Additionally, viral infections may trigger hemolytic complications in G6PDdef patients 17-19. Recently, two case-reports found that COVID-19 triggered hemolysis and methemoglobinemia in G6PDdef patients without an identifiable eliciting drug 20,21. Methemoglobinemia has been reported in other COVID-19 cases 22 and anti-malarial drugs known to induce hemolysis in G6PDdef, hydroxychloroquine and chloroquine, have been used to treat COVID-19. To date, seven case studies reported hydroxychloroquine/chloroquine triggered hemolysis in G6PDdef COVID-19 patients 23-27.
One week after NAC treatment was discontinued, hematological indexes began to decline, and the patient received 1.2 g daily IV NAC for one week. Upon discontinuation of the second round of NAC, hematological indexes declined with NAC treatment improving hematological indexes for a third time, suggesting NAC may be beneficial for the treatment of G6PDdef in AHA. G6PD is a major source of NADPH and loss of G6PD function is detrimental in erythrocytes; it causes G6PD deficiency (G6PDdef), a potentially hemolytic disorder 1. G6PD deficiency is common, affecting between 400 million to 500 million people worldwide.
- Recently, two case-reports found that COVID-19 triggered hemolysis and methemoglobinemia in G6PDdef patients without an identifiable eliciting drug 20,21.
- AG1 improved the activity and stability of several Class II and Class III variants, including the common Mediterranean and A− and Canton, by stabilizing dimeric G6PD in vitro, in cellulo, and in vivo models 101.
- Left untreated, infants with severe jaundice can develop brain damage (kernicterus).
- Healthcare providers use different treatments based on the situation.
Several commonly used medications should be avoided by those with G6PD deficiency. These include antibiotics like sulfamethoxazole and anti-malarial drugs like chloroquine. It’s important to consult with healthcare providers to ensure medications are safe before use.
Lessons from Antioxidant Treatments
These findings suggest that glucose-mediated inhibition of G6PD and G6PDdef contribute to loss of ß-cell function and may increase susceptibility to diabetic complications. A G6PD deficiency diagnosis means different things for different people. You can take care of yourself by recognizing the triggers that increase your risk of hemolytic anemia and avoiding them. It may mean developing healthy habits, like getting enough rest and not smoking.
Medications to Avoid in Patients with G6PD Deficiency Due to Risk of Hemolysis
A deficiency happens when you’re born with a variant (mutation) in the gene your body needs to make G6PD. Therapeutic routes and molecular targets are summarized (Figure 4, Key Figure) and questions regarding these routes as drug targets remain largely unanswered (see Outstanding Questions). We present potential treatment strategies for G6PDdef in hopes of motivating the development of new therapies. The interest of the pharmaceutical industry will increase only after more epidemiological studies confirm that G6PDdef is an important unmet need for a variety of common acute and chronic diseases. Recently, a case-study reported a G6PDdef patient with COVID-19 was treated with hydroxychloroquine, which triggered AHA, and NAC resolved hematological indexes and hemolysis on three different occasions 25. The patient received 90 g of intravenous (IV) NAC, which immediately improved hematological indexes.
Currently, the pathophysiology for kernicterus/hyperbilirubinemia-induced sensorineural hearing loss is unknown and only a few studies have explored the role of G6PDdef in auditory disorders 31,32. Additionally, the role G6PD plays in kernicterus-induced brain damage remains elusive. G6PD deficiency is a genetic disorder that affects your red blood cells. While most people with this condition don’t have symptoms, it does increase your risk of hemolytic anemia (low red blood cells). For individuals with G6PD deficiency, certain medications can cause oxidative stress leading to hemolytic anemia. These medications increase the risk of red blood cells breaking down, which can lead to serious health problems.
Symptoms and Causes
These results demonstrate that a single small molecule can partially correct the catalytic activity and stability of multiple common G6PD variants. Although AG1’s effect on catalytic activity is important, stabilization of dimeric G6PD is likely an important feature; enzyme stability is a major determinant of residual activity in erythrocytes 99,100. Therefore, a small molecule that increases G6PD medications the stability of G6PD may be an effective therapeutic, though its efficacy may not be evident until tested in an in vivo model.
Interestingly, treatment of patient derived erythroblasts and non-hemopoietic cells with HDACi sodium butyrate (NaBu) increased transcriptional upregulation of the G6PD gene, while having no effect on other genes in the glycolytic or PPP pathway. SP1 binding induced G6PD transcription, mRNA production, and protein translation, which lead to a subsequent increase in Class I-III G6PDdef protein levels and activity, restoring it to that of WT or greater. Suberoylanilide hydroxamic acid (SAHA), another HDACi, produced similar results to NaBu, demonstrating transcriptional activation is not HDACi specific 80-82. Modeling GSH metabolism in erythrocytes predicts that a 50% increase in plasma L-cysteine (LC) will improve GSH levels when the GSH oxidation rate is increased by 20% 66. However, a 50% increase in plasma LC levels may be difficult to achieve in vivo; high doses of LC are required to compensate for poor bioavailability but are limited by toxicity 67. N-acetyl-cysteine (NAC), an LC prodrug, has been developed to improve LC bioavailability and can be delivered orally at high doses, with minimal side effects 68.
