Glucose-6-phosphate dehydrogenase deficiency

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

G6PD catalyses the first step of the pentose phosphate pathway, producing NADPH that keeps glutathione reduced. Mature red cells depend on this system to neutralise oxidants. Variants that reduce enzyme activity leave haemoglobin and membrane proteins vulnerable during infection, fava-bean exposure or treatment with certain oxidant medicines. Denatured haemoglobin precipitates as Heinz bodies; splenic macrophages remove affected membrane to create bite cells, while more severe injury causes intravascular rupture, haemoglobinuria and renal stress.

Inheritance is X linked, but sex alone cannot exclude disease. Hemizygous males generally express one variant, while heterozygous females have a mosaic red-cell population and can range from unaffected to clinically significant deficiency. Prevalence is higher in people with African, Mediterranean, Middle Eastern and parts of Asian ancestry, reflecting historic malaria selection, yet ancestry guides suspicion rather than diagnosis. Neonates may develop important hyperbilirubinaemia, and rare severe variants cause chronic non-spherocytic haemolytic anaemia rather than episodic disease.

Acute diagnosis combines exposure history, a DAT-negative haemolysis pattern and enzyme activity, recognising timing limitations. Older deficient cells are preferentially destroyed, while reticulocytes have more G6PD activity; recent donor cells further distort the assay. A later repeat can therefore be essential. Treatment removes the oxidant, treats infection, protects renal perfusion and uses red-cell transfusion for clinical oxygen-delivery need. Prevention depends on an accurate electronic record, patient information, medicine-by-medicine checking and neonatal planning for affected families.

Key points

G6PD deficiency is an X-linked red-cell enzyme disorder that impairs NADPH and reduced-glutathione defence; heterozygous females can be clinically affected because X-chromosome inactivation is variable.
Many people are asymptomatic between episodes. Infection, fava beans and specific oxidant medicines cause abrupt jaundice, dark urine, pallor, fatigue, abdominal or back pain and falling haemoglobin.
The film may show bite cells and blister cells after splenic removal of Heinz-body-containing membrane; supravital staining detects Heinz bodies but is timing dependent and specialist led.
Confirm haemolysis with reticulocytes, bilirubin, LDH, haptoglobin, renal function, urinalysis and film. DAT is usually negative and helps identify an immune alternative.
A normal enzyme activity result during acute haemolysis or soon after transfusion can be falsely reassuring because deficient older cells have disappeared and reticulocytes or donor cells predominate.
Stop the precipitating medicine or food, treat infection and support hydration, renal function and oxygen delivery. There is no routine drug that reverses an acute enzyme defect.
Rasburicase is contraindicated in G6PD deficiency because hydrogen peroxide generation can provoke severe haemolysis and methaemoglobinaemia; assess at-risk ancestry before treatment when time permits.
Give the patient and primary-care record a diagnosis-specific medicine warning, explain that risk depends on the exact drug and context, and check current BNF and product information rather than relying on memory.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

X-linked genetic variants

Pathogenic G6PD variants reduce enzyme stability or activity; hemizygous males are often more consistently affected, while lyonisation creates variable expression in heterozygous females.

Infective oxidative stress

Bacterial and viral infections generate oxidants and inflammatory stress, making acute illness a common precipitant of haemolysis in susceptible red cells.

Medicine and chemical exposure

Rasburicase, dapsone, primaquine and other agents identified in current BNF or product guidance can exceed red-cell antioxidant capacity.

Foods and metabolic stress

Fava beans classically trigger favism, while diabetic ketoacidosis and other severe physiological stressors may contribute alongside infection or medicine exposure.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
NADPH generation falls
Reduced pentose-phosphate-pathway enzyme activity limits red-cell NADPH production because mature erythrocytes lack alternative organelle-based antioxidant systems.
2
Glutathione remains oxidised
Insufficient NADPH prevents efficient regeneration of reduced glutathione, allowing hydrogen peroxide and other oxidants to accumulate during stress.
3
Haemoglobin and membrane oxidise
Denatured haemoglobin forms Heinz bodies and membrane proteins become rigid, fragile and susceptible to intravascular rupture or splenic removal.
4
Vulnerable cells are selected
Older enzyme-poor erythrocytes are destroyed first, leaving younger reticulocytes with higher residual activity and temporarily altering the measured enzyme result.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Acute oxidant episodeRed flag

Jaundice, pallor, dark urine, fatigue and back or abdominal pain beginning after infection, fava beans or a recognised medicine suggests triggered haemolysis.

Oxidative film pattern

Bite cells, blister cells, polychromasia and specialist supravital Heinz-body staining support oxidant injury but vary with sampling time.

Intravascular severityRed flag

Haemoglobinuria, rapid haemoglobin fall, rising creatinine, oliguria, hyperkalaemia, chest pain or syncope indicates organ-threatening haemolysis and urgent support.

Neonatal presentationRed flag

Early or rapidly rising jaundice in a baby with relevant ancestry or family history raises G6PD-related hyperbilirubinaemia and requires urgent bilirubin management.

Female heterozygous disease

A woman with a convincing trigger-dependent phenotype may have clinically important mosaic deficiency despite an intermediate or apparently normal screening result.

Chronic variant

Persistent jaundice, anaemia, splenomegaly, gallstones and reticulocytosis without a discrete trigger suggests a rarer chronic non-spherocytic haemolytic phenotype.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
FBC, serial haemoglobin and absolute reticulocytesFirst step
Why
Quantify severity, trajectory and marrow compensation.
Interpretation and limitations
Reticulocytosis supports regeneration but may lag early. A falling haemoglobin despite removing the trigger suggests continuing destruction, inadequate marrow response or another diagnosis and raises transfusion urgency.
02
Bilirubin, LDH, haptoglobin and renal profile
Why
Confirm haemolysis and detect pigment-related organ injury.
Interpretation and limitations
Indirect bilirubin and LDH rise while haptoglobin is consumed; creatinine and potassium define renal risk. Interpret liver disease, inflammation and other tissue injury alongside the pattern.
03
Peripheral film and DAT
Why
Identify oxidative morphology and exclude a common immune alternative.
Interpretation and limitations
Bite and blister cells support oxidant damage; polychromasia reflects recovery. DAT is generally negative, while spherocytes with immune coating redirect assessment towards AIHA or a transfusion reaction.
04
Quantitative G6PD activity
Why
Demonstrate reduced enzyme function and establish future medicine risk.
Interpretation and limitations
Interpret with assay range, sex, reticulocyte count and transfusion timing. A result during acute haemolysis can miss deficiency and should be repeated after recovery when clinical suspicion remains.
05
Urinalysis and fluid assessment
Why
Detect haemoglobinuria and guide renal-protective supportive care.
Interpretation and limitations
Dipstick blood with few red cells suggests haem pigment; microscopy helps separate haemoglobinuria from haematuria. Volume depletion, falling urine output and rising creatinine increase urgency.
06
Genetic or specialist enzyme assessment
Why
Resolve equivocal female, chronic or discordant phenotypes and support family counselling.
Interpretation and limitations
Discuss testing with haematology or genomics when activity is intermediate, transfusion prevents interpretation, chronic haemolysis persists or relatives and future high-risk medicines require clarification.
07
Neonatal bilirubin measurement
Why
Identify dangerous hyperbilirubinaemia before neurological toxicity develops.
Interpretation and limitations
Plot bilirubin by postnatal age and gestation through NICE CG98 and treat at the applicable line; visual inspection alone is insufficient to grade severity.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Autoimmune haemolytic anaemia

Spherocytes and a positive DAT support immune coating, whereas oxidant exposure, bite or blister cells and a negative DAT favour G6PD-related injury.

Unstable haemoglobin disorder

Heinz bodies and episodic oxidative haemolysis also occur with unstable haemoglobin variants, requiring haemoglobin and genetic investigation when enzyme testing is normal.

Hereditary spherocytosis

Lifelong jaundice, splenomegaly, family history, spherocytes and membrane-test abnormalities suggest chronic membrane loss rather than trigger-dependent oxidant episodes.

Microangiopathic haemolysis

Schistocytes, thrombocytopenia and neurological, renal or cardiac injury indicates fragmentation and requires urgent TTP or secondary-microangiopathy assessment.

Other enzyme deficiencies

Pyruvate kinase and rarer red-cell enzyme disorders can cause DAT-negative inherited haemolysis, often with a more chronic phenotype and different assay pattern.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Acute haemolysisRemove the oxidant and protect organsFirst stepDark urine, jaundice and falling haemoglobin occur during infection or after a plausible food, medicine or chemical exposure.

1Stop the suspected trigger, treat infection promptly, use ABCDE and obtain FBC, reticulocytes, film, bilirubin, LDH, haptoglobin, DAT, renal profile, potassium, urinalysis and group and screen.
2First linePreferredEscalationFirst-line care is supportive hydration and renal, urine-output and oxygen-delivery monitoring; red-cell transfusion is the preferred escalation for clinically important symptomatic anaemia rather than a fixed universal number.
3EscalationEscalate shock, chest pain, syncope, oliguria, hyperkalaemia, rapidly falling haemoglobin or diagnostic uncertainty to senior haematology, renal, transfusion and critical-care support.

02Confirm laterInterpret enzyme activity around cell ageThe episode is compatible with oxidative haemolysis but enzyme activity is normal, intermediate or confounded by transfusion.

1DefinitiveRecord the exact exposure, timing, reticulocyte count, transfusion and film phenotype, and preserve the acute result without treating it as definitive exclusion.
2PreferredAlternativeThe preferred confirmation is repeat quantitative activity after haemolysis and transfusion effects have resolved; an alternative specialist genetic route is useful for discordant female or chronic phenotypes.
3EscalationMaintain precautionary avoidance of the convincing trigger and escalate high-stakes future treatment decisions, such as oxidant antimalarial or tumour-lysis therapy, to haematology and pharmacy.

