What is the significance of normocytic anemia, elevated Lactate Dehydrogenase (LDH), and indirect bilirubin, in relation to the glucose transporter gene encoding phosphoenolpyruvate (PEP) to pyruvate?

From the Guidelines

The laboratory findings of normocytic anemia, elevated lactate dehydrogenase (LDH), and increased indirect bilirubin suggest hemolytic anemia, specifically pyruvate kinase deficiency, which involves a defect in the glucose transporter that encodes the enzyme responsible for converting phosphoenolpyruvate (PEP) to pyruvate in glycolysis, and diagnosis should be confirmed by RBC PK activity assay by spectrophotometry and/or molecular testing of PKLR gene 1.

Key Findings

• Normocytic anemia, elevated LDH, and increased indirect bilirubin are indicative of hemolytic anemia, specifically pyruvate kinase deficiency.
• Pyruvate kinase deficiency is a genetic disorder that impairs red blood cell energy metabolism, leading to premature destruction of erythrocytes.
• Diagnosis of pyruvate kinase deficiency should be based on a combination of clinical presentation, laboratory data, and molecular testing.

Diagnostic Approach

• Clinical presentation: variable chronic anemia and/or splenomegaly and/or jaundice, with normal or near-normal red cell morphology 1.
• Laboratory data: complete blood count, RBC morphology, markers of hemolysis (reticulocyte count, LDH, unconjugated bilirubin, haptoglobin) 1.
• Biochemical testing: RBC PK activity assay by spectrophotometry, and/or molecular testing of PKLR gene 1.

Management

• Treatment typically includes folic acid supplementation, blood transfusions for severe anemia, and splenectomy in selected cases with severe disease.
• Patients should avoid oxidative medications that may worsen hemolysis and maintain adequate hydration.
• Regular monitoring of hemoglobin levels is essential.

Molecular Testing

• Molecular testing of PKLR gene is highly recommended to confirm the diagnosis of pyruvate kinase deficiency, particularly in cases with decreased enzyme activity 1.
• Next-generation sequencing (NGS) panels are a reliable alternative method for diagnosis of pyruvate kinase deficiency, especially in neonates, transfusion-dependent patients, or samples with prolonged shipping times 1.

From the Research

Laboratory Findings

• Normocytic anemia, elevated lactate dehydrogenase (LDH), and increased indirect bilirubin are indicative of hemolytic anemia 2, 3
• These laboratory findings suggest the premature destruction of red blood cells, which can be chronic or life-threatening 2
• Elevated LDH and increased indirect bilirubin are common markers of hemolysis, although normal LDH levels can also be observed in some cases of autoimmune hemolytic anemia 4

Possible Causes

• Hemolytic anemia can be caused by various mechanisms, including poor deformability of red blood cells, antibody-mediated destruction, fragmentation, oxidation, or direct cellular destruction 2
• Extrinsic nonimmune causes of hemolytic anemia include thrombotic microangiopathies, direct trauma, infections, systemic diseases, and oxidative insults 2
• Immune-mediated hemolysis can be secondary to malignancies, autoimmune disorders, drugs, and transfusion reactions 3

Glucose Transporter and Glycolysis

• The glucose transporter plays a crucial role in the glycolytic pathway, which converts glucose to pyruvate, generating energy for red blood cells 2, 3
• Enzymopathies, such as glucose-6-phosphate dehydrogenase deficiency, can lead to hemolysis in the presence of oxidative stress 3