Azathioprine Metabolite Measurements in the Treatment of Autoimmune Hepatitis in Pediatric Patients: A Preliminary Report

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Abstract
Potential adverse effects of azathioprine (AZA), such as neutropenia and hepatotoxicity, make its use in autoimmune hepatitis (AIH) problematic. To determine longitudinal AZA metabolite levels in a cohort of children with AIH, correlate them with therapeutic effects, medication-induced toxicity and adherence. From January 2000 to January 2002, 122 blood samples from 30 pediatric patients with AIH were prospectively analyzed. Ten patients had previously been treated with AZA (mean dose of 1.3mg/kg/day) for an average of 30 months. At the outset, 24 patients were taking steroids and 10 had cirrhosis/hypersplenism. Routine biochemical studies, 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) levels were assessed every 8 weeks. Red blood cell thiopurine methyltransferase (TPMT) enzyme activity was determined in each patient. AZA dose was adjusted to achieve a target 6-TG level 235-450 pmoles per 8 × 108 RBC. 8/10 patients who had previously been treated with standard doses of AZA had 6-TG below target levels. Increasing AZA mean dose by 50% in those patients resulted in 6/10 patients in target range; ALT levels and steroid requirements were reduced. AZA dosing was safely increased in patients with cirrhosis/hypersplenism. In spite of normal TPMT levels, 64% of patients did not make measurable concentrations of 6-MMP. Inappropriately low 6-TG levels revealed non-adherence in 5 patients. Two patients were identified with AZA hepatotoxicity. AZA metabolite testing in children with AIH is useful in identifying medication toxicity and non-adherence. AZA dose escalation is safe and may be required in order to achieve 6-TG target levels described for inflammatory bowel disease.