SN3 SHORT NOTE 5M ★ High-yield

Describe G6PD deficiency with its pathogenesis, precipitating factors and diagnosis.

Pathology · 2nd Professional — Para-Clinical

Definition

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzyme defect of the hexose monophosphate shunt, causing episodic intravascular haemolysis on exposure to oxidant stress.

The commonest enzymopathy in man, affecting some 400 million people
X-linked recessive — males affected, females usually carriers, though lyonisation may make a carrier symptomatic
Confers protection against falciparum malaria, which explains its distribution in malarial regions, including parts of India

Pathogenesis

G6PD catalyses the first step of the hexose monophosphate shunt → Generating NADPH → NADPH maintains glutathione in its reduced form → Reduced glutathione detoxifies hydrogen peroxide and free radicals → Without it, oxidant stress goes unopposed → Haemoglobin is oxidised and precipitates as HEINZ bodies → Heinz bodies are removed by splenic macrophages leaving "bite" cells; severe damage causes intravascular haemolysis

The red cell has no other source of NADPH and cannot synthesise new enzyme, having no nucleus — which is why it is uniquely vulnerable
Older cells have the least enzyme, so haemolysis is self-limiting in the common Mediterranean and African variants: the young cells that replace them have enough enzyme

Precipitating Factors

Category	Examples
Drugs	Primaquine and chloroquine (antimalarials), sulphonamides and co-trimoxazole, nitrofurantoin, dapsone, nalidixic acid, quinolones, aspirin in high dose, vitamin K analogues, methylene blue
Infection	The commonest trigger overall — any acute infection, especially viral hepatitis, pneumonia and typhoid
Food	Fava beans ("favism") — chiefly with the Mediterranean variant
Metabolic	Diabetic ketoacidosis; the neonatal period
Naphthalene	Mothballs, including through clothing

Diagnosis

During the crisis — haemoglobinuria, anaemia, jaundice, a raised reticulocyte count
Peripheral smear — bite cells, blister cells and HEINZ bodies (which require a supravital stain such as methyl violet, as they are not seen on a routine film)
G6PD enzyme assay is diagnostic
The assay must not be done during or just after a crisis — the deficient old cells have been destroyed and the young reticulocytes are enzyme-rich, so the result may be falsely normal. Test 2 to 3 months later

CLINICAL PEARL

Testing at the wrong time gives a falsely normal result, and this trips people up constantly. The crisis itself removes exactly the cells that would have shown the deficiency. If the clinical picture fits, treat as deficient and confirm the assay months later, when the red cell population has aged again.

Applied Aspects

Treatment is avoidance — the patient must be given a written list of drugs and foods to avoid, and should carry it
Acute crisis — stop the precipitant, hydrate to protect the kidneys, and transfuse if severe; most episodes are self-limiting
Screening before primaquine is standard in malaria programmes, since radical cure of vivax malaria requires it and is a real hazard in the deficient — directly relevant in India
Neonatal jaundice is a common presentation and may cause kernicterus if not treated promptly
Rasburicase and methylene blue are contraindicated, the latter paradoxically, since it depends on NADPH to work

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