Is NADPH (Nicotinamide adenine dinucleotide phosphate) decreased in G6PD (Glucose-6-phosphate dehydrogenase) deficiency?

NADPH Levels in G6PD Deficiency

Yes, NADPH is decreased in G6PD deficiency, which is the fundamental biochemical defect that leads to the clinical manifestations of this disorder. 1

Pathophysiology of G6PD Deficiency

G6PD (Glucose-6-phosphate dehydrogenase) is a critical enzyme in the hexose monophosphate shunt (also called pentose phosphate pathway), which is the primary source of NADPH in red blood cells. The pathway works as follows:

• G6PD catalyzes the first step in the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphogluconolactone
• This reaction simultaneously reduces NADP+ to NADPH
• NADPH is essential for:
  • Maintaining glutathione in its reduced form, which protects cells from oxidative damage
  • Serving as a cofactor for various metabolic reactions
  • Supporting red blood cell membrane integrity

In G6PD deficiency, the enzyme's activity is reduced or absent, resulting in:

• Decreased NADPH production 2
• Reduced ability to regenerate glutathione
• Impaired protection against oxidative stress
• Increased vulnerability to hemolysis when exposed to oxidative agents

Clinical Implications of Decreased NADPH

The decreased NADPH levels in G6PD deficiency have several important clinical implications:

1. Hemolytic Anemia: When exposed to oxidative stressors (certain drugs, infections, fava beans), G6PD-deficient red blood cells cannot generate sufficient NADPH to counteract oxidative damage, leading to hemolysis 3

2. Methylene Blue Ineffectiveness: Methylene blue, the primary treatment for methemoglobinemia, requires NADPH to be effective. In G6PD deficiency, insufficient NADPH means methylene blue therapy may be ineffective and potentially harmful 1

3. Neutrophil Dysfunction: Severe G6PD deficiency can impair neutrophil function, particularly neutrophil extracellular trap (NET) formation, leading to increased susceptibility to bacterial infections 4

4. Diabetic Complications: G6PD deficiency may accelerate microvascular complications in diabetes, with studies showing increased prevalence of proliferative retinopathy in G6PD-deficient diabetic patients 5

Management Considerations

The decreased NADPH levels in G6PD deficiency necessitate specific management approaches:

• Avoid Oxidative Drugs: Patients with G6PD deficiency should avoid medications that can trigger hemolysis, including dapsone, primaquine, and sulfonamides 1

• Alternative Treatments: For conditions typically treated with oxidative drugs, alternative medications should be used:

  • For methemoglobinemia: Ascorbic acid (Vitamin C) is the treatment of choice instead of methylene blue 1
  • For conditions requiring dapsone: Alternative non-oxidative medications should be considered 1

• G6PD Testing: Screening for G6PD deficiency is recommended before starting therapy with oxidant drugs, especially in patients from predisposing racial or ethnic backgrounds (African, Mediterranean, Southeast Asian) 1

• Infection Prevention: In severe G6PD deficiency cases with impaired neutrophil function, consideration of antibiotic prophylaxis may be warranted 4

Variants and Severity

The degree of NADPH reduction correlates with the severity of the G6PD variant:

• GdA- (African variant): Found in 10-15% of Black men and women, causes milder, self-limited hemolysis 1
• Gdmed (Mediterranean variant): Found predominantly in men from Mediterranean regions, India, and Southeast Asia, associated with more severe hemolysis that can be life-threatening 1

The severity of NADPH reduction also affects enzyme stability. Research has shown that the binding of "structural" NADP+ (distinct from catalytic NADP+) is important for long-term stability of the G6PD enzyme, with certain mutations affecting this binding and resulting in more severe clinical manifestations 6.

Conclusion

The decreased NADPH production in G6PD deficiency is the central biochemical defect that explains the clinical manifestations of this disorder, particularly the susceptibility to hemolysis when exposed to oxidative stress. Understanding this mechanism is crucial for appropriate management and prevention of complications in affected individuals.