The G6PD enzyme is vital to the production of NADPH and therefore to the production of glutathione and nitric oxide.
Glutathione is a potent antioxidant that protects tissues and cell membranes from free radical damage and oxidative stress. Glutathione also supports the breakdown of toxic compounds in the body. Nitric oxide is essential to vasodilation and endothelial health.
G6PD deficiency is the most common enzyme deficiency seen in humans. Low levels are associated with genetic and acquired deficiency, hemolytic anemia, oxidative stress, metabolic syndrome, diabetes, cardiovascular disease, vitamin D deficiency, infection, and autoimmunity. High levels may be protective.
Standard Range: 2.2 - 17 U/g Hb
The ODX Range: 11 - 15 U/g Hb
Low levels of G6PD are associated with metabolic acidosis (Eziokwu 2018), decreased glutathione, diminished antioxidant activity, increased oxidative stress, and hemolysis. Low levels are observed in inherited G6PD deficiency and acquired deficiency or impairment, including metabolic syndrome, obesity, diabetes, and stress (increased aldosterone). A G6PD deficiency increases the risk of hemolytic anemia, fibrosis, vitamin D deficiency, autoimmune disorders, infections, hypertension, and cardiovascular disease (Jain 2020). Riboflavin deficiency can reduce the activity of G6PD and compromise glutathione status (Tardy 2020).
High levels of G6PD aren’t considered clinically relevant at this time. Overexpression of this antioxidant enzyme may help protect endothelial cells from oxidative stress and damage (Gheita 2014).
The glucose 6-phosphate dehydrogenase (G6PD) enzyme is utilized in the pentose phosphate pathway that generates NADPH, a critical compound in glutathione metabolism, and, therefore, in antioxidant defense. Glutathione protects cells from free radical damage, especially highly vulnerable red blood cells (Richardson 2021). The NADPH molecule is also used as a cofactor in nitric oxide (NO) synthesis. A G6PD deficiency not only impairs synthesis of NO, but also causes hyperglycemia which can increase advanced glycosylated end products which further impair nitric oxide activity (Gaskin 2001). NADPH is also an important factor in the synthesis of fatty acids, cholesterol, steroids, and DNA. NADPH can be generated by enzymes other than G6PD in most cells but not in RBCs which are more susceptible to a deficiency of G6PD (Luzzatto 2016).
Ultimately, a deficiency of G6PD leaves cells, especially RBCs, susceptible to oxidative stress and results in inflammation, hemolysis, and impaired endothelial and macrophage function. Hyperglycemia and glycosylation of proteins can further impair G6PD activity (Jain 2020).
G6PD deficiency is the most common inborn error of metabolism and the most prevalent enzyme deficiency worldwide. It contributes to hemolytic anemia and increased susceptibility to oxidative, metabolic, infectious, and degenerative diseases, though the degree of deficiency depends on the genetic variant. In one study, low levels of G6PD were seen in Sjogren’s disease and even lower levels in rheumatoid arthritis, especially when coupled with metabolic syndrome. In this study, healthy controls had a mean G6PD of 13.13 U/g Hb, while levels were 11.55 in Sjogren’s, 7.72 in rheumatoid arthritis, and 4.61 in those with both rheumatoid arthritis and metabolic syndrome (Gheita 2014). These findings are not surprising given the role of G6PD in countering oxidative stress and chronic inflammation.
The insufficiency of reduced glutathione that results from G6PD deficiency contributes to the oxidation of hemoglobin and Heinz body formation (Nassef 2013). Heinz bodies are precipitates of denatured hemoglobin that results from excess oxidative stress and hemolysis (Pagana 2021).
G6PD deficiency should be screened for in the neonatal period (Gheita 2014). In a sample of 24 newborns, the mean normal G6PD level using standard methodology was 11.1 U/g Hb, while the mean level with G6PD deficiency was 1.4 U/g Hb (Bhutani 2015).
One 24-year-old individual with an undiagnosed G6PD deficiency (3.8 U/g Hb) presented with severe rhabdomyolysis, metabolic acidosis, and significantly elevated bilirubin, AST, ALT, CRP, and ferritin (Eziokwu 2018). This case highlights the importance of addressing G6PD deficiency as early as possible. The reference interval for G6PD in this case study was 8.6-18 U/g Hb.
