hemolytic anemia caused by a decrease in the activity of erythrocyte enzymes is most often associated with a deficiency of enzymes involved in glycolysis, the pentose cycle, or in the glutathione system. Currently, more than 20 red blood cell fermentopathies have been described. The most common and important enzymes are described below.
Glucose-6-Phosphate Dehydrogenase Deficiency Anemia
Anemia due to deficiency of glucose-6-phosphate dehydrogenase (G-6-PD) is the most common red blood cell enzyme. Redundancy of Gb-FD in erythrocytes is observed in more than 300 million people on the globe.
In red blood cells, the G-6-FD enzyme catalyzes the reaction:
G-6-PD + NADO + = 6-phosphogluconate + NADP • N
The structural gene and the regulatory gene responsible for the synthesis of G-6-PD are located on the X chromosome. G-b-FD deficiency is inherited as an incompletely dominant trait linked to the floor. The enzyme activity in male carriers of the defect is usually below 10% of normal. In women with homozygous carriage of the defect, the enzyme activity in red blood cells is absent; in women with heterozygous carriage of the defect, the enzyme activity is about 50%.
At present, two variants of G-6-FD deficiency are most fully studied:
• option A- (found mainly in homozygous carriers of African descent, African type);
• option B- (most often found in ethnic groups of the Mediterranean, Mediterranean type).
The sign “-” means the insufficiency of G-6-FD;
“A” and “B” characterize the electrophoretic mobility of the enzyme.
Hemolytic anemia with a deficiency of the G-6-FD enzyme is caused by a disruption in the functioning of the pentose metabolic cycle, a disruption in the formation of ATP in red blood cells, and a defect in the glutathione system. These changes sharply reduce the ability of red blood cells to withstand hydrogen peroxide, free radical compounds that occur when lipid peroxidation is activated.
The main factor causing erythrocyte hemolysis in patients with G-6-FD deficiency is usually taking certain medications that stimulate lipid peroxidation in the erythrocyte membrane and cause the formation of peroxides, free radical compounds and oxidative denaturation of hemoglobin and membrane proteins. In normal red blood cells containing a sufficient amount of G-6-PD, an optimal amount of glutathione is formed, which, with the participation of the enzyme glutathione peroxidase, contributes to the destruction of peroxide compounds. With Gb-FD deficiency, these antioxidant mechanisms are impaired. Red blood cell hemolysis occurs predominantly in the vascular bed, less often intracellular hemolysis is observed.
The list of drugs that provoke the development of hemolysis in patients with hereditary Gb-FD deficiency is presented in the table.
It must be emphasized that, in addition to drugs, erythrocyte hemolysis can also be triggered by other factors - viral and bacterial infections, diabetic ketoacidosis, uremia, the ingestion of horse beans (vicia fava) and inhalation of pollen from these plants (favism).
First of all, old erythrocytes undergo hemolysis, because G-6-FD deficiency is most pronounced in them. The activity of this enzyme in young red blood cells and reticulocytes is slightly reduced.
Factors causing hemolysis in patients with hereditary red blood cell deficiency of the glucose-6-phosphate dehydrogenase enzyme
1. Antimalarial drugs
• chloroquine, delagil;
2. Nonsteroidal anti-inflammatory drugs
• acetylsalicylic acid,
3. Antibacterial agents
• nitrofuran compounds;
• nalidixic acid (nevigraion);
5. Anti-TB drugs
• rifamlicin 6 antiarrhythmic drugs
• procainamide (procainamide)
7. Eating horse beans (favism)
• acute respiratory viral;
• viral hepatitis;
• Infectious mononucleosis;
• bacterial pneumonia
9. Diabetic ketoacidosis
The disease is more common among African-American men, among residents of the countries of the Mediterranean, Central Asia, and the Caucasus. Clinical manifestations can be of varying severity depending on the intensity of hemolysis. In children, the disease can manifest itself already in the neonatal period with hemolytic jaundice, which should be differentiated from jaundice due to serological conflict.
In adults, deficiency in red blood cells G-6-FD can be manifested by chronic nonsferocytic hemolytic anemia, acute intravascular hemolysis, favism or asymptomatic.
Chronic hemolytic anemia (non-spherocytic). This form is characterized by symptoms of hemolytic anemia - jaundice, unconjugated hyperbilirubinemia, normocytic anemia.
