Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis

Background/Aims: Azathioprine is a key drug in the management of autoimmune hepatitis (AIH), with effects mediated via conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP), the latter controlled by thiopurine methyltransferase (TPMT). Our aims were to evaluate the role of TPMT genotyping and phenotyping and to examine 6-TG and 6-MMP metabolite levels in patients with AIH. Methods: TPMT genotyping and phenotyping was performed on 86 patients with AIH, and metabolites evaluated in assessable patients. Results: Eighty-six patients with AIH received azathioprine; 22 developed toxicity and 4/22 were heterozygous for TPMT alleles. Cirrhosis was more common amongst patients who developed toxicity (12/22 (54.5%) versus 19/64 (29.6%), P = 0.043). Patients who required persistent prednisone at equivalent azathioprine doses had a higher mean fibrosis stage (P = 0.044). TPMT activity, but not metabolites, was lower in patients with stage III/IV fibrosis versus stage I/II fibrosis (30 +/- 1.92 versus 35.2 +/- 1.93, P = 0.044). Azathioprine dose significantly correlated with measured 6-TG levels (r = 0.409, P < 0.0001) and 6-MMP levels (r = 0.387, P < 0.001). Conclusions: Advanced fibrosis but not TPMT genotype or activity predicts azathioprine toxicity in AIH. Overlap in 6-TG and 6-MMP metabolite levels is noted whether or not steroid therapy is used to maintain remission. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.