03Prevent recurrenceMake future prescribing and neonatal care safeG6PD deficiency is confirmed or remains highly probable after a characteristic episode.

1Code the diagnosis and reaction accurately, provide written advice on fava beans, infection and medicine checking, and reconcile repeat prescriptions using current BNF and individual product information.
2First lineAlternativeBefore rasburicase or another high-risk oxidant medicine, first-line prescribing safety is to verify G6PD status in at-risk patients when clinically feasible and use the supported alternative when deficiency is present.
3EscalationFor pregnancy and newborn care, communicate parental or family deficiency to maternity and neonatal teams and escalate jaundice immediately through age-specific bilirubin measurement and NICE treatment thresholds.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Rasburicase lowers uric acid in selected tumour-lysis settings but has no treatment role in G6PD deficiency and creates an oxidant by-product.

Rasburicase

Do not administer to a patient with confirmed G6PD deficiency; use the tumour-lysis protocol's supported alternative and specialist metabolic monitoring instead.

The SmPC contraindicates use in G6PD deficiency because severe haemolysis and methaemoglobinaemia can occur. Assess higher-risk ancestry before treatment when feasible, stop immediately if either reaction develops and seek urgent specialist care rather than reflexively using methylene blue, which may worsen haemolysis in G6PD deficiency.

Supports accelerated erythropoiesis in rare chronic non-spherocytic haemolytic disease rather than treating the enzyme defect or an acute episode.

Folic acid for chronic haemolysis

A specialist may prescribe 5 mg by mouth once daily when a chronic haemolytic variant creates sustained increased folate requirement; review duration regularly.

Check vitamin B12 status before prolonged use and avoid routine indefinite prescribing after a single brief episode. Continued haemolysis needs specialist diagnosis, gallstone and transfusion review.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Severe acute anaemia

Rapid intravascular and extravascular destruction can cause syncope, cardiac strain, shock or critical oxygen-delivery failure, particularly with continuing oxidant exposure.

Acute kidney injury

Filtered free haemoglobin, dehydration and haemodynamic compromise can damage renal tubules during brisk intravascular haemolysis episodes.

Neonatal hyperbilirubinaemia

Accelerated bilirubin production with immature neonatal clearance can cause severe jaundice and bilirubin encephalopathy without timely surveillance and treatment.

Recurrent avoidable episodes

Failure to communicate the diagnosis and check future medicines exposes patients repeatedly to preventable haemolysis, hospital admission and transfusion.

Chronic haemolytic anaemia

Rare severe variants cause ongoing destruction, jaundice, splenomegaly, gallstones, folate demand and transfusion burden rather than isolated triggered attacks.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During an acute episode, trend symptoms, observations, haemoglobin, reticulocytes, bilirubin, LDH, renal function, potassium, urine output and urine colour until destruction is clearly resolving.
After transfusion, reassess clinical oxygen delivery and haemoglobin and document donor-cell confounding before scheduling repeat enzyme activity.
Arrange repeat quantitative G6PD testing after recovery when the acute result was normal or intermediate despite a convincing phenotype, with timing agreed by the laboratory.
For chronic variants, monitor haemoglobin, reticulocytes, jaundice, splenomegaly, gallstones, folate status, transfusion burden and iron loading through haematology.
Ensure the diagnosis, implicated exposure and medicine warning appear in the GP, hospital, pharmacy and patient-held record, and review them after every care transition.
For at-risk newborns, follow bilirubin clinically and biochemically through the neonatal plan and safety-net poor feeding, lethargy and deepening jaundice urgently.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Young red cells test better

Reticulocytes contain more residual enzyme than older cells. Selective destruction during a crisis enriches the sample with cells that can mask deficiency.

Women can have clinically important disease

Random X-chromosome inactivation creates a spectrum of enzyme activity, so sex and a single screening result cannot overrule a convincing phenotype.

Infection is a major trigger

A new medicine may attract attention, but inflammatory oxidative stress from the illness itself can be the principal precipitant or act synergistically.

Bite cells record splenic editing

Macrophages remove Heinz-body-containing membrane, leaving semicircular defects. The precipitated haemoglobin may already be gone when the routine film is examined.

Lists require current checking

Medicine risk depends on dose, indication and evidence. The live BNF and product information are safer than an inherited photocopied avoidance list.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding G6PD deficiency because the patient is female.
02
Accepting normal enzyme activity during brisk acute haemolysis as definitive.
03
Continuing a plausible oxidant medicine while waiting for confirmation.
04
Calling every DAT-negative haemolysis G6PD deficiency without film and exposure evidence.
05
Giving rasburicase before assessing G6PD risk when the clinical timeline allows testing.
06
Using an outdated universal medicine list instead of current BNF and product guidance.
07
Failing to communicate family risk and neonatal jaundice planning.