Paeds · haematology-oncology-and-transfusion
G6PD deficiency and enzymopathies
Also known as Glucose-6-phosphate dehydrogenase deficiency · Favism · G6PD deficiency · Red cell enzymopathy · Oxidative haemolysis
Fellowship guide to glucose-6-phosphate dehydrogenase deficiency and the red-cell enzymopathies in children. Covers the X-linked loss of the pentose phosphate pathway enzyme that leaves red cells unable to regenerate NADPH and reduced glutathione, the WHO classification of variants by enzyme activity from Class I severe to Class V increased, the global prevalence of roughly 330 to 400 million people concentrated across sub-Saharan Africa, the Mediterranean, the Middle East, South and Southeast Asia and linked to historic malaria protection, the acute haemolytic crisis triggered by infection, fava beans and oxidant drugs such as primaquine, tafenoquine, rasburicase, methylene blue and dapsone, the neonatal jaundice that carries a high kernicterus risk, the diagnostic blood film with bite cells, blister cells and Heinz bodies on a supravital stain with a negative direct antiglobulin test, the critical pitfall that the G6PD assay is falsely normal during acute haemolysis and must be repeated two to three months later, the supportive management with trigger withdrawal and transfusion of leucodepleted packed red cells 10 to 20 mL per kilogram for a haemoglobin under 70 g/L or symptomatic anaemia, and the lifelong trigger-avoidance counselling and family screening under the 2023 Clinical Pharmacogenetics Implementation Consortium guideline.
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- A G6PD assay performed during an acute haemolytic crisis may read falsely normal because the surviving cells are young enzyme-rich reticulocytes, so a normal result during a crisis must never exclude the diagnosis and the assay is repeated two to three months later
- Primaquine, tafenoquine, rasburicase, methylene blue and dapsone must never be given to a G6PD-deficient child without confirming a normal enzyme status, because they are strong oxidant triggers of severe haemolysis
- A G6PD-deficient neonate can develop kernicterus at a bilirubin level lower than the standard exchange threshold, so a lower threshold for phototherapy and exchange transfusion is used and early bilirubin encephalopathy is actively sought
- Dark tea- or cola-coloured urine with sudden pallor and jaundice in a boy of African, Mediterranean, Middle Eastern or Asian ancestry is acute intravascular haemolysis until proven otherwise
- Symptomatic heterozygous females from skewed X-inactivation can have crises and are easily missed because the family history is male-line
- Methylene blue used to treat methaemoglobinaemia in a G6PD-deficient patient both fails to work and precipitates haemolysis
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- Recognises the X-linked inheritance and the global prevalence of glucose-6-phosphate dehydrogenase deficiency
- Lists the common oxidant triggers of acute haemolysis including fava beans, infection and specific drugs
- Identifies acute haemolytic anaemia and neonatal jaundice as the main presentations
- Explains the pentose phosphate pathway and the loss of NADPH and reduced glutathione as the mechanism of oxidative haemolysis
- Interprets the blood film, the negative direct antiglobulin test, and the timing pitfall of the G6PD assay during a crisis
- Applies the Clinical Pharmacogenetics Implementation Consortium 2023 drug guidance and screens the family
- The four triggers of acute haemolysis and the written trigger-avoidance advice given to families
- Recognition and management of an acute haemolytic crisis including the transfusion thresholds
- Counselling families on the X-linked inheritance and the need to test siblings and the maternal line
- Bedside assessment of a child with sudden jaundice and dark urine after an oxidant trigger
- Communication of the diagnosis, the trigger-avoidance list, and the safety-net to the family
- Coordination of neonatal phototherapy and exchange transfusion decisions in glucose-6-phosphate dehydrogenase hyperbilirubinaemia
- Level 1: Recognises glucose-6-phosphate dehydrogenase deficiency as a common inherited cause of haemolysis and neonatal jaundice
- Level 2: Applies the mechanism, the trigger list, and the investigation including the assay timing pitfall
- Level 3: Manages the acute crisis, counsels the family, and coordinates neonatal screening and follow-up
- X-linked inheritance and global epidemiology of glucose-6-phosphate dehydrogenase deficiency
- The pentose phosphate pathway and the role of NADPH and reduced glutathione in protecting the red cell
- Drugs to avoid and the falsely normal assay during acute haemolysis
- History and examination of a child with acute haemolytic anaemia
- Communication of the trigger-avoidance counselling to a family
- Assessment of a neonate with severe hyperbilirubinaemia
