G6PD Deficiency
Definition
X-linked recessive hereditary disorder caused by mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene → reduced activity of G6PD enzyme.
Pathophysiology
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that catalyses the first step in the pentose phosphate pathway
- The pentose phosphate pathway produces NADPH
- NADPH keeps glutathione in its reduced form which neutralises oxidative stress
Importantly, red blood cells depend entirely on G6PD for NADPH production because they lack mitochondria.
In G6PD deficiency:
- ↓ NADPH production
- ↓ Glutathione
- RBCs cannot neutralise oxidative stress → haemolysis upon triggers
Clinical Features
Mainly affects males (due to X-linked recessive pattern).
Clinical course: [Ref]
- Patients with G6PD deficiency are usually asymptomatic
- Some cases can manifest early with neonatal jaundice
- Patients become symptomatic (usually in childhood) when exposed to triggers that increase oxidative stress (→ haemolytic episodes)
Clinical important triggers: [Ref]
- Infections – most common
- Certain drugs
- Primaquine, tafenoquine (anti-malarial medication) (but NOT other antimalarials like chloroquine, mefloquine, artemisinin derivatives)
- Nitrofurantoin
- Dapsone
- Sulfonamides (commonly trimethoprim-sulfamethoxazole / co-trimoxazole)
- Rasburicase
- Fava beans (due to the presence of oxidant compounds)
Haemolytic episodes in G6PD deficiency typically present acutely with rapid onset (hours to days after exposure) of: [Ref]
- Fatigue
- Pallor
- Jaundice
- Dark urine (haemoglobinuria)
- Sometimes back / abdominal pain
Investigation and Diagnosis
Similar to clinical features of G6PD deficiency, the following findings are only seen during or after a haemolytic episode.
Laboratory Tests
G6PD deficiency is non-immune mediated, therefore there would be -ve Coombs test. [Ref1][Ref2]
Non-specific haemolysis markers: [Ref1][Ref2]
- Normocytic normochromic anaemia
- Low Hb
- Normal mean corpuscular volume
- Normal mean corpuscular haemoglobin
- Low haptoglobin
- High reticulocyte
- High unconjugated bilirubin
- High LDH
Peripheral Blood Smear
- Heinz bodies (denatured haemoglobin due to oxidative stress – appears as small dark round dots inside the RBCs)
- Bite cells (notched RBCs, due to splenic removal of Heinz bodies)
Confirmatory Test
Test of choice: quantitative G6PD enzyme activity assay [Ref]
- ↓ Activity confirms G6PD deficiency
G6PD enzyme activity assay should be performed outside of acute haemolytic episodes (after clinical and laboratory remission) to avoid false -ve results.
Rationale: During haemolytic episodes there are compensatory reticulocytosis, which have naturally higher G6PD activity than ‘old’ RBCs.
Management
Acute Treatment
Acute treatment during haemolytic episodes include: [Ref]
- Immediate withdrawal of causative drug
- Prompt treatment of underlying infection or other precipitating factors
- Supportive care
- Maintain adequate hydration
- Monitor for ongoing haemolysis
- If severe anaemia develops → red cell transfusion (but rarely required)
Long-Term Management
There are currently no disease-modifying therapy available. [Ref]
Patient education is key: [Ref]
- To avoid oxidative triggers (provide written lists of contraindicated food and medications)
- Seek prompt treatment for infections
- Genetic counselling where appropriate (screening is performed via quantitative G6PD enzyme activity assay)
Clinical important triggers: [Ref]
- Infections – most common
- Certain drugs
- Primaquine, tafenoquine (anti-malarial medication) (but NOT other antimalarials like chloroquine, mefloquine, artemisinin derivatives)
- Nitrofurantoin
- Dapsone
- Sulfonamides (commonly trimethoprim-sulfamethoxazole / co-trimoxazole)
- Rasburicase
- Fava beans (due to the presence of oxidant compounds)