Pyruvate kinase deficiency

A rare inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells.

Associated with chronic hemolytic anemia.

Both autosomal dominant and recessive inheritance have been observed with the disorder.

Typically, the inheritance is autosomal recessive.

Autosomal recessive enzymopathy in RBCs.

It has no significant carrier state manifestations so often, no sign of it is found in a family before someone in the family is born with it.

Most patients have compound heterozygous mutations in the gene encoding the L and R isozymes of pyruvate kinase (PKLR), with more than 300 mutations.

Red blood cell pyruvate kinase deficiency results in impaired glucose utilization and reduced ATP generation in red cells, which leads to compromised red cell membrane homeostasis and hemolysis.

Reduced ATP production in red cells shortens their lifespan and causes hemolysis.

The prevalence of pyruvate kinase deficiency is around 51 cases per million in the population.

The prevalence of clinically heterogeneous disease is estimated to be between 3.2 and 8.5 cases per million among Western countries.

An estimated 1 to 3000 people in the US have PK deficiency, correlating to a prevalence of one and 100,000 to 1 and 300,000 people.

The prevalence of PK deficiency is higher in certain regions where malaria is endemic.

Pyruvate kinase deficiency is the second most common cause of enzyme-deficient hemolytic anemia, following G6PD deficiency.

It is characterized by mutations in the PKLR gene encoding red cell pyruvate kinase enzyme, which is critical for maintaining red blood cell energy levels, and therefore, the normal red cell lifespan.

Because red blood cells lack mitochondria, red blood cell energy production is entirely dependent on the glycolytic pathway for the formation of ATP, which is catalyzed by pyruvate kinase. PKD causes swelling and premature destruction of red blood cells which manifests as anemia and other complications including gallstones, pulmonary hypertension, thrombotic complications, osteoporosis, and iron overload.

Iron overload is another common manifestation of the disease.

Patients have limiting constitutional symptoms and fatigue.

Symptoms can be extremely varied among those suffering from pyruvate kinase deficiency.

Some patients are largely asymptomatic.

The majority of cases are detected at birth.

Some individuals present symptoms only during times of great physiological stress such as pregnancy, or with acute illnesses.

Symptoms are primarily seen in childhood.

Smptoms of pyruvate kinase deficiency are:

Mild to severe hemolytic nemia




Icteric sclera


Leg ulcers



Shortness of breath

In typical childhood presentation, hemolytic anemia of an unclear etiology is the initial diagnosis ruling out other family history of thalassemia, sickle cell or other hereditary hemolytic anemias and ultimately making the diagnosis.

In adults the typical presentation is inaccurately diagnosed as hereditary spherocytosis or Coombs-negative autoimmune hemolytic anemia.

Patients with PK deficiency have symptoms of anemia, with reduced exercise tolerance, decreased ability to perform at work or school, and reduced ability to concentrate.

Some patients may have jaundice.

Patients may develop psychosocial problems.

Patients may manifest gallstones and extramedullary hematopoiesis may develop with hepatosplenomegaly and or extra medullary hematopoetic pseudotumors.

Reduced bone density and osteopenia or osteoporosis develop in most patients, sometimes at a very young age.

The level of 2,3-biphosphoglycerate is elevated: 1,3-biphosphoglycerate, a precursor of phosphoenolpyruvate which is the substrate for Pyruvate kinase, is increased and so the Luebering-Rapoport pathway is overactivated.

This leads to a rightward shift in the oxygen dissociation curve of hemoglobin, decreasing the hemoglobin affinity for oxygen.

This rightward shift in the oxygen dissociation curve of hemoglobin, decreases the hemoglobin affinity for oxygen and allows patients to tolerate anemia surprisingly well.

There are four pyruvate kinase isoenzymes.

Two of the four pyruvate kinase isoenzymes are encoded by the PKLR gene which are used in the liver and erythrocytes.

Pyruvate kinase deficiency is most commonly an autosomal recessive trait.

Mostly homozygotes have symptoms of the disorder.

Patients who are compound heterozygotes can also show clinical signs.

Pyruvate kinase is the last enzyme involved in the glycolytic pathway.

PK transfers the phosphate group from phosphenol pyruvate to a waiting adenosine diphosphate (ADP) molecule, resulting in both adenosine triphosphate (ATP) and pyruvate.

PKD in erythrocytes results in an inadequate amount of or complete lack of the enzyme, blocking the completion of the glycolytic pathway, which is associated with a deficiency in the red blood cells of ATP and pyruvate.

Because mature RBCs lack a nucleus and mitochondria, they lack the ability to synthesize new proteins.

RBCs without mitochondria, are dependent on the anaerobic generation of ATP during glycolysis for their energy requirements.

With insufficient ATP in an erythrocyte, all active processes stop.

The sodium potassium ATPase pumps are the first to stop.

As the cell membrane is more permeable to potassium than sodium, potassium leaks out.

Intracellular fluid becomes hypotonic, and water moves out of the cell.

As the erythrocyte shrinks, cellular death occurs, this is how pyruvate kinase results in hemolytic anaemia

Red blood cells are destroyed by lack of ATP at a larger rate than they are being created.

Diagnosis of pyruvate kinase deficiency can be done by full blood counts

Direct enzyme assays can determine pyruvate kinase levels in erythrocytes separated by density centrifugation, as well as direct DNA sequencing.

These two diagnostic techniques are complementary to each other.

The main screening test is a PK enzyme essay with a sensitivity rate of approximately 90%.

Improving  the sensitivity of the PK enzyme assay can be achieved by measuring red cell hexokinase and calculating a PK to hexokinase enzyme activity ratio: recent transfusions invalidate this study.

genetic testing for a PK deficiency can confirmed the diagnosis.mike

Most patients do not require treatment.

There is no cure.

Current management includes: blood transfusion, splenectomy and supportive care.

The most common treatment is blood transfusions, especially in infants and young children.

Bone marrow transplantation is a treatment option, but is associated with substantial risk of graft versus host disease and death.

In severe cases splenectomy reduces severe anemia and the need for blood transfusions, as most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen

Pyruvate kinase deficiency occurs worldwide, with northern Europe, and Japan having an increased prevalence.

Administration of mitapivat is associated with a rapid increase in hemoglobin level of 50% of adults with PKD, with sustained response during a median follow up of 29 months (Grace RF).

Mitapivat is a small red blood cell pyruvate kinase activator.

Mitapivat in patients with pyruvate kinase deficiency significantly increases hemoglobin level, decreases hemolysis and improves patient outcomes.

Patients without at least one non–R479H missense mutation do not respond to mitapivat.

Mitapivat responses are associated with a 3.5 g/dL increase in hemoglobin.


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