Pyruvate kinase deficiency: causes, symptoms, diagnosis, treatment

The deficiency in pyruvate kinase activity is the second most frequent cause of hereditary hemolytic anemia after the G-6-PD deficiency. It is inherited autosomally recessively, manifested by chronic hemolytic (nesferocytic) anemia, occurs at a frequency of 1:20 000 in the population, observed in all ethnic groups.

Pathogenesis of pyruvate kinase deficiency

Due to the insufficiency of pyruvate kinase in the erythrocyte, a glycolysis block appears, which leads to insufficient generation of adenosine triphosphate (ATP). As a result of the decrease in the level of ATP in the mature erythrocyte, cation transport is lost - the loss of potassium ions and the absence of an increase in the concentration of sodium ions in the erythrocyte, resulting in a decrease in the concentration of monovalent ions and dehydration of the cell.

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 the formation of ATP (adenosine triphosphate). The enzyme is allosteric activated by fructose-1,6-diphosphate (P-1,6-DF) and is inhibited by the formed ATP. With a deficiency of pyruvate kinase in erythrocytes, 2,3-diphosphoglycerate and other glycolysis products accumulate. 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. Deficiency of ATP also affects the synthesis of nicotinamide adenine dinucleotide (NAD). Since the level of glycolysis is limited by the availability (amount) of NAD, inadequate synthesis of NAD promotes further reduction of ATP formation and provokes hemolysis of red blood cells. The disease is inherited by autosomal recessive type.

Diagnosis of pyruvate kinase deficiency

It is based on the determination of the activity of pyruvate kinase in erythrocytes, as a rule, 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 the patients.

Hematologic indices

In the general blood test, signs of hemolytic nonsferocytic anemia are found:

• the concentration of hemoglobin is 60-120 g / l;
• hematocrit - 17-37%;
• normochromy;
• normocytosis (in children up to a year 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.

Osmotic resistance of erythrocytes before incubation is not changed, after incubation is reduced, corrected by the addition of ATP.

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

Activity of pyruvate kinase of erythrocytes 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 an 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 NADH fluorescence in ultraviolet light: phosphoenolpyruvate, NADH and lactate dehydrogenase are added to the test blood, applied to filter paper and examined in ultraviolet light. With pyruvate kinase deficiency pyruvate is not formed, and NADH is not used, as a result, fluorescence persists for 45-60 minutes. Normally, the fluorescence disappears after 15 minutes.

Symptoms of pyruvate kinase deficiency

The disease can be detected at any age, but more often manifests itself in the first years of a child's life. The severity of the condition varies, anemia may be severe, not induced by medication. Jaundice usually develops from birth. Hemolysis is localized intracellularly, occurs evenly in various organs containing reticuloendothelial cells. In patients, paleness of the skin, jaundice, splenomegaly is revealed. Almost always there is splenomegaly. With age, gallstone disease develops, a secondary iron overload and a change in the bones of the skeleton (due to frequent transfusions of the erythrocyte mass). Aplastic crises are provoked by parvovirus B19 infection.

Treatment of pyruvate kinase deficiency

Folic acid is 0.001 g / day daily.

Substitution therapy with erythrocyte mass to maintain a hemoglobin level of more than 70 g / l.

Splenectomy is used only when the need for transfusions of erythrocyte mass exceeds 200-220 ml / kg per year (with Ht of erythrocyte mass of 75%), splenomegaly accompanied by pain in the left hypochondrium and / or threat of rupture of the spleen, as well as hypersplenism phenomena. Before the surgical treatment it is necessary to vaccinate the patient against meningococcal, pneumococcal and hemophilic infection of type B.

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

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