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Case details

A 2-year-old black girl was referred to the hematologist after her pediatrician found her to be severely anemic with splenomegaly and jaundice. Her mother gave a possible history of a “ blood problem” in her family but did not know for sure.

Her hemoglobin electrophoresis was normal, and the complete blood count (CBC) revealed a normocytic anemia. The platelet and white blood cell counts were normal. On the peripheral smear, there were many bizarre erythrocytes, including spiculated cells. A diagnosis of pyruvate kinase deficiency was made.

What is the underlying biochemical mechanism for this disorder?

How is this disorder inherited?

Case discussion

The girl has hemolytic anemia and jaundice due to pyruvate kinase deficiency.

Pyruvate Kinase Deficiency (Pkd)

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 to times of physiologic stress or infection.


Autosomal recessive.


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. 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 (Na-K ATPase pump).


Fig. 1: Pathway of anaerobic glycolysis in RBCs

Basic Concept

As shown in Figure 1, two mols of ATP are formed per mole of glucose metabolized by the glycolytic cycle. The primary final product of glucose metabolism by glycolysis in the RBC is not pyruvate, as in other tissues most of the time, but lactate. Since RBCs have no mitochondria, NAD+ cannot be regenerated by shuttling NADH produced in glycolysis into the mitochondrial electron transport system. Therefore, the only option to continue glycolysis is to regenerate NAD+ from NADH by reducing pyruvate to lactate in the lactate dehydrogenase reaction. But lactate is not the sole product of RBC glycolysis. Methemoglobin reductase uses some of the NADH produced by glycolysis to reduce methemoglobin (Fe3+) back to active hemoglobin (Fe2+) capable of binding O2 for transport to the tissues. Thus, the final products are a mixture of lactate and pyruvate with lactate being the primary product.

In tissues other than the RBC, pyruvate has alternative metabolic fates that, depending on the tissue, include gluconeogenesis, conversion to acetyl-CoA by pyruvate dehydrogenase for further metabolism to CO2 in the tricarboxylic acid (TCA) cycle, transamination to alanine or carboxylation to oxaloacetate by pyruvate carboxylase.

In the RBC, however, the restricted enzymatic endowment precludes all but the conversion to lactate. The pyruvate and lactate produced are end products of RBC glycolysis that are transported out of the RBC to the liver where they can undergo the alternative metabolic conversions described above.

How does compromise of pyruvate kinase (PK) activity lead to anemia? Pyruvate kinase lies at the end of the glycolytic pathway in RBCs followed only by lactate dehydrogenase. Pyruvate kinase activity is critical for the pathway and therefore critical for energy production. If ATP is not produced in amounts sufficient to meet the energy demand, then those functions are compromised. Energy is required to maintain the Na+/K+ balance within the RBC and to maintain the flexible discoid shape of the cell. In the absence of sufficient pyruvate kinase activity and therefore ATP, the ionic balance fails, and the membrane becomes misshapen. Cells reflecting pyruvate kinase insufficiency rather than a change in membrane composition are removed from the circulation by the macrophages of the spleen. This results in an increased number of circulating reticulocytes and possibly bone marrow hyperplasia, which is a biological response to lowered RBC count as a result of hemolysis of erythrocytes.

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 functions also.

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 three-fold increases of 2, 3-bisphosphoglycerate 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.

There are two distinct genes encoding PK activity. One is located on chromosome 1 and encodes the liver and erythrocyte PK proteins (identified as the PKLR gene) and the other is located on chromosome 15 and encodes the muscle PK proteins (identified as the PKM gene). The muscle PKM gene directs the synthesis of two isoforms of muscle PK termed PK-M1 and PK-M2. Deficiencies in the PKLR gene are the cause of the most common form of inherited non spherocytic anemia.

Enzyme defects that have been described include decreased substrate affinity, increased product inhibition, decreased response to activator, and thermal instability.


• Although pyruvate kinase deficiency (PKD) occurs worldwide, most cases have been reported in northern Europe, Japan, as well as in the United states

No sex preference has been detected for pyruvate kinase deficiency.

• 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 Manifestations

• Birth history reveals—severe anemia, severe jaundice, kernicterus or 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

• Family history consistent with autosomal recessive inheritance

• Frontal bossing

• Jaundice

• Abdomen—Splenomegaly mild to moderate, upper right quadrant tenderness, Murphy sign positive

• Extremities—Chronic leg ulcers


• 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. 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.


In patients with mild to moderate disease, care is predominantly supportive in nature.

• 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.

• Bone marrow transplantation can be performed.

Surgical care—Splenectomy is indicated only for patients with severe anemia.


• Monitor the Hematocrit value carefully during times of physiologic stress.

• If the defects in the parents are known, prenatal diagnosis using deoxyribonucleic acid (DNA) testing is possible.


• 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.

• Ischemic stroke has been reported in previously undiagnosed young adults with pyruvate kinase deficiency.

• Multiple-transfusion therapy can cause iron overload.

• Blood transfusions expose a person to the risk of contracting certain infections that are not well detected

(e.g. human immunodeficiency virus [HIV] disease, hepatitis C).

• Repeated transfusions during pregnancy increase the risk of alloimmunization, which may lead to fetal complications.


• 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.

• Hydrops fetalis has been reported in a severely affected fetus.

Things to remember

1. Pyruvate kinase deficiency (PKD) is an erythrocyte enzymopathy involving the Embden-Meyerhof pathway of anaerobic Glycolysis.

2. A discrepancy between erythrocyte energy requirements and ATP-generating capacity produces irreversible membrane injury, resulting in cellular distortion, rigidity, dehydration and premature erythrocyte destruction by the spleen and liver.

3. Although inheritance is clinically autosomal recessive; most affected individuals are compound heterozygous for 2 different mutant alleles.

4. In patients with mild to moderate disease, care is predominantly supportive in nature.

5. Splenectomy is indicated only for patients with severe anemia.

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