G6PD deficiency and enzymopathies: Viva

Branch 1: Recognising the problem and the mechanism

The candidate should immediately recognise this as a direct-antiglobulin-test-negative intravascular haemolysis in a boy of African ancestry after a viral trigger, which places G6PD deficiency at the top of the differential. The combination of sudden jaundice, dark urine, pallor, a high reticulocyte count, a negative direct antiglobulin test, and bite cells with Heinz bodies is the blood-film signature of oxidative haemolysis. The candidate should state the diagnosis aloud as the problem representation and confirm that the film findings are pathognomonic when combined with the negative direct antiglobulin test. [1]

The examiner will probe the mechanism. The candidate should explain that G6PD generates NADPH through the pentose phosphate pathway, that NADPH keeps glutathione reduced, and that reduced glutathione neutralises the oxidants generated in the red cell. In deficiency, oxidants denature haemoglobin into Heinz bodies, the spleen pits them out to form bite cells, and the membrane lyses. The candidate should explain why red cells are uniquely vulnerable, namely that they have no nucleus and cannot replace the deficient enzyme, so the oldest cells with the least residual activity are lysed first. [1][2]

Branch 2: The diagnostic trap

The examiner will ask how the diagnosis is confirmed and will set the timing trap. The candidate should state that the definitive test is a quantitative G6PD enzyme assay on a red cell lysate, but that the assay may be falsely normal during an acute crisis. The reason is that the enzyme-deficient older red cells are lysed first, leaving behind the young reticulocytes that carry the highest enzyme activity. The candidate must state that a normal assay during a crisis never excludes the diagnosis and that the assay is repeated two to three months later, once the red cell population has returned to its normal age distribution. [2]

The examiner may press on what to do if the assay done today returns normal. The candidate should answer that the clinical and film diagnosis stands regardless, the child is treated as G6PD-deficient, and the assay is repeated in two to three months. The candidate should also mention that symptomatic heterozygous females from skewed X-inactivation can be missed and may need a quantitative assay or genotyping, and that genotyping identifies the specific variant. [2]

Branch 3: The management and transfusion decision

The candidate should outline the management as trigger withdrawal, hydration, folic acid, and monitoring. The trigger here is the viral illness, which is treated supportively. The candidate should state that most crises are self-limited and need supportive care alone, and that the African variant is usually self-limited because the deficient old-cell cohort is cleared. [9]

The examiner will ask when to transfuse. The candidate should give the threshold clearly: transfuse leucodepleted packed red cells 10 to 20 mL per kilogram for a haemoglobin under 70 g per litre or any symptomatic anaemia with haemodynamic compromise. This child, with a haemoglobin of 62 g per litre and pallor, meets the threshold, so he is crossmatched and transfused. The candidate should name the indications for intensive care, namely acute kidney injury from haemoglobinuria, uncontrolled haemolysis, and haemodynamic instability. [9]

Branch 4: Lifelong counselling and pharmacogenetic prescribing

The examiner will ask what the family is told at discharge. The candidate should describe a written trigger-avoidance list, naming the strong oxidant drugs to avoid under the 2023 Clinical Pharmacogenetics Implementation Consortium guideline: primaquine, tafenoquine, rasburicase, methylene blue, and dapsone, plus fava beans, naphthalene mothballs, and henna. The candidate should explain the X-linked inheritance and the need to screen male siblings and the maternal line, and provide a written card and a clear safety-net. [6]

The examiner may probe a prescribing scenario. The candidate should state that primaquine and tafenoquine for vivax or ovale radical cure require a confirmed normal G6PD status first, that methylene blue for methaemoglobinaemia is contraindicated because it requires the deficient NADPH and is itself an oxidant, and that rasburicase for tumour lysis prophylaxis should only follow a confirmed normal status. The candidate should close by affirming that the prognosis is excellent with trigger avoidance and that the family should carry the avoidance list at all times. [6]