Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder that affects the enzyme responsible for protecting red blood cells from oxidative damage. Individuals with this deficiency are prone to hemolysis, the rupture of red blood cells, particularly when exposed to certain triggers such as infections, specific medications, chemicals, and fava beans. This condition is more prevalent in regions such as Africa, Asia, the Middle East, and Mediterranean Europe, and predominantly affects males, with females often being carriers who experience milder symptoms.
The deficiency results from mutations in the G6PD gene, leading to inadequate production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), a critical component in defending against oxidative stress. Symptoms of hemolysis can include weakness, jaundice, and abdominal pain, which require medical evaluation, especially in newborns who are at risk of developing jaundice and potential brain damage. Diagnosis typically involves screening tests that measure NADPH production in red blood cells.
Treatment mainly focuses on avoiding known triggers and managing symptoms, as most individuals with G6PD deficiency lead relatively normal lives. However, those with severe forms of the deficiency may face significant health risks, including kidney failure and complications from hemolysis. Awareness of this condition and its management is essential for affected individuals to prevent serious health outcomes.
Glucose-6-phosphate dehydrogenase deficiency
ALSO KNOWN AS: Favism
DEFINITION Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder in which red blood cells (RBCs) lack normal amounts of this enzyme, which is responsible for preventing oxidative damage to the cell. Under conditions that cause oxidative injury (infection, exposure to certain drugs and chemicals, and ingestion of fava beans) deficient RBCs rupture, causing anemia.
Risk Factors
The condition is prevalent in Africa, Asia, the Middle East, and Mediterranean Europe. It also affects people throughout the world whose ancestry originates from those areas. As an X-linked disorder, its fullest expression is seen most commonly in males. In addition to infection and eating fava beans, common triggers include certain antibiotics (mostly sulfa derivatives), the antimalarial medicine primaquine, and various chemicals (such as naphthalene, trinitrotoluene, methylene blue, and henna).
Etiology and Genetics
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme of the hexose monophosphate pathway of glucose metabolism. It is also the only pathway in RBCs that produces reduced nicotinamide adenine dinucleotide phosphate (NADPH), a compound critical to producing reduced glutathione, which inactivates harmful oxidants resulting from both normal functions (hemoglobin and oxygen interactions) and superimposed factors (infection, exogenous chemicals). When G6PD function is compromised or abnormal, this protective mechanism fails, and red blood cells rupture and die (hemolysis).
The gene for G6PD is on the long arm of the X chromosome in band Xq28. About 160 mutations have been identified, mostly single point substitutions. About 400 biochemical variants of the enzyme have been described on the basis of electrophoretic properties, kinetic activity, and other biochemical characteristics. However, further study with modern techniques of molecular biology suggests that some of these apparent variants actually stem from the same mutation.
The World Health Organization (WHO) has classified G6PD abnormalities into five categories, depending upon the degree of enzyme deficiency and the severity of the resulting syndrome. Class I mutations cause severe enzyme deficiency and chronic hemolytic anemia; types II and III are progressively less severe; and types IV and V result in normal or increased enzyme production.
Some common alleles are named according to letters, based on electrophoretic mobility of the enzyme, and by + or − indicating relative activity of the enzyme. Wild type is designated G6PD B. Two variants common in Africa are G6PD A+ and G6PD A- (the latter also occurs in 10 to 15 percent of African Americans). They are classified as WHO Types IV and III, respectively. Other alleles are named descriptively. The Mediterranean variants are prevalent in southern Europe, the Middle East, India, and other parts of Asia. They tend to cause more consequential illness and fall into WHO Class II.
Because the gene is X-linked, hemizygous men who inherit an affected X chromosome are most commonly affected clinically. Heterozygous women are less likely to experience symptoms. They are genetic mosaics, and by the Lyon hypothesis, each cell randomly inactivates one X chromosome. The result is approximately 50 percent normal G6PD activity. In fact, the observation that heterozygous women rarely experience severe symptoms and have higher enzyme levels than affected males was cited as evidence supporting the Lyon hypothesis. In areas where a large percentage of the population carries the deficiency (such as parts of Africa), homozygous females are seen frequently, and they experience clinical manifestations.
The overlap in geographical distribution of G6PD deficiency and malaria led to conjecture that this genetic cause of hemolysis may confer a protective survival benefit. Population studies and in vitro work support this theory.
Symptoms
Symptoms of hemolysis may include weakness, lightheadedness, palpitations, nausea, pain in the back or abdomen, jaundice, and discolored urine. Newborns may develop jaundice and kernicterus (brain damage) resulting in seizures. Pain, jaundice, discolored urine, and seizures all require prompt medical evaluation; evaluation of other symptoms should be dictated by the degree of discomfort.
Screening and Diagnosis
Routine neonatal screening is not done in the United States because of low prevalence. Testing may be advisable, however, when family history suggests the condition. A common method for screening and diagnosis relies on production of fluorescent NADPH from the reaction between NADP and glucose-6-phosphate; G6PD deficient cells produce too little NADPH for visible fluorescence. False negatives occur immediately after a hemolytic event, as older RBCs with the lowest G6PD content die, leaving younger cells with higher concentrations. Heterozygous females also test negative. Other methods include spectrophotometry, dye decoloration, and polymerase chain reaction.
Treatment and Therapy
Hemolysis in adults with G6PD deficiency usually requires no treatment except to address the cause. Infection should be treated if specific therapy is available. Implicated medications should be stopped or changed. Severe anemia may necessitate transfusion or supplements of iron and folate. Neonatal jaundice usually responds to phototherapy; exchange transfusion sometimes is required.
Prevention and Outcomes
Affected individuals should avoid known agents of hemolysis, particularly fava beans, the most potent triggers. They should seek treatment for infections that might precipitate hemolysis. For most with G6PD deficiency, the condition is mild. Those with Class I and II mutations may experience severe hemolysis resulting in kidney failure, even death. Gallstones sometimes occur, the result of accumulated hemoglobin pigment. Kernicterus in neonates may cause permanent brain damage or death.
Further Reading
Cappellini, Fiorelli G. “Glucose-6-Phosphate Dehydrogenase Deficiency.” Lancet 371 (2008): 64-74. Print.
Frank, Jennifer E. “Diagnosis Management of G6PD Deficiency.” American Family Physician 72 (2005): 1277–282. Print.
"Glucose-6-Phosphate Dehydrogenase Deficiency." MedlinePlus. Natl. Lib. of Medicine, 24 Feb. 2014. Web. 1 Dec. 2015.
Luzzatto, Lucio, and Vincenzo Poggi. "Glucose-6-Phosphate Dehydrogenase Deficiency." Nathan and Oski's Hematology and Oncology of Infancy and Childhood. Ed. Stuart H. Orkin et al. 8th ed. Philadelphia: Elsevier, 2015. 609–29. Print.
Nussbaum, Robert L., Roderick R. McInnes, and Huntingdon F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Price, Elizabeth A., Stavroula Otis, and Stanley L. Schrier. "Red Blood Cell Enzymopathies." Hematology: Basic Principles and Practice. Ed. Ronald Hoffman et al. 6th ed. Philadelphia: Elsevier, 2013. Print. 581–91.
Richardson, S. Russ and Gerald F. O'Malley. Glucose-6-Phosphate Dehydrogenase Deficiency. StatPearls, 2022, National Library of Medicine, https://www.ncbi.nlm.nih.gov/books/NBK470315/. Accessed 5 Sept. 2024.