Glucose-6-phosphate Dehydrogenase Deficiency

An X-linked enzymopathy affecting the pentose phosphate pathway, the sole source of NADPH in mature red blood cells, which is required to regenerate reduced glutathione and protect the cell against oxidative stress. Deficiency renders red cells vulnerable to oxidant-induced haemolysis, making it the commonest human enzyme deficiency worldwide, with a distribution mirroring historical malaria endemicity (heterozygote protection against malaria, analogous to sickle trait).

Pathophysiology

Under oxidative stress, haemoglobin denatures and precipitates as Heinz bodies, which are removed by splenic macrophages (producing "bite cells") or trigger direct intravascular haemolysis. X-linked inheritance means males (hemizygous) are typically affected; heterozygous females have variable enzyme activity due to random X-inactivation (lyonisation) and can range from asymptomatic to significantly affected.

Variants: numerous allelic variants exist with different degrees of enzyme deficiency and clinical severity, broadly grouped by WHO class from severe chronic non-spherocytic haemolytic anaemia (class I, rare) through the common African (A-) and Mediterranean variants (both associated with episodic haemolysis on oxidant exposure) to variants with no clinical consequence.

Triggers

• Oxidant drugs: dapsone, primaquine and related antimalarials, sulfonamides, nitrofurantoin, rasburicase, methylene blue (contraindicated as antidote in G6PD deficiency).
• Fava beans (broad beans) --- "favism", particularly severe with the Mediterranean variant.
• Infection, which is actually the commonest trigger overall (oxidative stress from the inflammatory response).
• Diabetic ketoacidosis and other acute metabolic stress.
• Naphthalene (mothballs).

• Most individuals are entirely asymptomatic between episodes.
• Acute haemolytic episode: sudden onset within hours to days of exposure to a trigger, with fatigue, pallor, jaundice, dark urine (haemoglobinuria), and back/abdominal pain in severe cases.
• Severity is typically self-limiting in the common variants, since only older (more enzyme-depleted) red cells are destroyed, sparing younger cells with relatively preserved enzyme activity --- haemolysis is often self-terminating even without treatment.
• Neonatal jaundice, which can be severe and cause kernicterus if unrecognised --- G6PD deficiency is a significant contributor to neonatal hyperbilirubinaemia in endemic populations, and screening is recommended in some settings.
• Rare chronic non-spherocytic haemolytic anaemia in class I severe variants, with ongoing baseline haemolysis independent of triggers.

• Full blood count and film during an acute episode: bite cells, blister cells, Heinz bodies (visible with special stains), reticulocytosis.
• Haemolysis markers: elevated LDH and unconjugated bilirubin, reduced haptoglobin.
• G6PD enzyme activity assay, the definitive test --- critically, this should ideally be checked several weeks after an acute haemolytic episode, since the reticulocyte-rich blood present during/immediately after a crisis has higher enzyme activity (younger cells) and can produce a falsely normal or borderline result, masking true deficiency.
• Genetic testing available for variant characterisation where relevant.
• Neonatal screening in high-prevalence populations, particularly with a family history or significant unexplained jaundice.

• Avoidance of known oxidant triggers is the mainstay of management --- full counselling on drugs, fava beans and other precipitants, with a card or alert system for the patient to carry.
• Acute haemolytic episode: remove/stop the trigger, supportive care with hydration, transfusion if anaemia is severe or symptomatic, monitor renal function given risk of acute kidney injury from haemoglobinuria/haemoglobin cast nephropathy in severe intravascular haemolysis.
• Do not use methylene blue as an antidote for methaemoglobinaemia in G6PD-deficient patients, since it depends on NADPH generation and is both ineffective and potentially harmful (can worsen haemolysis).
• Neonatal jaundice: standard phototherapy protocols, with a lower threshold for intervention given the risk of rapid, severe unpredictable haemolysis and kernicterus; exchange transfusion for severe hyperbilirubinaemia.
• Folic acid supplementation is reasonable given increased erythropoietic turnover in those with frequent episodes.
• Genetic counselling regarding X-linked inheritance pattern.
• Screening of family members where a case is identified, particularly before prescribing known oxidant drugs to relatives.