# Glucose-6-Phosphate Dehydrogenase Deficiency

G6PD deficiency is an X-linked red-cell enzymopathy in which oxidative infection, drugs, or fava beans can precipitate hemolysis; clinical care hinges on confirming enzyme deficiency, recognizing assay limitations, stopping exposures, treating the trigger, and preventing high-risk drug administration.

**Clinical question:** How should clinicians confirm, manage, and prevent hemolysis in patients with suspected or known G6PD deficiency?

Updated: 2026-08-24T18:32:24.053169+00:00

## What matters in practice
- Order a G6PD enzyme assay when acute nonimmune hemolysis follows infection, oxidant medication exposure, or fava-bean ingestion; smear review and blood testing support the diagnosis. [2][8][12]
- A normal or near-normal G6PD result during an acute hemolytic episode does not necessarily exclude deficiency, because the most enzyme-deficient erythrocytes may have been destroyed; repeat phenotypic testing after recovery when suspicion remains. [18]
- Before prescribing primaquine or tafenoquine, document G6PD status; tafenoquine is contraindicated with deficient or unknown status because of hemolytic-anemia risk. [1][3]
- Rasburicase is contraindicated in G6PD deficiency because it can cause hemolytic anemia and methemoglobinemia. [24]
- In neonates, G6PD deficiency increases risk for severe indirect hyperbilirubinemia and kernicterus; bilirubin surveillance should not rely on anemia or routine hemolysis indices alone. [7][13][22]

## Approach to acute hemolysis in a patient with possible G6PD deficiency

Act on the hemolytic syndrome and exposure history before definitive enzyme confirmation.

Suspect G6PD-related hemolysis when acute anemia or jaundice follows an intercurrent infection, an oxidative medication, fava-bean ingestion, henna exposure, or another acute oxidative stressor. G6PD deficiency causes nonimmune hemolytic anemia because impaired red-cell antioxidant capacity increases susceptibility to oxidative injury. [2][8][12][22]

Immediately stop a suspected oxidant exposure and identify and treat the precipitating infection or acute illness. Obtain a CBC with hemoglobin, reticulocyte count, bilirubin fractions, lactate dehydrogenase, haptoglobin, creatinine, urinalysis, and peripheral smear review to establish hemolysis severity and detect complications such as hemoglobinuria or kidney injury. G6PD-associated episodes may be clinically significant enough to produce severe hyperbilirubinemia and renal failure. [2][16]

Use direct antiglobulin testing when the presentation could represent immune hemolysis rather than an oxidant episode. Persistent anemia after trigger removal, marked splenomegaly, multilineage cytopenias, or an atypical smear should redirect the evaluation toward concurrent hemolytic, marrow, hepatic, infectious, or inherited red-cell disease rather than attributing all anemia to G6PD deficiency. Coexisting disorders can independently contribute to anemia and cytopenias. [12]
- Document the exact medication, start date, dose, and timing of hemolysis; drug-associated episodes may occur with antimalarials, antibiotics, anti-inflammatory agents, and other oxidant exposures. [12][22]
- Ask specifically about fava beans and henna, which are recognized nonpharmacologic oxidative precipitants. [8][22]
- Escalate care for rapidly falling hemoglobin, severe hyperbilirubinemia, hemoglobinuria, oliguria, or suspected methemoglobinemia; these findings indicate a potentially severe oxidant reaction. [16][24]

*Exposure-directed actions in suspected G6PD-related oxidative hemolysis. [1][8][12][22][24]*

| Clinical branch | Key discriminator | Immediate action |
| --- | --- | --- |
| Infection-associated episode | Acute illness temporally associated with anemia, jaundice, or hemoglobinuria. [2][12][22] | Evaluate and treat the infection while measuring hemolysis and renal parameters; avoid adding oxidant drugs when alternatives are available. [2][12] |
| Drug-associated episode | Hemolysis begins after an oxidative medication, particularly an 8-aminoquinoline antimalarial or other implicated drug exposure. [1][3][12][22] | Stop the suspected agent, document the reaction, and obtain confirmatory G6PD testing after the acute episode if needed. [1][2][18] |
| Rasburicase exposure | Hemolysis or methemoglobinemia after rasburicase. [24] | Do not administer further rasburicase; treat as a high-risk oxidant reaction and evaluate for methemoglobinemia and hemolysis. [24] |
| Food or chemical exposure | Fava-bean ingestion or henna exposure precedes hemolysis. [8][22] | Remove exposure, treat the hemolytic episode, and provide written avoidance counseling after recovery. [2][8] |

## Confirm deficiency without misreading the enzyme assay

Phenotypic enzyme testing is the core diagnostic test, but timing and sex-linked mosaicism affect interpretation.

