Deficiency of glucose-6-phosphate dehydrogenase: causes, symptoms, diagnosis, treatment

The most common enzyme is the deficiency of glucose-6-phosphate dehydrogenase - identified in about 300 million people; on the second place a deficiency of pyruvate kinase activity, found in several thousand patients in the population; The remaining types of enzyme defects of red blood cells are rare.

Prevalence

Deficiency of glucose-6-phosphate dehydrogenase is unevenly distributed among the population of different countries: most often occurs in European countries located on the Mediterranean coast (Italy, Greece), among Sephardic Jews, as well as in Africa and Latin America. The lack of glucose-6-phosphate dehydrogenase is widely registered in the former malarial regions of Central Asia and the Caucasus, especially in Azerbaijan. It is known that patients with tropical malaria who have a deficiency of glucose-6-phosphate dehydrogenase, died less often, since erythrocytes with an enzyme deficiency contained less malarial plasmodium than normal erythrocytes. Among the Russian population, a deficiency in glucose-6-phosphate dehydrogenase activity occurs in about 2% of people.

Although the deficiency of this enzyme is found everywhere, the extent of the deficit varies among different ethnic groups. The following variants of enzyme deficiency in erythrocytes have been established: A ⁺, A ", B ⁺, B" and variant Canton.

• The variant of glucose-6-phosphate dehydrogenase B ⁺ is normal (100% activity of G-b-PD), the most common among Europeans.
• The variant of glucose-6-phosphate dehydrogenase B "is Mediterranean, the activity of erythrocytes containing this enzyme is extremely low, often less than 1% of the norm.
• The variant of glucose-6-phosphate dehydrogenase A ⁺ - activity of enzymes in erythrocytes is almost normal (90% of the activity of variant B ⁺ )
• The variant of glucose-6-phosphate dehydrogenase A is African, the activity of the enzyme in erythrocytes is 10-15% of the norm.
• The variant of glucose-6-phosphate dehydrogenase Canton - among the inhabitants of Southeast Asia; the enzyme activity in erythrocytes is significantly reduced.

It is interesting to note that the "pathological" enzyme of variant A "is fairly close to the normal variants of glucose-6-phosphate dehydrogenase B ⁺ and A ⁺ in terms of electophoretic mobility and some kinetic properties.The differences between them are in stability.It turned out that in young erythrocytes the activity of the variant enzyme And almost does not differ from that of variant B. However, in mature erythrocytes the picture changes dramatically because the half-life in the erythrocytes of the variant A enzyme is approximately 5 times (13 days) less than the enzymes in In Rianta (62 days). That is, the lack of activity of glucose-6-phosphate dehydrogenase variant A "is the result of much faster than normal, the denaturation of the enzyme in the red blood cells.

The frequency of different types of insufficiency of glucose-6-phosphate dehydrogenase varies in different countries. Therefore, the frequency of persons "responding" to hemolysis for the effect of provoking factors varies from 0 to 15%, and in some localities it reaches 30 %.

Insufficiency of glucose-6-phosphate dehydrogenase is inherited recessively, linked to the X chromosome. Women can be both homozygous (enzyme activity in erythrocytes is absent) and heterozygous (enzyme activity is 50%) by carriers of the defect. In men, the enzyme activity is usually below 10 / o, which causes severe clinical manifestations of the disease.

The pathogenesis of glucose-6-phosphate dehydrogenase

Glucose-6-phosphate dehydrogenase is the first enzyme of pentose phosphate glycolysis. The main function of the enzyme is to restore NADPH to NADPH, necessary for the transition of oxidized glutathione (GSSG) to the reduced form. Reduced glutathione (GSH) is required to bind reactive oxygen species (peroxides). Pentosophosphate glycolysis provides the cell with energy.

Insufficient enzyme activity lowers the energy reserves of the cell and leads to the development of hemolysis, the severity of which depends on the amount and variant of glucose-6-phosphate dehydrogenase. Depending on the severity of the deficit, three classes of G-6-FD variants are distinguished. Deficiency of glucose-6-phosphate dehydrogenase is linked to the X chromosome, it is inherited recessively. Male patients are always hemizygotic, females are homozygous.

