title: Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis.
abstract: OBJECTIVE
  Corticosteroids alone or in conjunction with azathioprine (AZA) is the standard treatment in autoimmune hepatitis (AiH). Individual variations in thiopurine (TP) metabolism may affect both drug efficacy and toxicity. Our aim was to investigate the utility of thiopurine methyltransferase (TPMT) as well as thioguanine nucleotide (TGN) and methylthioinosine monophosphate (meTIMP) metabolite measurements with regard to clinical outcome.
  
  
  METHODS
  Two hundred thirty-eight patients with AiH were included in this cross-sectional study. TPMT status was assessed in all patients, while TGN and meTIMP were measured in patients with ongoing TP medication. Clinical outcome was evaluated by liver tests and the ability to withdraw steroids.
  
  
  RESULTS
  TPMT genotyping (n=229) revealed 207 (90.4%) wild-type and 22 heterozygous patients. One hundred forty-three patients had ongoing TP therapy with AZA (n=134) or mercaptopurine (MP; n=9); response was judged as complete response (CR) in 113 patients and partial response (PR) in 30 patients. Both TP dose (1.64 vs 1.19 mg/kg; p=0.012) and TPMT activity (14.3 vs 13.5; p=0.05) were higher in PR, resulting in similar TGN levels (PR: 121 pmol/8 x 10(8) red blood cells [RBC]; CR: 113 pmol/8 x 10(8) RBC; p=0.33) but higher meTIMP levels in PR (1350 vs 400 pmol/8 x 10(8) RBC; p=0.004). Patients able to withdraw steroids or who were using 5 mg prednisolone daily were treated with lower TP doses than patients on higher steroid doses (1.15 vs 1.18 vs 1.82 mg/kg; p<0.001).
  
  
  CONCLUSIONS
  TP metabolite measurements are of clinical value in AiH patients who do not respond to standard TP treatment and for the identification of a shifted metabolism, which may demand an alternative treatment strategy.
authors.affiliation: Department of Gastroenterology and Nutrition, University Hospital, 22185 Lund, Sweden. Ulf.Hindorf@skane.se
authors.forename: Ulf
authors.initials: U
authors.lastname: Hindorf
authors.forename: Khatoon
authors.initials: K
authors.lastname: Jahed
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.forename: Hans
authors.initials: H
authors.lastname: Verbaan
authors.forename: Hanne
authors.initials: H
authors.lastname: Prytz
authors.forename: Sven
authors.initials: S
authors.lastname: Wallerstedt
authors.forename: Mårten
authors.initials: M
authors.lastname: Werner
authors.forename: Rolf
authors.initials: R
authors.lastname: Olsson
authors.forename: Einar
authors.initials: E
authors.lastname: Björnsson
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
authors.forename: Sven H C
authors.initials: SH
authors.lastname: Almer
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D019693:Hepatitis, Autoimmune / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000097:blood*; D008875:Middle Aged; D011379:Prognosis; D013866:Thioguanine / Q000097:blood*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000097:blood; D013873:Thionucleotides / Q000097:blood*; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D015415:Biomarkers; D013873:Thionucleotides; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine