Pyruvate Kinase Deficiency

Definition and Pathophysiology

Pyruvate kinase deficiency (PKD) is the most frequent enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia, characterized by ATP depletion in red blood cells leading to chronic hemolysis of variable severity 1, 2
PKD is an autosomal recessive disorder caused by mutations in the PKLR gene, resulting in defective pyruvate kinase enzyme activity 3, 4
The enzyme catalyzes one of the two major steps of ATP production in red blood cells, converting phosphoenolpyruvate to pyruvate while generating ATP 2, 4
Since mature RBCs lack mitochondria, they are completely dependent on glycolysis for ATP production to maintain cell integrity and critical functions 4, 5
PKD leads to ATP depletion, affecting cell viability, and causes accumulation of glycolytic intermediates up to 3-fold normal levels 2, 6
Increased 2,3-DPG causes a rightward shift in the oxygen dissociation curve, allowing patients to tolerate anemia better than expected 7

PKD has a worldwide geographical distribution with no precise prevalence figures 2, 8
Estimated prevalence in Caucasian populations ranges from 1:100,000 to 5:100,000 4, 8
Over 600 families and more than 300 mutations in the PKLR gene have been reported in the literature 5, 9

Four PK isozymes exist in mammalian tissues 2, 4
The L-type and R-type isozymes are encoded by the PKLR gene under tissue-specific promoters 4, 6
The M1 and M2 isozymes are encoded by the PKM gene through alternative mRNA splicing 4, 6
During erythroid differentiation, the M2 isoenzyme is progressively replaced by the R-type isoform 4, 6
PKD is transmitted as an autosomal recessive trait, with clinical symptoms confined to compound heterozygous and homozygous patients 2, 4

Common manifestations include chronic hemolytic anemia of variable severity, jaundice, and gallstones 5, 10
Severe cases may present with neonatal indirect hyperbilirubinemia 10
Complications can include iron overload and bilirubin gallstones 7, 10

PKD should be suspected in patients with variable chronic anemia, splenomegaly, and/or jaundice 10
Diagnostic approach includes complete blood count, RBC morphology, markers of hemolysis, and PK enzyme activity assay by spectrophotometry 10
Blood testing for PK enzyme activity should be delayed at least 50 days after transfusion to minimize the effect of donor red cells 7

Patients with PKD require irradiated blood components to prevent transfusion-associated graft-versus-host disease 7
Regular monitoring is essential, with hematology visits at least every 6 months regardless of transfusion status

Patients with PKD may tolerate anemia better than expected due to increased 2,3-DPG levels 7