Pyruvate kinase deficiency
- Josef T Prchal, MD
Josef T Prchal, MD
- Professor of Medicine
- University of Utah
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Donald H Mahoney, Jr, MD
Donald H Mahoney, Jr, MD
- Section Editor — Pediatric Hematology
- Professor of Pediatrics
- Baylor College of Medicine
Pyruvate kinase (PK) deficiency is the most common cause of congenital non-spherocytic chronic hemolytic anemia and is the result of an erythrocyte enzyme defect. It is an autosomal recessive condition caused by a deficiency of erythrocytic PK. Although the gene frequency for PK deficiency is far lower than that for glucose-6-phosphate dehydrogenase (G6PD) deficiency, the vast majority of patients inheriting G6PD deficiency never suffer acute or chronic hemolysis, whereas chronic hemolysis of variable severity is common in those with PK deficiency.
The molecular biology, clinical presentation, diagnosis, and treatment of PK deficiency are reviewed here [1,2]. An approach to the patient with suspected hemolytic anemia and an overview of the congenital hemolytic anemias in children are presented separately. (See "Diagnosis of hemolytic anemia in the adult" and "Overview of hemolytic anemias in children".)
Pyruvate kinase (PK) enzymes consist of several isoforms; they are products of two distinct M and PK LR genes both encoding an enzyme that catalyzes the transphosphorylation of phosphoenolpyruvate into pyruvate and ATP:
●The M (muscle) gene is expressed in muscle, brain, white blood cells, and platelets; it is located on chromosome 15q22. The M1 and M2 isoforms are the result of a differential processing of this single gene transcript. The M2 isoform is the dominant fetal form, and it is replaced after birth largely by the M1 isoform. The M2 isoform persists in adult life in white cells and platelets. In erythroid progenitors, it is progressively replaced by the R form.
●The L (liver) and R (red cell) isoenzymes are encoded by the LR gene on chromosome 1q21; these isoforms vary because of a differential use of tissue-specific promoters, as well as different exons at the 5' coding region. The R form, unique to erythrocytes, is 33 amino acids larger than the L form, which is unique to hepatocytes.
- van Wijk, R. Erythrocyte enzyme disorders. In: Williams Hematology, 9th edition, Kaushansky K, Lichtman MA, Prchal JT, et al. (Eds), McGraw-Hill, New York, NY 2015. p.689.
- Gregg XT, Prchal JT. Red blood cell enzymopathies. In: Hematology: Basic Principles and Practice, 7th edition, Hoffman R, Benz E. (Eds), Elsevier, 2016.
- Wang C, Chiarelli LR, Bianchi P, et al. Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. Blood 2001; 98:3113.
- Valentine WN, Paglia DE. The primary cause of hemolysis in enzymopathies of anaerobic glycolysis: a viewpoint. Blood Cells 1980; 6:819.
- Beutler E. The primary cause of hemolysis in enzymopathies of anaerobic glycolysis: "A viewpoint". A commentary. Blood Cells 1980; 6:827.
- Rice L, Alfrey CP. The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem 2005; 15:245.
- Sandoval H, Thiagarajan P, Dasgupta SK, et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 2008; 454:232.
- Song J, Yoon D, Christensen RD, et al. HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis. J Mol Med (Berl) 2015; 93:857.
- Oski FA, Marshall BE, Cohen PJ, et al. The role of the left-shifted or right-shifted oxygen-hemoglobin equilibrium curve. Ann Intern Med 1971; 74:44.
- Alfrey CP, Rice L, Udden MM, Driscoll TB. Neocytolysis: physiological down-regulator of red-cell mass. Lancet 1997; 349:1389.
- Nathan DG, Oski FA, Miller DR, Gardner FH. Life-span and organ sequestration of the red cells in pyruvate kinase deficiency. N Engl J Med 1968; 278:73.
- Mentzer WC Jr, Baehner RL, Schmidt-Schönbein H, et al. Selective reticulocyte destruction in erythrocyte pyruvate kinase deficiency. J Clin Invest 1971; 50:688.
- Aizawa S, Kohdera U, Hiramoto M, et al. Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency. Am J Hematol 2003; 74:68.
- Aizawa S, Harada T, Kanbe E, et al. Ineffective erythropoiesis in mutant mice with deficient pyruvate kinase activity. Exp Hematol 2005; 33:1292.
- Shimizu T, Uehara T, Nomura Y. Possible involvement of pyruvate kinase in acquisition of tolerance to hypoxic stress in glial cells. J Neurochem 2004; 91:167.
- Zanella A, Fermo E, Bianchi P, et al. Pyruvate kinase deficiency: the genotype-phenotype association. Blood Rev 2007; 21:217.
- Diez A, Gilsanz F, Martinez J, et al. Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression. Blood 2005; 106:1851.
- BOWMAN HS, MCKUSICK VA, DRONAMRAJU KR. PYRUVATE KINASE DEFICIENT HEMOLYTIC ANEMIA IN AN AMISH ISOLATE. Am J Hum Genet 1965; 17:1.
- Christensen R, Chair of Department of Neonatology, and Prchal JT, both of University of Utah. Personal communication, 2016.
- Pissard S, Max-Audit I, Skopinski L, et al. Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations. Br J Haematol 2006; 133:683.
- Neubauer B, Lakomek M, Winkler H, et al. Point mutations in the L-type pyruvate kinase gene of two children with hemolytic anemia caused by pyruvate kinase deficiency. Blood 1991; 77:1871.
- Zanella A, Bianchi P, Fermo E, et al. Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients. Br J Haematol 2001; 113:43.
