title: Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology, Duke University Medical Center, Durham, NC 27710, USA. michael.heneghan@kingsch.nhs.uk <michael.heneghan@kingsch.nhs.uk>
authors.forename: Michael A
authors.initials: MA
authors.lastname: Heneghan
authors.forename: Michael L
authors.initials: ML
authors.lastname: Allan
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bornstein
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muir
authors.forename: David A
authors.initials: DA
authors.lastname: Tendler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D013866:Thioguanine / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine; D011241:Prednisone