Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease.
BACKGROUND
Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid 'triple therapy' improved renal graft survival.


OBJECTIVE
To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study.


METHODS
Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co-therapy with low-dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co-therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests.


RESULTS
Of 11 patients (three Crohn's disease, eight ulcerative colitis) treated, nine (82%) remain in long-term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu-like symptoms. Two stopped: one nausea, one abnormal liver function (stealosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions.


CONCLUSIONS
Allopurinol co-therapy with low-dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long-term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses.
Ansari
A
A
Department of Gastroenterology, Guy's and St Thomas' Hospitals, London, UK. azhar.ansari@gstt.nhs.uk
Elliott
T
T
Baburajan
B
B
Mayhead
P
P
O'Donohue
J
J
Chocair
P
P
Sanderson
J
J
Duley
J
J
D000328:Adult; D000368:Aged; D000493:Allopurinol / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D000493:Allopurinol; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase