23 - Iron overload associated with pyruvate kinase deficiency  pp. 251-253

Iron overload associated with pyruvate kinase deficiency

By James C. Barton et al.

Image View Previous Chapter Next Chapter



Pyruvate kinase (PK) deficiency (OMIM #266200) is caused by mutations in the PKLR gene that encodes PK (chromosome 1q21). This disorder is the most common erythrocyte enzyme defect that causes hereditary non-spherocytic hemolytic anemia. It is transmitted as an autosomal recessive trait. On the basis of gene frequency, it was estimated that the prevalence of homozygous PK deficiency is 51 cases per million in the US white population. Based on data in a health registry, it was estimated that the prevalence of PK deficiency in northern England is 3.3 per million. PK deficiency has a worldwide distribution, but may be more common among individuals of northern European descent. Herein, the pathophysiology of PK deficiency is discussed. The clinical manifestations of this disorder are reviewed with emphasis on the complication of iron overload.

Etiology and pathogenesis

Mature erythrocytes depend on the glycolytic production of adenosine triphosphate (ATP) to meet metabolic requirements. Deficiencies in several glycolytic enzymes can result in hemolytic anemia. These types of hemolytic anemia are not associated with a distinctive morphologic abnormality of erythrocytes, and thus are known collectively as congenital non-spherocytic hemolytic anemias. Most of these disorders are rare and are transmitted as autosomal recessive disorders.

PK deficiency is the most common erythrocyte glycolytic enzymopathy. The predominant PK isoenzyme present in erythrocytes is the R form, encoded by PKLR. Multiple mutations can lead to PK deficiency, and the type of mutation may determine in part the severity of the clinical phenotype.

Andersen FD , d'Amore F , Nielsen FC , van Solinge W , Jensen F , Jensen PD . Unexpectedly high but still asymptomatic iron overload in a patient with pyruvate kinase deficiency. Hematol J 2004; 5: 543.
Baronciani L , Beutler E . Molecular study of pyruvate kinase deficient patients with hereditary non-spherocytic hemolytic anemia. J Clin Invest 1995; 95: 1702–9.
Baronciani L , Bianchi P , Zanella A . Hematologically important mutations: red cell pyruvate kinase (2nd update). Blood Cells Mol Dis 1998; 24: 273–9.
Bett JH , Wilkinson RK , Boyle CM . Iron overload associated with congenital pyruvate kinase deficiency and high dose ascorbic acid ingestion. Aust NZ J Med 1985; 15: 270.
Beutler E , Gelbart T . PK deficiency prevalence and the limitations of a population-based survey. Blood 2000; 96: 4006.
Boivin P , Galand C. [Iron overload in congenital hemolytic anemia caused by pyruvate kinase deficiency. A major late complication.] Presse Med 1990; 19: 1087–90.
Carey PJ , Chandler J , Hendrick A , et al. Prevalence of pyruvate kinase deficiency in northern European population in the north of England. Northern Region Haematologists Group. Blood 2000; 96: 4005–6.
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: 789–93.
Hilgard P , Gerken G . Liver cirrhosis as a consequence of iron overload caused by hereditary non-spherocytic hemolytic anemia. World J Gastroenterol 2005; 11: 1241–4.
Kanno H , Fujii H , Hirono A , Miwa S. cDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (Thr384–Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia. Proc Natl Acad Sci USA 1991; 88: 8218–21.
Larochelle A , De Braekeleer M , Marceau D , de Medicis E . Miami Short Reports. Advances in Gene Technology: The Molecular Biology of Human Genetic Disease. New York, IRL Press, 1991.
Muir WA , Beutler E , Wasson C . Erythrocyte pyruvate kinase deficiency in the Ohio Amish: origin and characterization of the mutant enzyme. Am J Hum Genet 1984; 36: 634–9.
Muller-Soyano A , Tovar de Roura E , Duke PR , et al. Pyruvate kinase deficiency and leg ulcers. Blood 1976; 47: 807–13.
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: 683–9.
Richard RE , Weinreich M , Chang KH , Ieremia J , Stevenson MM , Blau CA . Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency. Blood 2004; 103: 4432–9.
Rowbotham B , Roeser HP . Iron overload associated with congenital pyruvate kinase deficiency and high dose ascorbic acid ingestion. Aust NZ J Med 1984; 14: 667–9.
Salem HH , van der Weyden MB , Firkin BG . Iron overload in congenital erythrocyte pyruvate kinase deficiency. Med J Aust 1980; 1: 531–2.
Vukelja SJ . Erythropoietin in the treatment of iron overload in a patient with hemolytic anemia and pyruvate kinase deficiency. Acta Haematol 1994; 91: 199–200.
Zachee P , Staal GE , Rijksen G , De Bock R , Couttenye MM , De Broe ME . Pyruvate kinase deficiency and delayed clinical response to recombinant human erythropoietin treatment. Lancet 1989; 1: 1327–8.
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: 485–90.
Zanella A , Bianchi P , Fermo E . Pyruvate kinase deficiency. Haematologica 2007; 92: 721–3.
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: 653–61.
Zanella A , Fermo E , Bianchi P , Valentini G . Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol 2005; 130: 11–25.