G6PD Deficiency
X-linked recessive enzyme deficiency causing episodic haemolytic anaemia triggered by oxidative stress (infections, drugs, fava beans). Most common enzymopathy worldwide, affecting ~400 million people.
Key Facts
Most common human enzymopathy: ~400 million affected worldwide; X-linked recessive (predominantly affects males) Episodic intravascular haemolysis triggered by oxidative stress: infections (most common trigger), drugs, fava beans (favism) Drug triggers: primaquine, dapsone, ciprofloxacin, nitrofurantoin, sulfasalazine, rasburicase; avoid in G6PD-deficient patients Blood film during crisis: bite cells (hemighosts), blister cells, Heinz bodies (denatured Hb — supravital stain) G6PD assay: diagnostic — but may be falsely normal during acute crisis (reticulocytes have higher G6PD); retest 2–3 months after episode Usually asymptomatic between crises: no chronic haemolysis in most variants (except class I severe variants) Neonatal jaundice: may be severe and prolonged; important cause in endemic populations Populations: Mediterranean (class II — severe), African (class III — moderate), Southeast Asian
Overview
Key Facts
G6PD deficiency is the most common human enzymopathy, an X-linked condition causing episodic haemolytic anaemia when RBCs are exposed to oxidative stress.
Epidemiology
- ~400 million affected worldwide
- X-linked recessive: affects males predominantly; females may be affected if homozygous or through lyonisation
- Prevalent in Africa, Mediterranean, Middle East, Southeast Asia
- Evolutionary advantage: protection against Plasmodium falciparum malaria
Aetiology
- Mutations in G6PD gene on X chromosome
-
200 variants classified by WHO into 5 classes:
- Class I: severe chronic haemolysis (rare)
- Class II: severely deficient (<10% activity; Mediterranean variant)
- Class III: moderately deficient (10–60%; African A- variant)
Pathophysiology
- G6PD is rate-limiting enzyme in pentose phosphate pathway (hexose monophosphate shunt)
- Generates NADPH → maintains reduced glutathione → protects against oxidative damage
- Deficiency → oxidative stress damages Hb → Heinz body formation → membrane damage → haemolysis
- Older RBCs more susceptible (G6PD activity declines with RBC age)
- Mediterranean variant: more severe (G6PD activity very low even in reticulocytes)
Clinical Presentation
Acute Haemolytic Crisis
- Occurs 1–3 days after oxidative trigger
- Jaundice (dark urine — intravascular haemolysis/haemoglobinuria), pallor
- Back/abdominal pain
- Fatigue, malaise
- Dark urine ('coca-cola' coloured)
- Self-limiting in African variant (young reticulocytes have adequate G6PD)
Triggers
- Infections: most common trigger (any acute illness)
- Drugs: primaquine, dapsone, ciprofloxacin, nitrofurantoin, sulfasalazine, sulfonamides, rasburicase, methylene blue
- Fava beans (broad beans): favism (especially Mediterranean variant)
- Diabetic ketoacidosis
- Naphthalene (mothballs)
Neonatal
- Prolonged neonatal jaundice (2nd–3rd day)
- May be severe → kernicterus risk
Red Flags
- Severe intravascular haemolysis with renal failure
- Neonatal jaundice requiring exchange transfusion
- Haemolysis after starting a new drug
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Autoimmune haemolytic anaemia | DAT positive, spherocytes | DAT (Coombs) |
| Hereditary spherocytosis | Spherocytes, DAT negative, EMA test positive | EMA binding, family history |
| Pyruvate kinase deficiency | Chronic haemolysis, no Heinz bodies | PK enzyme assay |
| Malaria | Travel history, fever, parasites on film | Thick/thin blood film |
Diagnosis / Investigation
During Crisis
- FBC: anaemia (may be severe), raised reticulocytes (after 3–5 days)
- Blood film: bite cells (hemighosts), blister cells, polychromasia, contracted cells
- Heinz body preparation (supravital stain): denatured Hb inclusions within RBCs
- LDH: raised (intravascular haemolysis)
- Bilirubin (unconjugated): raised
- Haptoglobin: low/undetectable
- Urinalysis: haemoglobinuria (dark urine)
- DAT: NEGATIVE (not immune-mediated)
Definitive Diagnosis
- G6PD enzyme assay: quantitative measurement of G6PD activity
- CAUTION: may be falsely normal during/shortly after crisis (reticulocytes have higher G6PD activity)
- Retest 2–3 months after acute episode for accurate result
- Genetic testing: available for specific variants
Management
Acute Crisis
- Remove trigger: stop offending drug, treat infection
- Supportive: IV fluids, maintain renal perfusion
- Transfusion: if severe anaemia (Hb <70 g/L or symptomatic)
- Folic acid 5mg daily: during recovery
- Monitor renal function: intravascular haemolysis → AKI risk
Prevention (KEY)
- Avoid oxidative triggers: provide drug avoidance list to patient
- Medical alert bracelet/card
- Dietary: avoid fava beans (Mediterranean variant)
- Check G6PD status BEFORE prescribing: primaquine, dapsone, rasburicase, nitrofurantoin
- Neonatal screening: in endemic populations
Referral Criteria
- Haematology: confirmed G6PD deficiency, genetic counselling
- Emergency: severe haemolytic crisis
Prognosis
- Between crises: normal life expectancy; usually completely well
- Acute crisis: self-limiting in most cases (especially African A- variant)
- Mediterranean variant: more severe crises; may require transfusion
- Neonatal: jaundice usually manageable; severe cases rare
- With education and trigger avoidance: excellent prognosis
Other Relevant Information
Common Drug Triggers
| Drug | Risk |
|---|---|
| Primaquine | High |
| Dapsone | High |
| Rasburicase | High (CONTRAINDICATED) |
| Ciprofloxacin | Moderate |
| Nitrofurantoin | Moderate |
| Sulfasalazine | Moderate |
| Methylene blue | High |
| Co-trimoxazole | Moderate (high dose) |