The National Organization for Rare Disorders estimates that 400 million people worldwide are living with glucose-6-phosphate dehydrogenase (G6PD) deficiency.1 Prevalence of the disorder is highest in Africa, Asia, the Middle East, Latin America, and the Mediterranean.2 G6PD deficiency affects about 10% of black males in the United States, and as many as 24% are carriers.1,3,4 The deficiency is an X-linked recessive inherited genetic disorder in which a mutation of the G6PD gene results in inefficient or absent expression and corresponding enzyme deficiency.1
The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection or certain medications or foods (Figure 1).
Although G6PD deficiency is recognized worldwide, the clinical and research focus has been in malarial endemic areas due to the correlation between malaria and G6PD deficiency prevalence.5 G6PD mutations may afford protection against malaria, but a clear link has not been established, and patients with G6PD deficiency are susceptible.6
In the United States, the military recognized the importance of identifying individual G6PD status in personnel deploying to areas where malaria is endemic, because some medications increase the risk of potentially severe hemolytic reactions in patients with G6PD deficiency. To ensure safe prophylaxis, the Department of Defense issued a formal policy that all personnel being deployed to malaria endemic regions must be screened for G6PD deficiency. In addition, screening is now required for all personnel entering military service.7,8
As significantly changing global demographics fostered by migration and immigration continue, diseases or conditions that were rare in Western countries, including G6PD, are likely to become more common in the United States.9,10 Additional influences affecting changing patient populations include medication prescription practices, availability of over-the-counter medications, and cultural influences in the agricultural and food-market industries. With globalization of food trends and agricultural production, immigration, international travel, and the widespread exposure to prescription and over-the-counter medications, G6PD-deficient patients potentially are at increased risk for a hemolytic event. Consequently, in populations at risk, healthcare providers should inquire about G6PD status when taking a health history, consider G6PD screening, and recognize G6PD deficiency in the differential diagnosis for certain conditions.
CAUSE AND EPIDEMIOLOGY
G6PD deficiency is an X-linked disorder resulting from an alteration or mutation of the G6PD gene located at the distal end of the long arm of the X chromosome.1,7 Because the condition is X-linked, the disorder is often considered and reported as more common in males; however, heterozygous females are actually the more common genotype.1,9 The expression of the genetic mutation is more common in males, as heterozygous females will likely not develop full-blown deficiency due to favorable X-chromosome inactivation.1,5 Homozygous female genotypes are extremely rare.1,5,10 Complete G6PD inactivation is incompatible with life and may result in spontaneous abortion.11-13
Genetic variations of G6PD deficiency are still being identified either at the DNA level or by biochemical properties. An updated G6PD allele definition table listing 188 variants with corresponding World Health Organization (WHO) classification and likely phenotype is available through the Clinical Pharmacogenetics Implementation Consortium.14 The WHO classification system for the disorder is based on the extent of enzyme deficiency and hemolysis (Table 1).1,10,15 This system of classification is relatable to the hundreds of genetic severity variants and enzyme activity levels possible with the genetic disorder.12 Clinicians may use this table as a risk-assessment tool when considering the need for patient screening. In the United States, prevalence is highest among men of black and Mediterranean descent (10% to 14%).1,5 Worldwide prevalence by ethnicity is shown in Table 2.1,16
The G6PD enzyme is critical to the conversion of nicotinamide adenine dinucleotide phosphate (NADP) to nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) during cellular metabolism within the pentose phosphate pathway. The conversion of NADP to NADPH is critical for the production of glutathione, an important antioxidant that helps protect erythrocytes against oxidative stress.9Figure 2 outlines the biochemical interactions.17 In G6PD-deficient cells, hemolysis can occur in response to free radicals and reactive oxygen species created by stressors such as infection, certain foods and medications, and even diet or lifestyle choices.3,9,10 Deficiency in G6PD may cause a reduction in the number of active enzyme molecules as well as reduced efficiency of cellular catalysis.12 Because erythrocytes carry oxygen, they are particularly vulnerable to oxidative stress when catalytically deficient.12 Furthermore, G6PD deficiency decreases erythrocytes' ability to respond to hydrogen peroxide oxidative stressors resulting from the formation of methemoglobin, a condition that may result in cyanosis, dysrhythmias, seizures, and death.18,19
Clinical manifestations of G6PD deficiency are caused by reduced enzyme activity or a reduction in active molecules, which reduces catalytic efficiency.12 This reduction in catalysis results in reduced production of protective glutathione in the pentose phosphate pathway. When G6PD-deficient erythrocytes are exposed to certain triggers or peroxide-producing substances, hemoglobin and erythrocyte membranes are oxidized, causing hemolysis.20