Certain medications may trigger hemolysis in G6PD deficient individuals. A reduction in hemoglobin and an increase in bilirubin in G6PD-deficient individuals taking low-dose aspirin following ischemic stroke may indicate the presence of hemolysis and worsening outcomes (Chen 2021). Other medications may induce hemolytic anemia in those with G6PD deficiency as well. Even high-dose vitamin C may need to be avoided in this group (Quinn 2017).
Consumption of fava beans and some synthetic dyes can precipitate hemolytic anemia in those with G6PD deficiency and should be avoided (Lee 2017). Other foods, including falafel, chickpeas, and broad beans may also trigger hemolysis in those with G6PD deficiency (Hagag 2018), Sulfites and quinine should also be avoided with a G6PD deficiency (Noland 2020).
A 2017 systematic review of 32 publications comprising 10 herbal and dietary supplements found no or insufficient evidence of increased risk of hemolysis with vitamins C, E, and K, Gingko biloba, or alpha lipoic acid in those with G6PD deficiency. However, an increased risk was observed for henna. Researchers note that green tea and its extracts have been reported to trigger hemolysis in G6PD-deficient individuals. They also note that high doses of vitamin C, e.g., 20-40 grams per day, may trigger hemolysis in these individuals. Ingestion of the herbal supplements Acalypha indica and Coptis chinensis may also cause adverse reactions with G6PD deficiency (Lee 2017 Adverse Effects).
Bhutani, Vinod K et al. “Point-of-Care Quantitative Measure of Glucose-6-Phosphate Dehydrogenase Enzyme Deficiency.” Pediatrics vol. 136,5 (2015): e1268-75. doi:10.1542/peds.2015-2122
Chen, Yicong et al. “Association between aspirin-induced hemoglobin decline and outcome after acute ischemic stroke in G6PD-deficient patients.” CNS neuroscience & therapeutics vol. 27,10 (2021): 1206-1213. doi:10.1111/cns.13711
Eziokwu, Akaolisa S, and Dana Angelini. “New Diagnosis of G6PD Deficiency Presenting as Severe Rhabdomyolysis.” Cureus vol. 10,3 e2387. 28 Mar. 2018, doi:10.7759/cureus.2387
Gaskin, R S et al. “G6PD deficiency: its role in the high prevalence of hypertension and diabetes mellitus.” Ethnicity & disease vol. 11,4 (2001): 749-54.
Gheita, Tamer Atef et al. “Subclinical reduced G6PD activity in rheumatoid arthritis and Sjögren's Syndrome patients: relation to clinical characteristics, disease activity and metabolic syndrome.” Modern rheumatology vol. 24,4 (2014): 612-7. doi:10.3109/14397595.2013.851639
Hagag, Adel A et al. “Study of Glucose-6-Phosphate Dehydrogenase Deficiency: 5 Years Retrospective Egyptian Study.” Endocrine, metabolic & immune disorders drug targets vol. 18,2 (2018): 155-162. doi:10.2174/1871530317666171003160350
Jain, Sushil K et al. “The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID-19.” Free radical biology & medicine vol. 161 (2020): 84-91. doi:10.1016/j.freeradbiomed.2020.10.002
Lee, Shaun Wen Huey et al. “What G6PD-deficient individuals should really avoid.” British journal of clinical pharmacology vol. 83,1 (2017): 211-212. doi:10.1111/bcp.13091
Nassef, Yasser E., et al. "Evaluation of G6PD activity and antioxidants status in jaundiced Egyptian neonates." International Journal 5.12 (2013): 550-559.
Noland, Diana, Jeanne A. Drisko, and Leigh Wagner, eds. Integrative and functional medical nutrition therapy: principles and practices. Springer Nature, 2020.
Northrop-Clewes, Christine A, and David I Thurnham. “Biomarkers for the differentiation of anemia and their clinical usefulness.” Journal of blood medicine vol. 4 11-22. 20 Mar. 2013, doi:10.2147/JBM.S29212
Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.
Quinn, Joseph et al. “Effect of High-Dose Vitamin C Infusion in a Glucose-6-Phosphate Dehydrogenase-Deficient Patient.” Case reports in medicine vol. 2017 (2017): 5202606. doi:10.1155/2017/5202606
Richardson, S. Russ. and Gerald F. O'Malley. “Glucose 6 Phosphate Dehydrogenase Deficiency.” StatPearls, StatPearls Publishing, 26 July 2021.
Tardy, Anne-Laure et al. “Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.” Nutrients vol. 12,1 228. 16 Jan. 2020, doi:10.3390/nu12010228