The indicated symptoms are not pronounced during the remission period, however, under the influence of intercurrent infections and after taking certain medications, anemia and jaundice increase significantly. A marked exacerbation of the disease can manifest itself in the form of a hemolytic crisis, during which vomiting, fever, jaundice and anemia intensify.
Acute intravascular hemolysis is a severe clinical form of the disease, usually occurs 3-4 days after taking a drug that can cause hemolysis. The main clinical manifestations of this form of Gb-FD deficiency are:
• high body temperature;
• Strong headache;
• repeated vomiting with an admixture of bile in vomit;
• loose stools, intensely colored;
• severe jaundice (the skin is painted in an intense lemon yellow color);
• lack of splenomegaly;
• a significant drop in the level of hemoglobin and the number of reticulocytes in the peripheral blood (often the severity of anemia depends on the dose of the drug that caused hemolysis);
• urine intense dark color;
• a sharp increase in blood levels of unconjugated bilirubin.
In severe prolonged course of acute intravascular hemolysis, the development of acute renal failure is possible. Cancellation of the drug that caused hemolysis leads to a gradual (within 3-4 days) cessation of hemolysis. In some cases, acute intravascular hemolysis occurs due to vaccination, acute respiratory viral infection, and diabetic ketoacidosis.
Favism is a form of hereditary hemolytic enzymopathic anemia associated with the consumption of horse beans or the inhalation of flower pollen. In all patients with favism, G-b-PD deficiency in erythrocytes is noted, however, the factor directly causing hemolysis with favism has not been conclusively established. Favism may occur during the first use of horse beans, but may occur for the first time after their repeated use. The clinical picture of favism is very variable. In some patients, these are symptoms of mild hemolysis (acute or chronic) with mild jaundice and anemia, in others the disease manifests itself as a severe hemolytic crisis (the symptoms are described above) with pronounced jaundice, anemia, fever, vomiting, and abdominal pain.
In this case, an increase in the liver and spleen is often noted. In the urine, hemoglobin is often detected (urine is dark or even black). In the most severe cases, acute renal failure develops.
The asymptomatic form of Gb-FD deficiency is characterized by a complete absence of clinical symptoms, a satisfactory condition and can only be diagnosed with targeted determination of Gb-FD activity in red blood cells.
General blood test - with exacerbation of the disease, normochromic anemia, an increased number of reticulocytes are noted.
The detection of Heinz-Erlich bodies in red blood cells (more often at the beginning of a hemolytic crisis) is extremely characteristic. In patients with a normally functioning spleen, the Heinz-Erlich bodies can quickly disappear.
A red blood cell with Heinz bodies.
To detect bodies, a blood smear is incubated with acetylphenylhydrazine and then stained with crystal violet. At the same time, HB is denatured and looks like rounded blue clumps. In normal red blood cells, from 1 to 4 Heinz bodies can be seen, with pathological situations 5 or more.
The most important diagnostic sign is the detection of “bitten” red blood cells in a blood smear. These are red blood cells with small marginal defects; it is assumed that they are formed during the destruction of red blood cells with Heinz bodies in the spleen.
"Bitten" red blood cell (dermacyte).
The red blood cell looks like someone has bitten it.
During an exacerbation of the disease in the blood, the leukocyte count increases with a shift of the leukocyte formula to the left.
Urinalysis - in the period of an exacerbation of the disease, urobilin is detected in the urine, during a hemolytic crisis - protein, sometimes hyaline cylinders and red blood cells, hemoglobinuria is often determined.
Analysis of feces - in the period of exacerbation of the disease, an increased content of stercobilin is noted, which explains the dark color of feces.
Biochemical analysis of blood - the content of unconjugated (indirect) bilirubin is increased, the activity of G-6-PD in red blood cells is reduced, an increase in the level of serum iron and free hemoglobin is possible. Myelogram - in sternal punctate pronounced hyperplasia of the red, hematopoietic germ.
Diagnosis of hereditary hemolytic anemia due to Gb-FD deficiency is carried out on the basis of the above clinical picture, the detection in red blood cells of a large number of Heinz bodies, "bitten" red blood cells (dematocytes), and low Gb-FD activity in red blood cells.
Pyruvate kinase deficiency anemia
The disease occurs with a frequency of 1 in 20,000 newborns, is transmitted through an autosomal recessive pathway. There are two pyruvate kinase isoenzymes in human erythrocytes: PK-R1, (prevails in young red blood cells) and PK-R2 (prevails in old red blood cells).
