eMedicine Specialties > Endocrinology > Metabolic Disorders

Pyruvate Kinase Deficiency: Differential Diagnoses & Workup

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Thomas G DeLoughery, MD, Professor of Medicine and Pathology, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health Sciences University
Contributor Information and Disclosures

Updated: Dec 18, 2008

Differential Diagnoses

Acute Myelogenous Leukemia
Hemolytic Anemia
Anemia
Hemolytic-Uremic Syndrome
Aplastic Anemia
Low LDL Cholesterol (Hypobetalipoproteinemia)
Bilirubin, Impaired Conjugation
Malaria
Disseminated Intravascular Coagulation
Paroxysmal Nocturnal Hemoglobinuria
Elliptocytosis, Hereditary
Pernicious Anemia
Folic Acid Deficiency
Sickle Cell Anemia
Glucose-6-Phosphate Dehydrogenase Deficiency
Spherocytosis, Hereditary
Hematologic Disease and Pregnancy
Splenic Abscess
Hemoglobin C Disease
Thrombotic Thrombocytopenic Purpura

Other Problems to Be Considered

Abetalipoproteinemia
Cholesterol acyltransferase deficiency
Cold agglutinin immune hemolysis
Hereditary stomatocytosis
Mechanical or diseased heart valve
Phosphatidylcholine hemolytic anemia
Tangier disease

Workup

Laboratory Studies

  • Cell indices
    • The hematocrit value ranges from 17-37%. Lower values occur in early childhood and during the neonatal period, with a 3- to 9-point rise after early childhood.
    • Erythrocytes are normochromic and macrocytic.
    • The reticulocyte count may be increased by 5-15%. Paradoxically, a high reticulocyte count, as high as 70%, may occur after splenectomy.
    • Leukocyte and platelet counts range from normal to slightly increased.
  • Cell morphology
    • Morphologic abnormalities are not a prominent finding, but hallmarks of accelerated erythropoiesis, such as polychromatophilia, anisocytosis, poikilocytosis, and nucleated red blood cells, may be present.
    • Siderocytes, target cells, Pappenheimer bodies, Howell-Jolly bodies, and crenated red blood cells may be observed postsplenectomy.
  • Hemoglobin indices
    • Concurrent with the hematocrit value, the hemoglobin concentration varies from 6-12 g/dL, with a lower concentration early in life.
    • Hemoglobin electrophoresis reveals normal hemoglobin with normal levels of F and A2 hemoglobins.
  • Hemolytic anemia tests
    • Erythrocyte lifespan is moderately to severely reduced, depending on the severity of the anemia. Radiochromium labeling reveals an immediate period of destruction, followed by a shortened lifespan for the remainder of labeled cells. The results of this test can help to determine candidacy for splenectomy, because a high rate of immediate destruction suggests significant splenic activity.
    • Erythrocyte osmotic fragility is normal.
    • The Coombs test result is negative.
    • The Ham test result is negative.
    • The Donath-Landsteiner antibody is absent.
    • Cold agglutinins are absent.
    • Incubated Heinz body formation is usually abnormal.
  • Hemoglobin metabolic indices
    • Indirect hyperbilirubinemia reflects the severity of the hemolytic process. Levels of 6 mg/dL are not uncommon, and levels greater than 20 mg/dL have been reported.
    • Haptoglobin is reduced in proportion to disease severity.
  • Enzyme deficiency testing
    • The precise diagnosis depends on detecting the deficient enzyme.7 The enzyme activity rate in most patients who are deficient is 5-25% of normal.
    • Simple, specific enzyme testing is available, but false-negative results can occur, especially when the defect is due to a compound heterozygous mutation, because kinetic variables are not measured accurately under such circumstances. Measurement of the intermediates proximal to the enzyme defect, specifically 2,3-diphosphoglycerol and glucose-6-phosphate, help to confirm the diagnosis.
  • Deoxyribonucleic acid (DNA) testing
    • Because of the large number of gene mutations that result in pyruvate kinase deficiency, DNA analysis is limited. However, some exceptions should be noted.
    • Mutations have been found to affect specific groups. For example, particular mutations have been identified in highly affected groups such as the Pennsylvania Amish.
    • When the mutation is known, the DNA analysis can be limited to specific mutations. This is also useful in prenatal diagnosis.

Imaging Studies

  • In severe anemia, radiographs may demonstrate findings of marrow expansion.
  • Biliary tract obstruction may occur as a consequence of this disorder, requiring imaging of the biliary tree.

Other Tests

  • In general, despite significant deficiencies of the liver isoenzyme of pyruvate kinase, results from liver function testing show hyperbilirubinemia unless the patient has iron overload due to multiple erythrocyte transfusions.8,9

Histologic Findings

Pathologic and histologic findings include normoblastic erythroid hyperplasia of the bone marrow, extramedullary hematopoiesis, splenic and hepatic hemosiderosis and splenic congestion, reticuloendothelial hyperplasia, and erythrophagocytosis.

More on Pyruvate Kinase Deficiency

Overview: Pyruvate Kinase Deficiency
Differential Diagnoses & Workup: Pyruvate Kinase Deficiency
Treatment & Medication: Pyruvate Kinase Deficiency
Follow-up: Pyruvate Kinase Deficiency
References
Further Reading
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References

  1. Kedar P, Hamada T, Warang P, et al. Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes. Clin Genet. Aug 28 2008;[Medline].

  2. Yavarian M, Karimi M, Shahriary M, et al. Prevalence of pyruvate kinase deficiency among the south Iranian population: quantitative assay and molecular analysis. Blood Cells Mol Dis. May-Jun 2008;40(3):308-11. [Medline].

