Glucose 6 phosphate dehydrogenase deficiency symptoms. Clinical pharmacology and pharmacotherapy

Hereditary deficiency of erythrocyte enzymes most often manifests itself when the body is exposed to certain toxins and drugs in the form of acute hemolysis, less often - chronic hemolysis. Among them, G-6PD deficiency is the most common.

G-6PD is the first enzyme of anaerobic glycolysis or pentose shunt. It plays a big role in eliminating toxic peroxides in red blood cells. G-6FD is a polymer consisting of 2-6 units; a dimer of two chains - the active form of the enzyme; its concentration in the cell depends on the concentration of NADP, which increases under the influence of oxidants, leading to an increase in G-6PD activity.

There are more than 100 variants of G-6FD. In people of different races, different G-6PD isoenzymes are found in erythrocytes, somewhat different in their activity and stability. In most cases, enzyme deficiency remains asymptomatic under normal conditions and manifests itself in hemolytic crises when taking oxidizing medications. Sometimes, with more severe G-6PD deficiency, hemolysis occurs chronically. It always occurs when peroxides accumulate in erythrocytes, which contribute to the oxidation of hemoglobin (the appearance of Heinz bodies) and lipids of the erythrocyte membrane.

The genetic transmission of G-6PD deficiency is gender-linked. The corresponding gene is located on the X chromosome in a locus close to the color blindness locus and distant from the hemophilia locus. Men who are carriers of the altered gene always detect clinical manifestations this pathology. In heterozygous women, the manifestations are mild or absent, and vice versa, in rare homozygous women there is severe enzymopenia.

According to some estimates, there are more than 100 million carriers of the pathological gene. G6PD deficiency is especially common among dark-skinned individuals, including 10% of dark-skinned Americans and 10-30% of dark-skinned Africans. This pathology is also common in the Mediterranean basin, the Middle East, and Saudi Arabia. It is also found in the Far East - China, Southeast Asia. In some cases, there is a clear protective effect of this pathology against malaria.

Clinic. The severity of the disease is related to the intensity of the deficiency. A slight deficiency (within 20% of the norm) can manifest itself as acute drug-induced hemolysis, a more pronounced one - neonatal jaundice, chronic hemolysis.

Episodes of acute hemolysis almost always occur under the influence of an oxidizing drug, which was first described during treatment with primaquine. Later, the effect of other antimalarials, sulfonamides, nitrofuran derivatives (furadonin), some analgesics (amidopyrine, aspirin) and other drugs (quinidine, amylgan, benemid, etc.) also became known. Liver and kidney failure (with impaired excretion of medications from the body) favors acute hemolysis due to G-6PD deficiency.

After taking medications, hemolysis develops within 2-3 days with anemia, fever, jaundice, and in the case of massive hemolysis, hemoglobinuria. Anemia is usually moderate, normochromic, with an increase in the number of reticulocytes; Heinz bodies are found in red blood cells. Anemia increases by the 10th day. Then, from the 10th to the 40th day (even if the medication is not stopped), repair occurs, anemia decreases, the number of red blood cells increases with high reticulocytosis (up to 25-30%), reflecting the intensity of bone marrow hematopoiesis. Finally, the so-called equilibrium phase begins, during which there is no anemia, although hemolysis and active hematopoiesis still continue. Subsequent recovery is due to the fact that “old” red blood cells, sensitive to the drug, are gradually destroyed, and newly formed ones contain a larger amount of G-6PD and are resistant to hemolysis. However, this resistance is relative (taking large doses of the drug can cause hemolysis) or temporary. These manifestations, with a rather favorable course, are more typical for people with dark skin. In persons with white and yellow skin, the manifestations of G-6PD deficiency may be more severe. Intense hemolysis is accompanied by fever, shock, hemoglobinuria, and anuria. The severity of symptoms does not decrease unless the drug is discontinued. The disease is provoked by many different medications, primarily those mentioned above, which are sometimes administered in small doses and for a short period of time. Some infections (influenza, viral hepatitis) can also provoke acute hemolysis.