Due to the variability of gene mutation expression and enzyme deficiency, patients may experience different clinical manifestations depending on their WHO classification, type or extent of trigger, and lifestyle choices.9,18 The three main types of triggers are infections, certain medications, and certain foods.1,3,10
Infection is the most commonly cited cause of acute hemolytic anemia in patients with G6PD deficiency, particularly in those with severe deficiency and cytomegalovirus, hepatitis A and B, pneumonia, or typhoid fever.10,21 Infection, whether bacterial, viral, or fungal, produces reactive oxygen species through the inflammatory response, to which deficient cells are particularly susceptible.3 G6PD deficiency also may increase susceptibility to infection through these mechanisms:
- in leukocytes, a decrease in reactive oxygen species production within the pentose phosphate pathway reduces the microbicidal activity of phagocytes
- impaired formation of reactive oxygen species-dependent neutrophil extracellular traps reduces extracellular defense mechanisms against bacterial and fungal pathogens.22
Because medications are a common trigger of hemolysis in patients with G6PD, several organizations have focused on identifying these medications and their relative risk of hemolytic anemia according to ethnicity. As noted above, the US military recognized the risk of antimalarial prophylaxis in patients with G6PD deficiency. Certain medications can be used with caution but may require lower doses, particularly in patients with more severe forms of deficiency.3 Examples of more commonly prescribed medications to be avoided or used with caution in G6PD deficiency are shown in Table 3.3,11,18,21 A more complete list can be found on the Italian G6PD Deficiency Association website.21 Discrepancies between lists of medications to avoid, particularly for some antibiotics, are due to the inability to determine whether the patient's clinical manifestations were caused by the medication or underlying or preexisting infection.18
Additional medicinal herbs, products, and foods that may trigger hemolysis include various types of beans (in addition to fava), tonic or quinine water, camphor, menthol, mothballs (naphthalene), and henna.23 Hemolytic anemia occurring after consumption of fava beans is known as favism, and is the most common form of acute hemolytic anemia.24 Upon ingestion, highly reactive redox compounds are produced in the gastrointestinal tract and enter the bloodstream, producing the damaging reactive oxygen species or stressors.24 At the same time, hemoglobinuria causes decreased nitric oxide, affecting vasomotor tone and resulting in abdominal pain.24 Fava beans (also known as faba, broad, or horse beans) are used more commonly for food and feed in China, Ethiopia, Egypt, and Australia, but are being grown on small- to medium-sized farms in the United States and can be found with increasing frequency at farmers' markets in the Pacific Northwest.25,26 In addition, fava bean products can be ordered online and are marketed as dried flavored salad toppers in some mainstream, large-scale supermarkets. The global market for fava beans is expected to reach 5.2 million tons by 2024 due to their varied use, which includes bread and pasta additives, and their nutritional value.27
Neonatal jaundice due to hyperbilirubinemia is one of the most common newborn conditions requiring medical care.1 The condition is commonly physiologic; however, when jaundice is severe, refractory investigation is required. Infants with G6PD deficiency are twice as likely to develop neonatal jaundice than the general population, and jaundice can be more frequent and severe if the infant is premature.5 Signs and symptoms include yellowing of skin, sclera, and mucous membranes. Irritability, lethargy, poor feeding, vomiting, and fever in newborns with hyperbilirubinemia may indicate kernicterus, which can be fatal if not treated.1 Although the pathophysiology differs, hemolytic anemia and resulting jaundice due to favism can occur in newborns who breastfeed from mothers who ingest fava beans.25 G6PD deficiency also has been found to be a risk factor for neonatal sepsis.28
Part of the evaluation for atypical neonatal jaundice is a check for G6PD deficiency. Newborns with G6PD deficiency and jaundice will show high and persistent indirect hyperbilirubinemia that can become severe, increasing the risk of kernicterus if not treated.29,30 Infants with the genetic allele mutation associated with Gilbert syndrome may be even more at risk.31 Treatment includes initiation of phototherapy and exchange transfusion at lower total bilirubin levels than for infants without G6PD deficiency levels. The American Academy of Pediatrics (AAP) subcommittee on hyperbilirubinemia has published clinical practice guidelines for the management of hyperbilirubinemia in newborns.32
In children, hemolytic anemia resulting from G6PD deficiency may present with fatigue, irritability, and pallor. Decreased oxygenation due to erythrocyte lysis may result in shortness of breath and tachycardia. Patients with methemoglobinemia may appear cyanotic, and severe cases can cause dysrhythmias, seizures, and death.18 Fever, dark urine, low back pain, abdominal pain, and splenomegaly may occur, in addition to abdominal pain, nausea, or diarrhea.1 Hemolytic anemia associated with favism, which is more common and more severe in children, may present 1 to 2 days after ingestion with slight fever and either lethargy or irritability.1
