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Autoimmune, Cholestatic and Biliary Disease
Article first published online: 7 SEP 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 4, pages 1401–1408, October 2012
How to Cite
Dhaliwal, H. K., Anderson, R., Thornhill, E. L., Schneider, S., McFarlane, E., Gleeson, D. and Lennard, L. (2012), Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis. Hepatology, 56: 1401–1408. doi: 10.1002/hep.25760
Potential conflict of interest: Nothing to report.
Financial support for the laboratory consumables used in this study was provided by Bardhan Research and Education Trust of Rotherham Ltd. (Barnsley, UK).
- Issue published online: 4 OCT 2012
- Article first published online: 7 SEP 2012
- Accepted manuscript online: 5 APR 2012 04:36AM EST
- Manuscript Accepted: 26 MAR 2012
- Manuscript Received: 17 FEB 2012
Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH), but up to 18% of patients are unresponsive. AZA is a prodrug, and the formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (i.e., TGNs and methylmercaptopurine nucleotides [MeMPNs]), thiopurine methyltransferase (TPMT) activity, therapeutic response, and toxicity in adult patients with AIH prescribed a stable dose of AZA for the maintenance of remission. Red blood cell (RBC) TGNs and MeMPNs were measured in serial blood samples over a 2-year period. The average TGNs (avTGNs) and MeMPNs (avMeMPNs) concentrations for each patient were used for analysis. Therapeutic response was defined as the ability to maintain remission, defined as a normal serum alanine aminotransferase (ALT) level (ALT <33 IU/mL). Patients who maintained remission (n = 53), compared to those who did not (n = 17), tended to be on lower doses of AZA (1.7 versus 2.0 mg/kg/day; P = 0.08), but had significantly higher concentrations of avTGN (237 versus 177 pmol/8 × 108 RBCs; P = 0.025). There was no difference in MeMPN concentrations or TPMT activities between the two groups. There was a negative correlation between ALT and avTGN (rs = −0.32; P = 0.007). An avTGN concentration of >220 pmol/8 × 108 RBCs best predicted remission, with an odds ratio of 7.7 (P = 0.003). There was no association between TGN, MeMPN, or TPMT activity and the development of leucopenia. Two patients developed AZA-induced cholestasis and the avMeMPN concentration was higher in those patients, compared to those who did not (14,277 versus 1,416 pmol/8 × 108 RBCs). Conclusion: TGN concentrations of >220 pmol/8 × 108 RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations. (HEPATOLOGY 2012)