- Kanno H, Fujii H, Hirono A, et al. Identical point mutations of the R-type pyruvate kinase (PK) cDNA found in unrelated PK variants associated with hereditary hemolytic anemia. Blood 1992; 79:1347.
- Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood 2000; 95:3585.
- Morimoto M, Kanno H, Asai H, et al. Pyruvate kinase deficiency of mice associated with nonspherocytic hemolytic anemia and cure of the anemia by marrow transplantation without host irradiation. Blood 1995; 86:4323.
- Whitney KM, Goodman SA, Bailey EM, Lothrop CD Jr. The molecular basis of canine pyruvate kinase deficiency. Exp Hematol 1994; 22:866.
- Viprakasit V, Ekwattanakit S, Riolueang S, et al. Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. Blood 2014; 123:1586.
- van Oirschot BA, Francois JJ, van Solinge WW, et al. Novel type of red blood cell pyruvate kinase hyperactivity predicts a remote regulatory locus involved in PKLR gene expression. Am J Hematol 2014; 89:380.
- Fung RH, Keung YK, Chung GS. Screening of pyruvate kinase deficiency and G6PD deficiency in Chinese newborn in Hong Kong. Arch Dis Child 1969; 44:373.
- Mohrenweiser HW. Functional hemizygosity in the human genome: direct estimate from twelve erythrocyte enzyme loci. Hum Genet 1987; 77:241.
- Pissard S, de Montalembert M, Bachir D, et al. Pyruvate kinase (PK) deficiency in newborns: the pitfalls of diagnosis. J Pediatr 2007; 150:443.
- Ferreira P, Morais L, Costa R, et al. Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency. Eur J Pediatr 2000; 159:481.
- Amankwah KS, Dick BW, Dodge S. Hemolytic anemia and pyruvate kinase deficiency in pregnancy. Obstet Gynecol 1980; 55:42S.
- Mainwaring CJ, James CM, Butcher J, Clarke S. Haemolysis and the combined oral contraceptive pill? Br J Haematol 2001; 115:710.
- Min-Oo G, Fortin A, Tam MF, et al. Pyruvate kinase deficiency in mice protects against malaria. Nat Genet 2003; 35:357.
- Ayi K, Min-Oo G, Serghides L, et al. Pyruvate kinase deficiency and malaria. N Engl J Med 2008; 358:1805.
- Leblond PF, Lyonnais J, Delage JM. Erythrocyte populations in pyruvate kinase deficiency anaemia following splenectomy. I. Cell morphology. Br J Haematol 1978; 39:55.
- Leblond PF, Coulombe L, Lyonnais J. Erythrocyte populations in pyruvate kinase deficiency anaemia following splenectomy. II. Cell deformability. Br J Haematol 1978; 39:63.
- Chandler FW Jr, Prasse KW, Callaway CS. Surface ultrastructure of pyruvate kinase-deficient erythrocytes in the Basenji dog. Am J Vet Res 1975; 36:1477.
- Beutler E. Red cell metabolism: A manual of biochemical methods, Grune and Stratton, New York 1984.
- Lestas AN, Kay LA, Bellingham AJ. Red cell 3-phosphoglycerate level as a diagnostic aid in pyruvate kinase deficiency. Br J Haematol 1987; 67:485.
- Miwa S, Nishina T, Kakehashi Y, et al. Studies on erythrocyte metabolism in a case with hereditary deficiency of H-subunit of lactate dehydrogenase. Nihon Ketsueki Gakkai Zasshi 1971; 34:228.
- Baronciani L, Beutler E. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A 1993; 90:4324.
- Baronciani L, Beutler E. Prenatal diagnosis of pyruvate kinase deficiency. Blood 1994; 84:2354.
- Tanphaichitr VS, Suvatte V, Issaragrisil S, et al. Successful bone marrow transplantation in a child with red blood cell pyruvate kinase deficiency. Bone Marrow Transplant 2000; 26:689.
- Zanella A, Berzuini A, Colombo MB, et al. Iron status in red cell pyruvate kinase deficiency: study of Italian cases. Br J Haematol 1993; 83:485.
- Zanella A, Bianchi P, Iurlo A, et al. Iron status and HFE genotype in erythrocyte pyruvate kinase deficiency: study of Italian cases. Blood Cells Mol Dis 2001; 27:653.
- Hilgard P, Gerken G. Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia. World J Gastroenterol 2005; 11:1241.
- Finkenstedt A, Bianchi P, Theurl I, et al. Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency. Br J Haematol 2009; 144:789.
- Mojzikova R, Koralkova P, Holub D, et al. Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in the PKLR gene (p.Arg518fs), and low hepcidin to ferritin ratios. Br J Haematol 2014; 165:556.
- Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014; 46:678.
- Sandoval C, Stringel G, Weisberger J, Jayabose S. Failure of partial splenectomy to ameliorate the anemia of pyruvate kinase deficiency. J Pediatr Surg 1997; 32:641.
- Tani K, Yoshikubo T, Ikebuchi K, et al. Retrovirus-mediated gene transfer of human pyruvate kinase (PK) cDNA into murine hematopoietic cells: implications for gene therapy of human PK deficiency. Blood 1994; 83:2305.
- MOLECULAR BIOLOGY
- Mechanism for hemolysis
- Compensatory increase in oxygen delivery
- Disturbed iron metabolism
- CLINICAL AND LABORATORY FINDINGS
- Hemolytic anemia
- Possible protection from malaria
- Markers of hemolysis
- Reduced PK enzymatic activity
- When to test
- Diagnostic criteria
- Differential diagnosis
- Iron overload
- Folic acid
- Hematopoietic cell transplantation
- Gene transfer
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS