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Hemolytic anemia due to red cell pyruvate kinase deficiency

ORPHA766
Synonym(s) Pyruvate kinase deficiency of erythrocytes
Prevalence 1-9 / 100 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • D55.2
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Disease definition

Hemolytic anemia due to red cell pyruvate kinase (PK) deficiency is a metabolic disorder characterized by a variable degree of chronic nonspherocytic hemolytic anemia.

Epidemiology

PK deficiency is the most frequent cause of congenital nonspherocytic hemolytic anemia with a prevalence estimated at 1/20,000 in the general white population.

Clinical description

Clinically, PK-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. Chronic icterus, gallstones and splenomegaly are common findings.

Etiology

Erythrocyte PK deficiency is caused by mutations in the PKLR gene (1q22). To date, more than 190 mutations in PKLR have been reported. PK is a key regulatory enzyme of glycolysis and two major metabolic abnormalities result from PK deficiency: ATP depletion and increased 2,3-diphosphoglycerate (2,3-DPG) content. The precise mechanisms that cause extravascular hemolysis are as yet unknown, but an important feature involves the selective sequestration of PK-deficient young red blood cells, in particular reticulocytes, by the spleen. The increased 2,3-DPG levels ameliorate the anemia by lowering the oxygen-affinity of hemoglobin.

Diagnostic methods

Diagnosis may be considered on the basis of the clinical features and laboratory findings: a variable degree of anemia, reticulocytosis, increased non-conjugated bilirubin, and decreased levels of haptoglobin. Red blood cell morphology is essentially normal. PK deficiency is diagnosed by measuring PK enzymatic activity. Importantly, due to the fact that the enzymatic activity is red cell age-dependent, a deficiency of PK may be masked by reticulocytosis. Confirmation of the diagnosis requires molecular characterization.

Differential diagnosis

Secondary PK deficiency has also been reported, occurring in the context of hematological diseases (acute/chronic leukemia, myelodysplastic syndromes and sideroblastic anemia; see these terms). In case of persistent normocytic hemolytic anemia in which hemoglobin abnormalities and antiglobulin reactions have been excluded, spherocytes are absent, and osmotic fragility is normal, the diagnosis of hereditary nonspherocytic hemolytic anemia should be considered.

Genetic counseling

Erythrocyte PK deficiency is an autosomal recessive disease.

Management and treatment

The mainstay of treatment is blood transfusion and, in severe cases, splenectomy. The latter should be based on the patient's ability to tolerate the anemia. As a result of splenectomy, reticulocyte counts often increase and transfusion needs are reduced. Bone marrow transplantation can cure PK deficiency but is rarely performed.

Prognosis

Prognosis is variable depending on the severity of the anemia, but as in other chronic hemolytic disorders, gallstones and iron overload may develop, requiring appropriate treatment.

Expert reviewer(s)

  • Dr R. [Richard] VAN WIJK

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