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Glucose-6-Phosphate Dehydrogenase Deficiency
Introduction
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme found in the cytoplasm of all cells in the body. It is a housekeeping enzyme that plays a vital role in preventing cellular damage from reactive oxygen species (ROS). It does this by providing substrates to prevent oxidative damage. Erythrocytes are particularly vulnerable to ROS due to their role in oxygen transport and their inability to replace cellular proteins as mature cells. Inherited deficiencies of G6PD can result in acute hemolytic anemia during increased ROS production. This may be caused by stress or exposure to foods containing high amounts of oxidative substances, such as fava beans or certain medications. In particular, anti-malarial agents are strongly associated with inducing hemolytic anemia in patients with G6PD deficiency. Below are medications more commonly used in the United States that have been shown to trigger a hemolytic crisis in those with G6PD deficiency; however, a more comprehensive list of medications to be avoided has been published by the Italian G6PD Deficiency Association and can be found at www.g6pd.org.[1][2][3][4] Common medications to be avoided or used with caution in G6PD-deficient patients include:
- Acetaminophen
- Acetylsalicylic acid
- Chloramphenicol
- Chloroquine
- Colchicine
- Diaminodiphenyl sulfone
- Diphenhydramine
- Glyburide
- Isoniazid
- L-Dopa
- Methylene blue
- Nitrofurantoin
- Phenazopyridine
- Primaquine
- Rasburicase
- Streptomycin
- Sulfacetamide
- Sulfanilamide
- Sulfapyridine
- Sulfacytine
- Sulfadiazine
- Sulfaguanidine
- Sulfamethoxazole
- Sulfisoxazole
- Trimethoprim
- Tripelennamine
- Vitamin K
Etiology
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Etiology
The Gd gene codes for the G6PD enzyme. This gene is located on the long arm of the X chromosome and, therefore, follows X-linked inheritance. Deficiency of G6PD may be due to mutations that change the protein structure and, therefore, reduce its activity or the amount of enzyme produced. There are 186 known human G6PD mutations; most point mutations affect a single nucleotide. None of the mutation patterns seen in humans cause complete inactivation of G6PD since this would be lethal to a developing embryo.[5][6][7]
Epidemiology
G6PD is the most common human enzyme defect, affecting over 400 million people worldwide. Men are more commonly affected than women due to X-linked inheritance. It is most prevalent in tropical and subtropical areas. Interestingly, evidence suggests that G6PD deficiency is protective against uncomplicated malaria but not severe malaria cases. The protective mechanism for G6PD deficiency and malaria is still being investigated. With regards to ethnicity, G6PD deficiency is more common in people of African, Mediterranean, or Asian descent, likely owing to its suggested protective effect from malaria.
Pathophysiology
G6PD is the catalyst in the rate-limiting first step of the pentose phosphate pathway, which uses glucose-6-phosphate to convert nicotinamide adenine dinucleotide phosphate (NADP) into its reduced form, NADPH. In red blood cells, NADPH is critical in preventing damage to cellular structures caused by oxygen-free radicles. It does this by serving as a substrate for the enzyme glutathione reductase. Reduced glutathione can be used to convert hydrogen peroxide to water and prevent damage to cellular structures, particularly the cell wall of red blood cells (RBCs), since they have limited capacity for repair once they mature.[8][9][10]
History and Physical
Although most patients remain asymptomatic throughout their lives, the clinical manifestations of G6PD deficiency depend on their age. In newborns, G6PD deficiency is recognized as a serious risk factor for the development of neonatal hyperbilirubinemia. Neonates with G6PD deficiency are 2 times more likely to develop hyperbilirubinemia than the general population, and approximately 20% of kernicterus cases are associated with G6PD deficiency. Symptoms of kernicterus in a newborn include lethargy, extreme sleepiness, and poor muscle tone. Although rare, G6PD deficiency should be considered in neonates who develop jaundice in the first 24 hours of life, who have a history of a sibling with neonatal jaundice, or who have a bilirubin level greater than the 95th percentile. In adults, common symptoms and exam findings of G6PD deficiency include those of hemolytic anemia or possibly red blood cell sequestration by the spleen. These manifestations include pallor, jaundice, fatigue, splenomegaly, and dark urine.