With pyruvate kinase deficiency in the red blood cell, glycolysis and ATP formation are disrupted. This, in turn, disrupts the transport of cations, there is a loss of potassium and water by an erythrocyte and an increase in calcium content, the ability of red blood cells to change their shape decreases, and subsequently erythrocyte dehydration and its hemolysis occurs. The disease manifests itself in the first years of life, is characterized by the symptoms of chronic hemolytic anemia with severe reticulocytosis, hyperbilirubinemia due to unconjugated bilirubin, splenomegaly. In a general analysis of blood, a mild microcytosis with poikilocytosis, fragmentation of red blood cells, but microspherocytosis and Heinz bodies is noteworthy.
Quite often, the disease progresses and persistent and severe anemia develops.
The diagnosis is verified by determining the decreased activity of pyruvate kinase in red blood cells. The osmotic resistance of red blood cells is normal.
Glucose phosphatisomerase deficiency anemia
Glucose phosphatisomerase (GPI) is the second key enzyme in anaerobic glycolysis; under the influence of GPI, glucose-6-phosphate in erythrocyte is converted to fructose-6-phosphate. The gene that controls the synthesis and activity of GPI is located on the 19th chromosome, a mutation in the region of this gene leads to a decrease in the activity of GPI.
In heterozygotes, the disease proceeds without clinical manifestations, since the activity of GPI reaches 60% compared with the norm. In homozygotes, the activity of GPI is reduced to 15-30% compared with the norm and the disease manifests itself clinically with all signs of chronic hemolytic anemia, the degree of which can be different.
In the analysis of peripheral blood, a decrease in the content of red blood cells and hemoglobin is determined, awl-shaped red blood cells, ovalocytes are sometimes detected. A biochemical blood test reveals hyperbilirubinemia. In many children, chronic hemolytic anemia due to a deficiency in red blood cells of GPI is accompanied by muscle weakness and mental retardation.
Hereditary hemolytic anemia caused by erythrocyte fermentopathy also includes very rare anomalies: deficiency of phosphofructokinase, aldolase, triosephosphatisomerase, 3-phosphoglycerate kinase and 2,3-diphosphoglyceratmutase activity. They are manifested by the symptoms of chronic hemolytic anemia, verified by determining the activity of these enzymes in red blood cells.
Anemia associated with impaired nucleotide metabolism
Anemia associated with impaired nucleotide metabolism is due to a decrease in the activity of enzymes involved in the metabolism of nucleotides in the red blood cell. This leads to inhibition of the formation of ATP in the red blood cell, a change in the content of K +, Na +, Ca ++ in them, a disruption in the functional state of the erythrocyte membrane, a decrease in the synthesis of glutathione, and a shortening of the life span of red blood cells.
This group of hemolytic anemia includes anemia caused by the following disorders of the nucleotide metabolism in red blood cells:
• deficiency of adenylate kinase activity;
• hyperactivity of adenosine deaminase;
• deficiency of pyrimidine-5-nucleotidase activity.
Clinically, these diseases are manifested by chronic hemolytic anemia. Differential diagnostic differences between anemia caused by impaired nucleotide metabolism have not been developed in detail. Verification of the diagnosis is carried out by determining the activity of these enzymes in red blood cells.
Glutathione reductase deficiency anemia
Glutathione reductase is one of the enzymes of the glutathione cycle. With a deficiency of this enzyme, the synthesis of glutathione in the erythrocyte is impaired, which reduces the ability of the latter to withstand the damaging effects of free radical and peroxide compounds.
In recent years, evidence has appeared that glutathione reductase deficiency is rarely hereditary, and more often acquired, due to a deficiency in food riboflavin. Red blood cell hemolysis usually occurs spontaneously, less often - is provoked by taking medications.
Clinical and laboratory manifestations of the disease are as follows:
• normochromic anemia with reticulocytosis in the peripheral blood and Heinz bodies in red blood cells;
• jaundice with a high blood content of unconjugated bilirubin;
• hyperplasia of the red hematopoietic germ (according to the myelogram);
• increased blood levels of iron and a decrease in haptoglobin;
• a decrease in the content of reduced glutathione in red blood cells.
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Anemia due to a change in the activity of erythrocyte enzymes
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