gms | German Medical Science

Introduction: In the treatment of moderate to severe autoimmune hepatitis, the immunosuppressant azathioprine is added to corticosteroids to attain and to maintain remission. Azathioprine is a prodrug which is bioactivated to 6-thioguanine nucleotides (6-TGN) by a number of enzymatic steps, while competing steps lead to the potentially hepatotoxic, but therapeutically inactive methylmercaptopurine nucleotides (MMPN). Since these metabolic steps show large interindividual variabilities, partially caused by genetic variation in the activities of the enzymes involved, therapeutic monitoring of 6-TGN and MMPN in patients has been proposed, but there is continuing debate about its usefulness and therapeutic ranges.

Methods: In this retrospective cohort study, records of patients with autoimmune hepatitis who were treated at the University Hospital Zurich with azathioprine and in whom at least one quantification of 6-TGN and MMPN has been carried out between 2002 and 2013, were evaluated. The study was approved by the Ethics Committee of the Canton of Zurich. Only records of patients who had not refuses research access to their data were included. The main objectives were to find relationships between azathioprine doses, concentrations of 6-TGN and MMPN, and clinical outcome parameters. Remission status was assessed using clinical and laboratory information.

Results: Records of 19 female and 10 male patients with autoimmune hepatitis were included. The median age at diagnosis was 54 (range 17-77) years, the median dose of azathioprine was 2.03 (range 0.4-5.4) mg / kg bodyweight /day, and this dose had been maintained unchanged since a median of 8.75 (range 0-70) months. The median 6-TGN concentrations were 234.5 (range 50-896) pmol/8 x 10^8 red blood cells, median MMPN concentrations were 872.5 (range 100-13’664) pmol/8 x 10^8 red blood cells. Overall, there was no statistically significant correlation between azathioprine dose and 6-TGN concentrations, but a weak correlation between dose and MMPN concentrations was observed. For the entire group of patients, no relationship between 6-TGN concentrations and remission status was found, while in patients with liver cirrhosis, higher 6-TGN concentrations were associated with remission. No common therapeutic range for all patients with autoimmune hepatitis was substantiated.

Conclusion: This study underlines the complex association between azathioprine dose, metabolite blood concentrations and therapy response.