Confirm suspected disease with a blood-based G6PD enzyme activity assay and peripheral-smear review. In routine practice, the diagnosis is made from blood testing that includes smear examination and a specific enzyme assay. [2]

Interpret enzyme activity in the clinical context. During or shortly after hemolysis, selective destruction of the most deficient erythrocytes can leave younger circulating cells with relatively higher activity, producing a falsely reassuring phenotypic result. If clinical suspicion remains high after a normal acute-phase test, repeat enzyme activity testing after hematologic recovery. [18]

Do not use a limited genotyping panel as the sole exclusion test when the clinical question is functional deficiency, particularly in heterozygous females. X-inactivation creates a wide range of normal-to-deficient erythrocyte proportions, so genotype does not reliably predict the degree of enzyme deficiency in heterozygotes; phenotypic testing is therefore more informative for functional risk in this group. [18]

Laboratory cutoffs are assay-, age-, and population-dependent. Published newborn screening programs have used a fluorescent spot test followed by quantitative enzyme testing for reduced activity, but a threshold from one laboratory should not be transferred to another laboratory's assay. [9]
- Record recent transfusion and timing of the hemolytic event when ordering or interpreting enzyme activity, because circulating donor or young erythrocytes can alter the measured phenotype. [18]
- Use genotyping as an adjunct when variant identification is needed, but recognize that an untested or unusual mutation may be missed. [18]
- In a symptomatic female with a nondiagnostic genotype, prioritize quantitative enzyme phenotype rather than assuming carrier status is clinically silent. [18]

### When to test

Test patients with otherwise unexplained acute nonimmune hemolysis after infection, fava beans, or an oxidative drug; test before prescribing 8-aminoquinoline antimalarial therapy; and evaluate neonates with clinically significant indirect hyperbilirubinemia when G6PD deficiency is plausible. [1][2][7][8][22]

*Interpretation pitfalls in G6PD assessment. [9][18]*

| Situation | Interpretive risk | Next step |
| --- | --- | --- |
| Acute hemolysis | Measured activity may be falsely reassuring after preferential loss of the most deficient erythrocytes. [18] | Repeat quantitative enzyme testing after recovery if pretest probability remains high. [18] |
| Heterozygous female | Genotype does not predict functional enzyme deficiency because X-inactivation yields variable proportions of deficient erythrocytes. [18] | Use a phenotypic enzyme assay to assess functional deficiency. [18] |
| Reduced newborn screening result | Screening identifies infants requiring confirmatory evaluation but does not replace quantitative assessment. [9] | Confirm with quantitative enzyme testing and/or mutation analysis according to the screening pathway. [9] |

## Prevent avoidable oxidant hemolysis

The highest-value intervention is durable documentation of deficiency and avoidance of known high-risk exposures.

After confirmed deficiency, place G6PD deficiency and any implicated drug reaction prominently in the medication record, counsel the patient to avoid oxidative triggers, and provide a written exposure plan. Most individuals remain asymptomatic unless exposed to infection, fava beans, or oxidative medications; prevention therefore centers on anticipatory avoidance rather than chronic treatment. [2][8]

For malaria radical cure or prophylaxis decisions, do not prescribe tafenoquine unless G6PD testing has documented acceptable status. FDA labeling states that all patients must be tested before tafenoquine initiation and lists G6PD deficiency or unknown G6PD status as contraindications because of hemolytic-anemia risk. [1]

Primaquine also carries a clinically important hemolysis risk in G6PD deficiency. Severe G6PD deficiency is a contraindication; when primaquine is considered in mild to moderate deficiency, FDA-linked labeling requires individualized risk-benefit assessment, baseline hemoglobin and hematocrit, and close hematologic monitoring including assessment at day 3 and day 8. [1]

Avoid rasburicase in known G6PD deficiency. The drug is contraindicated because hemolytic anemia and methemoglobinemia can occur; a patient with unknown status who is likely to require rasburicase should undergo G6PD assessment before exposure when clinical circumstances permit. [24]
- Before tafenoquine: verify and document G6PD status; deficient or unknown status is a contraindication. [1]
- Before primaquine: verify G6PD status; do not use in severe deficiency. [1]
- If primaquine is used despite mild to moderate deficiency: obtain baseline hemoglobin and hematocrit and monitor hematologically at day 3 and day 8. [1]
- During primaquine monitoring: stop and urgently evaluate dark urine or a marked fall in hemoglobin or erythrocyte count as possible hemolysis. [1]

*High-consequence medication decisions in G6PD deficiency. [1][3][24]*

| Agent | G6PD decision | Required safeguard |
| --- | --- | --- |
| Tafenoquine | Contraindicated with G6PD deficiency or unknown G6PD status. [1] | Test all patients before initiation. [1] |
| Primaquine | Do not prescribe for severe deficiency; mild to moderate deficiency requires individualized risk-benefit assessment. [1] | Obtain baseline hemoglobin and hematocrit; monitor hematologically at day 3 and day 8 if treatment is undertaken. [1] |
| Rasburicase | Contraindicated in G6PD deficiency. [24] | Avoid because hemolytic anemia and methemoglobinemia may occur. [24] |

## Treat G6PD deficiency as a bilirubin risk factor in neonates

Neonatal jaundice may be the first manifestation and can be severe despite limited hematologic evidence of hemolysis.

