Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis.
OBJECTIVE
Toxicity and efficacy of azathioprine is governed partly by the activity of thiopurine methyltransferase (TPMT). Azathioprine has been used for many years, with corticosteroids or alone, for the treatment of autoimmune hepatitis (AIH) but no studies of TPMT phenotype and genotype in relation to response to the drug in AIH have been published.


METHODS
Erythrocyte TPMT activities were measured by a radioincorporation assay in 72 consecutive outpatients with AIH, 53 of whom were genotyped for the commonest defective alleles in Europeans (TPMT*3A, *3B and *3C) by restriction fragment length polymorphism analysis.


RESULTS
TPMT activities were significantly lower in patients intolerant of azathioprine (group I, n=15) than in those who sustained remission on azathioprine alone (group II, n=28; P=0.003) and those who tolerated azathioprine but continued to require corticosteroids (group III, n=29; P<0.0001), and were higher in group III than in group II (P=0.034). Ten patients with defective alleles (all heterozygotes) had significantly lower TPMT activities (P=0.002). However, in 25% there was discordance between phenotype and/or genotype and response to azathioprine.


CONCLUSIONS
TPMT phenotyping or genotyping may be advisable before institution of azathioprine therapy in AIH but neither approach invariably predicts response to the drug.
Langley
Peter G
PG
Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
Underhill
James
J
Tredger
J Michael
JM
Norris
Suzanne
S
McFarlane
Ian G
IG
D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage*; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005838:Genotype; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine