Glucose 6 phosphate dehydrogenase deficiency. Clinical pharmacology and pharmacotherapy
E.A. Skornyakova, A.Yu. Shcherbina, A.P. Prodeus, A.G. Rumyantsev
Federal State Institution Federal Research Center for Pediatric Hematology, Oncology and Immunology of Roszdrav,
RGMU, Moscow
Some primary immunodeficiency conditions are at the intersection of several specialties, and often patients with one or another defect are observed not only by an immunologist, but also by a hematologist. For example, the group of phagocytosis defects includes congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD). This most common enzymatic deficiency is the cause of a wide range of syndromes, including neonatal hyperbilirubinemia, hemolytic anemia, and repeated infections characteristic of phagocytic pathology. In individual patients, these syndromes can be expressed to varying degrees.
Epidemiology
G6PD deficiency occurs most frequently among people living in Africa, Asia, the Mediterranean, and the Middle East. The widespread prevalence of G6PD deficiency correlates with the geographic distribution of malaria, leading to the theory that carriage of G6PD deficiency provides partial protection against malaria infection.
Pathophysiology
G6PD catalyzes the conversion of nicotinamide adenine dinucleotide phosphate (NADP) to its reduced form (NADPH) in the pentose phosphate pathway of glucose oxidation (see figure). NADPH protects cells from damage by free oxygen. Since red blood cells do not synthesize NADPH in any other way, they are the most sensitive to the aggressive effects of oxygen.
Due to the fact that due to G6PD deficiency, the greatest changes occur in red blood cells, these changes are the most well studied. However, abnormal responses to certain infections (eg, rickettsiosis) in such patients raise concerns about abnormalities in the cells of the immune system.
Genetics
The gene encoding glucose-6-phosphate dehydrogenase is located on the distal part of the long arm of the X chromosome. More than 400 mutations have been discovered, most mutations occurring sporadically.
Diagnostics
Diagnosis of G6PD deficiency is made by quantitative spectrophotometric analysis or, more commonly, a rapid fluorescent spot test that detects the aggregate of the reduced form (NADPH) versus NADP.
In patients with acute hemolysis, tests for G6PD deficiency may be falsely negative because older red cells with lower levels of the enzyme have undergone hemolysis. Young red blood cells and reticulocytes have normal or subnormal levels of enzymatic activity.
G6PD deficiency is one of a group of congenital hemolytic anemias and its diagnosis should be considered in children with a family history of jaundice, anemia, splenomegaly or cholelithiasis, especially of Mediterranean or African origin. Testing should be considered in children and adults (especially males, Mediterranean, African or Asian descent) with an acute hemolytic reaction secondary to infection, use of oxidative drugs, ingestion of legumes, or exposure to mothballs.
In countries where G6PD deficiency is common, newborn screening is performed. WHO recommends newborn screening in all populations with an incidence of 3-5% or more in the male population.
Hyperbilirubinemia of newborns
Neonatal hyperbilirubinemia occurs at twice the population average in boys with G6PD deficiency and in homozygous girls. Quite rarely, hyperbilirubinemia is observed in heterozygous girls. The mechanism of development of neonatal hyperbilirubinemia in such patients is not clear enough.
In some populations, G6PD deficiency is the second most common cause of kernicterus and neonatal death, while in other populations the disease is almost unknown, reflecting the varying severity of mutations specific to different ethnic groups.
Acute hemolysis
Acute hemolysis in patients with G6PD deficiency is caused by infection, consumption of legumes, and intake of oxidative drugs. Clinically, acute hemolysis is manifested by severe weakness, pain in the abdominal cavity or back, possibly an increase in body temperature to febrile levels, jaundice that occurs due to an increase in the level of indirect bilirubin, and darkening of the urine. Cases of acute renal failure have been described in adult patients.
Drugs that cause an acute hemolytic reaction in patients with G6PD deficiency attack the antioxidant defense of red blood cells, which leads to their breakdown (see table).
Hemolysis usually continues for 24-72 hours and ends by 4-7 days. Particular attention should be paid to the administration of oxidative drugs to nursing women, since, when secreted in milk, they can provoke hemolysis in a child with G6PD deficiency.
Although G6PD deficiency may be suspected in patients who have a history of hemolysis after eating legumes, not all of them will develop such a reaction in the future.
Infection is the most common cause of acute hemolysis in G6PD-deficient patients, although the exact mechanism is unclear. It is assumed that leukocytes can release oxygen free radicals from phagolysosomes, which causes oxidative stress for red blood cells. The most common causes of hemolysis are salmonellosis, rickettsial infections, beta-hemolytic streptococcus, Escherichia coli, viral hepatitis, and influenza virus type A.
Chronic hemolysis
In chronic hemolytic anemia, which is usually caused by sporadic mutations, hemolysis occurs during the metabolism of red blood cells. However, under conditions of oxidative stress, acute hemolysis may develop.
Immunodeficiency
Glucose-6-phosphate dehydrogenase is an enzyme that is found in all aerobic cells. Enzyme deficiency is most pronounced in erythrocytes, but in patients with G6PD deficiency, not only erythrocyte functions are affected. Neutrophils use reactive oxygen species for intra- and extracellular killing of infectious agents. Therefore, for normal functioning of neutrophils, a sufficient amount of NADPH is necessary to provide antioxidant protection to the activated cell. With NADPH deficiency, early apoptosis of neutrophils is observed, which in turn leads to an inadequate response to some infections. For example, rickettsiosis in such patients occurs in a fulminant form, with the development of disseminated intravascular coagulation syndrome and a high incidence of death. According to the literature, in in vitro studies, the induction of apoptosis in G6PD-deficient cells is significantly higher compared to controls. There is a correlation between increased apoptosis and the number of “breakages” during DNA “doubling”. However, disorders that occur when there is insufficient antioxidant protection in granulocytes and lymphocytes have been little studied.
Therapy
Treatment of patients with G6PD deficiency should be based on the principle of avoiding possible trigger factors in order to prevent the development of acute hemolysis.
Hyperbilirubinemia in newborns, as a rule, does not require a special approach to therapy. As a rule, the appointment of phototherapy gives a quick positive effect. However, in patients with G6PD deficiency, monitoring of serum bilirubin levels is necessary. If the level increases to 300 mmol/l, an exchange transfusion is indicated to prevent the development of kernicterus and the onset of irreversible disorders of the central nervous system.
Therapy for acute hemolysis in patients with G6PD deficiency does not differ from that for hemolysis of other origins. In case of massive breakdown of red blood cells, blood transfusion may be indicated to normalize gas exchange in tissues
It is very important to avoid prescribing oxidative drugs that can cause acute hemolysis and lead to worsening of the condition. When diagnosing a mutation in a heterozygous woman, it is advisable to carry out prenatal diagnosis in a male fetus.
Recommended reading
1. Ruwende C., Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria // J Mol Med 1998;76:581-8.
2. Glucose 6 phosphate dehydrogenase deficiency. Accessed July 20, 2005, at: http://www.malariasite.com/malaria/g6pd.htm.
3. Beutler E. G6PD deficiency // Blood 1994;84:3613-36.
4. Iwai K., Matsuoka H., Kawamoto F., Arai M., Yoshida S., Hirai M., et al. A rapid single-step screening method for glucose-6-phosphate dehydrogenase deficiency in field applications // Japanese Journal of Tropical Medicine and Hygiene 2003;31:93-7.
5. Reclos G.J., Hatzidakis C.J., Schulpis K.H. Glucose-6-phosphate dehydrogenase deficiency neonatal screening: preliminary evidence that a high percentage of partially deficient female neonates are missed during routine screening // J Med Screen 2000;7:46-51.
6. Kaplan M., Hammerman C., Vreman H.J., Stevenson D.K., Beutler E. Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes // J Pediatr 2001;139:137-40.
7. Corchia C., Balata A., Meloni G.F., Meloni T. Favism in a female newborn infant whose mother ingested fava beans before delivery // J Pediatr 1995;127:807-8.
8. Kaplan M., Abramov A. Neonatal hyperbilirubinemia associated with glucose-6-phosphate dehydrogenase deficiency in Sephardic-Jewish neonates: incidence, severity, and the effect of phototherapy // Pediatrics 1992;90:401-5.
9. Spolarics Z., Siddiqi M., Siegel J.H., Garcia Z.C., Stein D.S., Ong H., et al. Increased incidence of sepsis and altered monocyte functions in severely injured type A-glucose-6-phosphate dehydrogenase-deficient African American trauma patients // Crit Care Med 2001;29:728-36.
10. Vulliamy T.J., Beutler E., Luzzatto L. Variants of glucose 6-phosphate dehydrogenase are due to missense mutations spread throughout the coding region of the gene // Hum Mutat 1993; 2.159-67.
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 exhibit clinical manifestations of 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 drugs 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 assessing the results of these tests at different stages of patient observation, there may be 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.
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 enzyme defects in erythrocytes are rare.
Prevalence
Glucose-6-phosphate dehydrogenase deficiency unevenly distributed among the population of different countries: most often found in residents of European countries located on the Mediterranean coast (Italy, Greece), among Sephardic 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 enzyme of option A in erythrocytes is approximately 5 times less (13 days) than that of 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.
The incidence of different types of 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.
- 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.
- 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.
- 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: antimalarials, sulfonamide drugs, nitrofurans.
Acute intravascular hemolysis usually develops 48-96 hours after a patient takes a drug with oxidative properties.
Drugs that cause hemolysis in persons with deficiency of glucose-6-phosphate dehydrogenase activity in erythrocytes
| Drugs that cause clinically significant hemolysis | Drugs, in some cases having hemolytic effect, but not clinically causing severe hemolysis under “normal” conditions (e.g. 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 |
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, 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 an acute hemolytic crisis, the child’s general condition is severe, with severe headache and 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 be fatal. After discontinuation of the drugs causing the crisis, hemolysis gradually stops.
- 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 young children the process is especially 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.
- 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 is noted with a shift in the 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.
When the hemoglobin concentration decreases to less than 60 g/l, replacement therapy with red blood cells is carried out (quality requirements and calculation of the volume of red blood cells are presented below).
Splenectomy is used only in the development of secondary hypersplenism, since the operation does not lead to the cessation of hemolysis.
The most studied form of hereditary erythropathies. This syndrome often occurs when the patient is given certain medications, eats Vicia fava beans, or inhales the pollen of these plants (favism). The disease is widespread among residents of European countries located on the Mediterranean coast (Italy, Greece), as well as in Africa and Latin America. G-6-PD deficiency has been recorded in the former malarial regions of Central Asia and Transcaucasia, especially in Azerbaijan, where the deficiency of enzyme activity among residents is 7-8%, while in other regions of the CIS it is 0.8-2%.ETIOLOGY. A disease that develops as a result of G-6-PD deficiency in red blood cells. It is assumed that oxidizing agents, including medicinal ones, in such an erythrocyte reduce the reduced glutathione, which, in turn, creates conditions for oxidative denaturation of enzymes, hemoglobin, constituent components, and the erythrocyte membrane and entails intravascular hemolysis or phagocytosis. Currently, 59 potential hemolytics have been identified for this type of enzymopathy. The group of drugs that necessarily cause hemolysis in case of G-6-PD deficiency includes: antimalarials, sulfonamides, nitrofuran derivatives (furadonin, furatsilin, furazolidone), aniline derivatives, naphthalene and its derivatives, methylene blue, phenylhydrazine. Vaccines can cause hemolysis in patients with G6PD deficiency. The course of the disease usually worsens under the influence of intercurrent infections, especially viral ones. Hemolysis of G-6-PD-deficient erythrocytes can also be caused by endogenous intoxications and a number of plant products.
The structural gene and gene regulator that determine the synthesis of G-6-PD are located on the X chromosome, therefore the inheritance of a deficiency in the activity of this enzyme in erythrocytes is linked to the X chromosome. The location of the locus responsible for the synthesis of G-6-PD on the X chromosome is known quite accurately. G6PD deficiency is inherited as an incompletely dominant, sex-linked trait.
