2 Thiopurine

methyltransferase (TPMT) level was normal (53 nmol/g, range 35-79). Subsequently she started azathioprine (AZA) 75 mg daily (1 mg/kg). Her ALT and IgG normalized 6 weeks later. Following prednisolone reduction to 10 mg, her ALT increased to 147 IU/L despite AZA compliance. Forty milligrams prednisolone was reinstituted. On tapering to 10 mg she developed persistently fluctuating ALT (40-80 IU/L) despite increased AZA to 150 mg (2 mg/kg). A rise of ALT to 133 IU/L required 40 mg prednisolone again. Repeat liver biopsy revealed steatosis but much reduced interface hepatitis. Thiopurine metabolite levels (Lennard method) revealed a 6-thioguanine (6-TGN-the active moiety) level of 100 pmol/8 × 108 red blood cells (RBC) (normal range 250-450) and a 6-methyl mercaptopurine (6-MMP) level of 5800 pmol/8 × 108 RBC, consistent with hypermethylation selleck chemicals llc and preferential shunting to 6-MMP. Allopurinol 100 mg once daily was added and her AZA dose reduced by 75%. Subsequently, her ALT normalized within 4 weeks (Fig. 1). This combination corrected her metabolite levels (6-TGN 202 pmol/8 × 108 RBC and 6-MMP 196 pmol/8 × 108 RBC). Prednisolone was withdrawn after 3 months; her ALT remains 10-15 IU/L 12 months later. AZA is essential in managing AIH, often obviating the need for long-term prednisolone. Between 3%-13% of inflammatory bowel disease (IBD) and AIH patients will develop AZA-induced

hepatotoxicity,3-5 which may be difficult to distinguish from AIH nonresponse or relapse without liver check details biopsy. In this setting, measuring thiopurine metabolites can provide diagnostic guidance. The finding of increased 6-MMP >5700 pmol/8 × 108 RBC with low or normal 6-TGN (“shunting”) is associated with hepatotoxicity and other side effects including nausea, anorexia, and influenza-like symptoms in IBD patients.5 Our patient’s persistently elevated ALT was consistent with AZA-induced hepatotoxicity (raised ALT secondary to high 6-MMP.) Repeat liver biopsy revealed prednisolone-induced

上海皓元医药股份有限公司 steatosis with only mildly active AIH. High 6-MMP levels do not always cause hepatotoxicity, however. Allopurinol acts through inhibition of xanthine oxidase, producing preferential AZA breakdown by the TPMT enzymatic pathway resulting in higher 6-TGN and lower 6-MMP (Fig. 2), although the exact mechanism is not fully understood. The combination requires AZA dose reduction to prevent excess 6-TGN production. This is the first reported adult case of allopurinol co-therapy in AIH for the management of AZA-induced hepatotoxicity. This strategy allowed our patient to discontinue prednisolone and avoid alternative immunosuppression. A study into the utility of measuring thiopurine metabolites identified AZA-induced hepatotoxicity, although the investigators found no role for measuring levels to monitor treatment response.