eMedicine Specialties > Endocrinology > Metabolic Disorders

Pyruvate Kinase Deficiency

Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
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

Updated: Dec 18, 2008

Introduction

Background

Pyruvate kinase deficiency (PKD) is one of the most common enzymatic defects of the erythrocyte. This disorder manifests clinically as a hemolytic anemia, but surprisingly, the symptomatology is less severe than hematologic indices indicate. Presumably, this is due to enhanced oxygen delivery as a result of the defect. The clinical severity of this disorder varies widely, ranging from a mildly compensated anemia to severe anemia of childhood. Most affected individuals do not require treatment. Individuals who are most severely affected may die in utero of anemia or may require blood transfusions or splenectomy, but most of the symptomatology is limited to early life and to times of physiologic stress or infection.

Pathophysiology

Pyruvate kinase deficiency (PKD) is an erythrocyte enzymopathy involving the Embden-Meyerhof pathway of anaerobic glycolysis. Erythrocytes have evolved without oxidative phosphorylation to form adenosine triphosphate (ATP), the compound essential for providing the erythrocyte energy. Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate. This is 1 of 2 glycolytic reactions in the erythrocyte that result in the production of ATP. A discrepancy between erythrocyte energy requirements and ATP-generating capacity produces irreversible membrane injury, resulting in cellular distortion, rigidity, and dehydration. This leads to premature erythrocyte destruction by the spleen and liver. Low ATP levels are responsible for erythrocyte intracellular electrolyte concentration disruption, due to failure of the adenosine triphosphatase cation pump.

The hexose monophosphate shunt and glutathione synthetic pathway protect the erythrocyte against destruction from free radicals and oxidative stress. Loss of adequate ATP diminishes their function.

Young reticulocytes retain mitochondria that produce ATP through oxidative phosphorylation. However, this comes at a price, a 6- to 7-fold higher oxygen requirement. Paradoxically, this can lead to the demise of any reticulocyte, because its journey through the spleen, an environment deficient in glucose and oxygen, is lengthened by its adhesive tendency. In such an environment, the reticulocyte is at an increased risk of metabolic failure.

Important intermediates proximal to the PK defect influence erythrocyte function. Two- to 3-fold increases of 2,3-diphosphoglycerol levels result in a significant rightward shift in the hemoglobin-oxygen dissociation curve. Physiologically, the hemoglobin of affected individuals has an increased capacity to release oxygen into the tissues, thereby enhancing oxygen delivery. Thus, for a comparative hemoglobin and hematocrit level, an individual with PKD has an enhanced exercise capacity and fewer symptoms. This is particularly advantageous during pregnancy, because it enhances transfer of oxygen to the fetal blood. This most likely adds to the particularly benign course of this disease in many affected individuals. Women with PKD typically do not require transfusions during pregnancy.

PK exists as 4 isoenzymes. Two isoenzymes are encoded by a genetic locus on band 15q22, while the 2 others are encoded by a genetic locus on band 1q21. The former isoenzymes (ie, PK-M1, PK-M2) are found in striated muscle, brain, fetus, leukocytes, platelets, lungs, spleen, kidneys, and adipose tissue. The latter isoenzymes (ie, PK-L, PK-R) are found in liver, normoblasts, reticulocytes, and erythrocytes.^1,2 The liver and erythroid precursors are capable of activating PK-M2 activity, but this is not the enzyme used under normal conditions.

In persons with PKD, band 1q21 is defective, resulting in deficient liver and red blood cell isoenzymes. The liver can compensate for the gene defect in 2 ways. First, because the enzyme deficiency results in a less efficient enzyme rather than a nonfunctioning enzyme, a greater quantity of enzyme can be produced. In addition, the liver can use residual PK-M2 activity. Early in maturation, erythroid precursors use the PK-M2 isoenzyme. However, as the cell matures, the PK-R isoenzyme replaces the PK-M2 enzyme. Because the erythrocyte cannot produce any new protein, it cannot compensate by increasing the quantity of isoenzyme or using residual PK-M2 isoenzyme.