Chronic hemolytic anemia due to G-6PD deficiency occurs only in people of the white race. Anemia is found in newborns and young children. It remains moderately expressed, sometimes complicated by acute hemolysis or erythroblastopenia. Growth disturbances and serious complications characteristic of sickle cell disease and thalassemia are not observed.

As a diagnosis, a simple, indicative test is the detection of Heinz bodies. Spontaneously or after incubation in the presence of phenylhydrazine, inclusions representing precipitates of hemoglobin derivatives are found in a significant proportion of erythrocytes with G-6PD deficiency. Heinz bodies are nonspecific and occur in patients with other erythrocyte enzymopathies, toxic anemia, and hemoglobin instability. A number of methods for semi-qualitative determination of G-6PD deficiency make it possible to identify it before the development of hemolysis. Most of them are based on the use of the sensitivity of a colored indicator to the phenomenon of the conversion of NADP to NADH, which occurs under the influence of G-6PD. Thus, the Motulski test is based on measuring the discoloration time of cresyl diamond. The Brewer test evaluates the rate of reduction of methemoglobin by methylene blue.

Enzyme activity is quantified using spectrophotometry and colorimetry. When evaluating the results of these tests on different stages The patient's observations may contain errors, associated, in particular, with the fact that high reticulocytosis can mask G-6PD deficiency, since these cells contain a larger amount of the enzyme.

Treatment this pathology is symptomatic. In acute hemolysis with a large drop in hemoglobin, blood transfusions are performed. The insufficiently justified use of medications that cause acute hemolysis in G-6PD deficiency should be avoided.

All symptoms of glucose-6-phosphate dehydrogenase deficiency are combined into 5 syndromes (a stable set of symptoms united by a single development).

Anemic (that is, from the blood system):

• weakness, decreased performance;
• dizziness;
• fainting conditions;
• ringing in the ears, flashing “flies” before the eyes;
• shortness of breath (rapid breathing) and palpitations with little physical activity;
• stabbing pain in the chest.

Hemolytic syndrome. Erythrocytes (red blood cells) are destroyed within the blood vessels, releasing hemoglobin or hemosiderin (a product of hemoglobin breakdown) through the kidneys. Symptoms:

• change in urine color (it becomes red, brown, black);
• pain in the lumbar region;
• swelling (mainly of the face).

Thrombotic syndrome – the formation of thrombi (blood clots), mainly inside small vessels as a result of stimulation of blood clotting during the destruction of red blood cells. There are several symptoms.

• Pain:
  • in the bones;
  • in the tips of the fingers;
  • at the tips of the ears and nose.

• Formation of ulcers (deep defects) on the anterior surface of the legs.

Hemolytic crisis syndrome (sharp increase in destruction of red blood cells). Symptoms:

• increased body temperature;
• severe pain in the lumbar region;
• darkening of urine (it becomes darker than usual).

Syndrome of developmental anomalies (disorders). Appears from the moment of birth, intensifies in childhood. Symptoms:

• tower (that is, elongated in height) skull;
• protruding zygomatic arches;
• narrow eye sockets;
• thickening of areas of the ribs at the point of their attachment to the sternum (the central bone of the front surface chest);
• shortening of fingers;
• curvature of the legs, etc.

Forms

According to the degree of severity, depending on the content of hemoglobin (a special substance of red blood cells (red blood cells) that carries oxygen) in the blood, they are distinguished:

• mild anemia (hemoglobin from 90 to 110 g/l, that is, grams of hemoglobin per 1 liter of blood);
• moderate anemia (hemoglobin from 90 to 70 g/l);
• severe anemia (hemoglobin less than 70 g/l).

The patient’s well-being depends not so much on the level of hemoglobin, but on the characteristics of his body, the presence chronic diseases, the rate of decrease in hemoglobin levels.

Normally, in men, the hemoglobin content in the blood is 130/160 g/l. Situations in which blood hemoglobin is from 110 to 130 g/l are intermediate between normal and anemia.

Causes

Cause Glucose-6-phosphate dehydrogenase deficiency is an inherited disorder in the structure of genes (carriers of hereditary information). Defective genes can be inherited from one or both parents - in this case the disease will be more severe.

Risk factors for hemolytic crises (a sharp increase in the destruction of erythrocytes - red blood cells).

• Physical:
  • prolonged exposure to sunlight;
  • hypothermia;
  • overheating.

Under the influence of these factors, red blood cells begin to be destroyed more severely.

• Chemical:
  • industrial (oil and gas processing products, varnishes, paints, gasoline, etc.) - inhaling the vapors of these substances, getting them on the skin, or entering the body with food and water can become dangerous;
  • medications (painkillers, antimicrobial agents, vitamin K (necessary for the liver’s synthesis of coagulation factors), etc. Medicines are risk factors only for some people who have structural features of the body (which ones are still unknown), including when taking medications unjustifiably .

• Biological – negative emotions, infections, injuries, surgeries, eating fava beans.

All these factors increase the decrease in the activity of glucose-6-phosphate dehydrogenase (a special enzyme in red blood cells), which leads to increased destruction and a greater than usual decrease in the level of hemoglobin (a special substance in red blood cells that carries oxygen).

Diagnostics

• Analysis of the medical history and complaints (when (how long ago) general weakness, pain in bones and fingers, loss of appetite, shortness of breath, etc. appeared, with which the patient associates the occurrence of these symptoms).
• Life history analysis. Does the patient have any chronic diseases, are there any hereditary diseases (transmitted from parents to children), does the patient have bad habits, did he take any medications, did he come into contact with toxic (poisonous) substances, did the patient stay for a long time under direct sunlight, hypothermia or overheating, etc.
• Physical examination. The color of the skin is determined (pallor is characteristic of anemia), the front surface of the legs is examined (possible presence of ulcers - deep defects), the pulse may be rapid, arterial pressure- reduced.
• Blood analysis. With the development of anemia (a decrease in the level of hemoglobin in the blood - a special substance of erythrocytes - red blood cells - that carries oxygen), a decrease in the number of erythrocytes and reticulocytes (precursor cells of erythrocytes) is determined with an increase in their size, a decrease in the level of hemoglobin, a decrease in the number of platelets (blood platelets). The shape and size of the blood cells remain normal. The color indicator (the ratio of the hemoglobin level multiplied by 3 to the first three digits of the number of red blood cells) does not change: normally this indicator is 0.86-1.05.
• Analysis of urine. In the urine, mainly during a hemolytic crisis (a sharp increase in the destruction of red blood cells), free hemoglobin (that is, outside the red blood cells) and hemosiderin (a product of hemoglobin breakdown) are determined, which should not normally be present.
• Blood chemistry. The level of cholesterol (a fat-like substance), glucose (a simple carbohydrate), creatinine (a breakdown product of protein), uric acid (a breakdown product of substances from the cell nucleus) is determined to identify concomitant organ damage, and electrolytes (potassium, sodium, calcium).
• Determination of glucose-6-phosphate dehydrosenase activity is an accurate method of diagnosis.
• A study of bone marrow obtained by puncturing a bone, most often the sternum (the central bone on the front surface of the chest to which the ribs are attached). In the bone marrow, with a deficiency of glucose-6-phosphate dehydrogenase, increased formation of red blood cells of normal size and shape is determined.
• Electrocardiography (ECG). An increase in heart rate, disturbances in the nutrition of the heart muscle, and, less commonly, cardiac arrhythmias are detected.
• Genetic examination (study of the hereditary properties of the body) of relatives of a patient with glucose-6-phosphate dehydrogenase deficiency, as well as determination of their activity of this enzyme, allows us to identify people with a decrease in the activity of this enzyme and give them recommendations for the prevention of hemolytic crises (a sharp increase in the destruction of red blood cells) .
• Consultation is also possible.

Treatment of glucose-6-phosphate dehydrogenase deficiency

• Impact on the cause Glucose-6-phosphate dehydrogenase deficiency is currently impossible. Genetic studies are carried out (that is, studies of genes that carry hereditary information) with the aim of introducing into the patient’s body genes that provide normal level glucose-6-phosphate dehydrogenase.
• Bone marrow transplantation carried out in cases of severe deficiency of glucose-6-phosphate dehydrogenase activity. Bone marrow transplantation allows you to partially replace the bone marrow of a patient with a damaged cell structure with healthy donor bone marrow. The appearance of full-fledged red blood cells in the bloodstream significantly reduces the risk of hemolytic crises.
• Rapid replenishment of red blood cells (red blood cells) - transfusion of red blood cells (red blood cells isolated from donor blood) or (preferably) washed red blood cells (donor red blood cells devoid of potentially dangerous donor proteins on their surface) for health reasons (that is, if the patient’s life is at risk). There are two conditions that threaten the life of a patient with anemia:
  • anemic coma (loss of consciousness with lack of response to external stimuli due to insufficient oxygen supply to the brain as a result of a significant or rapidly developing decrease in the number of red blood cells);
  • severe anemia (that is, the blood hemoglobin level is below 70 g/l).

Complications and consequences

Complications of glucose-6-phosphate dehydrogenase deficiency.

• Anemia (decrease in the level of hemoglobin - a special substance in red blood cells - red blood cells - that carries oxygen) is the main complication of glucose-6-phosphate dehydrogenase deficiency. Some patients may never experience it.
• Anemic coma is a loss of consciousness with a lack of response to external stimuli due to insufficient oxygen supply to the brain as a result of a significant or rapidly developing decrease in the number of red blood cells.
• Chronic renal failure (impairment of all kidney functions) develops when the kidneys are damaged by the breakdown products of red blood cells.
• Deterioration of condition internal organs, especially in the presence of chronic diseases (for example, heart, kidneys, etc.).

Forecast worsens with frequently recurring hemolytic crises (episodes of sharply increased destruction of red blood cells), a significant decrease in hemoglobin levels, and the development of chronic renal failure.

Prevention of glucose-6-phosphate dehydrogenase deficiency

• Prevention of glucose-6-phosphate dehydrogenase deficiency involves determining the activity of this enzyme in potential parents. It is proposed to refuse pregnancy in cases of high risk of having a child with a severe deficiency of glucose-6-phosphate dehydrogenase activity.
• Prevention of hemolytic crises consists of eliminating provoking factors (for example, taking certain medications, eating fava beans, excessive psycho-emotional stress, etc.).

Additionally

• Glucose-6-phosphate dehydrogenase deficiency is the most common type of hemolytic (that is, associated with increased destruction of red blood cells) anemia.
• According to the World Health Organization (WHO), more than 100 million people suffer from this disease worldwide, mainly in countries with hot climates.
• In Russia, a decrease in the activity of the enzyme glucose-6-phosphate dehydrogenase is detected in approximately every fiftieth person. Each of them can develop anemia.
• During the period between hemolytic crises (a sharp increase in the destruction of red blood cells), the patient may experience no discomfort, but in general analysis blood, normal levels of red blood cells and hemoglobin are determined.
• Men get sick more often than women.

G-6-PD deficiency is the most common red blood cell enzymopathy, affecting more than 100 million people worldwide. It has a high prevalence (10-20%) in individuals originally from Central Africa, the Mediterranean, the Middle East and the Far East. Many different gene mutations have been described, leading to the development of various clinical picture in different populations.

G-6-FD- an enzyme that limits the rate of reactions in the pentose phosphate cycle and is necessary to prevent oxidative damage to red blood cells. Erythrocytes with G-6-PD deficiency are sensitive to oxidative-induced hemolysis.

G-6-PD deficiency is X-linked and therefore predominantly affects males. Heterozygous females are usually clinically normal because they have about half the normal G6PD activity.

Female faces gender can be affected if they are homozygous or, more often, when by chance normal X chromosomes are inactivated to a greater extent compared to pathological ones (terminal lyonization - Lyon's hypothesis, which consists in the fact that in every XX cell one of the chromosomes is inactivated, which occurs by chance) . In Mediterranean, Middle Eastern, and Asian populations, affected males have very low or absent enzyme activity in their red blood cells.

In affected representatives Afro-Caribbean population there is 10-15% of normal enzymatic activity. In young red blood cells, enzymatic activity may be normal, while in older red blood cells it is deficient.

Clinical manifestations of glucose-6-phosphate dehydrogenase deficiency

In children The following clinical signs are usually present. Table of contents of the topic "Blood diseases of children":

The most common fermentopathy is glucose-6-phosphate dehydrogenase deficiency - detected in approximately 300 million people; in second place is deficiency of pyruvate kinase activity, found in several thousand patients in the population; other types of erythrocyte enzyme defects are rare.

Prevalence

Glucose-6-phosphate dehydrogenase deficiency is unevenly distributed throughout the population different countries: most often found among residents of European countries located on the Mediterranean coast (Italy, Greece), among Sephardi Jews, as well as in Africa and Latin America. Glucose-6-phosphate dehydrogenase deficiency is widely reported in former malarial areas 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 red blood cells with enzyme deficiency contained fewer malarial plasmodia than normal red blood cells. Among the Russian population, deficiency of glucose-6-phosphate dehydrogenase activity occurs in approximately 2% of people.

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

• The glucose-6-phosphate dehydrogenase B + variant is normal (100% G-6-PD activity), most common in Europeans.
• The variant of glucose-6-phosphate dehydrogenase B" is Mediterranean; the activity of red blood cells containing this enzyme is extremely low, often less than 1% of normal.
• Option glucose-6-phosphate dehydrogenase A + - enzyme activity in erythrocytes is almost normal (90% activity of option B +)
• The variant of glucose-6-phosphate dehydrogenase A" is African; the activity of the enzyme in erythrocytes is 10-15% of normal.
• Variant of glucose-6-phosphate dehydrogenase Canton - 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 in electrophoretic mobility and some kinetic properties to the normal variants of glucose-6-phosphate dehydrogenase B + and A +. The differences between them lie in stability. It turned out that in young erythrocytes the activity of the variant enzyme A is almost no different from that of option B. However, in mature erythrocytes the picture changes dramatically.This is due to the fact that the half-life of the enzyme of option A in erythrocytes is approximately 5 times less (13 days) than the enzymes of option B (62 days). there is insufficient activity of glucose-6-phosphate dehydrogenase variant A" is the result of a much faster than normal denaturation of the enzyme in erythrocytes.

Frequency different types Glucose-6-phosphate dehydrogenase deficiency varies in different countries. Therefore, the frequency of people “responding” 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, linked to the X chromosome. Women can be either homozygous (no enzyme activity in red blood cells) or heterozygous (enzyme activity is 50%) carriers of the defect. In men, enzyme activity is usually below 10/o, 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 to convert 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.

Insufficient 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 type 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 X-linked and is inherited recessively. Male patients are always hemizygous, female patients are always homozygous.

The most important function of the pentose cycle is to ensure sufficient production 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, necessary to maintain it in its 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 erythrocyte in the form of inclusions - Heinz-Ehrlich bodies. The erythrocyte with inclusions is quickly removed from the circulating blood either by intravascular hemolysis, or Heinz bodies with part of the membrane and hemoglobin are phagocytosed by the cells of the reticuloendothelial system and the erythrocyte takes on the appearance of a “bitten” (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 identified.

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

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

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

Newborns with erythrocyte glucose-6-phosphate dehydrogenase deficiency have hyperbilirubinemia with signs of hemolytic anemia, but there is usually no evidence of serological conflict between mother and child. The severity of hyperbilirubinemia may vary, and bilirubin encephalopathy may develop.

1. Chronic nonspherocytic hemolytic anemia

It is found mainly among residents of Northern Europe.

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

1. 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. To the group medicines, which necessarily cause hemolysis include: antimalarial drugs, sulfonamide drugs, nitrofurans.

Acute intravascular hemolysis usually develops 48-96 hours after administration to the patient. medicinal product, which has oxidizing properties.

