What is the first step in working up pyruvate kinase deficiency?

From the Guidelines

The first step in working up pyruvate kinase deficiency is to suspect the disease based on clinical presentation, including variable chronic anemia, splenomegaly, jaundice, and normal or near-normal red cell morphology 1.

Key Clinical Parameters

• Chronic anemia and/or splenomegaly and/or jaundice with normal or near-normal red cell morphology
• Transfusion-dependent cases of unknown etiology
• Haemolytic patients with unexplained severe neonatal indirect hyperbilirubinemia
• Presence of high reticulocyte number in splenectomised patients with no diagnosis

Initial Laboratory Data

• Complete blood count (CBC) is mandatory, with a mean agreement of 97% among experts 1
• RBC morphology should also be evaluated, with a median agreement of 100% among experts 1
• Markers of haemolysis, such as reticulocyte count, LDH, unconjugated bilirubin, and haptoglobin, should be assessed

Next Steps

After suspecting pyruvate kinase deficiency based on clinical presentation and initial laboratory data, the next step would be to perform a biochemical test, specifically a red blood cell pyruvate kinase (PK) activity assay by spectrophotometry, which is considered the reference test for diagnosis 1. However, it is essential to consider the storage time of the sample and the sample anticoagulant used, as these can affect the accuracy of the PK enzyme assay results 1. Molecular testing, such as sequencing of the PKLR gene, may be necessary to confirm the diagnosis, especially in cases with decreased PK activity 1.

From the Research

Diagnosis of Pyruvate Kinase Deficiency

• The first step in working up pyruvate kinase deficiency involves a high index of suspicion and judicious use of laboratory tests, including pyruvate kinase enzyme assay and genetic analysis of the PKLR gene 2
• A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests, requiring a comprehensive diagnostic approach 2
• The diagnosis of PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis 3

Key Considerations

• The spectrum of genotypes, variants, and phenotypes of PK deficiency is broad, commonly requiring a multimodal approach including enzyme and genetic testing for accurate and reliable diagnosis 4
• Current treatment approaches are supportive and include transfusions, splenectomy, and chelation, with the goal of managing complications and improving quality of life 3, 5
• Novel therapies in development, such as disease-modifying therapies and gene therapy, may transform the way in which PKD is managed in the future 4, 5, 6

International Expert Guidelines

• The International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency provide evidence-based recommendations for the clinical care of patients with PK deficiency, including diagnosis, monitoring, and management of chronic complications 6
• The guidelines emphasize the importance of individualized care, with decisions to transfuse and/or splenectomise made on a case-by-case basis 6