Glucose 6 Phosphate Dehydrogenase (G6PD) Deficiency


Article Author:
S. Russ Richardson


Article Editor:
Gerald O'Malley


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
5/2/2019 11:54:24 PM

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 the prevention of 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 inability to replace cellular proteins as mature cells. Inherited deficiencies of G6PD can result in acute hemolytic anemia during times of increased ROS production. This may be caused by stress or exposure to certain foods that contain high amounts of oxidative substances, for example, fava beans, or certain medications.  In particular, anti-malarial agents have a strong association 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.

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

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 currently 186 known human G6PD mutations, and most are point mutations affecting 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.

Epidemiology

G6PD is the most common human enzyme defect known, affecting upward of 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, there is evidence to suggest 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 to 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 mature.

History and Physical

Although most patients remain asymptomatic throughout their life, the clinical manifestations of G6PD deficiency depend on the age of the patient.

  • In newborns, G6PD deficiency is recognized as a serious risk factor for the development of neonatal hyperbilirubinemia. Neonates with G6PD deficiency are two 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 have a bilirubin level of 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. Some of these manifestations include pallor, jaundice, fatigue, splenomegaly, and dark urine.

Evaluation

 Neonatal evaluation:

  • In newborn infants, assess the presence of jaundice by first examining the skin for a yellow appearance in a room that is well lit. More objective measurements include obtaining total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) in newborns. An hour-specific bilirubin nomogram can be used to risk stratify newborn patients with elevated bilirubin levels to help determine 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 that have 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 by a quantitative spectrophotometric analysis.

Children and adult evaluation:

  • The evaluation of older patients presenting with complications of G6PD deficiency begins with a complete history to include new medications and screening for a family history of similar symptoms. It is also important to evaluate for possible infection, as the stress of an 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.

Treatment / Management

Neonates:

  • In the neonatal patient, 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.

Children and adults:

  • In older patients, management depends primarily on the overall clinical picture. Less severe presentations may be managed with supportive care and discontinuation and avoidance of the offending agents. Treat any infections as indicated by history and exam. More severe cases may require transfusions.

Differential Diagnosis

Many disease processes may resemble the pathophysiology of G6PD deficiency. Therefore differential considerations should include:

  • Autoimmune hemolytic anemia
  • Bilirubin conjugation disorders (e.g., 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 who are deficient in G6PD lack sufficient NADPH to properly reduce methylene blue. Unreduced methylene blue can cause further oxidative damage in the G6PD-deficient patient resulting in hemolysis and even death. Therefore, it is important that patients who are known or suspected to have any degree of G6PD deficiency not 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

The diagnosis and management of 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 and 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 medications to ensure that none is associated with this disorder.


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Glucose 6 Phosphate Dehydrogenase (G6PD) Deficiency - Questions

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Which of the following drugs is known to cause anemia due to hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency?



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Which of the following does not cause hemolytic anemia in G6PD-deficiency?



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Which of the following drugs is NOT known to cause anemia due to hemolysis in patients with G6PD deficiency?



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The parents of a boy with glucose-6-phosphate dehydrogenase deficiency are concerned about their next child. Which of the following is a correct statement?



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A teenager is affected by a genetic disease that does not affect his father who is not a carrier. The mother has 4 siblings. One brother and a sister are not carriers and are not affected. The other brother has the disease and the other sister is a carrier. Which of the following could be the disease?



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The parents of a 14-year-old boy with G6PD deficiency are concerned about their next child. Which of the following approximates the risk of their next child having the same disorder?



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G6PD (glucose-6-phosphate dehydrogenase) deficiency is LEAST common in which of the following ethnic groups?



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G6PD deficiency is inherited in what fashion?



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The presence of Heinz bodies on the peripheral blood smear is a feature of which of the following disorders?



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Which of the following chemicals, when ingested, is NOT associated with hemolytic crisis in patients with G6PD deficiency?



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Which of the following is NOT a feature of hemolytic crises in patients with G6PD deficiency?



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An army recruit is given an malarial quinine-based medicine, and then develops hemolytic anemia the next day. Which enzyme is most likely deficient?



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An African American female is given an antibiotic to treat a UTI; two days later she has routine blood work drawn that reveals Heinz bodies and bite cells. Etiology?



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Red blood cells are dependent on the pentose phosphate pathway for the production of NADPH. Without NADPH red blood cells are susceptible to destruction from oxidative stress. A patient presents with hemolytic anemia and is found to be missing the enzyme involved in the first reaction of the pentose phosphate pathway. What enzyme is this patient missing?



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A female with malaria is placed on primaquine but develops a hemolytic anemia. What is the most likely cause of the anemia?



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A 1-year-old has von Gierke disease or glucose-6-phosphatase deficiency. What lab values would be expected?



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A 5-year-old African American male is brought in for yellow skin and dark urine for 4 days. He is on trimethoprim/sulfamethoxazole for acute otitis media. Laboratories show decreased hemoglobin and hematocrit, but renal functions are normal. Bilirubin is elevated, but transaminases are normal. What is the most probable diagnosis?



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A family is assayed for RBC G6PD deficiency. Father is normal, mother and her four sons are all deficient (approximately 0). There are no daughters. From this evidence you could say:



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Which of the following is most likely to cause hemolytic anemia due to erythrocyte deficiency of glucose-6-phosphate dehydrogenase (G6PD)?



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Which of the following drugs is known to cause hemolytic anemia in patients with glucose 6 phosphate dehydrogenase (G6PD) deficiency?



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Glucose 6 Phosphate Dehydrogenase (G6PD) Deficiency - References

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;     [PubMed]
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. 2019 Apr 9;     [PubMed]
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;     [PubMed]
Chu CS,Freedman DO,Gorgas WC, Tafenoquine and G6PD: A Primer for Clinicians. Journal of travel medicine. 2019 Apr 3;     [PubMed]
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;     [PubMed]
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;     [PubMed]
Puthumana JS,Regenold WT, Glucose-6-phosphate dehydrogenase activity in bipolar disorder and schizophrenia: Relationship to mitochondrial impairment. Journal of psychiatric research. 2019 May;     [PubMed]
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;     [PubMed]
Pes GM,Parodi G,Dore MP, Glucose-6-phosphate dehydrogenase deficiency and risk of cardiovascular disease: A propensity score-matched study. Atherosclerosis. 2019 Mar;     [PubMed]
Kwok MK,Leung GM,Au Yeung SL,Schooling CM, Glucose-6-phosphate dehydrogenase deficiency and metabolic profiling in adolescence from the Chinese birth cohort:     [PubMed]
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;     [PubMed]
Tripathi P,Kumar R,Agarwal S, Spectrum and hematological profile of hereditary anemia in North Indians: SGPGI experience. Intractable     [PubMed]
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;     [PubMed]
Benchimol M,Madeira LB,de Oliveira-Souza R, Late-Life Presentation of Unsuspected G6PD Deficiency. Case reports in critical care. 2018;     [PubMed]
Belfield KD,Tichy EM, Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2018 Feb 1;     [PubMed]

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