Drugs that cause hemolysis in persons with deficiency of glucose-6-phosphate dehydrogenase activity in erythrocytes

Drugs that cause clinically significant hemolysis	Drugs that in some cases have a hemolytic effect, but do not cause clinically significant hemolysis under “normal” conditions (for example, in the absence of infection)
Analgesics and antipyretics
Acetanilide	Phenacetin, acetylsalicylic acid (large doses), antipyrine, aminopyrine, para-aminosalicylic acid
Antimalarial drugs
Pentaquine, pamaquine, primaquine, quinocide	Quinacrine (Atabrine), Quinine, Chloroquine (Delagil), Pyrimethamine (Daraprim), Plasmoquine
Sulfonamide 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, thiazolphone (promizole)	Sulfoxone
Antibiotics
	Levomycetin (chloramphenicol), novobiocin sodium salt, amphotericin B
Tuberculostatic drugs
	Sodium para-amonosalicylate (PAS-sodium), isonicotinic acid hydrazide, its derivatives and analogues (isoniazid, rimifon, ftivazid, tubazid)
Other medicines
Naphthols (naphthalene), phenylhydrazine, toluidine blue, trinitrotoluene, neosalvarsan, nalidoxic acid (nevigramone)	Ascorbic acid, methylene blue, dimercaprol, vitamin K, colchicine, nitrites
Plant products
	Fava bean (Vicia fava), hybrid verbena, field pea, man's fern, blueberry, blueberry

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

Clinically during acute hemolytic crisis general state the child is severe, there is a strong headache, febrile fever. The skin and sclera are pale icteric. The liver is most often enlarged and painful; the spleen is not enlarged. Repeated vomiting mixed 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 discontinuation of the drugs causing the crisis, hemolysis gradually stops.

1. Favism.

Associated with eating fava beans (Vicia fava) or inhaling pollen from certain legumes. Favism may occur upon first contact with beans or be observed in individuals who previously consumed these beans but did not have any manifestations of the disease. Boys predominate among the patients. Favism most often affects children aged 1 to 5 years, in children early age The process is particularly difficult. Relapses of the disease are possible at any age. The time interval between consumption of fava beans and the development of a hemolytic crisis ranges from several hours to several days. The development of a crisis may be preceded by prodromal signs: weakness, chills, headache, drowsiness, lower back pain, abdominal pain, nausea, vomiting. Acute hemolytic crisis is characterized by pallor, jaundice, hemoglobinuria, which lasts up to several days.

1. Asymptomatic form.

Laboratory data

The hemogram of patients with glucose-6-phosphate dehydrogenase deficiency reveals normochromic hyperregenerative anemia of varying severity. Reticulocytosis can be significant, in some cases reaching 600-800%, normocytes appear. Anisopoikilocytosis, basophilic punctation of erythrocytes, polychromasia are noted, and sometimes fragments of erythrocytes (schizocytes) may be visible. At the very beginning of the hemolytic crisis, as well as during the period of compensation for hemolysis after special staining of the blood smear, Heinz-Ehrlich bodies can be detected in red blood cells. During the crisis, in addition, leukocytosis with a shift is noted leukocyte formula to the left.

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

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

To verify the deficiency of glucose-6-phosphate dehydrogenase in erythrocytes, methods of direct determination of enzyme activity in erythrocytes 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 enzymopathies, autoimmune hemolytic anemia.

Glucose-6-phosphate dehydrogenase treatment

It is necessary to avoid taking medications that provoke hemolysis. It is recommended to take folic acid.

If the hemoglobin concentration decreases to less than 60 g/l, replacement therapy red blood cell mass (quality requirements and calculation of the volume of red blood cell mass are presented below).

Deficiency of glucose-6-phosphate dehydrogenase (G-6-PD) activity is the most common hereditary abnormality of red blood cells, leading to hemolytic crises (exacerbation as a result of intense destruction of red blood cells), associated with taking a number of drugs. Outside of a crisis (exacerbation), the well-being and condition of a person with this disease is fully compensated. It is known that a number of drugs, primarily antimalarials, can cause acute hemolytic anemia in some individuals. Drug intolerance is often observed among members of the same family. It has been established that after a hemolytic crisis in people, large inclusions appear in their red blood cells, which are called Heinz bodies. After placing the erythrocytes of persons who have suffered an acute hemolytic crisis caused by taking any drug into a test tube with the substance acetylphenylhydrazine, many Heinz bodies appear in the erythrocytes (much more than in healthy people). The first description of a deficiency in the activity of the G-6-PD enzyme dates back to 1956. Low enzyme activity was found in individuals taking the antimalarial drug primaquine for prophylactic purposes. At the same time, an acute hemolytic crisis developed. Independently of these studies, another scientist in 1957 discovered a deficiency of the same enzyme in red blood cells young man from Iran, who had periodic hemolytic crises without taking any medications.