The most important function of the pentose cycle is to provide sufficient formation of the reduced nicotinamide adenine dinucleotide phosphate (NADP) to convert the oxidized form of glutamine to the reduced form. This process is necessary for the physiological deactivation of oxidant compounds, such as hydrogen peroxide, accumulating in the erythrocyte. Reducing the level of reduced glutathione or the activity of glucose-6-phosphate dehydrogenase, necessary to maintain it in a reduced form, under the influence of hydrogen peroxide, oxidative denaturation of hemoglobin and membrane proteins occurs. Denatured and precipitated hemoglobin is found in the erythrocyte in the form of inclusions - Heinz-Ehrlich bodies. Erythrocyte with inclusions is rapidly removed from the circulating blood either by intravascular hemolysis or by the body of Heinz with a part of the membrane and hemoglobin phagocytosed by the cells of the reticuloendothelial system and the erythrocyte takes the form of "nadkusannogo" (degmacite).

Symptoms of glucose-6-phosphate dehydrogenase

The disease can be detected in a child of any age. Five clinical forms of manifestation of glucose-6-phosphate dehydrogenase deficiency in erythrocytes are revealed.

1. Hemolytic disease of newborns, not associated with serological conflict (group or Rh incompatibility).

Associated with variants of glucose-6-phosphate dehydrogenase B (Mediterranean) and Canton.

Most common in newborns are Italians, Greeks, Jews, Chinese, Tajiks, Uzbeks. Possible triggering factors of the disease are the intake of vitamin K by the mother and child; use in the treatment of umbilical wounds antiseptics or dyes; use of napkins treated with mothballs.

In newborns with deficiency of glucose-6-phosphate dehydrogenase in erythrocytes, hyperbilirubinemia with signs of hemolytic anemia is observed, but there is usually no evidence of serological conflict between mother and child. The severity of gyerbilirubinemia may be different, possibly the development of bilirubin encephalopathy.

2. Chronic nonsferocytic hemolytic anemia

It occurs mainly among the inhabitants of Northern Europe.

Observed in older children PI adults; the increase in hemolysis is noted under the influence of intercurrent infections and after taking medications. Clinically there is a constant moderate pallor of the skin, mild icterism, slight splenomegaly.

3. Acute intravascular hemolysis.

Occurs in apparently healthy children after taking medications, less often due to vaccination, viral infection, diabetic acidosis.

Currently, 59 potential hemolytic agents have been identified in the deficiency of glucose-6-phosphate dehydrogenase. The group of drugs that necessarily cause hemolysis include: antimalarials, sulfonamide preparations, nitrofurans.

Acute intravascular hemolysis develops, as a rule, 48-96 hours after admission to patients with a drug that has oxidative properties.

Medicinal preparations that cause hemolysis in persons with insufficient activity of glucose-6-phosphate dehydrogenase in erythrocytes

Drugs that cause clinically expressed hemolysis	Preparations, in some cases having a hemolytic effect, but not causing clinically pronounced hemolysis under "normal" conditions (for example, in the absence of infection)
Analgesics and antipyretics
Acetanilide	Fenacetin, acetylsalicylic acid (large doses), antipyrine, aminopyrine, paraaminosalicylic acid
Anti-malarial drugs
Pentahin, Pamakhin, Primachin, Quinocide	Hinacrine (atabrine), quinine, chloroquine (delagil), pyrimethamine (daraprim), plasmocine
Sulfanilamide preparations
Sulfanilamide, sulfapyridine, sulfacetamide, salazo-sulfapyridine, sulfamethoxypyridazine (sulfapyridazine), sulfacyl sodium, sulfamethoxazole (bactrim)	Sulfadiazine (sulfazine), sulfatiazole, sulfamerazine, sulfazoxazole
Nitrofurans
Furacillin, furazolidone, furadonin, furagin, furazoline, nitrofurantoin
Sulfones
Diaminodiphenylsulfone, thiazolphone (promisol)	Sulfoxone
Antibiotics
	Levomycetin (chloramphenicol), novobiocin sodium salt, amphotericin B
Tuberculostatic drugs
	Sodium para-monosalicylate (PASK-sodium), isonicotinic acid hydrazide, its derivatives and analogs (isoniazid, rimifon, ftivazid, tubazid)
Other medications
Naphthols (naphthalene), phenylhydrazine, toluidine blue, trinitrotoluene, neo-salvarsan, nadoxic acid (neviramone)	Ascorbic acid, methylene blue, dimercaprol, vitamin K, colchicine, nitrites
Vegetable products
	Horse beans (Vicia fava), verbena hybrid, field peas, fern male, blueberry, blueberry