Enzyme defects that have been described include decreased substrate affinity, increased product inhibition, decreased response to activator, and thermal instability. Mutations that strongly perturb enzyme kinetics and thermostability are associated with severe PKD.³ One severe form of PKD, PK Beppu, is associated with persistence of the PK-M2 isoenzyme.

Frequency

United States

Pyruvate kinase deficiency (PKD) and glucose-6-phosphate deficiency are the most common erythrocyte enzymopathies. PKD is the most common enzymopathy of anaerobic glycolysis. The prevalence rate of a heterozygous carrier of 1 deficient PK gene is believed to be approximately 1%. Screening an American population for the 4 most common gene mutations demonstrates an estimated prevalence of 51 cases per million persons in the white population.⁴ This is 50 times higher than the number of individuals who were diagnosed with PKD at a major pyruvate kinase assay laboratory in the United States over a 25-year period, suggesting that this disorder is frequently underdiagnosed.

International

Although pyruvate kinase deficiency (PKD) occurs worldwide, most cases have been reported in northern Europe and Japan, as well as in the United States. The prevalence rate of having 1 deficient PK gene has been estimated in Germany at 1% and in Hong Kong at 3%. The prevalence of diagnosed cases in the northern health region of the United Kingdom is 3.2 cases per million population.⁵ This is not based on genetic diagnosis or a gene screening survey.

Mortality/Morbidity

• Pyruvate kinase deficiency (PKD) is associated with a wide range of morbidity, with some individuals manifesting a mild, compensated, chronic hemolytic anemia that does not require medical intervention, and with other individuals presenting with a severe hemolytic anemia that in most cases only requires transfusions during childhood.
• Morbidity and mortality correlate with disease severity and usually depend on complications.
• Hydrops fetalis can occur.

Race

• Although pyruvate kinase deficiency is observed worldwide, it is particularly common among the Pennsylvania Amish, in whom the disorder can be traced to a single immigrant couple. Affected individuals can have severe, life-threatening manifestations and can require long-term transfusion therapy and splenectomy in early childhood.
• The particular mutation responsible for the deficiency differs between populations. For example, the 1529A mutation is believed to cause at least 1 gene mutation in most affected white persons from the United States and Europe. Other individuals, such as Portuguese, Spanish, and Italian persons, are affected by the 1456T mutation. Asian persons in the United States appear to be affected by the 1468T mutation.

Sex

• No sex preference has been detected for pyruvate kinase deficiency.

Age

• The age of onset for inherited pyruvate kinase deficiency (PKD) correlates with severity. Persons with severe disease usually have onset in the neonatal period or infancy. In most affected persons, PKD is detected during childhood, but in individuals who are mildly affected, PKD may not be detected until late adulthood.
• Acquired PKD is usually secondary to a particular disease. In such cases, the age of onset varies with the primary disease.

Clinical

History

• Birth history
  • Severe anemia
  • Severe jaundice
  • Kernicterus
  • History of exchange transfusion
• Anemia, mild to severe
  • Growth delay
  • Failure to thrive
  • May become symptomatic during times of physiological stress, including acute illness, particularly viral, and pregnancy
  • Cholecystolithiasis, usually after the first decade of life, but possibly in childhood
• Family history consistent with autosomal recessive inheritance

Physical

• Growth
  • Symmetrical growth delay
  • Failure to thrive
• Dysmorphology - Frontal bossing
• Skin -Jaundice
• Head, ears, eyes, nose, and throat - Icteric sclera
• Abdomen
  • Splenomegaly, mild to moderate
  • Upper right quadrant tenderness
  • Murphy sign
• Extremities - Chronic leg ulcers

Causes

• Medical conditions, such as acute leukemia, preleukemia, and refractory sideroblastic anemia, as well as complications from chemotherapy, can cause an acquired pyruvate kinase deficiency. This type is more common and milder than the hereditary type.
• More than 100 genetic defects of the PK gene have been detected.^1,2 Most defects are missense mutations, but splicing mutations, insertions, and deletions also occur. Although inheritance is clinically autosomal recessive, most affected individuals are compound heterozygous for 2 different mutant alleles. Homozygous individuals are usually the product of consanguineous mating.⁶

Differential Diagnoses

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.