A deficiency in the activity of this enzyme is always transmitted linked to the X chromosome. The linkage of the mutant gene to gender results in a significant predominance of men among individuals with this disease. It manifests itself in men who inherited this pathology from their mother with her X chromosome, in women who inherited the disease from both parents, and in some women who inherited the disease from one of the parents.

Most often, G-6-PD deficiency occurs in European countries located on the Mediterranean coast - in Greece and Italy. Enzyme activity deficiency is widespread in some countries in Latin America and Africa.

The first stage of drug metabolism in the body is its transition to an active form, which can cause changes in the structure of the erythrocyte membrane. The active form of the drug interacts with hemoglobin. This produces a certain amount of hydrogen peroxide. In healthy people, an acute hemolytic crisis develops when a significant amount of the drug is administered (toxic dose). A crisis can occur when recovery systems are unable to cope with excess hydrogen peroxide produced in red blood cells. At the same time, Heinz bodies appear in red blood cells. The spleen releases red blood cells from these bodies, and part of the surface of the red blood cells is lost, which leads to their premature death.

Experts from the World Health Organization divide the variants of G-6-PD enzyme deficiency into 4 classes in accordance with the emerging manifestations and level of enzyme activity in red blood cells.

1st class- variants that are accompanied by chronic hemolytic anemia.

2nd class- variants with a level of enzyme activity in erythrocytes of 0-10% of the norm, carriage of which determines the absence of hemolytic anemia outside of exacerbation, and exacerbations are associated with taking medications or eating faba beans.

3rd grade- variants with a level of enzyme activity in red blood cells of 10-60% of normal, in which there may be mild signs of hemolytic anemia associated with medication.

4th grade- variants with a normal or close to normal level of enzyme activity without any manifestations.

Hemolytic anemia at birth of a child occurs with a deficiency of the G-6-PD enzyme of both the 1st and 2nd classes. The activity of G-6-PD in erythrocytes does not always correspond to the severity of the resulting manifestations of the disease. With many variants of the 1st class, 20-30% enzyme activity is determined, and with zero activity, some carriers do not experience any manifestations of the disease. This is due, firstly, to the properties of the mutant enzymes themselves, and secondly, to the rate of drug neutralization in the liver.

Most often, deficiency of G-6-PD enzyme activity does not give any manifestations without provocation. In most cases, hemolytic crises begin after taking certain medications, primarily sulfonamide drugs (norsulfazole, streptocide, sulfadimethoxine, sodium albucid, etazol, biseptol), antimalarials (primaquine, quinine, quinine), nitrofuran derivatives (furazalidone, furadonin, furagin, 5-NOK, negram, nevigramon), drugs for the treatment of tuberculosis (tubazid, ftivazid), anthelminthic drug niridazole (ambilhar). If there is a deficiency in the activity of the G-6-PD enzyme, the antimalarial drug delagil can be used, and among sulfonamide drugs, only phthalazole can be used. Some drugs in large doses cause hemolytic crises, and in small doses they can be used for deficiency of G-6-PD enzyme activity. These medications include acetylsalicylic acid (aspirin), amidopyrine, phenacetin, chloramphenicol, streptomycin, artane, and antidiabetic sulfonamide drugs.

Manifestations of the disease may occur on the 2-3rd day from the start of taking the medicine. Initially, a slight yellow discoloration of the eyes appears, and the urine becomes dark. If you stop taking the medicine during this period, then a severe hemolytic crisis does not develop, otherwise on the 4th or 5th day a hemolytic crisis may occur with the release of black, sometimes brown, urine, which is associated with the breakdown of red blood cells inside blood vessels. The hemoglobin content during this period may decrease by 20-30 g/l or more. In severe cases of the disease, the temperature rises, a sharp headache, pain in the limbs, vomiting, and sometimes diarrhea appear. Shortness of breath occurs, blood pressure decreases. The spleen is often enlarged, sometimes the liver.

