PYRUVATE KINASE DEFICIENCY

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 hematological 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 times of physiologic stress or infection.

Pathophysiology

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 results 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 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.

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. 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. One severe form of PKD, PK Beppu, is associated with persistence of the PK-M2 isoenzyme.

Frequency

United States

PKD and glucose-6-phophate deficiency are the most common erythrocyte enzymopathies. PKD is the most common enzymopathy of anaerobic glycolysis. The prevalence rate of a heterozygous carrier of one deficient PK gene in 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. This is 50 times higher than the number of individuals diagnosed with PKD at a major PK assay laboratory in the United States over the past 25 years, suggesting this disorder is frequently underdiagnosed.

International

Although PKD occurs worldwide, most cases have been reported in northern Europe and Japan, along with the United States. The prevalence rate of having one 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. This is not based on genetic diagnosis or a gene screening survey.

Mortality/Morbidity

  • 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 other individuals presenting with a severe hemolytic anemia that usually only requires transfusions during childhood.
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  • Morbidity and mortality correlate with disease severity and usually depend on complications.
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  • Hydrops fetalis can occur.

Race

  • Although PKD 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.
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  • The particular mutation responsible for the deficiency is different for various races. For example, the 1529A mutation is believed to cause at least one gene mutation in most affected white persons from the United States and Europe. Others, 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.

Age

  • Age of onset of inherited 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.
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  • Acquired PKD is usually secondary to a particular disease. In such cases, the age of onset varies with the primary disease.

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