Pyruvate kinase deficiency: causes, symptoms, diagnosis, treatment

Deficiency of pyruvate kinase activity is the second most common cause of hereditary hemolytic anemia after G6PD deficiency. It is inherited in an autosomal recessive manner, manifests itself as chronic hemolytic (non-spherocytic) anemia, occurs with a frequency of 1:20,000 in the population, and is observed in all ethnic groups.

Pathogenesis of pyruvate kinase deficiency

Due to the deficiency of pyruvate kinase in the erythrocyte, a block of glycolysis occurs, which leads to insufficient generation of adenosine triphosphate (ATP). As a result of the decrease in the level of ATP in the mature erythrocyte, the transport of cations is disrupted - the loss of potassium ions and the absence of an increase in the concentration of sodium ions in the erythrocyte, as a result of which the concentration of monovalent ions decreases and dehydration of the cell occurs.

Pyruvate kinase is one of the main enzymes of the glycolytic pathway. Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate to pyruvate and thus participates in the glycolytic reaction of ATP (adenosine triphosphate) formation. The enzyme is allosterically activated by fructose-1,6-diphosphate (F-1,6-DP) and inhibited by the resulting ATP. With pyruvate kinase deficiency, 2,3-diphosphoglycerate and other glycolysis products accumulate in erythrocytes. The concentration of ATP, pyruvate and lactate in erythrocytes is reduced. Paradoxically, the concentration of adenosine monophosphate (AMP) and ADP in erythrocytes is also reduced mainly due to the dependence of ATP on phosphoribosyl pyrophosphate synthetase and other enzymes involved in the synthesis of adenine nucleotides. ATP deficiency also affects the synthesis of nicotinamide adenine dinucleotide (NAD). Since the rate of glycolysis is limited by the availability (quantity) of NAD, insufficient NAD synthesis contributes to a further decrease in ATP formation and provokes hemolysis of red blood cells. The disease is inherited in an autosomal recessive manner.

Diagnosis of pyruvate kinase deficiency

Based on the determination of pyruvate kinase activity in erythrocytes, as a rule, the activity is reduced to 5-20% of the norm. To confirm the hereditary nature of the disease, it is necessary to examine the parents and relatives of patients.

Hematological parameters

A general blood test reveals signs of hemolytic nonspherocytic anemia:

• hemoglobin concentration - 60-120 g/l;
• hematocrit - 17-37%;
• normochromia;
• normocytosis (in children under one year of age and with high reticulocytosis, macrocytosis is possible);
• reticulocytes 2.5-15%, after splenectomy - up to 70%;
• morphological features:
  • polychromasia of erythrocytes;
  • anisocytosis;
  • poikilocytosis;
  • the presence of normoblasts is possible.

The osmotic resistance of erythrocytes before incubation is not changed, after incubation it is reduced, and is corrected by the addition of ATP.

Autohemolysis is significantly increased and is corrected by the addition of ATP, but not glucose.

The activity of erythrocyte pyruvate kinase is reduced to 5-20% of normal, the content of 2,3-diphosphoglycerate and other intermediate metabolites of glycolysis is increased by 2-3 times; due to the increase in the content of 2,3-diphosphoglycerate, the oxygen dissociation curve is shifted to the right (the affinity of hemoglobin for oxygen is reduced).

The screening test is based on the fluorescence of NADH under ultraviolet light: phosphoenolpyruvate, NADH and lactate dehydrogenase are added to the blood being tested, applied to filter paper and examined under ultraviolet light. In the case of pyruvate kinase deficiency, pyruvate is not formed and NADH is not used, as a result of which fluorescence persists for 45-60 minutes. Normally, fluorescence disappears after 15 minutes.

Symptoms of Pyruvate Kinase Deficiency

The disease can be detected at any age, but most often manifests itself in the first years of a child's life. The severity of the condition varies, severe anemia may be observed, not induced by taking medications. Jaundice usually develops from birth. Hemolysis is localized intracellularly, occurs uniformly in various organs containing reticuloendothelial cells. Patients have pale skin, jaundice, splenomegaly. Splenomegaly is almost always present. With age, cholelithiasis, secondary iron overload and changes in skeletal bones (due to frequent transfusions of red blood cells) develop. Aplastic crises are provoked by parvovirus B19 infection.

Treatment of pyruvate kinase deficiency

Folic acid 0.001 g/day daily.

Replacement therapy with red blood cells to maintain hemoglobin levels above 70 g/l.

Splenectomy is used only when the need for red blood cell transfusions increases above 200-220 ml/kg per year (with red blood cell Ht of 75%), splenomegaly accompanied by pain in the left hypochondrium and/or the threat of spleen rupture, as well as in cases of hypersplenism. Before surgical treatment, the patient must be vaccinated against meningococcal, pneumococcal and Haemophilus influenzae type B infection.

It is undesirable to use salicylates, since under conditions of pyruvate kinase deficiency, salicylates provoke a disruption of oxidative phosphorylation in mitochondria.

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