Thiopurine-Induced Liver Injury in Patients With Inflammatory Bowel Disease: A Systematic Review

Abstract

The mean prevalence of azathioprine (AZA) or 6-mercaptopurine (MP)-induced liver injury in patients with inflammatory bowel disease was approximately 3%, and the mean annual drug-induced liver disorder rate was only 1.4%. However, this low figure calculated from retrospective studies contrasts with a much higher incidence (>10%) reported by a prospective study. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis). A small percentage of patients present with a slight elevation of liver tests (LTs) that do not have clinical implications and LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of the immunomodulator. However, when abnormalities in LTs are more marked, the dose of AZA/MP may be reduced 50%, with posterior clinical and analytical controls. With this strategy, LTs frequently normalize spontaneously, and the initial AZA/MP dose may be cautiously prescribed again. Thiopurines may induce an unusual severe cholestatic jaundice that may not regress but even progress despite thiopurine withdrawal. Therefore, these drugs should be completely withdrawn, and not only tapered, in those patients presenting clinically significant jaundice. Despite a lack of evidence that monitoring of LTs is necessary in patients receiving AZA/MP, routinely performed laboratory controls including LTs seem recommendable. However, the optimal monitoring schedule remains to be established. As long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction of 6-thioguanine, this drug should not be administered outside a clinical trial setting. (Am J Gastroenterol 2007;102:1518-527).

The long-term risk of continuous immunosuppression using thioguanides in inflammatory bowel disease

“…The mechanisms of hepatic insult include a drug-induced hepatitis, cholestasis and nodular regenerative hyperplasia of the liver. A recent review found that the mean prevalence of AZA or 6-MP-induced liver injury in patients with IBD was approximately 3%, and mean annual drug-induced liver disorder rate was only 1.4% [Gisbert et al 2007]. In a series of 396 IBD patients taking 6-MP, drug hepatitis was noted in 0.3%.…”

A review of liver disorders in inflammatory bowel disease (IBD)

“…Routine liver enzyme monitoring is advised. The medication can be continued with mild abnormalities without clinical symptoms; but should be discontinued when patient develops jaundice or abnormalities persists despite lowering the dose of Azathioprine or 6-MP [118].…”

Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

“…Thiopurine-induced liver toxicity is also a relevant issue. It's incidence varies between 3% and 10% of AZA-exposed patients and it can be classified into different entities: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (the later resulting in raised portal pressures, venoocclusive disease or peliosis hepatis) [9] . The majority of these syndromes respond to drug withdrawal.…”