A 40-year-old woman has autoimmune hepatitis (AIH) and cirrhosis. She is on azathioprine 75 mg/day and prednisolone 5 mg/day. Her TPMT enzyme activity is low (detected retrospectively). She develops pancytopenia. What is the mechanism of azathioprine toxicity in this context?

• A Inhibition of thiopurine methyltransferase leading to increased 6-methylmercaptopurine hepatotoxicity
• B Accumulation of 6-thioguanine nucleotides (6-TGN) causing bone marrow suppression ✓
• C Direct mitochondrial toxicity independent of TPMT activity
• D Azathioprine-induced autoimmune aplastic anemia via T-cell activation

Explanation

Azathioprine is metabolised to 6-mercaptopurine (6-MP), which is then converted to active 6-thioguanine nucleotides (6-TGN, cytotoxic/myelosuppressive) or inactivated by TPMT to 6-methylmercaptopurine (6-MMP, hepatotoxic). Patients with low or absent TPMT activity shunt more drug toward 6-TGN accumulation, causing severe myelosuppression (leukopenia, thrombocytopenia, anaemia). This is why TPMT genotyping or phenotyping is recommended before azathioprine initiation. Conversely, high TPMT activity shunts toward 6-MMP, risking hepatotoxicity.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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