Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency leads to an impaired regeneration of reduced glutathione, an important antioxidant, which makes RBCs more susceptible to oxidative stress and can result in episodic hemolytic anemia. The condition is inherited in an X-linked recessive pattern and is the most common human enzyme deficiency worldwide. It primarily affects males of African, Asian, and Mediterranean descent. G6PD deficiency is usually asymptomatic, but a sudden surge in oxidative stress (e.g., after infection, consumption of fava beans, or various drugs) may lead to a life-threatening hemolytic crisis. Diagnostic findings include signs of intravascular hemolysis (e.g., normocytic anemia, ↑ LDH, and ↓ haptoglobin), Heinz bodies, and bite cells on blood smear. Management mainly consists of preventing hemolysis by avoiding triggers.

• G6PD deficiency is the most common human enzyme deficiency.
• Prevalence: ∼ 400 million worldwide ^[1]
• Affects primarily males of African, Mediterranean, and Asian descent ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• X-linked recessive inheritance
• G6PD is the rate-limiting enzyme of the pentose phosphate pathway (also known as the hexose monophosphate shunt). This pathway yields NADPH, which is essential for converting oxidized glutathione back to its reduced form. Reduced glutathione is capable of neutralizing reactive oxygen species (ROS) and free radicals and therefore protecting RBCs from oxidative damage.
• In the absence of reduced glutathione (e.g., due to G6PD deficiency), RBCs become susceptible to oxidative stress that can damage erythrocyte membranes, resulting in intravascular and extravascular hemolysis.
• Causes of increased oxidative stress are triggers of hemolytic crisis and include:
  • Fava beans
  • Drugs: antimalarial drugs (e.g., chloroquine, primaquine), sulfa drugs (e.g., trimethoprim-sulfamethoxazole), nitrofurantoin, isoniazid, dapsone, NSAIDs, ciprofloxacin, chloramphenicol
  • Bacterial and viral infections (most common cause): Severe enzymatic deficiency can inhibit respiratory burst activity due to reduced NADPH production in phagocytes.
  • Inflammation: During an inflammatory reaction free radicals are produced and can diffuse into RBCs.
  • Metabolic acidosis

• Most patients are asymptomatic.
• Recurring hemolytic crises may occur, especially following triggers
  • Arise within 2–3 days after increased oxidative stress ^[3]
  • Sudden onset of back or abdominal pain
  • Jaundice
  • Dark urine
  • Transient splenomegaly
• Recurrent severe infections causing symptoms of chronic granulomatous disease

• Blood smear
  • Heinz bodies: Oxidative stress causes hemoglobin denaturation. Hemoglobin then precipitates as small inclusions within the erythrocytes.
  • Bite cells: due to macrophages selectively removing the denatured hemoglobin inclusions of RBCs
• Signs of intravascular hemolysis
  • Normocytic anemia
  • ↑ Reticulocyte count
  • ↑ Unconjugated bilirubin
  • ↑ LDH
  • ↓ Haptoglobin
  • Hemoglobinuria ^[2]
• Screening test: fluorescent spot test
  • Add glucose-6-phosphate and NADP → measure NADPH fluorescence
  • Normal G6PD activity produces fluorescent NADPH out of NADP, while in G6PD deficiency a lack of fluorescence is seen.
  • Semi-quantitative
• Confirmatory test: quantitative G6PD enzyme analysis

Ideally, both the screening and confirmatory tests should be performed during remission.

Stress makes me want to bite into some Heinz ketchup: ↑ Oxidative stress in patients with G6PD deficiency may lead to the detection of Heinz bodies and bite cells on the peripheral blood smear.

• Avoid triggers (see “Pathophysiology” above)
• Blood transfusions should be performed only in rare, severe cases.

• Selective advantage in areas of endemic malaria: : As with sickle cell anemia, carriers of the G6PD deficiency may be less severely affected by malaria, especially if the disease is caused by Plasmodium falciparum. ^[4]