In a neonate with significant indirect hyperbilirubinemia, include G6PD deficiency in the etiologic evaluation, particularly when ancestry, family history, an affected sibling, or an unexplained bilirubin trajectory raises suspicion. G6PD deficiency is associated with neonatal jaundice, bilirubin encephalopathy, and severe hyperbilirubinemia that can cause kernicterus if not recognized. [7][8][13][22]

Do not dismiss G6PD deficiency because hemoglobin, reticulocyte count, or other routine hematologic indices do not show striking hemolysis. In G6PD-deficient neonates with severe hyperbilirubinemia, standard hematologic indices may correlate poorly with hemolysis, even though hemolysis contributes substantially to pathophysiology. [7]

Obtain quantitative G6PD testing when the result will alter bilirubin surveillance, exposure counseling, or family risk assessment. Newborn screening may identify infants with reduced activity, but confirmatory quantitative enzyme testing and, when used, mutation analysis are needed to characterize the result. [7][9]
- Use serial bilirubin assessment and timely jaundice-directed treatment rather than waiting for overt anemia in a neonate at risk for G6PD deficiency. [7][22]
- At discharge, document G6PD status or pending evaluation and reinforce prompt reassessment for worsening jaundice. Severe neonatal hyperbilirubinemia can progress to kernicterus. [7][22]

*Neonatal clues that should prompt consideration of G6PD testing. [7][8][13][22]*

| Finding | Clinical interpretation | Action |
| --- | --- | --- |
| Significant indirect hyperbilirubinemia | G6PD deficiency is associated with severe jaundice and bilirubin encephalopathy risk. [7][8][13] | Assess bilirubin trajectory and obtain G6PD testing when clinically indicated. [7][22] |
| Severe jaundice with limited anemia or routine hemolysis findings | Hematologic indices may not reliably reflect hemolysis in affected neonates. [7] | Continue bilirubin-focused surveillance; do not exclude G6PD deficiency on this basis. [7] |
| Positive or reduced-activity newborn screen | Screening requires confirmatory phenotypic and/or molecular evaluation. [9] | Arrange quantitative enzyme confirmation and document results for future drug safety. [9] |

## Longitudinal documentation and referral decisions

Most patients need preventive care rather than chronic hematologic therapy.

For patients with confirmed deficiency and no ongoing hemolysis, focus follow-up on exposure avoidance, medication reconciliation before new prescriptions, and recognition of recurrent hemolysis. Most affected individuals are asymptomatic for most or all of life, with episodes triggered by oxidative stress rather than a continuously active disease process. [2][8]

Refer to hematology when enzyme results remain discordant with a convincing clinical phenotype, when recurrent hemolysis occurs without a clear exposure, when chronic hemolysis is suspected, or when a specialized phenotypic/genotypic interpretation is needed in a heterozygous female. Genotype-phenotype discordance is especially relevant in females because X-inactivation makes genotype an unreliable predictor of red-cell functional deficiency. [18]

For a patient who may require an 8-aminoquinoline antimalarial, coordinate testing and treatment planning before travel or malaria therapy rather than addressing G6PD status after exposure. The safety requirements for tafenoquine and the monitoring requirements for selected primaquine use make pre-treatment planning clinically consequential. [1][3]
- Reconcile G6PD status before prescribing medications with potential oxidant risk and before administering rasburicase. [1][24]
- Document prior hemolysis triggers, including drug name and fava-bean or henna exposure, because prevention depends on trigger-specific avoidance. [8][12][22]
- Counsel family members that the disorder is X-linked; female relatives may have clinically meaningful phenotypic deficiency despite variable genotype-phenotype correlation. [2][18]

*Follow-up actions after a confirmed G6PD deficiency diagnosis. [1][2][8][18][24]*

| Care task | When | Purpose |
| --- | --- | --- |
| Update problem list and adverse-drug record | At diagnosis and after any hemolytic episode. [2][8] | Prevent repeat exposure to recognized oxidant triggers. [2][8] |
| Medication review | Before new prescriptions and before antimalarial or rasburicase treatment. [1][24] | Avoid contraindicated or high-risk oxidant agents. [1][24] |
| Repeat phenotypic testing | After recovery when acute-phase testing was normal but suspicion remains high. [18] | Address false reassurance caused by selective destruction of deficient erythrocytes. [18] |
| Hematology referral | Discordant results, recurrent unexplained hemolysis, chronic hemolysis, or complex female phenotype. [18] | Clarify alternate or coexisting causes and functional deficiency risk. [18] |

## References
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## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.