Pyruvate Kinase Deficiency

Pyruvate kinase (PK) deficiency is an autosomal recessive enzymopathy of glycolysis causing chronic non spherocytic haemolytic anaemia.

• PKLR mutations, most common red cell enzyme defect after G6PD; prevalence about 1 in 20,000 in white populations.
• ATP depletion leads to rigid red cells destroyed in the spleen; raised 2,3 DPG gives right shifted oxygen dissociation curve so patients tolerate anaemia well.
• Severity ranges from hydrops fetalis and neonatal exchange transfusion to compensated adult haemolysis.
• Complications: iron overload (even without transfusion), gallstones, extramedullary haematopoiesis, pulmonary hypertension, osteopenia.

• Neonatal jaundice, chronic anaemia, jaundice, splenomegaly.
• Aplastic crisis (parvovirus), haemolytic crises with infection.
• Leg ulcers, growth impairment, gallstones, delayed puberty.

• Anaemia (haemoglobin 6 to 10 g/dL), reticulocytosis (marked after splenectomy), echinocytes, normal osmotic fragility, negative direct antiglobulin test.
• PK enzyme activity assay (low), after leucocyte removal and transfusion washout.
• PKLR sequencing.
• Ferritin, liver iron MRI, ultrasound for gallstones.
• Exclude hereditary spherocytosis, G6PD deficiency, other enzymopathies.

• Supportive: folic acid 1 to 5 mg daily, transfusion for severe anaemia or crises, phototherapy and exchange transfusion in neonates.
• Mitapivat (PK activator) 5 mg twice daily, titrated to 20 mg and 50 mg twice daily, raises haemoglobin by 1.5 g/dL or more in about 50% of non transfused adults; monitor liver tests and bone density.
• Splenectomy for transfusion dependence or severe symptoms (reduces transfusion need in most; thrombotic risk, vaccinate beforehand, penicillin prophylaxis; delay until age 5 or older).
• Cholecystectomy at the time of splenectomy if gallstones.
• Iron chelation (deferasirox 20 mg/kg daily) according to liver iron and ferritin even in non transfused patients.
• Stem cell transplant in severe transfusion dependent cases.
• Genetic counselling; avoid oxidant drugs unnecessary.