Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury.

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Epidemiology and Etiology

Epidemiology

  • 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.

Etiology

  • 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 band Xq28 illustration

G6PD deficiency is an X-linked disorder found on band Xq28.

Image by Lecturio.

Pathophysiology

  • 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.
Table: Common oxidative stressors
DrugsFoodsOther
  • Sulfas (trimethoprim/sulfamethoxazole [TMP/SMX])
  • Quinolones
  • Nitrofurantoin
  • Aspirin/nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Methylene blue
  • Fava beans
  • Blue food coloring
  • Any infection (most common)
  • Naphthalene (mothballs)
  • Diabetic ketoacidosis

Clinical Presentation

  • History of a trigger for the oxidative stress
  • Episodic signs and symptoms of intravascular hemolytic anemia:
    • Pallor
    • Shortness of breath
    • Fatigue
    • Tachycardia
    • Flow murmur (best heard at upper sternal borders)
    • Jaundice
    • Hemoglobinuria (cola-colored urine), hematuria
    • Neonates (males): prolonged pathological jaundice/icterus
Urinary sample with hematuria

Urinary sample with hematuria

Image: “hematuria” by omicsonline.org. License: CC BY 4.0

Diagnosis

Glucose-6-phosphate dehydrogenase deficiency is suspected in cases of episodic hemolytic symptoms. Diagnostic testing should include the following:

  • CBC
    • ↓ 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

Management

  • 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.

Differential Diagnosis

  • 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 

References

  1. 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.
  2. 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 
  3. 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

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