Glucose-6-phosphate dehydrogenase (G6PD) deficiency
While there is a myriad of information about genetic diseases on the internet and in textbooks, not many people are aware of genetic diseases related to enzymatic dysfunction. This is especially important as enzymes are substances that slow down or speed up bodily chemical reactions. In this article, information about the most common type of enzyme-related genetic disease, G6PD deficiency, will be explored.
What exactly is G6PD deficiency?
Glucose-6-phosphate dehydrogenase (G6PD) is a very important enzyme that prevents damage to the cells in our bodies, particularly red blood cells (RBCs).1 G6PD deficiency is a genetic condition that occurs when there is a decrease in the amount or activity of this enzyme. While most people will have no symptoms, this condition can lead to the destruction of RBCs in some, a process called haemolysis.1,2 G6PD deficiency belongs to the class of congenital hemolytic anaemias (anaemia caused as a result of RBC breakdown).3
How important is G6PD in RBCs?
Unlike other cells, RBCs are directly involved in the transport of oxygen in the body, making them more vulnerable to damage by reactive oxygen species (ROS).1,2 G6PD prevents this damage, protecting RBCs from hemolysis. During periods of minimal stress in affected individuals, RBCs are in no immediate danger. However, in situations like infections or exposure to certain foods/drugs, this leads to the accelerated and premature breakdown (haemolysis) of RBCs.4 This in turn causes haemolytic anemia.
RBCs have a lifecycle of about three months, after which they are broken down into by-products, including bilirubin. In unaffected individuals or affected individuals not undergoing stress, RBCs break down at a normal rate, and the body clears the bilirubin produced.2,6 However, in hemolytic anaemia, RBCs are broken down faster than the body can clear them, leading to the accumulation of bilirubin. The accumulation of bilirubin causes jaundice (yellowing of the eyes and skin).7
How common is G6PD deficiency, and in what way is it inherited?
G6PD deficiency is the most common enzyme deficiency, affecting about 400 million people worldwide.1 Due to the mode of inheritance (X-linked recessive inheritance), it affects more males than females because males have one copy of the X chromosome (XY), and females have two copies (XX).4 However, women can be carriers and pass on the affected genes to their children. This condition also occurs more commonly in African, Asian, Mediterranean and Middle Eastern populations.2 There are few reports of G6PD deficiency in Caucasians.
Classification of severity levels
G6PD is classified based on levels of enzyme activity:3,4
- Class I: Highly deficient + chronic non-spherocytic hemolytic anaemia;
- Class II: Highly deficient – 1-10% of enzyme activity;
- Class III: Moderately deficient – 10-60% of enzyme activity;
- Class IV: Normal – 60-150% of enzyme activity; and,
- Class V: Increased activity - >150% of enzyme activity.
Classes I-III indicate the presence of G6PD deficiency.
Common triggers and factors leading to hemolysis.
The main triggers causing hemolysis are exposure to certain drugs, exposure to foods like fava beans, either by ingestion or inhalation of bean pollen (particularly in the Mediterranean population)9, infections, and other conditions like diabetes and heart attacks.3 Some of these drugs include antimalarials like primaquine and pamaquine, antimicrobials like sulphonamides, quinolones, dapsone, nitrofurantoin and niridazole, chemotherapy agents like doxorubicin and flutamide, analgesics like aspirin, and vitamin K.2,3,7 Symptoms can present within 2-3 days after exposure to the trigger.1
Risk factors for having G6PD deficiency include:3
- Gender: This condition occurs most commonly in males due to the pattern of inheritance. Females are usually carriers, although a few cases have been reported.
- Ethnicity/race: African, Asian (Middle Eastern) and Mediterranean populations are more likely to be affected than Caucasian populations.
- Family history: Having a family history of G6PD deficiency increases the likelihood of being affected.
Signs and symptoms to look out for
While most people will remain asymptomatic throughout their lives, the symptoms of G6PD deficiency are linked to the destruction of RBCs, causing hemolytic anaemia.8,9 Symptoms can be classified according to the age of affected individuals:
- In babies, symptoms include jaundice, reduced muscle tone, lethargy and sleepiness. This can lead to neurological defects or death if left untreated.3,9
- In adults, symptoms include jaundice, breathlessness, increased tiredness and fatigue, dark urine, fast heart rate, pain, fever and increased spleen and liver size. In some instances, this condition can lead to death.
When do I see my doctor?
While the condition is usually self-limiting,1,4 do not hesitate to seek medical advice if you begin to experience any of the symptoms of hemolytic anaemia listed above. It is advisable to seek medical advice if you feel generally unwell or have a clinical suspicion.
How is G6PD diagnosed?
As previously stated, while most affected individuals remain asymptomatic throughout life and may not be aware of the presence of this condition, when indicated, there are several ways G6PD deficiency can be diagnosed.8 In countries with populations with high prevalence, G6PD deficiency is screened for as part of a series of tests carried out to detect congenital diseases in newborns.1,2 In children and adults, the condition can be diagnosed via several methods, including:
- Fluorescence spot test (FST): This test is based on the inherent fluorescence of a substance produced by G6PD under ultraviolet (UV) light.5,8 Blood samples with normal levels of G6PD produce bright green fluorescent spots, while samples with inadequate levels of G6PD don’t. It is the most common diagnostic test for G6PD deficiency
- Lateral flow rapid diagnostic tests (RDTS): This test is used to identify samples with less than 30% of G6PD activity.5,8
- Standard G6PD test: This test measures G6PD activity and haemoglobin levels in blood samples.4
- Spectrophotometric assay: This test diagnoses G6PD deficiency based on the difference in the absorbance of light by a substance produced by G6PD.5,8
Diagnostic testing can be considered in individuals with significant family histories, especially males in the African, Asian, Mediterranean and Middle Eastern populations.2 Other blood tests including full blood count, peripheral blood smears, reticulocyte count, and Coombs’ test can also be carried out to confirm acute haemolytic anemia.3
Possible complications and associated conditions
In newborns, G6PD deficiency can increase the risk (by 50%) of developing neonatal hyperbilirubinemia, a condition characterized by excessive amounts of bilirubin in the blood. This is because bilirubin is one of the by-products of RBC breakdown.
G6PD-deficient individuals might also be more susceptible to developing sepsis and sepsis-related complications during infective processes.
While experiencing hemolytic anaemia is nothing to be desired, G6PD deficiency has a beneficial effect on affected individuals. Studies have shown that the condition can confer some protection against malaria caused by Plasmodium falciparum.4 While the exact mechanism isn’t known, researchers have suggested that it could be due to the parasite’s increased sensitivity to stress caused by reactive oxygen species (ROS). This is especially important in areas where malaria is endemic.2
How is G6PD deficiency managed and treated?
G6PD deficiency is a genetic condition and consequently, there is no cure. In asymptomatic individuals, no treatment is required. In most cases, this condition has no impact on life span and can be managed by maintaining a healthy lifestyle, eating a balanced and safe diet, and avoiding stressors.2,3 Individuals are encouraged to reduce alcohol intake, quit smoking, and engage in physical exercise. This has been shown to be the most effective management for G6PD deficiency. Healthcare professionals can help educate affected individuals on how to recognize and avoid triggers.7
In symptomatic individuals experiencing symptoms of hemolytic anaemia, hospital admission is required. Management includes treating the underlying cause and stopping exposure to identified triggers.2 Supportive care is provided during a hemolytic crisis, blood transfusions and oxygen therapy might be indicated in severe cases.2,3 With adequate treatment, most individuals will recover as the condition is self-limiting.4
G6PD is an enzyme that protects cells (particularly RBCs) from damage caused by ROS.2 G6PD deficiency is the most common type of enzyme deficiency affecting a significant number of people,2 via the X-linked pattern of inheritance. It affects more men than women.
Most affected individuals will remain asymptomatic and will require no medical intervention. However, in some instances, affected individuals will go on to develop hemolytic anaemia after exposure to certain foods or drugs, during infections or as a result of conditions like diabetes.4 In these instances, there is increased stress on the body. Symptoms can include yellow skin and eyes (jaundice), breathlessness, pain, increased tiredness and fatigue, dark urine, fast heart rate, fever and increased spleen and liver size.6
Management of the condition is usually supportive and involves stopping exposure to identified triggers and treating underlying causes. Most people will recover well because the condition is self-limiting, but presentation in some individuals can be very severe, leading to death.2,3 Doctors and nurses can educate affected individuals, helping them identify triggers and adopt healthy lifestyles. They can also provide information about drugs and food to avoid.7
In most cases, G6PD deficiency will have minimal impact on lifespan and quality of life. However, it is important for affected individuals to inform their GPs and medical team if visiting A&E or admitted to hospital. Also, people planning to start a family might need to discuss the likelihood of their children inheriting the affected genes.
- National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency. Accessed August 08, 2023.
- Harcke SJ, Rizzolo D, Harcke HT. G6PD deficiency: An update. JAAPA. 2019 Nov 1;32(11):21-6. Accessed August 08, 2023. Available from G6PD deficiency: An update : JAAPA (lww.com)
- Richardson SR, O'Malley GF. Glucose-6-Phosphate Dehydrogenase Deficiency. [Updated 2022 Sep 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Accessed August 09, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470315/
- Arolasafe Gbemisola J, Omodele I, Otohinoyi David A, Jeje Temitope O. Updates on Glucose 6-Phosphate Dehydrogenase (G6PD): From Prokaryotes to Human. IJSR, 2016 Apr 5;4. Accessed August 10, 2023. Available from Updates on Glucose 6-Phosphate Dehydrogenase (G6PD): From Prokaryotes to Human (researchgate.net)
- Types of G6PD clinical diagnostic tests [Internet]. PVIVAX. Available from: https://www.vivaxmalaria.org/diagnosis-treatment/g6pd-deficiency/types-of-g6pd-clinical-diagnostic-tests#:~:text=The%20fluorescent%20spot%20test%20(FST
- Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood, The Journal of the American Society of Hematology. 2020 Sep 10;136(11):1225-40. Accessed August 10, 2023. Available from Glucose-6-phosphate dehydrogenase deficiency - PubMed (nih.gov)
- Garcia AA, Koperniku A, Ferreira JC, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends in Pharmacological Sciences. 2021 Oct 1;42(10):829-44. Accessed August 10, 2023. Available from Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives: Trends in Pharmacological Sciences (cell.com)
- Roper D, Layton M, Rees D, Lambert C, Vulliamy T, De la Salle B, D'Souza C, British Society for Haematology. Laboratory diagnosis of G6PD deficiency. A British Society for Haematology Guideline. Br J Haematol. 2020. Accessed August 11, 2023. Available from Vulliamy_Laboratory Diagnosis of G6PD Deficiency_acceptd ms_2019.pdf (qmul.ac.uk)
- Howes RE, Battle KE, Satyagraha AW, Baird JK, Hay SI. G6PD deficiency: global distribution, genetic variants and primaquine therapy. Advances in parasitology. 2013 Jan 1;81:133-201.Accessed August 10, 2023. Available from G6PD Deficiency: Global Distribution, Genetic Variants and Primaquine Therapy - ScienceDirect