In rare cases, massive breakdown of red blood cells provokes intravascular coagulation with the formation of blood clots that close the lumen of blood vessels. This, in turn, can lead to impaired blood circulation in the kidneys and the development of acute renal failure.

A blood test reveals anemia with an increase in the number of immature forms of red blood cells (reticulocytes). The number of leukocytes increases. Sometimes, especially in children, the number of leukocytes can become very high (100 x 10 9 / L and higher). The platelet level usually does not change. A special study of red blood cells during a period of severe exacerbation of the disease reveals a large number of Heinz bodies. As a result of pronounced destruction of red blood cells, the content of free hemoglobin in the blood serum increases, and the content of bilirubin is often increased. Hemoglobin also appears in the urine.

Severe hemolytic crises are more common in children than in adults. With a pronounced deficiency of G-6-PD enzyme activity, hemolytic crises sometimes occur immediately after birth. This is a hemolytic disease of newborns, not associated with an immunological conflict between him and the mother. It can be as severe as hemolytic anemia associated with Rh incompatibility of mother and child, and can provoke severe jaundice with severe damage to the central nervous system.

Hemolytic crises due to deficiency of G-6-PD enzyme activity sometimes occur when infectious diseases(influenza, salmonellosis, viral hepatitis), regardless of medication, can be triggered by exacerbation when diabetes mellitus or the development of renal failure.

A small proportion of individuals with G6PD enzyme deficiency have persistent drug-related hemolytic anemia. In these cases, there is a slight enlargement of the spleen, hemoglobin does not decrease so much, and the level of bilirubin in the blood increases slightly. In such people, the disease may worsen either after taking the above medications or with infectious diseases.

Some individuals with G6PD deficiency develop favism-associated hemolytic anemia, called favism. Manifestations of favism consist of signs of rapid destruction of red blood cells, occurring faster than after taking medications, and digestive disorders associated with the direct effect of fava beans on the intestines. Hemolytic crises occur a few hours after eating beans, less often after 1-2 days, their severity depends on the number of beans eaten. Favism is often complicated by renal failure. Mortality with favism is higher than with forms caused by taking medications. When pollen is inhaled, hemolytic crises are often mild, but occur within a few minutes after contact with pollen.

Isolated hemolytic crises caused by taking male fern and eating blueberries and blueberries have been described.

The basis for identifying G-6-PD enzyme deficiency is the determination of enzyme activity using special research methods.

Treatment deficiency of the G-6-PD enzyme is necessary only with pronounced signs of acute destruction of red blood cells. In case of persistent hemolytic anemia with a deficiency of class 1 G-6-PD activity, the spleen is sometimes removed. In case of mild hemolytic crises with slight darkening of urine, slight yellowness of the sclera and a mild decrease in hemoglobin, discontinuation of the drug that caused the crisis, taking riboflavin 0.015 g 2-3 times a day, xylitol 5-10 g 3 times a day, and vitamin E preparations are required.

With pronounced signs of intravascular breakdown of erythrocytes, especially with favism, prevention of acute renal failure is necessary. Prevention of renal failure is carried out only in a hospital setting or intensive care unit and depends on the severity of the condition.

Red blood cells are transfused only in cases of severe anemia.

Prevention of hemolytic crises comes down to avoiding taking medications that can cause an exacerbation of the disease. In this case, such drugs must be replaced with analogues, which must be done by the attending physician.

Forecast. Persons with G-6-PD enzyme deficiency are practically healthy, and if followed preventive measures can be healthy throughout their lives. The performance of such people does not suffer. Chronic hemolytic anemia associated with G6PD deficiency is usually mild. As a rule, performance is completely preserved. The prognosis for acute hemolytic crises depends on the speed of withdrawal of the drug that caused the hemolytic crisis, age, condition of cardio-vascular system. With favism, the prognosis is worse, but preventive measures make mortality low even in cases complicated by acute renal failure.