Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis

Ulf Hindorf, Khatoon Jahed, Annika Bergquist, Hans Verbaan, Hanne Prytz, Sven Wallerstedt, Mårten Werner, Rolf Olsson, Einar Björnsson, Curt Peterson, Sven H.C. Almer

Rannsóknarafurð: Framlag til fræðitímaritsGreinritrýni

40 Tilvitnanir (Scopus)

Útdráttur

Background & Aims: 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 × 108 red blood cells [RBC]; CR: 113 pmol/8 × 108 RBC; p = 0.33) but higher meTIMP levels in PR (1350 vs 400 pmol/8 × 108 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.

Upprunalegt tungumálEnska
Síður (frá-til)106-111
Síðufjöldi6
FræðitímaritJournal of Hepatology
Bindi52
Númer tölublaðs1
DOI
ÚtgáfustaðaÚtgefið - jan. 2010

Athugasemd

Funding Information:
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. Excellent laboratory work was carried out by laboratory technicians Lena Svensson (genotyping) and Britt Sigfridsson (TPMT and metabolite measurements). This study was supported by the Swedish Medical Research Council, the Research Council in South-East Sweden (FORSS), Rut and Richard Juhlin’s foundation and, The Swedish Medical Society. MEDA AB company contributed 50% of costs for travel and accommodation to the SILK members; however, MEDA had no influence on the initiation or conduct of this study.

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