Adults may exhibit the same signs and symptoms as children to varying degrees according to their genetic variant and level of deficiency. In fact, heterozygous females may vary individually and over time due to X-chromosome inactivation and the variability in ratio of deficient to normal erythrocytes.18 Case studies involving potential rare complications in young men with G6PD deficiency include rhabdomyolysis after exertional activity with an upper respiratory infection and central retinal vein occlusion after completion of malaria prophylaxis.2,33 Additional research has studied the relationship between G6PD deficiency and several other clinical conditions, including endothelial damage and cardiovascular disease, diabetes and renal disease, and pulmonary arterial hypertension.34-38
Treatment of hemolytic anemia in a patient with G6PD deficiency depends on the extent of the anemia. In many cases, no treatment is required beyond treatment of an underlying infection or discontinuation of the trigger when applicable (for example, medication or food). Patients with more moderate cases may need short-term IV fluids to treat renal failure or prevent hemodynamic shock.1 Patients with severe disease and rapid rates of hemolysis may need blood transfusions, which are more likely needed in children, particularly when due to favism. Transfusion can be lifesaving.1
Avoiding oxidative stressors and the triggers producing them is the most effective management strategy for G6PD deficiency.10 After identifying and characterizing the presence and level of G6PD deficiency, healthcare professionals should obtain a thorough patient history, including over-the-counter medication use and dietary habits. Patient education involving trigger avoidance and recognition of the signs and symptoms of hemolytic anemia are critical, particularly in patients with a more severe form of deficiency and lower enzymatic activity level. Diet and lifestyle modifications may also help prevent complications. Excessive alcohol use, tobacco use, physical inactivity, and a poor or unbalanced diet all increase oxidative stress markers.9 Erythrocytes that are G6PD-deficient already are more susceptible to oxidative stress, which can further increase the potential for hemolysis.
SCREENING AND DIAGNOSTIC TESTING
Screening and diagnostic testing guidelines may differ according to the patient's geographic location, ethnicity, sex, and age. Universal newborn screening programs exist in many malaria-endemic areas, such as Asia, Africa, Europe, and the Middle East, but newborn screening in the United States is state-dependent.18 Specific information is available at www.babysfirsttest.org/newborn-screenings/states, a nationwide public health website focusing on the recommended uniform screening panel.4 In nonmalaria endemic regions such as the United States, G6PD deficiency may be more likely diagnosed during a clinical workup if it is part of the differential diagnosis, such as for congenital nonspherocytic hemolytic anemia, chronic hemolysis, or acute hemolytic anemia. AAP recommendations for testing are specific to newborns requiring phototherapy for neonatal jaundice with ethnicity, geographic origin, or family history suggestive of G6PD deficiency, or for infants failing to respond adequately to phototherapy.30,32
Routine screening of adults occurs during military service either upon entry or before deployment to an area requiring malaria chemoprophylaxis.7,8 Screening also may be considered for civilians traveling to malaria risk areas for business or leisure. Individual diagnostic testing in other adults is performed if G6PD deficiency is suspected due to clinical presentation, family history, or ethnicity. Initial laboratory findings in patients with acute hemolytic episodes due to G6PD deficiency may demonstrate a rapid decrease in hemoglobin concentration by 3 to 4 g/dL and the presence of microspherocytes, “bite” cells, “blister cells,” and Heinz bodies on peripheral blood smear.16
Multiple tests can be used to assess G6PD deficiency. They generally fall into two categories: quantitative and qualitative. In the United States, testing is almost always quantitative; qualitative testing is common where laboratory resources are limited.39 The qualitative fluorescent spot screening test or quantitative assay will demonstrate decreased G6PD enzyme activity; molecular genetic testing including polymerase chain reaction may be used to detect mutations.1,40 Importantly, young erythrocytes and reticulocytes may have up to five times higher G6PD enzyme activity; therefore, after severe hemolysis, the analysis can be falsely negative.2,33 False negatives also may occur after blood transfusion, and retesting may be required after 2 to 3 months when erythrocytes of all ages are present.40
Although G6PD deficiency is less known in Western countries, there are several compelling reasons to identify and educate patients and to ensure that healthcare providers recognize and understand the disorder. The knowledgeable patient can avoid triggers and reduce the risk of harmful clinical manifestations associated with increased oxidative stress. By recognizing the potential for G6PD deficiency in risk groups and being proactive with screening, clinicians may be able to improve patient quality of life and reduce healthcare costs associated with harmful clinical manifestations. This ability is becoming increasingly important as global migration, medication use, and dietary habits continue to influence patient populations in the United States.
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