Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis

Abstract

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 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)