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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Heneghan, MA; Allan, ML; Bornstein, JD; Muir, AJ; Tendler, DA

Published Date

  • October 2006

Published In

Volume / Issue

  • 45 / 4

Start / End Page

  • 584 - 591

PubMed ID

  • 16876902

Pubmed Central ID

  • 16876902

International Standard Serial Number (ISSN)

  • 0168-8278

Digital Object Identifier (DOI)

  • 10.1016/j.jhep.2006.05.011

Language

  • eng

Conference Location

  • Netherlands