eMedicine Specialties > Pediatrics: General Medicine > Hematology

Pyruvate Kinase Deficiency

Author: Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center
Contributor Information and Disclosures

Updated: Oct 6, 2009

Introduction

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

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, although 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 Media file 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 Media file 3) and leads to premature destruction of the RBC.

However, pyruvate kinase–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 pyruvate kinase 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 pyruvate kinase 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 pyruvate kinase–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 pyruvate kinase deficiency. Approximately 180 different mutations of this gene are known to cause pyruvate kinase–deficient hemolytic anemia. The clinical manifestations in patients with pyruvate kinase 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 pyruvate kinase 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

A study of pyruvate kinase–deficient erythrocytes has shown such cells to be protected against infection with Plasmodium falciparum malaria.³

Frequency

United States

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

International

Although only several hundred cases of pyruvate kinase deficiency have been reported in the literature, the prevalence is probably much higher. The frequent reports of the predominance of pyruvate kinase 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 study to screen newborns with jaundice for the presence of pyruvate kinase deficiency, 3.21% of all newborns with jaundice were found to be pyruvate kinase deficient, with a 30-40% reduction in the enzyme activity.⁴ A population survey demonstrated a heterozygote rate of 6% in Saudi Arabia, 1.4% in Germany, and only 0.14% in Ann Arbor, Michigan. 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 pyruvate kinase deficiency has been reported among the Pennsylvania Amish).

Mortality/Morbidity

Morbidity in the newborn with pyruvate kinase 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 pyruvate kinase 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. A recent report from the Netherlands revealed a fatal outcome in 2 newborns who presented with very severe pyruvate kinase–deficient hemolytic anemia that resulted in liver failure.⁵ No other explanation for the liver failure was identified.

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.

Iron overload is another serious complication of pyruvate kinase deficiency. In a report of 2 patients with pyruvate kinase deficiency and severe chronic hemolytic anemia who developed iron overload that resulted in liver cirrhosis, both were negative for mutations in the HFE gene.⁶ Iron overload is not an unusual complication, even in patients not receiving chronic transfusion. These patients are not different from others with chronic hemolysis, who tend to absorb more iron regardless of their iron storage status because of the associated active erythropoiesis. Patients with iron overload not related to chronic hemolysis, such as in hemochromatosis, are usually protected from absorbing more iron.

The cause of such discrepancy was not clear until recently, when a hepatic peptide known as hepcidin was described as a negative master regulator of iron absorption and release. In inflammation, the upregulated hepcidin prevents iron absorption, whereas, in iron deficiency anemia, a downregulated hepcidin allows iron to be absorbed. The loss of protection against iron absorption in patients with iron overload who have chronic hemolysis has been shown to be mediated by growth differentiation factor 15 (GDF15), a marrow factor which abrogates the effect of hepcidin to allow iron absorption in such patients.⁷ In this study, hepcidin level in patients with pyruvate kinase deficiency was 13-fold less than in the control group, whereas GDF15 was significantly higher in patients with pyruvate kinase than in control subjects.

Race

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

Sex

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

Age

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

Clinical

History

• Anemia, jaundice, and splenomegaly are the major findings in the newborn with pyruvate kinase (PK) deficiency.
• Heterozygotes have intermediate enzyme levels and are usually asymptomatic, while homozygotes manifest the clinical symptoms of pyruvate kinase deficiency.
• The severity of the condition widely varies, even among patients with the same level of deficiency. Such variability occurs because, in addition to the symptomatic homozygotes, compound heterozygotes with 2 different mutations (one can be qualitative and the other quantitative) also vary symptomatically.
• In older children, adolescents, and adults with pyruvate kinase deficiency, anemia may range from transfusion dependent to asymptomatic.

Physical

• See Pathophysiology and History.

Causes

• Pyruvate kinase deficiency is an inherited condition that is transmitted as an autosomal recessive gene.
• Affected individuals are either homozygous for a single mutation or doubly heterozygous for 2 different pyruvate kinase mutations.

• Search for CME/CE on This Topic »

• Pyruvate Kinase Deficiency (Endocrinology)
• 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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