eMedicine Specialties > Endocrinology > Metabolic Disorders

Pyruvate Kinase Deficiency

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

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

• Search for CME/CE on This Topic »

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• Kernicterus (Pediatrics: Cardiac Disease and Critical Care Medicine)
• Anemia, Chronic (Pediatrics: General Medicine)
• Hemolytic Disease of Newborn (Pediatrics: Cardiac Disease and Critical Care Medicine)

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