Glucose-6-phosphate dehydrogenase deficiency: causes, symptoms, diagnosis, treatment

The most common enzymopathy is glucose-6-phosphate dehydrogenase deficiency, found in approximately 300 million people; in second place is pyruvate kinase deficiency, found in several thousand patients in the population; other types of red blood cell enzymatic defects are rare.

Prevalence

Glucose-6-phosphate dehydrogenase deficiency is unevenly distributed among the populations of different countries: it is most often found in residents of European countries located on the Mediterranean coast (Italy, Greece), Sephardic Jews, as well as in Africa and Latin America. Glucose-6-phosphate dehydrogenase deficiency is widely recorded in the former malarial regions of Central Asia and Transcaucasia, 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 fewer malarial plasmodia than normal erythrocytes. Among the Russian population, deficiency of glucose-6-phosphate dehydrogenase activity occurs in approximately 2% of people.

Although deficiency of this enzyme is common worldwide, the severity of deficiency varies among ethnic groups. The following variants of enzyme deficiency in red blood cells have been identified: A ⁺, A", B ⁺, B" and the Canton variant.

• Glucose-6-phosphate dehydrogenase variant B ⁺ is normal (100% G6PD activity), most common in Europeans.
• Variant of glucose-6-phosphate dehydrogenase B" - Mediterranean; the activity of red blood cells containing this enzyme is extremely low, often less than 1% of the norm.
• Glucose-6-phosphate dehydrogenase variant A ⁺ - enzyme activity in erythrocytes is almost normal (90% of the activity of variant B ⁺ )
• The glucose-6-phosphate dehydrogenase D A variant is African, the enzyme activity in erythrocytes is 10-15% of the norm.
• Canton variant of glucose-6-phosphate dehydrogenase - in residents of Southeast Asia; enzyme activity in erythrocytes is significantly reduced.

It is interesting to note that the "pathological" enzyme of variant A" is very close to the normal variants of glucose-6-phosphate dehydrogenase B ⁺ and A ⁺ in electrophoretic mobility and some kinetic properties. The differences between them lie in stability. It turned out that in young erythrocytes, the activity of the enzyme of variant A is almost no different from that of variant B. However, in mature erythrocytes, the picture changes dramatically. This is due to the fact that the half-life of the enzyme of variant A in erythrocytes is approximately 5 times (13 days) less than that of the enzymes of variant B (62 days). That is, insufficient activity of glucose-6-phosphate dehydrogenase of variant A" is the result of a significantly faster than normal denaturation of the enzyme in erythrocytes.

The frequency of different types of glucose-6-phosphate dehydrogenase deficiency varies in different countries. Therefore, the frequency of people who "respond" with hemolysis to the action of provoking factors varies from 0 to 15%, and in some areas reaches 30 %.

Glucose-6-phosphate dehydrogenase deficiency is inherited recessively and is linked to the X chromosome. Women can be either homozygous (no enzyme activity in red blood cells) or heterozygous (50% enzyme activity). In men, enzyme activity is usually below 10/0, which causes pronounced clinical manifestations of the disease.

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 reduce NADP to NADPH, which is necessary for the conversion of oxidized glutathione (GSSG) to its reduced form. Reduced glutathione (GSH) is required to bind reactive oxygen species (peroxides). Pentose phosphate glycolysis provides the cell with energy.

Insufficiency of enzyme activity reduces 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 deficiency, 3 classes of G-6-PD variants are distinguished. Glucose-6-phosphate dehydrogenase deficiency is linked to the X chromosome and is inherited recessively. Male patients are always hemizygous, female patients are homozygous.

The most important function of the pentose cycle is to ensure sufficient formation of 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 oxidizing compounds such as hydrogen peroxide that accumulate in the red blood cell. When the level of reduced glutathione or the activity of glucose-6-phosphate dehydrogenase, which is necessary to maintain it in the reduced form, decreases, oxidative denaturation of hemoglobin and membrane proteins occurs under the influence of hydrogen peroxide. Denatured and precipitated hemoglobin is found in the red blood cell in the form of inclusions - Heinz-Ehrlich bodies. The erythrocyte with inclusions is quickly removed from the circulating blood either by intravascular hemolysis, or the Heinz bodies with part of the membrane and hemoglobin are phagocytized by cells of the reticuloendothelial system and the erythrocyte takes on a “bitten” appearance (degmacyte).

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 identified.

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

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

Most often occurs in newborns of Italians, Greeks, Jews, Chinese, Tajiks, and Uzbeks. Possible provoking factors for the disease are intake of vitamin K by the mother and child; use of antiseptics or dyes when treating the umbilical wound; use of diapers treated with mothballs.

In neonates with glucose-6-phosphate dehydrogenase deficiency, hyperbilirubinemia with features of hemolytic anemia is observed in red blood cells, but evidence of serologic conflict between mother and child is usually absent. The severity of hyperbilirubinemia may vary, and bilirubin encephalopathy may develop.

2. Chronic nonspherocytic hemolytic anemia

It is found mainly among residents of Northern Europe.

