Medications to Avoid in Patients with G6PD Deficiency Due to Risk of Hemolysis

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.

Neonatal Jaundice, Kernicterus, Hyperbilirubinemia

A branch of glucose metabolism, parallel to glycolysis, where glucose-6-phosphate is diverted to produce cellular NADPH and ribose-5-phosphate; metabolites important in redox homeostasis, nucleotide and fatty acid synthesis. Due to loss of hemoglobin O2 binding, symptoms are largely related to O2 deficiency. An endogenous antioxidant that protects the cell from oxidative stress by neutralizing ROS; upon reaction with ROS, GSH is converted to GSSH, where it is recycled back into GSH by glutathione reductase, using NADPH as a cofactor.

• At baseline, they have elevated levels of glycolytic metabolites related to NADH and ATP production, with a net increase in ATP levels 64.
• The most common sign is jaundice, which appears within the first few days of birth.
• Many people with G6PD deficiency likely never know because they don’t have symptoms.
• However, challenging patient erythrocytes in vitro with H2O2 revealed no change in the degree of hemolysis, despite improvements in hematological parameters 55.

You should also avoid eating fava beans while breastfeeding if your newborn has a G6PD deficiency. The compounds that can trigger hemolytic anemia can travel through breast milk. G6PD is important because it prevents too many “free radicals” from building up in your red blood cells. Free radicals are usually harmless substances found in all kinds of places, like the environment, fava beans and medicines. Currently, Tecfidera® (dimethyl fumarate), indicated for use in multiple sclerosis, is the only FDA approved activator of Nrf2.

What are G6PD deficiency symptoms?

• 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.
• Upon oxidant exposure, ascorbate is oxidized to dehydroascorbic acid (DHA) in the plasma and DHA is rapidly uptaken by erythrocyte glucose transporter 1 (GLUT1).
• There’s no cure for G6PD deficiency, but most people don’t experience issues if they avoid triggers.
• 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.
• However, the development of a gene therapy for G6PDdef presents a major challenge; the cost per Zynteglo® treatment course is set at $1.8 million with high costs common in gene therapy 114.

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.

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.

However, despite its reputable role as a therapeutic antioxidant, few cases report the use of NAC to treat G6PDdef (Table 2). G6PDdef is a major and well-known risk factor for jaundice and hyperbilirubinemia in newborns as hemolysis increases bilirubin levels in the serum 28. In newborns, bilirubin can cross the blood brain barrier and cause neurological issues such as kernicterus or acute bilirubin encephalopathy 29. Interestingly, newborns with kernicterus have a higher chance of developing sensorineural hearing loss 30, suggesting a role of G6PDdef in auditory disorders.

Medications to Avoid in Patients with G6PD Deficiency Due to Risk of Hemolysis

Additionally, viral infections may trigger hemolytic complications in G6PDdef patients 17-19. Recently, two case-reports found G6PD medications 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.

Antioxidants

Natural products such as curcumin, sulforaphane, and flavonoids have also been shown to activate Nrf2 94,95. Unfortunately, these molecules are electrophiles and lack target specificity, making them toxic 96,97. A small molecule or peptide inhibitor of the Keap1/Nrf2 protein interaction may increase target selectivity and overcome toxicity and remains an attractive target 98. As with all drugs, too much of anything can be a bad and chronic activation of Nrf2 may cause reductive stress 93.

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.

Lessons from Antioxidant Treatments

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.

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.

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.

Treatment Strategies for Glucose-6-Phosphate Dehydrogenase Deficiency: Past and Future Perspectives

Despite this, lower doses have been used to treat methemoglobinemia in G6PDdef patients (Table 1) 23,46-48; four case studies reported use of ascorbate to treat methemoglobinemia induced by rasburicase or other AHA triggers (Table 1). However, blood transfusions were used as co-treatments, masking the safety and efficacy profile of low-dose ascorbate. A combination therapy including oral NAC and a GCL activator, the rate limiting enzyme of GSH biosynthesis, may improve GSH levels in erythrocytes, protecting them against oxidative stress.

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.

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.