Management of Athletes With G6PD Deficiency: Does Missing an Enzyme Mean Missing More Games?

Abstract

Context:

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is likely the most prevalent enzyme deficiency on the planet, with an estimated 4.9% of people, or approximately 330 million individuals, across the globe affected by the disease. In the United States, 4% to 7% of the population is likely affected, but each year our nation’s major sport leagues become more international. It is important for medical professionals who treat athletes to understand how this genetic condition can affect the athletes we are working with, especially because exercise in itself results in oxidative stress.

Evidence Acquisition:

PubMed was searched for relevant articles published from 1980 to 2018. The search terms G6PD, athletes, military, and sports were used.

Study Design:

Clinical review.

Level of Evidence:

Level 4.

Results:

Though some case reports suggest a potential impact on athlete safety and performance, controlled studies demonstrate limited impact of exercise on oxidative stress in G6PD-deficient individuals. The care of athletes with G6PD deficiency does not drastically differ from the care of athletes without this condition. Most of the medications and supplements that are regularly given to athletes should not negatively affect their health.

Conclusion:

Although the care of athletes with G6PD deficiency is for the most part no different from the care of other athletes, there are certain situations (visiting areas where malaria is endemic) and medications for which it is important to recognize how your management should change. G6PD deficiency is not regularly screened for but could be considered if an athlete has known sickle cell disease or when traveling to areas where malaria is prevalent. Expanding our knowledge of G6PD deficiency will allow for better care of athletes.

Science and Clinical Presentation of G6pd Deficiency

In an unaffected human, glucose-6-phosphate dehydrogenase (G6PD) plays a key role in protecting red blood cells from oxidative injury by catalyzing the reduction of NADP+ (nicotinamide adenine dinucleotide phosphate) to NADPH (reduced form of NADP+) via the pentose phosphate pathway (Figure 1). Without adequate NADPH, oxidized glutathione cannot be reduced. As levels build up, red blood cells undergo hemolysis due to the oxidative stress created by the excess glutathione.²⁰ G6PD in the pentose phosphate pathway is an important physiologic response to oxidative stress (such as exercise). A study of 10 active (2 hours of exercise/day) and 10 sedentary individuals (0 hours of exercise) showed that exercise can increase G6PD activity 24 hours after aerobic activity in individuals who exercise 2 hours per day, but not in sedentary participants.⁷

Figure 1.

G6PD pathways. The top portion (A) represents the reaction pathway that protects the red blood cell (RBC) in individuals without an enzyme deficiency. The bottom portion (B) represents the pathway in individuals with glucose-6-phosphate dehydrogenase deficiency, resulting in increased RBC lysis. In the figure, a blue box indicates an oxidized component, yellow indicates a reduced component, and green represents an enzyme. NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of NADP+.

There are 5 different variants of the deficiency classified by the World Health Organization. The variants are differentiated based on the degree of enzyme deficiency and severity of the hemolytic response to oxidative stress. Classes I to III have enzyme deficiencies associated with a hemolytic response, class IV is considered the “wild type” with no measurable difference, while class V is associated with an increase in enzyme activity. Therefore, only the first 3 classes are considered clinically relevant.¹¹

Patients with G6PD deficiency are often asymptomatic. Certain foods (classically fava beans), antibiotics, and infection are known triggers for those affected by the disease.³ G6PD deficiency manifests during periods of oxidative stress, which causes hemolytic anemia characterized by fatigue, back and muscle pain, splenomegaly, and jaundice. Laboratory abnormalities may include anemia, reticulocytosis, hematuria, low haptoglobin, unconjugated hyperbilirubinemia, elevated liver enzymes, and elevated lactate dehydrogenase.⁵

As clinicians, we care for individuals who push their bodies and minds to extreme limits during training and competition. There are risks with this type of exertion, even in athletes with no prior medical history or intrinsic factors that may predispose them to injury, illness, or long-term sequelae. Such risks can be even higher when underlying medical conditions are present, and limitations may be needed. As we care for a patient population with a highly diverse ancestral background, we may come across athletes with conditions that, if not considered, could be detrimental to the athlete’s health by his or her activity or iatrogenic interventions. G6PD deficiency is one such condition. This review of the literature is designed to expose potential dangers in athletes with this condition.