  3. Valentini G, Chiarelli LR, Fortin R, et al. Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. J Biol Chem. Jun 28 2002;277(26):23807-14. [Medline]. [Full Text].

  4. Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood. Jun 1 2000;95(11):3585-8. [Medline]. [Full Text].

  5. 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. Dec 1 2000;96(12):4005-6. [Medline]. [Full Text].

  6. Ayi K, Min-Oo G, Serghides L, et al. Pyruvate kinase deficiency and malaria. N Engl J Med. Apr 24 2008;358(17):1805-10. [Medline]. [Full Text].

  7. Titapiwatanakun R, Hoyer JD, Crain K, et al. Relative red blood cell enzyme levels as a clue to the diagnosis of pyruvate kinase deficiency. Pediatr Blood Cancer. Dec 2008;51(6):819-21. [Medline].

  8. Andersen FD, d'Amore F, Nielsen FC. Unexpectedly high but still asymptomatic iron overload in a patient with pyruvate kinase deficiency. Hematol J. 2004;5(6):543-5. [Medline].

  9. Marshall SR, Saunders PW, Hamilton PJ, et al. The dangers of iron overload in pyruvate kinase deficiency. Br J Haematol. Mar 2003;120(6):1090-1. [Medline].

  10. Ghidini A, Korker VL. Severe pyruvate kinase deficiency anemia. A case report. J Reprod Med. Aug 1998;43(8):713-5. [Medline].

  11. Esen UI, Olajide F. Pyruvate kinase deficiency: an unusual cause of puerperal jaundice. Int J Clin Pract. Jul-Aug 1998;52(5):349-50. [Medline].

  12. 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. Sep 2000;26(6):689-90. [Medline].

  13. Kedar PS, Nampoothiri S, Sreedhar S, et al. First-trimester prenatal diagnosis of pyruvate kinase deficiency in an Indian family with the pyruvate kinase-Amish mutation. Genet Mol Res. Jun 30 2007;6(2):470-5. [Medline].

  14. Chou R, DeLoughery TG. Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency. Am J Hematol. Jul 2001;67(3):197-9. [Medline].

  15. Pincus M, Stark RA, O''Neill JH. Ischaemic stroke complicating pyruvate kinase deficiency. Intern Med J. Sep-Oct 2003;33(9-10):473-4. [Medline].

  16. Ferreira P, Morais L, Costa R, et al. Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency. Eur J Pediatr. Jul 2000;159(7):481-2. [Medline].

  17. Cazzola M. Pyruvate kinase deficiency. Haematologica. Jan 2005;90(1):1-2. [Medline].

  18. Glader BE, Lukens JN. Hereditary hemolytic anemias associated with abnormalities of erythrocyte glycolysis and nucleotide metabolism. In: Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams & Wilkins; 1999:1160-75.

  19. Hirono A, Kanno H, Miwa S. Pyruvate kinase deficiency and other enzymopathies of the erythrocyte. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Molecular and Metabolic Bases of Inherited Disease. 8th ed. 2001: McGraw-Hill; 2001:4637-64.

  20. McMullin MF. The molecular basis of disorders of red cell enzymes. J Clin Pathol. Apr 1999;52(4):241-4. [Medline]. [Full Text].

  21. Mentzer WC. Pyruvate kinase deficiency and disorders of glycolysis. In: Nathan DG, Orkin SH, eds. Nathan and Orkin's Hematology of Infancy and Childhood. 5th ed. Philadelphia, Pa: WB Saunders; 1998:665-703.

  22. Sabiston DC Jr. Splenectomy for anemia. In: Sabiston DC Jr, Lyerly HK, eds. Textbook of Surgery: the Biological Basis of Modern Surgical Practice. 15th ed. Philadelphia, Pa: WB Saunders; 1997:1203-6.

  23. Segel GB. Enzymatic defects. Section 3: hemolytic anemias. Part XX: disease of blood. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: WB Saunders; 2000:1488-93.

  24. Suvatte V, Tanphaichitr VS, Visuthisakchai S, et al. Bone marrow, peripheral blood and cord blood stem cell transplantation in children: ten years'' experience at Siriraj Hospital. Int J Hematol. Dec 1998;68(4):411-9. [Medline].

  25. Yawata Y. Nonimmune hemolytic anemia. In: Rakel RE, ed. Conn's Current Therapy 2000. 52nd ed. Philadelphia, Pa: WB Saunders; 2000:363-6.

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Further Reading

Related eMedicine topics:
 Anemia
Hemolytic Anemia
Hydrops Fetalis [Pediatrics: Cardiac Disease and Critical Care Medicine]
Hydrops Fetalis [Radiology]
Hemolytic Disease of Newborn
Pyruvate Kinase Deficiency [Pediatrics: General Medicine]

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Keywords

pyruvate kinase deficiency, anemia, glycolysis, pyruvate, hemolytic anemia, anemia symptoms, blood disease, symptoms of anemia, anemia treatment, anaemia, blood diseases, blood disorder, hydrops fetalis, blood disorders, pyruvate kinase, anemia and pregnancy, anaerobic glycolysis, hematologic disorder, enzyme defect, erythrocyte enzymopathy, PK Beppu, pyruvate kinase Beppu

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Contributor Information and Disclosures

Author

Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas G DeLoughery, MD, Professor of Medicine and Pathology, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health Sciences University
Thomas G DeLoughery, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American College of Physicians, American Society of Hematology, International Society on Thrombosis and Haemostasis, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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