6-mercaptopurine as an alternative to azathioprine in azathioprine-induced hepatoxicity

To the Editor: Hepatotoxicity from thiopurine drugs, azathioprine (AZA) and 6-mercatopurine (6-MP), can be grouped into 3 syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury.1 AZA and 6-MP have also been linked to histopathological changes of the liver including nodular regenerative hyperplasia.1,2 Currently, as 6-MP is more expensive than AZA, treatment guidelines for AZA and 6-MP usage describe initiating AZA treatment first and trying 6-MP treatment only after AZA failure.3,–5 As the majority of clinicians consider both medications equally effective, they may discontinue AZA once AZA-induced hepatotoxicity takes place, especially if liver dysfunction does not respond to AZA dose reduction. We describe 2 children with Crohn's disease (CD) who had hepatotoxicity after receiving AZA and went on to tolerate 6-MP without any side effects. An 11-year-old boy presented with a 6-week history of abdominal pain and 2–4 episodes per day of watery, nonbloody diarrhea. Biopsies during ileocolonoscopy showed ileal granulomas with acute and chronic inflammatory infiltrate. The patient was diagnosed with terminal ileocecal CD. The patient was started on exclusive polymeric feeding with AZA 2 mg/kg/day. Initially, the patient tolerated the AZA without significant side effects. Blood work to monitor for AZA toxicity were done weekly. Alanine transaminase (ALT) levels were normal (between 30–41 U/L) for the first 4 weeks after starting treatment with AZA. Four to 7 weeks after starting AZA treatment the patient's ALT levels increased to 53, 98, and 99 U/L. The AZA dose was halved and the patient's ALT levels decreased to below 50 U/L. Two months later the AZA dose was increased alternating days between 200 and 100 mg. The patient's ALT levels rose to 78, 76, and 97 U/L in the subsequent few weeks with no response to AZA dose reduction. The AZA treatment was terminated and the patients ALT levels returned to normal levels (less than 45 U/L) within 3 weeks. 6-MP 1.5 mg/kg was begun 3 weeks after the patient's ALT levels normalized. The patient's ALT levels remained normal for the following 5 months. No further hepatotoxicity or changes in ALT have occurred. Another 15 year-old-boy presented with a 3-week history of abdominal pain, nausea, lethargy, and recent weight loss. Ileal biopsies on ileocolonoscopy showed an inflammatory infiltrate and mildly disturbed villous architecture. The patient was diagnosed with terminal ileal CD. The patient was started on high-dose oral prednisone and enteral feeding to supplement his meals. The prednisone was weaned over the next 2 months. AZA 2 mg/kg was started prior to completely weaning the prednisone. Five and 6 weeks after beginning AZA the patient's ALT rose to 60 and 177 U/L, respectively. Halving the AZA dose did not decrease the ALT levels. AZA was discontinued and the patient's ALT level decreased to 39 and 26 U/L over the next 2 weeks. At this point, 6-MP 1.5 mg/kg was commenced. For the following 12 months no side effects or hepatotoxicity were observed since the patient switched to 6-MP. Although the mechanisms of action of 6-MP and AZA are very similar, some evidence has shown that a subset of adult patients who demonstrate hepatotoxicity to AZA will go on to be successfully treated with 6-MP.3,–5 In the 2 children presented, 6-MP was successfully used in 2 pediatric patients with CD after the patients showed hepatotoxicity to AZA. AZA and 6-MP are metabolized into active and inactive metabolites by the same enzymatic cascade. AZA, a pro-drug, is converted to 6-MP and its imidazole derivative by glutathione in the liver. 6-MP enters cells and is subject to 3 competing enzymatic pathways. 6-MP may be converted into 6-thiouric acid by xanthine oxidase or may be converted into 6-methylmercaptopurine (6-MMP) by thiopurine methyltransferase (TPMT). Both of these cascades lead to noncytotoxic metabolites.2 6-MP is converted to its cytotoxic and active metabolite 6-thioguanine nucleotide (TGN) in a pathway consisting of 3 enzymes: hypoxanthine guanine phophoribosyltransferase, inosine-5-monophosphate dehydrogenase, and guanidine-5-monophos- phate synthetase.6 The relative activity of these 3 enzymatic pathways determines the percentage of active TGN metabolites converted from a dose of AZA or 6-MP. TGN metabolites are purine antagonists and inhibit RNA, DNA, and protein synthesis. By doing so, they induce cytotoxicity and immunosuppression.6 TPMT is deficient in 1 in 300 patients. These patients, upon receiving AZA or 6-MP, convert the drugs into higher levels of the active TGN metabolites. Because of the increased action of the drugs they are at a high risk of developing potentially fatal neutropenia.7 Unfortunately, the presented patients did not have their TPMT activity and phenotype measured. Conversely, increased TPMT activity and 6-MMP levels have been shown in patients with increased transaminase levels.6 It is unlikely that the improvement of liver function was purely due to a dose reduction effect, as both patients liver dysfunction continued despite the dose reduction of AZA. As AZA conversion to 6-MP by glutathione produces an imidazole derivative byproduct, a possible explanation of how patients with AZA hepatotoxicity are able to tolerate 6-MP is imidazole derivative-mediated hepatotoxicity.8 In conclusion and in view of our experience with these 2 patients, we believe it is worthwhile trying 6-MP in children with inflammatory bowel disease (IBD) who develop liver dysfunction due to AZA. More research is needed to examine different mechanisms of hepatotoxicity of different thiopurine drugs.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.