Abstract:
About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine-induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34-year-old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6-MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 6-MMPN blood levels may help physicians to identify patients at risk of similar duct injury.
摘要:
约有15%至28%的接受硫嘌呤治疗的患者出现药物不良反应,如血液学和肝毒性。其中一部分与硫嘌呤S-甲基转移酶(TPMT)的多态性活性有关,硫嘌呤代谢的关键解毒酶。我们在此报告一例硫嘌呤诱导的导管减少症,并对硫嘌呤代谢进行了全面的药理分析。一个34岁的女人,有严重系统性红斑狼疮病史,最近引入硫唑嘌呤治疗,表现为轻度波动的转氨酶血液水平与肝细胞模式一致,在接下来的几周里演变成胆汁淤积模式。血液中的硫嘌呤代谢物测定显示,6-硫鸟嘌呤核苷酸(6-TGN)水平较低,6-甲基巯基嘌呤核糖核苷酸(6-MMPN)水平显着增加,以及不利的[6-MMPN:6-TGN]代谢物比例和高TPMT活性。经过大约六个月的噻嘌呤治疗,经颈静脉肝活检显示导管减少,硫唑嘌呤停药导致临床进一步改善。根据以前的文献报道,我们的案例支持导管减少是硫唑嘌呤的一种罕见的药物不良反应。反应机制未知,但可能涉及高6-MMPN血液水平,由于异常的硫嘌呤代谢(转换代谢)。通过测量6-TGN和6-MMPN血液水平的早期治疗药物监测可以帮助医生识别有类似导管损伤风险的患者。