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

Unlabelled: Potential adverse effects of azathioprine (AZA), such as neutropenia and hepatotoxicity, make its use in autoimmune hepatitis (AIH) problematic.

Objective: To determine longitudinal AZA metabolite levels in a cohort of children with AIH, correlate them with therapeutic effects, medication-induced toxicity and adherence.

Methods: 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 x 10 RBC.

Results: 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.

Conclusion: 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.