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J Hepatol. 2006 Oct;45(4):584-91. Epub 2006 Jun 23.

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

Author information

1
Department of Gastroenterology, Duke University Medical Center, Durham, NC 27710, USA. michael.heneghan@kingsch.nhs.uk <michael.heneghan@kingsch.nhs.uk>

Abstract

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.

PMID:
16876902
DOI:
10.1016/j.jhep.2006.05.011
[Indexed for MEDLINE]

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