- Diagnosis of glucose-6-phosphate dehydrogenase deficiency by enzyme assay and the timing of testing after a crisis
- Recognition and management of an acute haemolytic crisis and neonatal hyperbilirubinaemia
- Pharmacogenetic prescribing and family screening
- Recognition and resuscitation of a child with acute oxidative haemolysis
- Appropriate investigation and the direct antiglobulin test-negative interpretation
- Family counselling and pharmacogenetic prescribing decisions
- Glucose-6-phosphate dehydrogenase deficiency in the Canadian paediatric population including at-risk migrant communities
- Diagnosis and management of acute haemolysis and neonatal jaundice
- Screening before primaquine radical cure and family counselling
Overview & Definition
A previously well boy of Mediterranean ancestry eats a plate of fava beans on a Sunday. By Monday he is pale and his urine is the colour of strong tea. This is the textbook face of glucose-6-phosphate dehydrogenase deficiency, the most common inherited red-cell enzyme disorder in humans and the archetype of a red-cell enzymopathy. The defect lies in the enzyme that lets a red cell defend itself against oxidant stress, and without it a burst of oxidation shatters the cell from within whenever a trigger arrives. [1]
Glucose-6-phosphate dehydrogenase, or G6PD, is the first enzyme of the pentose phosphate pathway. It oxidises glucose-6-phosphate and in doing so reduces NADP to NADPH. That NADPH is the only way a mature red cell keeps its glutathione in the reduced, protective form that neutralises the hydrogen peroxide generated constantly inside the cell. Because a red cell has no nucleus and cannot make new enzyme, its survival depends entirely on the G6PD it was born with. When the gene is defective, the cell loses this defence, and any oxidant load, from an infection, a fava bean, or a drug, can denature the haemoglobin and rupture the membrane. [1]
The disease is X-linked, carried on the long arm of the X chromosome at Xq28, so it manifests fully in males and travels through carrier females. It affects an estimated 330 to 400 million people, roughly four to five per cent of the world's population, with the highest frequencies across sub-Saharan Africa, the Mediterranean, the Middle East, South and Southeast Asia, and parts of Latin America. The distribution mirrors the historical reach of falciparum malaria, because carrying one copy of the deficient gene protects partially against severe malaria, the classic balanced polymorphism. [2][3][4]
Three ideas make this topic central to the fellowship examination. The mechanism is examinable and elegant: the loss of NADPH and reduced glutathione explains every clinical and laboratory feature. The diagnosis has a single trap that examiners love, namely that the enzyme assay is falsely normal during an acute crisis and must be repeated weeks later. And the management is almost entirely preventive: identify and avoid the triggers, counsel the family, and screen the relatives, because most patients are perfectly well between crises. The 2023 Clinical Pharmacogenetics Implementation Consortium guideline gives the current prescribing standard. [5][6]
References11ShowHide
- [1]Cappellini MD, Fiorelli G Glucose-6-phosphate dehydrogenase deficiency. Lancet, 2008.PMID 18177777
- [2]Luzzatto L, Seneca E G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. Br J Haematol, 2014.PMID 24372186
- [3]Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis, 2009.PMID 19233695
- [4]Howes RE, Dewi M, Piel FB, Monteiro WM, et al Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malar J, 2013.PMID 24228846
- [5]Youngster I, Arcavi L, Schechmaster R, Akayzen Y, et al Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf, 2010.PMID 20701405
- [6]Gammal RS, Pirmohamed M, Somogyi AA, Morris SA, et al Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype. Clin Pharmacol Ther, 2023.PMID 36049896
- [7]Watchko JF Refractory Causes of Kernicterus in Developed Countries: Can We Eradicate G6PD Deficiency Triggered and Low-Bilirubin Kernicterus? Curr Pediatr Rev, 2017.PMID 28721814
- [8]Kaplan M, Herschel M, Hammerman C, Hoyer JD, Stevenson DK Neonatal hyperbilirubinemia in African American males: the importance of glucose-6-phosphate dehydrogenase deficiency. J Pediatr, 2006.PMID 16860133
- [9]Lau HK, Li CH, Lee AC Acute massive haemolysis in children with glucose-6-phosphate dehydrogenase deficiency. Hong Kong Med J, 2006.PMID 16603783
- [10]Prashanth GP, Al-Shafey M, Tandon A, Ismail S Fava Bean- Versus Non-Fava Bean-Induced Acute Hemolytic Crisis in Children With Glucose-6-Phosphate Dehydrogenase Deficiency: A Prospective Comparative Study. Pediatr Blood Cancer, 2025.PMID 39956941
- [11]Sadhewa A, Satyagraha AW, Alam MS, Adissu W, et al Performance of quantitative point-of-care tests to measure G6PD activity: An individual participant data meta-analysis. PLoS Negl Trop Dis, 2025.PMID 40132008