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.

high11 referencesUpdated 16 July 202624 min readVerification in progress

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Red flags

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 laterPrimaquine, 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 haemolysisA 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 soughtDark 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 otherwiseSymptomatic heterozygous females from skewed X-inactivation can have crises and are easily missed because the family history is male-lineMethylene blue used to treat methaemoglobinaemia in a G6PD-deficient patient both fails to work and precipitates haemolysis

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neonateinfanttoddlerpreschoolschool-ageadolescent

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preventive-medical-homeoutpatientwarded-acutenicupicurural-remotetelehealth

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Recognises the X-linked inheritance and the global prevalence of glucose-6-phosphate dehydrogenase deficiencyLists the common oxidant triggers of acute haemolysis including fava beans, infection and specific drugsIdentifies acute haemolytic anaemia and neonatal jaundice as the main presentationsExplains the pentose phosphate pathway and the loss of NADPH and reduced glutathione as the mechanism of oxidative haemolysisInterprets the blood film, the negative direct antiglobulin test, and the timing pitfall of the G6PD assay during a crisisApplies the Clinical Pharmacogenetics Implementation Consortium 2023 drug guidance and screens the familyThe four triggers of acute haemolysis and the written trigger-avoidance advice given to familiesRecognition and management of an acute haemolytic crisis including the transfusion thresholdsCounselling families on the X-linked inheritance and the need to test siblings and the maternal lineBedside assessment of a child with sudden jaundice and dark urine after an oxidant triggerCommunication of the diagnosis, the trigger-avoidance list, and the safety-net to the familyCoordination of neonatal phototherapy and exchange transfusion decisions in glucose-6-phosphate dehydrogenase hyperbilirubinaemiaLevel 1: Recognises glucose-6-phosphate dehydrogenase deficiency as a common inherited cause of haemolysis and neonatal jaundiceLevel 2: Applies the mechanism, the trigger list, and the investigation including the assay timing pitfallLevel 3: Manages the acute crisis, counsels the family, and coordinates neonatal screening and follow-upX-linked inheritance and global epidemiology of glucose-6-phosphate dehydrogenase deficiencyThe pentose phosphate pathway and the role of NADPH and reduced glutathione in protecting the red cellDrugs to avoid and the falsely normal assay during acute haemolysisHistory and examination of a child with acute haemolytic anaemiaCommunication of the trigger-avoidance counselling to a familyAssessment of a neonate with severe hyperbilirubinaemiaDiagnosis of glucose-6-phosphate dehydrogenase deficiency by enzyme assay and the timing of testing after a crisisRecognition and management of an acute haemolytic crisis and neonatal hyperbilirubinaemiaPharmacogenetic prescribing and family screeningRecognition and resuscitation of a child with acute oxidative haemolysisAppropriate investigation and the direct antiglobulin test-negative interpretationFamily counselling and pharmacogenetic prescribing decisionsGlucose-6-phosphate dehydrogenase deficiency in the Canadian paediatric population including at-risk migrant communitiesDiagnosis and management of acute haemolysis and neonatal jaundiceScreening before primaquine radical cure and family counselling

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Target exams

RACP General PaediatricsRACP DWERACP DCEMRCPCH TheoryMRCPCH ClinicalABP General PediatricsRCPSC Pediatrics

Red flags

Life stages

neonateinfanttoddlerpreschoolschool-ageadolescent

Care settings

preventive-medical-homeoutpatientwarded-acutenicupicurural-remotetelehealth

Clinical exam formats

written-only

Board mappings

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]

One-sentence answer for the exam

Glucose-6-phosphate dehydrogenase deficiency is an X-linked defect of the red-cell enzyme that regenerates NADPH, leaving the cell unable to maintain the reduced glutathione that protects it from oxidants, so that infection, fava beans and oxidant drugs trigger an acute direct-antiglobulin-test-negative intravascular haemolysis with bite cells, blister cells and Heinz bodies on the film. Most crises are self-limited and need only trigger withdrawal, hydration and monitoring; transfuse leucodepleted packed red cells 10 to 20 mL per kilogram for a haemoglobin under 70 g per litre or symptomatic anaemia. The critical pitfall is that the G6PD assay may be falsely normal during an acute crisis and must be repeated two to three months later, and lifelong trigger avoidance with family screening is the definitive management.

[1][6]

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References11Show ledger

[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

G6PD deficiency and enzymopathies

Also known as Glucose-6-phosphate dehydrogenase deficiency · Favism · G6PD deficiency · Red cell enzymopathy · Oxidative haemolysis

high11 referencesUpdated 16 July 202624 min readVerification in progress

Practise this topic

Overview & Definition

Paediatrics Fellowship Pro

You have read the opening of this topic. The complete unit — every section and its primary-source references — is part of the Paediatrics Fellowship fellowship atlas.

References11Show ledger

[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