Evaluation
In newborns, jaundice is assessed by examining the skin for a yellow appearance in a well-lit room. More objective measurements include obtaining total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) in newborns. An hour-specific bilirubin nomogram can risk-stratify newborn patients with elevated bilirubin levels to help determine the appropriate treatment. Although screening tests for G6PD deficiencies are available, they are not routinely performed in the United States. However, screening should be considered in newborns with severe jaundice resistant to phototherapy or who have a family history or ethnicity suggestive of G6PD deficiency. The most common screening method includes a rapid fluorescent spot test to detect the generation of NADPH from NADP. Screening can also be performed using quantitative spectrophotometric analysis.
The evaluation of older patients presenting with complications of G6PD deficiency begins with a complete history, including new medications and screening for a family history of similar symptoms. It is also important to evaluate for possible infection, as the stress of infection may trigger a hemolytic event in patients with G6PD deficiency. Laboratory studies include a complete blood count, bilirubin levels, reticulocyte count, serum aminotransferases, and lactate dehydrogenase. A peripheral blood smear may show signs of hemolysis, such as schistocytes and Heinz bodies.
Treatment / Management
In neonatal patients, treatment focuses on managing jaundice and preventing kernicterus. This includes phototherapy based on standard published guidelines. In severe cases, an exchange transfusion may be necessary.[11][12] In older patients, management depends primarily on the overall clinical picture. Less severe presentations may be managed with supportive care, discontinuation, and avoidance of the offending agents. Treat any infections as indicated by history and exam. More severe cases may require transfusions.[13][14](B3)
Differential Diagnosis
Many disease processes may resemble the pathophysiology of G6PD deficiency. Therefore, differential considerations should include:
- Autoimmune hemolytic anemia
- Bilirubin conjugation disorders (eg, Gilbert syndrome)
- Hemolytic disease of the newborn
- Hereditary spherocytosis
- Sickle cell anemia
- Thalassemia
Pearls and Other Issues
A special situation exists in the management of G6PD patients with methemoglobinemia. Methemoglobin (MetHg) forms in red blood cells when the iron in the heme group of hemoglobin molecules undergoes oxidation from the normal ferrous (Fe 2+) state to the ferric (Fe3+) state. This ferric state is a poor binder of oxygen. Symptoms of hypoxia begin to develop when the level of methemoglobin reaches 10%, and death can occur when the level reaches greater than 50%.
Methemoglobinemia should be considered in patients presenting with central cyanosis and hypoxia whose symptoms are resistant to supplemental oxygen. A specific antidote for severe acute methemoglobinemia is methylene blue. Intravenously injected methylene blue is reduced to leucomethylene blue through NADPH-dependent mechanisms. Leucomethylene blue is then used as a substrate to reduce methemoglobin back to hemoglobin. However, patients deficient in G6PD lack sufficient NADPH to reduce methylene blue properly. Unreduced methylene blue can cause further oxidative damage in the G6PD-deficient patient, resulting in hemolysis and even death. Therefore, patients known or suspected to have any G6PD deficiency mustn't receive methylene blue. Alternative therapies for G6PD deficient patients presenting with methemoglobinemia include transfusing packed red blood cells or providing hyperbaric oxygen therapy.
Enhancing Healthcare Team Outcomes
Diagnosing and managing G6PD deficiency is best done with an interprofessional team that includes a geneticist, pediatrician, internist, laboratory professional, pediatric nurses, and a hematologist. In newborns, the treatment focuses on managing jaundice and preventing kernicterus. In older patients, management depends primarily on the overall clinical picture. Less severe presentations may be managed with supportive care, discontinuation, and avoidance of the offending agents. Treat any infections as indicated by history and exam. More severe cases may require transfusions. The primary caregiver, nurse practitioner, and pharmacist must regularly evaluate the patient's medications to ensure that none is associated with this disorder.
