Excerpt from Pyruvate Kinase Deficiency

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Background

In 1952, Dacie described patients with congenital hemolytic anemia who presented with symptoms and clinical findings similar to those encountered in patients with hereditary spherocytosis (HS).¹ However, in the newly described anemia, the osmotic fragility was normal, and spherocytes were not encountered. In order to differentiate the 2 conditions, the term congenital nonspherocytic hemolytic anemia (CNSHA) type II was introduced. This term was used to describe a heterogenous group of congenital hemolytic anemias of the nonspherocytic type. When the addition of ATP to the incubated RBCs corrects the defect and stops the ongoing hemolysis, the condition is then characterized as CNSHA type II. The addition of glucose to the same specimen of incubated RBCs usually fails to correct the defect.

Pathophysiology

The mature RBC completely depends on glucose as a source of energy. Glucose is usually catabolized to pyruvate and lactate in the major anaerobic glycolytic pathway (see Image 1). In the process, ATP is generated (see Image 2) and plays a major role in maintaining a cation gradient in the RBC, thus protecting the RBC from premature death.

In patients with pyruvate kinase (PK) deficiency, a metabolic block is created in the pathway at the level of the deficient enzyme. Intermediate byproducts and various glycolytic metabolites proximal to the metabolic block accumulate in the RBCs, while such cells become depleted of the distal products in the pathway, such as lactate and ATP. The high level of 2,3-diphosphoglycerate (2,3-DPG; see Image 1) increases the patient's exercise tolerance despite severe anemia. The tolerance increases as a result of the right shift in the hemoglobin-oxygen dissociation curve. However, the lack of ATP disturbs the cation gradient across the red cell membrane, causing the loss of potassium and water, which causes cell dehydration, contraction, and crenation (see Image 3) and leads to premature destruction of the RBC.

However, PK-deficient reticulocytes can circumvent their defect by using the oxidative phosphorylation pathway to produce ATP. This ability is diminished when the reticulocytes are exposed to hypoxia or when they mature to adult red cells; this may explain (1) the ineffective erythropoiesis in the spleen of patients with PK deficiency, (2) why most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen, and (3) the paradoxic increase in reticulocytes after splenectomy.

Four tissue-specific subunits of PK are known; each subunit helps form an active enzyme for a specific tissue or organ. Both the R subunit (found in the red cell) and the L subunit (found in the liver) are produced from one gene: the PKLR gene, which is located on chromosome 1. For this reason, patients with PK-deficient red cells frequently manifest an associated deficiency in the liver. This fact may explain the high total bilirubin level and the occasional significant rise in the direct fraction in some newborns with PK deficiency. Approximately 180 different mutations of this gene are known to cause PK-deficient hemolytic anemia. The clinical manifestations in PKD patients and the molecular properties of the various mutations have poor correlation. Clinical severity depends on complex interaction of several factors other than the molecular property of the mutations.   

However, the survival of patients with severe PK deficiency depends on a compensatory expression of an isoenzyme (M2PK) widely distributed in various tissues, including the RBCs. In a recent study, the life-threatening course of the anemia was reportedly related to the additional absence of the compensatory enzyme M2PK in the RBCs of a patient with homozygous null mutation of PKLR gene.²

Frequency

United States

A recent population survey revealed the rate of heterozygotes (ie, carriers) for PK deficiency to be 0.14% in Ann Arbor, Mich.

International

Although only several hundred cases of PK deficiency have been reported in the literature, the prevalence is probably much higher. The frequent reports of the predominance of PK deficiency among individuals of northern European ancestry can be questioned based on the increasing number of new cases reported in recent years in different countries and among various ethnic groups. Access to advanced medical facilities, which only recently became available to other ethnic groups, is assumed to be responsible for many of the recent reports, indicating that prevalence in other ethnic groups probably matches the prevalence previously reported among persons of northern European ancestry. In India, in a recent study to screen newborns with jaundice for the presence of PKD, 3.21% of all newborns with jaundice were found to be PK deficient, with a 30-40% reduction in the enzyme activity.³ A population survey  conducted few years ago demonstrated a heterozygote rate of 6% in Saudi Arabia,1.4% in Germany, and only 0.14% in Ann Arbor, Mich.

As with any autosomal recessive condition, the incidence can be higher in ethnic groups and communities with history of consanguinity (eg, a high rate of PK deficiency has been reported among the Pennsylvania Amish).

Mortality/Morbidity

• Morbidity in the newborn with PK deficiency is usually the result of severe anemia, hyperbilirubinemia, or both combined with the adverse effects associated with the management of such conditions. However, the severity of PK deficiency widely varies; it may be the cause of death in utero (or shortly after birth from nonimmune hydrops fetalis) or may be mild and asymptomatic.
• Simple blood or exchange transfusions are of some concern despite the current safety measures used in blood preparation. Simple blood transfusion is an issue for the older patient who is transfusion dependent.
• Patients with splenectomies are at risk because of the procedure; such patients are susceptible to later infections.
• Another cause of morbidity is the development of gallstones. In a recent report, 2 patients with PK deficiency and severe chronic hemolytic anemia have developed iron overload, resulting in liver cirrhosis; both were negative for mutations in the HFE gene.⁴

Race

PK deficiency occurs in all races, although it is thought to be more common in persons of northern European and Chinese ancestry.

Sex

PK deficiency is inherited as an autosomal recessive trait; therefore, both sexes are usually equally affected.

Age

In severe forms, PK deficiency is usually symptomatic in newborns and may be life threatening. Milder cases of PK deficiency are usually missed earlier in life and may not produce any symptoms later in life.

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