The severity of hemolysis varies depending on the degree of enzyme deficiency and the dose of the drug taken.

Clinically, during an acute hemolytic crisis, the general condition of the child is severe, there is a severe headache, febrile fever. Skin covers and sclera pale-icteric. The liver is often enlarged and painful; the spleen is not enlarged. There are repeated vomiting with an admixture of bile, an intensely stained stool. A typical symptom of acute intravascular hemolysis is the appearance of urine in the color of black beer or a strong solution of potassium permanganate. With very intensive hemolysis, acute renal failure and DIC-syndrome can develop, which can lead to death. After the withdrawal of drugs that cause the crisis, hemolysis gradually stops.

4. Favism.

It is associated with eating horse beans (Vicia fava) or inhaling the pollen of some beans. Favism may occur on first contact with beans or observed in individuals who previously used these beans, but had no manifestations of the disease. Boys predominate among the patients. Favism often affects children aged 1 to 5 years, in young children, the process is particularly difficult. Relapses of the disease are possible at any age. The time interval between the use of horse beans and the development of the hemolytic crisis is from several hours to several days. Development of the crisis may be preceded by prodromal signs: weakness, chills, headache, drowsiness, back pain, abdominal pain, nausea, vomiting. An acute hemolytic crisis is characterized by pallor, jaundice, hemoglobinuria, which persists for several days.

5. Asymptomatic form.

Laboratory data

In the hemogram of patients with a deficiency of glucose-6-phosphate dehydrogenase, normochromic hyperregenerative anemia of various severity is revealed. Reticulocytosis can be significant, in some cases reaching 600-800%, normal cells appear. There is anisopyokylocytosis, basophilic puncture of erythrocytes, polychromasia, and sometimes fragments of erythrocytes (schizocytes) can be seen. At the very beginning of the hemolytic crisis, as well as in the period of hemolysis compensation after a special color of the blood smear, in the erythrocytes can be found the body of Heinz-Ehrlich. During the crisis, in addition, leukocytosis is observed with a shift of the leukocyte formula to the left.

Biochemically observed increase in bilirubin concentration due to indirect, a sharp increase in the level of free hemoglobin plasma, hypogaptoglobinemia.

In the bone marrow punctate, a sharp hyperplasia of the erythroid sprout is revealed, the number of erythroid cells can reach 50-75% of the total number of myelokaryocytes, and the phenomena of erythrophagocytosis are detected.

To verify the insufficiency of glucose-6-phosphate dehydrogenase in erythrocytes, methods for the direct determination of the enzyme activity in erythrocyte are used. The study is carried out in the hemolysis compensation period.

To confirm the hereditary nature of the disease, the activity of glucose-6-phosphate dehydrogenase must also be determined in the relatives of the patient.

Differential diagnosis

It is carried out with viral hepatitis, other enzymopathies, autoimmune hemolytic anemia.

Treatment of glucose-6-phosphate dehydrogenase

It is necessary to exclude the use of drugs that provoke hemolysis. Folic acid is recommended.

When the concentration of hemoglobin is reduced to less than 60 g / l, substitution therapy with erythrocyte mass is carried out (quality requirements and calculation of erythrocyte mass are presented below).

Splenectomy is used only in the development of secondary hypersplenism, since the operation does not lead to the termination of hemolysis.

[1], [2], [3], [4], [5], [6], [7]