References
Antwi-Baffour S, Adjei JK, Forson PO, Akakpo S, Kyeremeh R, Seidu MA. Comorbidity of Glucose-6-Phosphate Dehydrogenase Deficiency and Sickle Cell Disease Exert Significant Effect on RBC Indices. Anemia. 2019:2019():3179173. doi: 10.1155/2019/3179173. Epub 2019 Mar 19 [PubMed PMID: 31016042]
Yang WC, Tai S, Hsu CL, Fu CM, Chou AK, Shao PL, Li MJ. Reference levels for glucose-6-phosphate dehydrogenase enzyme activity in infants 7-90 days old in Taiwan. Journal of the Formosan Medical Association = Taiwan yi zhi. 2020 Jan:119(1 Pt 1):69-74. doi: 10.1016/j.jfma.2019.03.010. Epub 2019 Apr 10 [PubMed PMID: 30979648]
You X, Jiang W, Lu W, Zhang H, Yu T, Tian J, Wen S, Garcia-Manero G, Huang P, Hu Y. Metabolic reprogramming and redox adaptation in sorafenib-resistant leukemia cells: detected by untargeted metabolomics and stable isotope tracing analysis. Cancer communications (London, England). 2019 Apr 4:39(1):17. doi: 10.1186/s40880-019-0362-z. Epub 2019 Apr 4 [PubMed PMID: 30947742]
Chu CS,Freedman DO,Gorgas WC, Tafenoquine and G6PD: A Primer for Clinicians. Journal of travel medicine. 2019 Apr 3; [PubMed PMID: 30941413]
Lauden SM, Chongwain S, Achidi A, Helm E, Cusick SE, Krug A, Slusher TM, Lund TC. Prevalence of glucose-6-phosphate dehydrogenase deficiency in Cameroonian blood donors. BMC research notes. 2019 Apr 2:12(1):195. doi: 10.1186/s13104-019-4226-z. Epub 2019 Apr 2 [PubMed PMID: 30940186]
Tseghereda YG, Nganga JK, Kimang'a AN, Mehari TH, Weldemichael YG. Glucose-6-phosphate dehydrogenase deficiency allelic variants and their prevalence in malaria patients in Eritrea. The Pan African medical journal. 2018:31():46. doi: 10.11604/pamj.2018.31.46.16527. Epub 2018 Sep 20 [PubMed PMID: 30918572]
Puthumana JS, Regenold WT. Glucose-6-phosphate dehydrogenase activity in bipolar disorder and schizophrenia: Relationship to mitochondrial impairment. Journal of psychiatric research. 2019 May:112():99-103. doi: 10.1016/j.jpsychires.2019.03.004. Epub 2019 Mar 5 [PubMed PMID: 30875545]
Ong KIC, Iwagami M, Araki H, Khattignavong P, Soundala P, Keomalaphet S, Prasayasith P, Lorpachan L, Xangsayalath P, Pongvongsa T, Hongvanthong B, Brey PT, Kano S, Jimba M. Prevalence of G6PD Viangchan variant in malaria endemic areas in Lao PDR: an implication for malaria elimination by 2030. Malaria journal. 2019 Mar 12:18(1):75. doi: 10.1186/s12936-019-2715-0. Epub 2019 Mar 12 [PubMed PMID: 30866940]
Pes GM, Parodi G, Dore MP. Glucose-6-phosphate dehydrogenase deficiency and risk of cardiovascular disease: A propensity score-matched study. Atherosclerosis. 2019 Mar:282():148-153. doi: 10.1016/j.atherosclerosis.2019.01.027. Epub 2019 Jan 28 [PubMed PMID: 30731288]
Kwok MK, Leung GM, Au Yeung SL, Schooling CM. Glucose-6-phosphate dehydrogenase deficiency and metabolic profiling in adolescence from the Chinese birth cohort: "Children of 1997". International journal of cardiology. 2019 Apr 15:281():146-149. doi: 10.1016/j.ijcard.2019.01.100. Epub 2019 Jan 31 [PubMed PMID: 30739801]
Mohamed GS, Lemine SM, Cheibetta S, Mohamed A. [Neonatal screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency in Mauritania]. The Pan African medical journal. 2018:30():224. doi: 10.11604/pamj.2018.30.224.13947. Epub 2018 Jul 25 [PubMed PMID: 30574242]
Tripathi P, Kumar R, Agarwal S. Spectrum and hematological profile of hereditary anemia in North Indians: SGPGI experience. Intractable & rare diseases research. 2018 Nov:7(4):258-263. doi: 10.5582/irdr.2018.01093. Epub [PubMed PMID: 30560018]
Avalos S, Mejia RE, Banegas E, Salinas C, Gutierrez L, Fajardo M, Galo S, Pinto A, Mejia A, Fontecha G. G6PD deficiency, primaquine treatment, and risk of haemolysis in malaria-infected patients. Malaria journal. 2018 Nov 8:17(1):415. doi: 10.1186/s12936-018-2564-2. Epub 2018 Nov 8 [PubMed PMID: 30409136]
Benchimol M, Madeira LB, de Oliveira-Souza R. Late-Life Presentation of Unsuspected G6PD Deficiency. Case reports in critical care. 2018:2018():8198565. doi: 10.1155/2018/8198565. Epub 2018 Sep 25 [PubMed PMID: 30356359]
Level 3 (low-level) evidence