Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis.
Hepatology
; 56(4): 1401-8, 2012 Oct.
Article
in En
| MEDLINE
| ID: mdl-22488741
ABSTRACT
UNLABELLED 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 × 10(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/8 × 10(8) 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 × 10(8) RBCs). CONCLUSION:
TGN concentrations of >220 pmol/8 × 10(8) RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azathioprine
/
Hepatitis, Autoimmune
/
Immunosuppressive Agents
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Country/Region as subject:
Europa
Language:
En
Journal:
Hepatology
Year:
2012
Document type:
Article
Affiliation country:
United kingdom