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The clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study

Rachael F. Grace, Paola Bianchi, Eduard J. van Beers, Stefan W. Eber, Bertil Glader, Hassan M. Yaish, Jenny M. Despotovic, Jennifer A. Rothman, Mukta Sharma, Melissa M. McNaull, Elisa Fermo, Kimberly Lezon-Geyda, D. Holmes Morton, Ellis J. Neufeld, Satheesh Chonat, Nina Kollmar, Christine M. Knoll, Kevin Kuo, Janet L. Kwiatkowski, Dagmar Pospíŝilová, Yves D. Pastore, Alexis A. Thompson, Peter E. Newburger, Yaddanapudi Ravindranath, Winfred C. Wang, Marcin W. Wlodarski, Heng Wang, Susanne Holzhauer, Vicky R. Breakey, Joachim Kunz, Sujit Sheth, Melissa J. Rose, Heather A. Bradeen, Nolan Neu, Dongjing Guo, Hasan Al-Sayegh, Wendy B. London, Patrick G. Gallagher, Alberto Zanella and Wilma Barcellini

Key points

  • Pyruvate Kinase (PK) Deficiency manifests a broad spectrum in severity of anemia, which moderately improves after splenectomy.

  • Close attention to monitoring for iron overload, gallstones, and other complications is recommended in all patients with PK deficiency.

Abstract

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital non-spherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment in 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia requiring transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%) with many treated with exchange transfusions (46%). Young children, ≤5 years old, were often transfused until splenectomy. Splenectomy, reported for 150/254 (59%) patients, was associated with a median rise in hemoglobin of 1.6 g/dl and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included: higher pre-splenectomy hemoglobin (p=0.007), lower indirect bilirubin (p=0.005), and missense PKLR mutations (p=0.0017). Post-splenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%); however, other complications, such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, post-splenectomy sepsis, pulmonary hypertension, and leg ulcers, were not uncommon. Overall, 87/254 (34%) patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin.

  • Submitted October 25, 2017.
  • Accepted March 2, 2018.