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Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis.
MedLine Citation:
PMID:  22488741     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH) but up to 18% of patients are unresponsive. AZA is a pro-drug and formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (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. METHODS: Red blood cell (RBC) TGNs and MeMPNs were measured on serial blood samples over a two 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<33IU/ml). RESULTS: Patients who maintained remission (n=53) compared to those who did not (n=17) tended to be on lower doses of AZA (1.7 vs. 2.0 mg/kg/day; p=0.08) but had significantly higher concentrations of avTGN (237 vs. 177 pmol/8x10(8) 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 (r(s) =-0.32; p=0.007). An avTGN concentration of >220 pmol/8x10(8) RBCs best predicted remission, with an odds ratio 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 (14277 vs. 1416 pmol/8x10(8) RBCs). CONCLUSION: TGN concentrations of >220 pmol/8x10(8) RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations. (HEPATOLOGY 2012.).
Authors:
Dhaliwal Harpreet Kaur; Anderson Rory; Thornhill Elizabeth Louise; Schneider Sarah; McFarlane Elaine; Gleeson Dermot; Lennard Lynne
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-5
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 American Association for the Study of Liver Diseases.
Affiliation:
Clinical Pharmacology Unit, Department Human Metabolism, University of Sheffield, Sheffield, UK; Liver Unit, Royal Hallamshire Hospital, Sheffield, UK.
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