Treatment

Medical Care

In patients with mild to moderate disease, care is predominantly supportive in nature. However, splenectomy is useful in persons with severe disease.

• Red blood cell transfusion may be necessary if the hemoglobin value falls significantly. This tends to occur in early childhood and during periods when physiologic stress is present, such as when an infection exists or during pregnancy.
• Two studies that addressed pyruvate kinase deficiency (PKD) during pregnancy stated the following:
  • Uncomplicated pregnancy, delivery, and birth were reported, despite a decline in the hemoglobin value to 6.8 g/dL during pregnancy.¹⁰
  • Significant puerperal jaundice has been successfully treated with conservative measures.¹¹
• Bone marrow transplantation was performed on a 5-year-old boy with severe hemolytic anemia due to PKD and heterozygous hemoglobin E, using ABO-identical and HLA-identical marrow from his sister. A report published more than 3 years posttransplant indicated that the patient was still healthy at that time, without symptomatology of PKD.¹²

Surgical Care

Splenectomy is indicated only for patients with severe anemia.

• Splenectomy can reduce anemia, but hemolysis will not be abolished.
• The hemoglobin concentration typically increases by 1-3 g/dL.
• Transfusion requirements typically decrease.
• The danger of an aplastic crisis with infection is reduced.
• Growth delay, if present, may be reversed, and catch-up growth may ensue.
• Splenectomy does not improve mild anemia.
• Splenectomy should be performed by an experienced surgeon, especially in pediatric patients.
• Consider the susceptibility to infection following splenectomy, especially in children younger than 5 years.

Consultations

• A hematologist should be consulted for management and treatment.
• A surgeon should be consulted if splenectomy is considered.
• An anesthesiologist should be consulted for presurgical management if anemia is severe.
• A gastroenterologist may be necessary to help evaluate complications of the biliary tree.

Activity

High-impact contact sports are contraindicated in patients with significant splenomegaly.

Follow-up

Inpatient & Outpatient Medications

• Prophylactic antibiotics should be administered to young patients postsplenectomy.
• Supplemental folic acid and other B vitamins help to prevent deficiencies from increased erythrocyte production.
• Large doses of salicylates should be avoided in patients with severe anemia, because salicylates inhibit oxidative phosphorylation, thereby causing further ATP depletion.

Deterrence/Prevention

• Monitor the hematocrit value carefully during times of physiologic stress.
• If the defects in the parents are known, prenatal diagnosis using DNA testing is possible.¹³ Prenatal enzymatic testing is not optimal, because a large amount of fetal blood is required, and the test has a high rate of false-negative results.

Complications

• Cholecystolithiasis is common in the first decade of life for children with severe anemia.
• Splenectomy increases the risk of (1) sepsis by encapsulated bacteria for children and (2) thromboembolic disease for adults.¹⁴
• Ischemic stroke has been reported in previously undiagnosed young adults with pyruvate kinase deficiency.¹⁵
• Multiple-transfusion therapy can cause iron overload.^8,9
• Blood transfusions expose a person to the risk of contracting certain infections that are not well detected (eg, human immunodeficiency virus [HIV] disease, hepatitis C).
• Repeated transfusions during pregnancy increase the risk of alloimmunization, which may lead to fetal complications.

Prognosis

• Mild and moderate forms of the disease are associated with an excellent prognosis.
• Severe forms of the disease are mostly symptomatic during early childhood. Following early childhood, the disorder is much better tolerated.
• Most morbidity develops from the above-mentioned complications (see Complications).
• Hydrops fetalis has been reported in a severely affected fetus.¹⁶

Patient Education

• Patients should be educated to regularly use folic acid and B vitamin supplements and to avoid salicylates.
• The risk regarding splenectomy versus that of multiple transfusions should be discussed with the parents of children with severe anemia.
• If a child has splenomegaly, parents should be instructed to have the child refrain from participating in contact sports.
• Because the inheritance is phenotypically autosomal recessive, parents and patients should be educated about the low risk of reoccurrence.

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. 10^th 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. 8^th 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. 5^th 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. 15^th ed. Philadelphia, Pa: WB Saunders; 1997:1203-6.

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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

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.

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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