- You can take care of yourself by recognizing the triggers that increase your risk of hemolytic anemia and avoiding them.
- Therapeutic routes and molecular targets are summarized (Figure 4, Key Figure) and questions regarding these routes as drug targets remain largely unanswered (see Outstanding Questions).
- Additionally, three smaller clinical studies reported α-tocopherol did not improve hematological parameters or patient outcome 54,57,58 (Table 2).
- This article has been reviewed for accuracy by one of the licensed medical doctors working for Doctronic.
- Astaxanthin, a lipid soluble carotenoid pigment, increased the activity of purified G6PDWT in a dose-dependent manner, with a maximum 30% activation achieved at 0.64 mM astaxanthin, suggesting a direct mechanism 59.
- A) Ascorbate concentration increases in the plasma as a result of IV or oral administration.
What questions should I ask my healthcare provider?
Understanding which drugs can cause these reactions is essential for prevention. But if you don’t have enough G6PD, triggers (like eating fava beans) can cause too many free radicals to build up in your cells. If this leaves you with a low red blood cell count, you develop hemolytic anemia. But sometimes, triggers like certain medicines can cause serious problems, like hemolytic anemia.
A second molecular target of interest is transcription factor nuclear erythroid receptor 2 (Nrf2). Under basal conditions, Nrf2 levels are suppressed by Keap1-dependent-ubiquitination and subsequent proteasomal degradation. However, in the presence of electrophiles and oxidants, cysteine modifications deactivate Keap1 and in turn increase Nrf2 levels. Nrf2 exerts antioxidant effects by binding to antioxidant response elements and upregulating transcription of antioxidant defense enzymes, including G6PD 93. Although Class I mutations are rare and Class II/III largely asymptomatic, self-resolution from AHA is not guaranteed and blood transfusions not always viable.
Small Molecule Activators of Clinical G6PD Variants
Additionally, treatment with 8-aminoquinolines, the only anti-malarial drugs capable of eliminating the dormant liver forms of Plasmodium Vivax, induces AHA in G6PDdef, with G6PDdef found in geographic areas with a high incidence of malaria 6,7. This, combined with lack of reliable testing for G6PDdef, presents a major challenge in the eradication of malaria 8,9. Thus, prophylactic or combination therapies may be attractive strategies for treatment of G6PDdef and the eradication of malaria. Many people with G6PD deficiency likely never know because they don’t have symptoms. But others experience life-threatening events like a hemolytic crisis when they encounter a trigger. Inhibiting G6PD in neurons increases ROS, induces apoptosis, and induces neurodegeneration in both aging and neurodegenerative disease models 39-41.
This article has been reviewed for accuracy by one of the licensed medical doctors working for Doctronic. Your healthcare provider can best explain what to expect based on your diagnosis. There’s no cure for G6PD deficiency, but most people don’t experience issues if they avoid triggers.
A) HDACi exposes the G6PD core promoter; b) SP1, HAT, HDAC, and DNA polymerase localize to the core promoter to induce G6PD transcription in erythroid precursor cells and c,d) subsequently increase protein levels in new erythrocytes. However, HDAC5 and HDAC2 have been found to disrupt erythropoiesis and therefore, inhibition of these two HDACs may have adverse side effects. Other transcriptional modulators, such as a Nrf2/Keap1 protein-protein-interaction inhibitor, may also increase G6PD transcriptional output. E) G6PD variant biochemical properties will likely influence the efficacy of a transcriptional activator, with protein stability being a major determinant of residual protein levels in aging erythrocytes.
Management and Treatment
A housekeeping enzyme responsible for catalyzing the conversion of glucose-6-phosphate and NADP+ into 6-phosphoglucono-δ-lactone and NADPH. The discovery of AG1 has inspired the pursuit of other G6PD structural chaperones. In recent computational studies, AG1 was used as a scaffold for a structure-based pharmacophore screen where five compounds were identified as potential activators of G6PD 102. In addition, several AG1 analogs were developed; although none activated G6PD better than AG1, several displayed AG1-like activation and are better suited for in vivo studies – they lack a disulfide bond 103. Cleveland Clinic’s benign hematology experts provide personalized care and support. Healthcare providers usually start by taking a complete medical history and doing a physical exam.
What are G6PD deficiency symptoms?
Consequently, methemoglobinemia is inhibited; however, hyperoxy radicals, generated from the iron redox reaction, remain uncaptured 49. Thus, both DHA reduction and hyperoxy radicals generated via iron redox reactions contribute to a hemolytic phenotype in G6PDdef patients. Additionally, ascorbate, DHA, and glucose are all internalized by GLUT1; therefore, ascorbate may alter glucose uptake and consequent PPP-mediated GSH recycling, especially in G6PDdef. G6PDdef may increase cell susceptibility to viral infections such as hepatitis B 16, dengue fever, enterovirus 71, and coronavirus 229E 11.