Pyruvate kinase deficiency
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A newborn has jaundice severe enough to need exchange transfusion. By age 4 she has a chronic anemia with splenomegaly, an elevated reticulocyte count, and gallstones. The blood film shows no spherocytes, and osmotic fragility is normal. She looks better than her hemoglobin of 7 g/dL would suggest.
- Autosomal recessive, PKLR (the erythrocyte and liver isoform)
- The most common enzyme defect of glycolysis causing hereditary nonspherocytic hemolytic anemia
- Most affected people are compound heterozygotes, which is part of why severity varies so widely, from transfusion dependence to a well-compensated anemia found in adulthood
Pyruvate kinase catalyses the last ATP-generating step of glycolysis. The mature red cell has no mitochondria, so glycolysis is its only source of ATP. Without it the cell cannot maintain its membrane and is destroyed, mostly in the spleen.
The block also causes 2,3-bisphosphoglycerate to accumulate upstream. 2,3-BPG right-shifts the oxygen dissociation curve, so haemoglobin releases oxygen more readily to tissues. This is why these patients tolerate a given haemoglobin better than expected and why transfusion thresholds are set by symptoms rather than by number.
- Chronic hemolytic anemia of highly variable severity
- Neonatal jaundice, sometimes requiring exchange transfusion; hydrops in severe cases
- Splenomegaly, cholelithiasis from chronic hemolysis, often in childhood
- Iron overload even without transfusion, driven by ineffective erythropoiesis, so ferritin must be monitored in every patient
- Aplastic crisis with parvovirus B19 infection
- Pyruvate kinase enzyme assay, with two traps: reticulocytes are enzyme-rich so a high reticulocyte count can mask a deficiency, and a recent transfusion measures the donor's enzyme rather than the patient's
- PKLR sequencing, which is now often the first-line test and avoids both traps
- Blood film: nonspecific, no spherocytes; echinocytes may appear after splenectomy
- Normal osmotic fragility, which separates it from hereditary spherocytosis
Against the other common red cell enzymopathy
| Pyruvate kinase deficiency | G6PD deficiency | |
|---|---|---|
| Inheritance | Autosomal recessive | X-linked |
| Pattern | Chronic, ongoing | Episodic, triggered |
| Trigger | None needed | Oxidative stress: drugs, fava beans, infection |
| Film | Nonspecific | Bite cells, Heinz bodies |
| Pathway | Glycolysis (ATP) | Pentose phosphate (NADPH) |
- Folic acid supplementation for chronic hemolysis
- Transfusion guided by symptoms and growth rather than a fixed haemoglobin threshold, given the 2,3-BPG effect
- Splenectomy reduces transfusion requirement in severe disease; give the usual pre-splenectomy vaccinations and counsel on lifelong sepsis risk
- Monitor iron and chelate as needed, including in patients who have never been transfused
- Mitapivat, an oral pyruvate kinase activator, is approved for adults and raises haemoglobin in many non-transfusion-dependent patients
- Cholecystectomy for symptomatic gallstones
- Nonspherocytic hemolytic anemia with normal osmotic fragility and no oxidative trigger should raise pyruvate kinase deficiency.
- Check the reticulocyte count and transfusion history before trusting a normal enzyme assay. Both push the result toward normal in a genuinely affected patient.
- Iron overload is not only a transfusion problem here. Patients who have never been transfused still load iron, and it is a common oversight.