Pyruvate kinase deficiency

Doctors think of pyruvate kinase (PK) deficiency in a newborn with severe jaundice that has no clear cause. They also think of it in a child or adult with long-term anemia, jaundice or a large spleen, or in anyone who needs transfusions for no clear reason. First tests include a complete blood count, a reticulocyte (young red cell) count and markers of red cell breakdown, such as bilirubin, LDH and haptoglobin. Other tests rule out immune causes and other red cell disorders.

The key test measures PK enzyme activity in red blood cells. Results usually come back in 2 to 10 working days. Donor cells from a recent transfusion can make the result look falsely normal. Experts consider waiting at least 50 days after the last transfusion a safe gap before testing. A genetic test of the PKLR gene, alone or as part of a panel for inherited anemias, confirms the diagnosis. Genetic testing is also the more reliable way to find carriers in the family.

PK deficiency is not part of routine U.S. newborn screening. People who are rarely or never transfused are often diagnosed as adults. Their anemia may first be mistaken for iron deficiency, thalassemia trait or another, more common anemia. In up to 10 of every 100 people, standard gene tests find only one changed copy, and further testing may be needed.

Transfusion decisions consider symptoms and overall health. Iron chelation may be used when iron accumulates, with monitoring of the liver and other organs as appropriate.

Splenectomy can reduce red-cell destruction in selected patients, but it does not correct the enzyme defect. It carries long-term infection and clotting risks and may not eliminate transfusion needs.

Mitapivat, marketed as Pyrukynd, is approved for adults with pyruvate kinase deficiency in the United States and, since November 2022, in the European Union. It activates pyruvate kinase, but it does not work for everyone. The US label says its safety and effectiveness in children have not been established.

Allogeneic transplantation has been used in a small number of severely affected people. Its potential to correct blood production has to be weighed against graft failure, graft-versus-host disease and treatment-related death. It is not routine treatment for everyone needing transfusions.

PK deficiency ranges from severe anemia that starts before birth to anemia so mild it causes no symptoms. Some people need regular transfusions from birth into old age. Anemia tends to improve with age and is fairly steady in adulthood. People with two severe (non-missense) gene changes are more likely to have severe disease, but gene results do not predict everything.

Long-term health depends a great deal on finding and treating complications. Iron overload and gallstones are common, even in people with mild anemia or few transfusions. Other problems can include thin bones, high blood pressure in the lungs and leg ulcers. Experts advise checking iron in everyone with PK deficiency, starting in childhood. Infections and pregnancy can cause sudden drops in blood counts.

A donor stem cell transplant has been used in very few people. In a worldwide study of the 16 known cases, survival was better in children transplanted before age 10. The authors said needing transfusions is not, by itself, a reason for transplant. A medicine called mitapivat is approved for adults in the U.S. and the EU, and studies in children are still under way. No number can predict one person’s course.