Epidemiology and Etiology
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic enzyme disorder in humans.
- Found in malarial endemic regions (as it offers relative resistance to Plasmodium falciparum infection): Mediterranean countries, Africa, the Middle East
- Presents exclusively in males as it is X-linked recessive
- Females can be silent carriers.
- Mutation in the coding region of the G6PD gene
- A single nucleotide base change (single missense point mutation) that results in a single amino acid substitution in the enzyme
- Almost 200 different mutations are known.
- The mutation decreases the half-life of the enzyme.
- G6PD deficiency results in a defect of the pentose phosphate shunt during glycolysis.
- Inheritance is X-linked recessive (band Xq28).
- G6PD is the rate-limiting enzyme in the pentose phosphate pathway.
- G6PD enzyme is responsible for:
- Oxidation of glucose-6-phosphate
- Reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH
- NADPH maintains glutathione in its reduced form.
- Reduced glutathione is needed to neutralize oxidative metabolites.
- In RBCs, this is the only pathway that produces NADPH.
- Thus, a lack of G6PD results in a deficiency in NADPH and increased oxidative damage.
- Oxidative stressors can denature hemoglobin and cause intravascular hemolysis.
- Extravascular hemolysis would be due to splenic clearance of the deformed RBCs.
- History of a trigger for the oxidative stress
- Episodic signs and symptoms of intravascular hemolytic anemia:
- Shortness of breath
- Flow murmur (best heard at upper sternal borders)
- Hemoglobinuria (cola-colored urine), hematuria
- Neonates (males): prolonged pathological jaundice/icterus
Glucose-6-phosphate dehydrogenase deficiency is suspected in cases of episodic hemolytic symptoms. Diagnostic testing should include the following:
- ↓ Hb
- ↑ Reticulocytes
- ↑ Lactate dehydrogenase (LDH)
- ↓ Haptoglobin
- ↑ Bilirubin
- Peripheral blood smear
- Heinz bodies (visible with supravital stains such as new methylene blue or crystal violet, but not with routine Romanowsky dyes; rarely performed today)
- Bite cells, indicating RBC membrane damage
- Beutler test
- Done 2–3 weeks after an acute episode (which eliminates the oldest, most G6PD-deficient cells, so a period of time is allowed to pass to evaluate baseline levels)
- Quantifies NADPH/G6PD levels
- Prevention: avoid oxidative stressors (infections, drugs, consumption of fava beans)
- During hemolysis:
- If Hb < 9 with hemolysis: blood transfusion
- Neonatal jaundice: phototherapy or exchange transfusion
- Splenectomy should be considered in rare cases of chronic hemolytic anemia.
- Inherited hemolytic anemias:
- Other enzyme deficiencies (e.g., pyruvate kinase)
- Hemoglobinopathies (e.g., sickle cell disease, thalassemia)
- Membrane/cytoskeletal defects of RBC (e.g., hereditary spherocytosis)
- Acquired hemolytic anemias: may have an immune or non-immune etiology
- Luzzatto L. Glucose 6-phosphate deficiency. (2018). In Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 1, pp 714-717). New York, NY: McGraw-Hill.
- Glader, B. (2019). Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency. UpToDate. Retrieved September 1, 2020, from https://www.uptodate.com/contents/genetics-and-pathophysiology-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency?sectionName=Classification%20of%20G6PD%20variants&topicRef=7111&anchor=H5&source=see_link#H22470651
- Glader, B. (2020). Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency. UpToDate. Retrieved September 2, 2020, from https://www.uptodate.com/contents/diagnosis-and-management-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency