Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?
BACKGROUND
6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology.


OBJECTIVE
Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients.


METHODS
Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging.


RESULTS
Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia.


CONCLUSIONS
Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine.


CONCLUSIONS
6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.
Gilissen
L P L
LP
Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht, The Netherlands. lgi@sint.azm.nl
Derijks
L J J
LJ
Driessen
A
A
Bos
L P
LP
Hooymans
P M
PM
Stockbrügger
R W
RW
Engels
L G J B
LG
D000328:Adult; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D013866:Thioguanine / Q000009:adverse effects*
D013866:Thioguanine