Pyruvate kinase deficiency, one of the most common enzymatic defects of the erythrocyte, manifests clinically as a hemolytic anemia that can range from a mildly compensated anemia to severe anemia of childhood. It is caused by mutations in the PKLR gene. Surprisingly, however, the symptomatology is less severe than hematologic indices indicate. This is presumably due to enhanced oxygen delivery as a result of the defect.
Most affected individuals do not require treatment, although in the most severe cases, death may occur in utero as a result of anemia, or blood transfusions or splenectomy may be required, but most of the symptomatology is limited to early life and to times of physiologic stress or infection.
An international, multicenter registry that collected clinical data on patients with pyruvate kinase deficiency found that 93% of newborns were treated with phototherapy, and 46% were treated with exchange transfusions. Splenectomy was performed in 150 of 254 patients, or 59%, and was associated with a median increase in hemoglobin levels of 1.6 g/dL along with a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin, lower indirect bilirubin, and missense PKLR mutations. In total, 87 of 254 patients, or 34%, had both a splenectomy and cholecystectomy. In patients who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy.
(See the image below.)
Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency.
Signs and symptoms
The following are evident in pyruvate kinase deficiency:
Mild to severe normochromic and normocytic anemia
Symmetrical growth delay
Failure to thrive
Cholecystolithiasis: Usually after the first decade of life but possibly in childhood
Hyperbilirubinemia in the newborn
Mild to moderate splenomegaly
Chronic leg ulcers (adults)
The birth history of patients with pyruvate kinase deficiency includes severe anemia, severe jaundice,
kernicterus, and a history of exchange transfusion.
The minimal tests required to guide the investigation of pyruvate kinase deficiency include the following:
Complete blood count (CBC)
Differential blood count
Serum bilirubin level study
Peripheral blood film examination
Normochromic, normocytic, or macrocytic anemia, together with reticulocytosis in the absence of blood loss, is suggestive of hemolysis. A negative Coombs test result helps to exclude immune hemolysis.
The enzyme activity rate in most patients with pyruvate kinase deficiency is 5-25% of normal, with measurement of the intermediates (2,3-diphosphoglycerol and glucose-6-phosphate) proximal to the enzyme defect helping to confirm the diagnosis.
Other findings include the following:
Normoblastic erythroid hyperplasia of the bone marrow
Splenic and hepatic hemosiderosis and splenic congestion
Increased iron stores
Enzyme assay, as well as deoxyribonucleic acid (DNA) analysis with a polymerase chain reaction (PCR) assay or single-strand conformation polymorphism, can also be used to confirm the diagnosis of pyruvate kinase deficiency.
In patients with mild to moderate pyruvate kinase deficiency, care is predominantly supportive. Red blood cell transfusion may be necessary if the patient’s hemoglobin value falls significantly.
Supplemental folic acid is used extensively in individuals with hemolytic anemia to prevent the development of megaloblastic anemia.
Splenectomy is indicated only for patients with severe anemia.
The procedure does not abolish hemolysis or improve mild anemia, but it can reduce severe anemia and is frequently performed to minimize or eliminate the patient’s need for blood transfusion.