Epidemiology

G6PD deficiency is the most prevalent enzyme deficiency on the planet, with an estimated 4.9% of people, or approximately 330 million individuals, across the globe affected by the disease. The most densely affected populations are found in tropical and subtropical regions of Africa (7.5%), the Middle East (6%), Asia (4.7%), and Europe (3.8%, particularly the Mediterranean). Domestically, it is estimated that between 4% and 7% of the US population is affected, most of whom are descendants of African and Mediterranean origin.²³

A closer look at athletes and military recruits reveals that a small percentage of those subpopulations is affected by the disease. In the 1970s, a study of 101 African American athletes showed that 1.9% were G6PD deficient.²⁴ Also at this time, African American male Navy and Marine recruits were screened for the disease, and 12.6% were affected.²⁷ More recent data from over 63,000 Army recruits revealed that 2.5% of males and 1.6% of females (4.1% of African American females) were affected. African American and Asian recruits had the highest rates of G6PD deficiency, with class III and class IV variants being predominant in males and females, respectively.⁶

Additionally, the nation’s major sport leagues are becoming more international. As this trend continues, a growing number of individuals from the more densely affected regions will participate in US professional sports leagues. This is most prominently seen in the National Basketball Association (NBA) and Major League Soccer (MLS). NBA rosters for the 2017 season showed athletes from Africa (3%) and Europe (12%), with the MLS showing 6% from Africa and 11% from Europe (not including England).¹

Impact of Exercise

The definitive implications of exercise in individuals with G6PD deficiency are unknown. Clinical complications related to exercise and G6PD deficiency rely on insight from a small number of case studies of athletes with the disease. In a 4-patient case series of G6PD deficiency, 2 appeared to have activity-related complications.^4,9,17 These cases present nonspecific symptoms that can be seen in healthy patients after strenuous exercise. In some cases, G6PD deficiency was diagnosed after developing an exercise-related medical complication, while in other situations individuals knew they had G6PD deficiency or had other concomitant conditions placing them at increased risk.

In contrast, controlled studies have shown limited impact of exercise on oxidative stress in G6PD- deficient individuals, suggesting strenuous exercise independent of G6PD deficiency may have triggered symptomatology.¹⁴ Exercise can induce oxidative stress, and conditioned athletes can develop tolerance to oxidative stress.¹⁰ However, there is no measurable difference in the degree of oxidative stress between G6PD-deficient and normal controls. Two studies using oxidative stress biomarkers as an indicator of cell injury showed no difference in athletes with and without G6PD deficiency while performing intense aerobic exercise.^14,21 Similarly, eccentric exercise appears well tolerated in G6PD deficiency. A study of 9 male G6PD-deficient individuals with 9 male controls showed that an eccentric muscle-damaging exercise protocol caused muscle damage (increased serum creatine kinase), hemolysis (increased bilirubin), and oxidative stress with peak effects seen 2 to 3 days after exercise, but there was no difference between the groups.²⁶

Medications and Supplements

Nonsteroidal anti-inflammatory drugs and antimicrobials are prescribed to athletes more often than age-matched controls. Additionally, inappropriately high doses, as well as prescribing different medications of the same class, may occur in athletes.²⁸ Some medications can cause hemolysis in individuals with G6PD deficiency and must therefore be considered when prescribing to this population.^3,12

The list of medications that are likely unsafe in G6PD deficiency is quite short and does not include any medications that are frequently prescribed to athletes (Table 1, adapted from Luzzatto and Seneca¹⁹ and Youngster et al²⁸). We also acknowledge that some medications, such as acetaminophen, ibuprofen, and trimethoprim-sulfamethoxazole, were once considered unsafe.^3,28 Based on our review of the literature, we believe that medications not listed in Table 1 and even those once considered “unsafe” should be considered safe when prescribing to G6PD-deficient patients and given in usual, therapeutic doses. Alternatively, many medications providers often prescribe do not cause hemolysis in G6PD deficiency, such as steroids, muscle relaxers, cold relief medications, and antiallergy medications. There are unique circumstances in which a medication from Table 1 may be prescribed if the risk is appropriately evaluated. For example, an athlete with G6PD deficiency traveling to areas where malaria is prevalent would use mefloquine or atovaquone-proguanil as prophylaxis, but if resistance requires primaquine, then it should be considered. Additionally, patients with G6PD deficiency at risk for tumor lysis syndrome receive allopurinol to control hyperuricemia, but in the setting of impaired renal or cardiac function, then rasburicase is preferred.^15,19

Table 1.

Commonly encountered medications, foods, and substances that should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency

Substance	Substance Type	Class
Dapsone	Drug	Antimicrobial
Methylene blue	Drug	Toxicity medication
Nitrofurantoin	Drug	Antimicrobial
Phenazopyridine	Drug	Analgesic
Primaquine	Drug	Antimicrobial
Rasburicase/pegloticase	Drug	Gout medication
Acalypha indica	Traditional medicine
Coptis chinesis	Traditional medicine
Fava beans	Food
Henna	Exposure	Tattoo and dyes
Naphthalene	Exposure
Toluidine blue	Exposure	Cellular nuclei stain

Athletes are a unique patient population in that they are often looking to gain any type of competitive edge, especially relating to diet and supplements.² There is an association between hemolysis and legumes, especially fava beans, falafel (made from ground chickpeas, fava beans, or both), chickpeas, green peas, and green tea and its extracts.¹⁸ The association between herbal and dietary supplements and hemolysis is less clear than drugs and diet. There is evidence linking henna (topical) to hemolysis.¹⁸ Hemolysis has been seen with vitamin C at very high doses.¹⁸ Vitamin E, vitamin K, gingko, and α-lipoic acid are considered safe in G6PD deficiency.¹⁸ There have been small studies and case reports showing conflicting evidence of hemolysis with Acalypha indica (a weed in various parts of Asia used for its claimed anti-inflammatory, antimicrobial, and antitussive effects) and Coptis chinesis (commonly used herb in China for various ailments, including febrile illness).¹⁸ Interestingly, some supplements may be beneficial in G6PD deficiency. Vitamin E, a natural antioxidant, may be protective, and α-lipoic acid is a potent antioxidant to restore intracellular glutathione and thus may benefit G6PD-deficient individuals¹⁸ (Table 2). Additionally, a 10-athlete study found that l-cys supplementation may protect G6PD activity from reduction by increasing total antioxidant capacity and glutathione production.²⁵

Table 2.

Supplements that may be protective for patients with glucose-6-phosphate dehydrogenase deficiency

Supplement
Vitamin E
l-cys supplementation

Screening for G6PD Deficiency

Preparticipation screenings for hematologic disease currently focus on sickle cell status; there is no specific screening question for G6PD deficiency at any level of sport. Similarly, newborn screening for G6PD deficiency is not routinely performed in the United States. The American Academy of Pediatrics recommends testing for G6PD in jaundiced newborns receiving phototherapy whose family history, ethnicity, or geographic origin suggest the possibility of the condition or for infants whose response to phototherapy is poor.¹³ Once a patient has screened positive through an enzyme assay for reduction of NADP (acquired through a blood draw), it is often unnecessary to determine the specific variant because only classes I to III are clinically significant, and most cases are of class II or III, which have the same management.^11,22 However, the variability of hemolysis severity in the Chinese population can warrant variant (class I vs II) determination if there are continued complications despite conservative management.¹⁶

When and Who to Test?

G6PD deficiency should be considered as an etiology of unexplained rhabdomyolysis and hemolytic anemia, especially in male patients of African, African American, Asian, or Mediterranean descent. However, given the current paucity of evidence regarding the risk of exercise with G6PD deficiency, no current recommendations for screening in asymptomatic individuals exist. Therefore, specifically screening for it during preparticipation examination, either with a questionnaire or laboratory testing, is not warranted. In those with known G6PD deficiency, the usual medical practice of counseling should occur regarding medications and foods to avoid. G6PD deficiency and sickle cell trait/disease have similar geographic distributions and can occur together in up to 5% of men of African descent,⁸ so it is reasonable to consider testing athletes with sickle cell for G6PD deficiency if they present with unexplained rhabdomyolysis or for those who may be exposed to offending medications such as uric acid–lowering medications or chemotherapy agents. Screening could also be considered if an athlete travels to areas where malaria is prevalent. Prior to prescribing any of the medications that are likely unsafe in moderate to severe G6PD deficiency (classes I-III, Table 1) the clinician should consider testing for G6PD deficiency, especially in populations for whom G6PD deficiency is common, such as African American, Middle Eastern, and Mediterranean.^3,19

Conclusion

Although patients with G6PD deficiency were infrequently encountered in the past, the globalization of sports requires that a new perspective be considered. Based on these data, athletes with G6PD deficiency do not appear to be physically limited. Rather, physicians should be aware of potential problems, especially with medication.