Pyruvate Kinase Deficiency
- Infrequent genetic metabolic disease caused by a deficiency of pyruvate kinase enzyme, characterized by variable degrees of chronic non-spherocytic hemolytic anemia, leading to clinical manifestations ranging from fatal anemia at birth to fully compensated hemolysis without significant anemia.
- Pyruvate Kinase (PK): the last enzyme in the glycolytic pathway, catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate and yield adenosine triphosphate (ATP).
Causes:
- Red blood cell PK deficiency is caused by mutations in the PKLR gene located on chromosome 1q21.
- According to reports, there are more than 200 mutations in the PK-LR gene.
- It is inherited as an autosomal recessive genetic disease.
- PK is a key regulatory enzyme of glycolysis, the lack of PK leads to two main metabolic abnormalities: Depletion of the ATP and 2,3-diphosphoglycerate (2,3-DPG) content increased.
- The exact mechanism leading to extravascular hemolysis is unclear, but an important feature is that the spleen selectively sequestrates young red blood cells lacking PK and reticulocytes.
- Increased levels of 2,3-DPG improve anemia by reducing the oxygen affinity of hemoglobin.
Clinical Manifestations
- Commonly neonatal hyperbilirubinemia may require an exchange transfusion.
- Older children and adults suffer from chronic hemolysis, ranging from mild and compensatory to severe and the need for blood transfusion.
- Splenomegaly is common.
- Infection, surgery, and pregnancy can cause acute exacerbations of hemolysis.
- Parvovirus B19 infection may lead to an aplastic crisis.
Diagnosis
The diagnosis can be considered based on clinical characteristics and laboratory test results:
- Anemia of variable degrees increases unconjugated bilirubin levels and decreases haptoglobin levels.
- Reticulocytosis.
- Hereditary non-spherocytic hemolytic anemia.
- Echinocytosis (contracted spiculated cells)
- measuring PK enzymatic activity. Importantly, since enzyme activity is age-dependent on red blood cells, reticulocytosis may mask the lack of PK.
- Measuring another red blood cell age-specific enzyme, for example, hexokinase might be helpful.
- Confirmation of the diagnosis requires genetic testing.
Differential diagnosis
- Secondary PK deficiency has also been found in blood diseases (acute/chronic leukemia, myelodysplastic syndrome, and sideroblastic anemia).
- If persistent normal hemolytic anemia, abnormal hemoglobin, and antiglobulin reaction have been ruled out, no spherocytes and normal osmotic fragility, the diagnosis of hereditary nonspherocytic hemolytic anemia should be considered.
Treatment
- Neonatal hyperbilirubinemia may require exchange transfusions.
- Many elderly patients tolerate anemia well and do not require special treatment.
- Patients with severe hemolysis may require blood transfusion support.
- Splenectomy can be beneficial in severe cases.
- Daily intake of folic acid to support high red blood cell production: very important for women with EPKD who are planning to become pregnant.
- Bone marrow transplantation can cure PK deficiency, but it is rarely done.
- Small molecule activator therapy is nowadays in clinical trials.
Complications
- Iron overload.
- Hyperbilirubinemia.
- Gallstone.
- Splenomegaly
Prognosis
The prognosis depends on the severity of anemia, but like other chronic hemolytic diseases, gallstones and iron overload may develop, requiring appropriate treatment.
Pyruvate kinase deficiency is a condition in which red blood cell destruction occurs faster than it should. This can cause anemia (insufficient red blood cells). Most people with pyruvate kinase deficiency lead healthy lives.
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