Observed in older children PI adults; increased hemolysis is noted under the influence of intercurrent infections and after taking medications. Clinically, constant moderate pallor of the skin, mild icterus, and minor splenomegaly are noted.

3. Acute intravascular hemolysis.

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

Currently, 59 potential hemolytics have been identified for glucose-6-phosphate dehydrogenase deficiency. The group of drugs that necessarily cause hemolysis includes: antimalarial drugs, sulfonamides, nitrofurans.

Acute intravascular hemolysis usually develops 48-96 hours after the patient takes a drug with oxidizing properties.

Medicinal products causing hemolysis in individuals with deficiency of glucose-6-phosphate dehydrogenase activity in erythrocytes

Drugs causing clinically significant hemolysis	Drugs that in some cases have a hemolytic effect, but do not cause clinically significant hemolysis under “normal” conditions (e.g., in the absence of infection)
Analgesics and antipyretics
Acetanilide	Phenacetin, acetylsalicylic acid (high doses), antipyrine, aminopyrine, para-aminosalicylic acid
Antimalarial drugs
Pentaquine, pamaquine, primaquine, quinocide	Quinacrine (Atabrine), Quinine, Chloroquine (Delagyl), Pyrimethamine (Daraprim), Plasmaquine
Sulfanilamide drugs
Sulfanilamide, sulfapyridine, sulfacetamide, salazo-sulfapyridine, sulfamethoxypyridazine (sulfapyridazine), sulfacyl sodium, sulfamethoxazole (bactrim)	Sulfadiazine (sulfazine), sulfathiazole, sulfamerazine, sulfazoxazole
Nitrofurans
Furacillin, furazolidone, furadonin, furagin, furazolin, nitrofurantoin
Sulfones
Diaminodiphenylsulfone, thiazolfone (promizole)	Sulfoxone
Antibiotics
	Levomycetin (chloramphenicol), novobiocin sodium salt, amphotericin B
Tuberculostatic drugs
	Sodium para-ammonosalicylate (PAS sodium), isonicotinic acid hydrazide, its derivatives and analogues (isoniazid, rimifon, ftivazid, tubazid)
Other medications
Naphthols (naphthalene), phenylhydrazine, toluidine blue, trinitrotoluene, neosalvarsan, nalidoxic acid (nevigramon)	Ascorbic acid, methylene blue, dimercaprol, vitamin K, colchicine, nitrites
Plant-based products
	Broad beans (Vicia fava), hybrid verbena, field pea, male fern, blueberries, bilberries

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 child's general condition is severe, severe headache and febrile fever are observed. The skin and sclera are pale and icteric. The liver is most often enlarged and painful; the spleen is not enlarged. Repeated vomiting with bile and intensely colored stool are observed. A typical symptom of acute intravascular hemolysis is the appearance of urine the color of black beer or a strong solution of potassium permanganate. With very intense hemolysis, acute renal failure and DIC syndrome may develop, which can lead to death. After discontinuing the drugs causing the crisis, hemolysis gradually stops.

4. Favism.

Associated with eating fava beans (Vicia fava) or inhaling the pollen of some legumes. Favism may occur upon first contact with the beans or be observed in individuals who have previously eaten these beans but had no symptoms of the disease. Boys predominate among patients. Favism most often affects children aged 1 to 5 years; in young children, the process is especially severe. Relapses of the disease are possible at any age. The time interval between eating fava beans and the development of a hemolytic crisis ranges from several hours to several days. The development of the crisis may be preceded by prodromal symptoms: weakness, chills, headache, drowsiness, pain in the lower back, abdomen, nausea, vomiting. An acute hemolytic crisis is characterized by pallor, jaundice, hemoglobinuria, which persists for up to several days.

5. Asymptomatic form.

Laboratory data

In the hemogram of patients with glucose-6-phosphate dehydrogenase deficiency, normochromic hyperregenerative anemia of varying severity is revealed. Reticulocytosis can be significant, in some cases reaching 600-800%, normocytes appear. Anisopoikilocytosis, basophilic puncturation of erythrocytes, polychromasia are noted, sometimes erythrocyte fragments (schistocytes) can be seen. At the very beginning of the hemolytic crisis, as well as in the period of hemolysis compensation after special staining of the blood smear, Heinz-Ehrlich bodies can be found in the erythrocytes. During the crisis, in addition, leukocytosis with a shift in the leukocyte formula to the left is noted.

Biochemically, an increase in the concentration of bilirubin due to indirect bilirubin, a sharp increase in the level of free plasma hemoglobin, and hypohaptoglobinemia are observed.

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

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

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

Differential diagnosis

It is carried out with viral hepatitis, other enzyme deficiencies, and autoimmune hemolytic anemia.

Glucose-6-phosphate dehydrogenase treatment

It is necessary to exclude the intake of drugs that provoke hemolysis. It is recommended to take folic acid.

When the hemoglobin concentration drops below 60 g/l, replacement therapy with red blood cell mass is performed (quality requirements and calculation of the volume of red blood cell mass are presented below).

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

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