The variable manifestations of disease in pyruvate kinase deficiency and their management

Abstract

Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including pyruvate kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell pyruvate and ATP deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.

Figure 1.

Paravertebral extramedullary hematopoietic masses in pyruvate kinase deficiency. (A) Multiple transverse sections demonstrating paravertebral masses (arrows) in close proximity to nerve roots. (B) Sagittal section demonstrating a large paravertebral mass (bounded by arrows) extending from the vertebra.

Figure 2.

Lower extremity non-healing ulcer in an adult with pyruvate kinase deficiency. Note the location posterior to the medial malleolus.

Figure 3.

Our consensus, stepwise approach to laboratory workup of a patient with chronic hemolytic anemia. The initial workup includes hemolysis testing performed routinely. The second-pass workup is intended to rule out relatively common inherited entities (including hemoglobinopathies not identified in the initial workup) as well as paroxysmal nocturnal hemoglobinuria, particularly relevant if the patient presents in adulthood. The third-pass workup allows for identification of pyruvate kinase deficiency and red cell membrane abnormalities not diagnosed in prior steps. If this three-step workup is unrevealing, additional testing is recommended to diagnose particularly rare inherited and acquired causes of hemolytic anemia. The diagnostician may narrow or broaden the workup at each step as appropriate and as testing is available; for example, molecular PKLR and KLF1 testing can be reasonably performed earlier in the workup. Additionally, the clinician should be aware that many specialized tests are poorly standardized between laboratories. ^aDeficiency may result in a hemolytic picture due to ineffective erythropoiesis; folate may be low in chronic hereditary anemias due to rapid cell turnover. ^bAllows identification of most hemoglobinopathies. TTP: thrombotic thrombotic thrombocytopenic purpura; DIC: disseminated intravascular coagulopathy; PNH: paroxysmal nocturnal hemoglobinuria; DAT: direct antiglobulin test; ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13.

Figure 4.

The glycolytic pathway. Deficiency of pyruvate kinase results in diminished ATP production as well as buildup of pathway intermediates proximal to pyruvate kinase, most notably 2,3-diphosphoglycerate. Modified with permission from Grace and Glader. Glucose-6-P: glucose-6-phosphate; Fructose-6-P: fructose-6-phosphate; Fructose 1,6-DP: fructose 1,6-diphosphate; DHAP, dihydroxyacetone phosphate; G3P: glucose-3-phosphate; 1,3-DPG: 1,3-diphosphoglycerate; 2,3-DPG, 2,3- diphosphoglycerate; 3-PG: 3-phosphoglycerate; PEP: phosphoenolpyruvate. Blue: enzymes in glycolytic pathway that correlate with the more common glycolytic enzymopathies.