Azathioprine Hepatotoxicity — RACP Adult Medicine MCQ

Instant feedback + full explanation. One question, done properly.

HardClinical PharmacologyAzathioprine HepatotoxicityRACP Adult Medicine

A 58-year-old woman with autoimmune hepatitis on azathioprine develops nausea, vomiting, and a rising ALT. Her TPMT activity was normal at baseline. What is the most common reason for azathioprine-induced hepatotoxicity despite normal TPMT?

Educational content. Not a substitute for clinical judgement or local policy.

Reveal the answer and explanation

Correct answer: C — Dose-dependent intrinsic hepatotoxicity (idiosyncratic or cholestatic)

Azathioprine hepatotoxicity can occur even with normal TPMT activity. It manifests in three patterns: (1) Idiosyncratic hepatocellular injury (early – within weeks), (2) Cholestatic injury (can occur at any time), and (3) Nodular regenerative hyperplasia (with long-term use – causing non-cirrhotic portal hypertension). Dose-dependent hepatotoxicity from the azathioprine metabolite 6-methylmercaptopurine (6-MMP) can also occur. Checking 6-thioguanine and 6-MMP metabolite levels helps distinguish: high 6-MMP with low 6-TGN suggests preferential shunting and hepatotoxicity risk. Adding allopurinol (which shifts metabolism towards 6-TGN) is a strategy used in IBD but requires specialist guidance and dose reduction of azathioprine by 75%.

Reference: AMH – 2025 – Azathioprine; eTG – 2025 – Gastrointestinal