Pyruvate Kinase Deficiency

What pyruvate kinase deficiency is

Mature red blood cells have no nucleus or mitochondria, so they make all their energy (ATP) by breaking down glucose through a pathway called glycolysis. Pyruvate kinase controls the final step. Without enough of it, red cells run short of ATP. They cannot maintain their shape, water and salt balance, and become stiff and dehydrated. The spleen recognizes and removes them early, a process called hemolysis.

PK deficiency is the most common enzyme defect of glycolysis that causes hemolytic anemia. It is rare, estimated to affect somewhere around 1 in 20,000 to 1 in 300,000 people, and is more common among the Old Order Amish in Pennsylvania.

One quirk helps: the blocked pathway causes a buildup of a molecule (2,3-BPG) that helps red cells release oxygen to tissues. As a result, many people tolerate low hemoglobin levels better than expected.

How it is inherited

PK deficiency is autosomal recessive. The gene responsible is PKLR.

• People with one faulty copy are carriers and are healthy.
• When both parents are carriers, each pregnancy has a 25% chance of an affected child, a 50% chance of a carrier, and a 25% chance of neither.
• Brothers and sisters of an affected person should be offered testing.

Symptoms

Severity varies widely, even among siblings, and depends on the specific gene changes.

• Newborns: severe neonatal jaundice that may need phototherapy or exchange transfusion; severe cases are detected before birth with fetal anemia or swelling (hydrops)
• Children and adults: tiredness, pale skin, yellow skin or eyes, shortness of breath on exertion
• Enlarged spleen, sometimes felt as fullness under the left ribs
• Gallstones, from the bilirubin released by broken-down red cells, often from childhood
• Slow growth or delayed puberty in severely affected children
• Iron overload, even without transfusions, because the body absorbs more iron when red cell production is increased
• Other complications: leg ulcers, bone thinning, extramedullary hematopoiesis (blood formation outside the bone marrow) and, rarely, pulmonary hypertension

Crises

Infections can temporarily worsen anemia. Parvovirus B19 (fifth disease) can shut down red cell production for 1 to 2 weeks, causing a dangerous aplastic crisis. Pregnancy also often worsens anemia.

Diagnosis

1. Blood count and smear: anemia with high reticulocytes (young red cells). Unlike hereditary spherocytosis, the red cells are not spherical, and some may look prickly.
2. Signs of hemolysis: raised bilirubin and LDH, low haptoglobin, negative direct antiglobulin (Coombs) test, which rules out immune causes.
3. PK enzyme activity test: low activity confirms the diagnosis. It can be falsely normal for up to about 3 months after a transfusion, because donor cells contain normal enzyme.
4. Genetic testing of PKLR: confirms the diagnosis, is not affected by transfusion, and allows family testing. Often done as part of a hemolytic anemia gene panel.
5. Iron studies and liver MRI to measure iron overload.

Other causes to exclude include G6PD deficiency, thalassemia, hereditary spherocytosis and unstable hemoglobins.

Treatment

There is no cure other than a stem cell transplant, which is rarely used because of its risks. Care is supportive and tailored to severity, ideally with a hematologist experienced in rare anemias.

Supportive care

• Folic acid supplements, because red cell production is high
• Vaccines, including pneumococcal, meningococcal and Hib vaccines before splenectomy
• Regular monitoring of blood counts, iron, growth, gallbladder and bone health

Red blood cell transfusions

Used during infancy, crises, pregnancy and in severely affected people who need regular transfusions to grow and function. Decisions are based on symptoms and quality of life, not hemoglobin alone.

Splenectomy

Removing the spleen reduces red cell destruction and often raises hemoglobin by about 1 to 3 g/dL, reducing or ending transfusion needs. It is usually delayed until after age 5 because of the infection risk in young children. Afterwards, there is a lifelong risk of severe infections and a higher risk of blood clots. People need vaccines, sometimes daily antibiotics, and urgent care for any fever.

Iron chelation

Iron overload is common, even in people who are never transfused. Medicines that remove iron (deferasirox, deferoxamine, deferiprone) prevent damage to the liver, heart and hormone glands.

Mitapivat

Mitapivat (Pyrukynd) is an oral medicine that activates the remaining pyruvate kinase in red cells. Approved by the FDA in 2022 for adults with PK deficiency, it raises hemoglobin and reduces transfusion needs in many patients. It does not work in people with two gene changes that produce no functional enzyme at all, and it must be stopped gradually under medical supervision because sudden stopping can trigger hemolysis.

Gallbladder removal

Cholecystectomy is recommended for symptomatic gallstones, and often done at the same time as splenectomy if gallstones are present.

Outlook

Most people with PK deficiency live into adulthood and have families and careers. Long-term health depends on severity and on preventing complications, especially iron overload and post-splenectomy infections. Newer treatments, including mitapivat and gene therapy under study, are improving the outlook.

Frequently asked questions

Is pyruvate kinase deficiency life-threatening?

It can be in its most severe forms, especially before birth or in infancy, and through complications such as severe infections after splenectomy or untreated iron overload. With modern care, most people live into adulthood. Mild cases may cause only tiredness and jaundice.

How is PK deficiency inherited?

It is autosomal recessive. A person must inherit a faulty PKLR gene from both parents to have the disease. Carriers with one faulty copy are healthy. Two carrier parents have a 1 in 4 chance of an affected child in each pregnancy.

Can adults be diagnosed with PK deficiency?

Yes. People with mild disease may reach adulthood before diagnosis, often after gallstones, unexplained jaundice, an enlarged spleen or iron overload are investigated. Genetic testing is particularly useful in adults who have received transfusions, since enzyme tests can be misleading afterward.

Why do people with PK deficiency get iron overload without transfusions?

Ongoing red cell destruction drives the bone marrow to work harder, and the body responds by lowering hepcidin, the hormone that limits iron absorption from food. More iron is absorbed than needed, and it slowly builds up in the liver and heart. Regular monitoring catches this early.

What is the newest treatment for PK deficiency?

Mitapivat, approved in 2022 for adults, is the first medicine that targets the enzyme defect itself. Taken by mouth twice daily, it boosts the activity of the remaining pyruvate kinase, raising hemoglobin and reducing transfusions in many people. Gene therapy is being studied in clinical trials.