Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis.
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.
Hindorf
Ulf
U
Department of Gastroenterology and Nutrition, University Hospital, 22185 Lund, Sweden. Ulf.Hindorf@skane.se
Jahed
Khatoon
K
Bergquist
Annika
A
Verbaan
Hans
H
Prytz
Hanne
H
Wallerstedt
Sven
S
Werner
Mårten
M
Olsson
Rolf
R
Björnsson
Einar
E
Peterson
Curt
C
Almer
Sven H C
SH
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
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