PATHOGENESIS. It is known that in the erythrocyte G-6-PD catalyzes the reaction: glucose-6-phosphate + NADP = 6-phosphogluconate + NADPHBN. Therefore, in erythrocytes with reduced activity of the G-6-PD enzyme, the formation of reduced nicotinamide adenine dinucleotide phosphate (NADP) and oxygen binding are reduced, as well as the rate of methemoglobin reduction is reduced and resistance to the effects of various potential oxidants - ascorbic acid, methylene blue, etc. - is reduced.
In the mechanism of destruction of erythrocytes, great importance is attached to the reduced level of reduced glutathione and NADP in these cells - substances that are essential for the life of erythrocytes. According to some authors, hemolyzing agents lead to the formation of hydrogen peroxides. The appearance of the latter occurs either as a result of a direct oxidation reaction due to the oxygen of oxyhemoglobin (HbO3), or as a result of the formation of catabolites, i.e. intermediate breakdown products that directly oxidize hemoglobin into methemoglobin and reduced glutathione into the oxidized form. The latter mechanism is influenced by the catabolites of acetylsalicylic acid, aniline, phenacetin, and sulfonamides. Both mechanisms involve hemolysis with acetylphenylhydrazine, primaquine, and hydroquine.
In normal cells, medicinal substances activate the reactions of the pentose phosphate cycle, which helps to increase the content of reduced forms of glutathione and NADP in these cells, which take part in the neutralization of oxidants. In erythrocytes with insufficient G-6-PD activity, this mechanism is absent, therefore, when exposed to oxidizing agents and certain drugs, the activity of thiol enzymes is suppressed, destructive changes in hemoglobin occur, which leads to the hemolytic process.
The direct mechanism of hemolysis appears to be an increase in the permeability of the erythrocyte membrane with respect to sodium and potassium ions. An increase in the permeability of the erythrocyte membrane to these ions may be due to a decrease in activity, as well as a direct consequence of a violation of the glutathione cycle of erythrocytes. The oldest red blood cells, in which there is a low content of G-6-PD, are the first to decompose.
CLINICAL MANIFESTATIONS. The disease can be detected in a child of any age. G-6-PD deficiency is observed predominantly in males, who, as is known, have a single X chromosome. In women, clinical manifestations are observed mainly in cases of homozygosity, i.e. in the presence of two G-6-PD-deficient chromosomes.
There are five clinical forms of G-6-PD deficiency in erythrocytes: 1) acute intravascular hemolysis - the classic form of G-6-PD deficiency. It is found everywhere, but more often among representatives of the Caucasian and Mongoloid races. Develops as a result of taking medications, vaccinations, diabetic acidosis, due to a viral infection. Manifestations of hemolysis usually begin on the 3-6th day after taking a therapeutic dose of a particular drug; 2) favism associated with eating or inhaling pollen of certain legumes (Vicia fava); 3) hemolytic disease of newborns, not associated with hemoglobinopathy, with group or Rh incompatibility, sometimes complicated by kernicterus; 4) hereditary chronic hemolytic anemia (non-spherocytic), caused by G-6-PD deficiency in erythrocytes; 5) asymptomatic form.
Among neonates with red blood cell G6PD deficiency, hyperbilirubinemia with signs of hemolytic anemia is often observed, but in these cases there is usually no evidence of serological conflict between mother and child (negative Coombs test, no isoimmune antibodies are detected). The disease can be benign when hyperbilirubinemia does not reach a critical level and decreases along with the subsidence of the intensity of the hemolytic process. In more severe cases, bilirubin encephalopathy may develop.
In older children, G6PD deficiency may manifest itself in the form of chronic (nonspherocytic) hemolytic anemia, which usually worsens under the influence of intercurrent infections and after taking medications. A more common form of manifestation of this hereditary defect is hemolytic crises after taking medications in apparently healthy children. Acute hemolysis that occurs after taking medications leads to severe anemia, and hemoglobinuria is less common. Despite the relatively favorable course in most cases, some patients experience severe complications in the form of anuria and hypovolemic shock. In typical cases, the general condition of the child is severe, the skin is yellow in color. High fever, severe headache, and general weakness are noted. Repeated vomiting mixed with bile and loose, intensely colored stool may occur. There may be an enlargement of the liver, and less commonly, the spleen. In the peripheral blood, anemia with reticulocytosis and leukocytosis with a shift to myelocytes are expressed. Aniso-, poikilocytosis is noted, fragments of erythrocytes (schizocytes), polychromasia, basophilic punctuation of erythrocytes are visible.
A characteristic sign of intravascular hemolysis is hyperhemoglobinemia; when standing, the blood serum becomes brown due to the formation of methemoglobin. Hyperbilirubinemia is also observed at the same time. The content of bile pigments in the duodenal contents and in feces increases; urine may be the color of black beer or a strong solution of potassium permanganate, which is due to the release of hemoglobin, methemoglobin, as well as hemosiderin and urobilin. In very severe cases, anuria develops as a result of blockage of the renal tubules by blood and protein clots (“hemolytic kidney”), and sometimes microobstruction of the nephron with uremia, the development of disseminated intravascular coagulation syndrome and death is observed. An unfavorable outcome can also occur from coma, when, due to the rapid breakdown of red blood cells, vomiting of bile and a collapsed state develop. Hemolytic crisis immediately after birth may be accompanied by kernicterus with severe neurological symptoms.
Among the characteristic laboratory signs inherent in enzymopenic hemolytic anemia, it is necessary to note a decrease in hematocrit, hemoglobin and red blood cells, an increase in the concentration of bilirubin in the blood due to unconjugated bilirubin, hyperhemoglobinemia, hypohaptoglobinemia.
In the bone marrow, as in other hemolytic anemias, reactive hyperplasia of the erythrocyte lineage is detected, the cells of which in severe cases account for 50-70% of the total number of myelokaryocytes.
A special form of manifestation of enzymatic deficiency of erythrocytes is favism, in which hemolytic crises occur in patients when eating Vicia fava beans or even when inhaling the pollen of these plants. It has been established that some cases of favism are also caused by hereditary G-6-PD deficiency. As a result of clinical and experimental observations, it was found that the time interval between coming into contact with faba beans and the appearance of symptoms of the disease ranges from several hours to several days. In contrast, the interval between taking the drug and hemolysis of people with G-6-PD deficiency is 2-3 days.
Favism can occur upon first contact with beans or is observed in individuals who previously consumed these beans, but did not have any manifestations of the disease. Recurrences of favism are not uncommon; familial diseases of this type of hemolytic anemia have been recorded.
The nature of the substances contained in beans that cause a hemolytic crisis in individuals with G-6-PD deficiency has not yet been fully disclosed. It has been suggested that hemolysis is caused by plant pyrimidines - vicin, convicin, devicin, which, when entering the body, contribute to a catastrophic drop in the concentration of reduced glutathione and sulfhydryl groups in the red blood cell. Favism mainly affects children aged 1 to 14 years; the process is especially severe in young children, who make up approximately half of all patients. The ratio of boys and girls with favism is 7:1, which is explained by the peculiarities of hereditary transmission of G-6-PD deficiency of erythrocytes with the sex (X) chromosome.
The clinical picture of favism is very variable - from symptoms of mild hemolysis to hyperacute severe hemoglobinuric crisis. The development of a crisis may be preceded by prodromal phenomena in the form of weakness, chills, fever, headache, drowsiness, lower back pain, abdominal pain, nausea, and vomiting.
Acute hemolytic crisis is characterized by pallor, jaundice and hemoglobinuria. An objective examination reveals an enlarged liver, spleen, displacement of the borders of the heart and the appearance of anemic murmurs.
In hospitalized patients, there is a sharp decrease in the number of red blood cells in the peripheral blood, in most cases this figure is 1-2 10 / l. Patients with favism often exhibit pathological changes in the urine. Hemoglobinuria is detected within 1-3 days; longer hemoglobinuria usually does not occur. Sometimes large amounts of oxyhemoglobin and methemoglobin are found, due to which the urine becomes dark brown, red or even black. In severely ill patients, oliguria or even anuria with concomitant azotemia may occur. Kidney failure can be fatal.
The diagnosis of G6PD deficiency in erythrocytes should be based on direct determination of enzyme activity, which is currently available to many laboratories. As a preliminary study, especially in mass analyses, a semi-quantitative study of the enzyme by various methods based on a change in the color of the medium as a result of the enzyme reaction (Motulsky and Campbell, Bernstein, Fairbanks and Beutler test, etc.) is permissible. In special cases, it is advisable to use other methods - tests for the reduction of methemoglobin, for the stability of reduced glutathione in erythrocytes, for the formation of Heinz bodies, enzyme electrophoresis, etc. To confirm the hereditary nature of the disease, a study of G-6-PD activity should also be carried out in the patient’s relatives .
The differential diagnosis of enzymopenic hemolytic anemia is carried out primarily with viral hepatitis, then with hereditary microspherocytosis and immune forms of hemolytic anemia. At the second stage, the type of enzyme that is absent or reduced in its activity is clarified.
TREATMENT. Therapy for hemolytic anemia in children begins as soon as increased hemolysis is detected. Treatment of acute hemolytic crisis due to G-6-PD deficiency involves discontinuation of the drug that caused hemolysis.
In case of a mild hemolytic crisis with a slight decrease in hemoglobin, mild jaundice and hyperbilirubinemia, antioxidants (Revit, vitamin E preparations) are prescribed. Drugs are used that help increase reduced glutathione in erythrocytes, the amount of which decreases during hemolytic crises, xylitol 0.25-0.5 g 3 times a day with riboflavin - 0.6-1.5 mg per day with 3 oral doses . At the same time, phenobarbital (or zixorine) is given in a daily dose, depending on the age of children, 0.005-0.01 g for 10 days. Phenobarbital, having a bilirubin-conjugating effect, induces the glucuronyltransferase system of the liver.
In severe hemolytic crises with pronounced signs of intravascular hemolysis, prevention of acute renal failure is necessary. Depending on age, a 1-4% sodium bicarbonate solution is administered intravenously at a rate of 5 ml per 1 kg of body weight per day, which prevents the development of metabolic acidosis and acts as a weak diuretic that promotes the elimination of hemolysis products. As a weak diuretic and antiplatelet agent that improves renal function, a 2.4% solution of aminophylline is used intravenously at the rate of 4-6 mg per 1 kg per day in 250-500 ml of isotonic sodium chloride solution. Forced diuresis is supported by a 10% solution of mannitol (1 g per 1 kg of body weight). In case of threat of DIC syndrome, heparinized cryoplasma is prescribed from 5 to 10 ml per 1 kg of body weight per day. Heparinization is carried out by introducing heparin into a container with thawed plasma at the rate of 1 unit for each milliliter of injected plasma.
Red blood cell transfusions are used only in cases of severe anemia. In cases of prolonged anuria, the use of extracorporeal dialysis is indicated. In the neonatal period, with hyperbilirubinemia, it is necessary to perform a replacement blood transfusion to prevent kernicterus.
Clinical examination of patients with hemolytic anemia as a result of G-6-PD deficiency should be carried out in hematological centers. Prevention of manifestations of the hereditary G-6-PD defect includes its timely recognition, which makes it possible to prevent the prescription of potentially dangerous drugs. Eating fava beans is prohibited. It is necessary to protect the child from intercurrent infections.
(+38 044) 206-20-00
If you have previously performed any research, Be sure to take their results to a doctor for consultation. If the studies have not been performed, we will do everything necessary in our clinic or with our colleagues in other clinics.
You? It is necessary to take a very careful approach to your overall health. People don't pay enough attention symptoms of diseases and do not realize that these diseases can be life-threatening. There are many diseases that at first do not manifest themselves in our body, but in the end it turns out that, unfortunately, it is too late to treat them. Each disease has its own specific signs, characteristic external manifestations - the so-called symptoms of the disease. Identifying symptoms is the first step in diagnosing diseases in general. To do this, you just need to do it several times a year. be examined by a doctor, in order not only to prevent a terrible disease, but also to maintain a healthy spirit in the body and the organism as a whole.
If you want to ask a doctor a question, use the online consultation section, perhaps you will find answers to your questions there and read self care tips. If you are interested in reviews about clinics and doctors, try to find the information you need in the section. Also register on the medical portal Eurolab to keep abreast of the latest news and information updates on the site, which will be automatically sent to you by email.
Other diseases from the group Diseases of the blood, hematopoietic organs and certain disorders involving the immune mechanism:
| B12 deficiency anemia |
| Anemia caused by impaired synthesis and utilization of porphyrins |
| Anemia caused by a violation of the structure of globin chains |
| Anemia characterized by the carriage of pathologically unstable hemoglobins |
| Fanconi anemia |
| Anemia associated with lead poisoning |
| Aplastic anemia |
| Autoimmune hemolytic anemia |
| Autoimmune hemolytic anemia |
| Autoimmune hemolytic anemia with incomplete heat agglutinins |
| Autoimmune hemolytic anemia with complete cold agglutinins |
| Autoimmune hemolytic anemia with warm hemolysins |
| Heavy chain diseases |
| Werlhof's disease |
| von Willebrand disease |
| Di Guglielmo's disease |
| Christmas disease |
| Marchiafava-Miceli disease |
| Randu-Osler disease |
| Alpha heavy chain disease |
| Gamma heavy chain disease |
| Henoch-Schönlein disease |
| Extramedullary lesions |
| Hairy cell leukemia |
| Hemoblastoses |
| Hemolytic-uremic syndrome |
| Hemolytic-uremic syndrome |
| Hemolytic anemia associated with vitamin E deficiency |
| Hemolytic disease of the fetus and newborn |
| Hemolytic anemia associated with mechanical damage to red blood cells |
| Hemorrhagic disease of the newborn |
| Malignant histiocytosis |
| Histological classification of lymphogranulomatosis |
| DIC syndrome |
| Deficiency of K-vitamin-dependent factors |
| Factor I deficiency |
| Factor II deficiency |
| Factor V deficiency |
| Factor VII deficiency |
| Factor XI deficiency |
| Factor XII deficiency |
| Factor XIII deficiency |
| Iron-deficiency anemia |
| Patterns of tumor progression |
| Immune hemolytic anemias |
| Bedbug origin of hemoblastoses |
| Leukopenia and agranulocytosis |
| Lymphosarcoma |
| Lymphocytoma of the skin (Caesary disease) |
| Lymphocytoma of the lymph node |
| Lymphocytoma of the spleen |
| Radiation sickness |
| March hemoglobinuria |
| Mastocytosis (mast cell leukemia) |
| Megakaryoblastic leukemia |
| The mechanism of inhibition of normal hematopoiesis in hemoblastoses |
| Obstructive jaundice |
| Myeloid sarcoma (chloroma, granulocytic sarcoma) |
| Myeloma |
| Myelofibrosis |
| Disorders of coagulation hemostasis |
| Hereditary a-fi-lipoproteinemia |
| Hereditary coproporphyria |
| Hereditary megaloblastic anemia in Lesch-Nyan syndrome |
| Hereditary hemolytic anemia caused by impaired activity of erythrocyte enzymes |
| Hereditary deficiency of lecithin-cholesterol acyltransferase activity |
| Hereditary factor X deficiency |
| Hereditary microspherocytosis |
| Hereditary pyropoikilocytosis |
| Hereditary stomatocytosis |
| Hereditary spherocytosis (Minkowski-Choffard disease) |
| Hereditary elliptocytosis |
| Hereditary elliptocytosis |
| Acute intermittent porphyria |
| Acute posthemorrhagic anemia |
| Acute lymphoblastic leukemia |
| Acute lymphoblastic leukemia |
| Acute lymphoblastic leukemia |
| Acute low-grade leukemia |
| Acute megakaryoblastic leukemia |
| Acute myeloid leukemia (acute non-lymphoblastic leukemia, acute myelogenous leukemia) |
| Acute monoblastic leukemia |