de Boer N K H, Zondervan P E, Gilissen L P L, den Hartog G, Westerveld B D, Derijks L J J, Bloemena E, Engels L G J B, van Bodegraven A A, Mulder C J J
Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
Dig Liver Dis. 2008 Feb;40(2):108-13. doi: 10.1016/j.dld.2007.10.013. Epub 2007 Dec 20.
The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent.
We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use.
Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled.
Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed.
Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively.
We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.
已有人提议将6-硫鸟嘌呤用作炎症性肠病患者的挽救药物。关于6-硫鸟嘌呤短期疗效和毒性的初步数据很有前景；然而，有关其潜在肝毒性作用（结节性再生性增生）的报道对这些数据提出了质疑。我们认为这些肝脏组织学异常很可能与剂量或水平有关。
我们进行了一项前瞻性多中心研究，以探讨长期使用（与先前研究相比）低剂量6-硫鸟嘌呤的肝毒性潜力。
纳入连续使用6-硫鸟嘌呤至少30个月并同意接受肝活检的炎症性肠病患者。
由两名不了解临床数据的病理学家对肝活检标本进行评分。回顾了在开始6-硫鸟嘌呤治疗前和活检前测定的实验室参数。
分析了28份活检标本。大多数患者（89%）是对硫唑嘌呤和/或6-巯基嘌呤不耐受的炎症性肠病患者。26例患者（93%）未检测到结节性再生性增生的迹象；另外2例患者由于病理结果不明确，不能排除结节性再生性增生。6-硫鸟嘌呤的平均剂量、6-硫鸟嘌呤核苷酸水平、使用持续时间和累积剂量分别为19.5mg、564 pmol/8×10⁸红细胞、38个月和22491mg。
我们已经证明，炎症性肠病患者采用低剂量6-硫鸟嘌呤维持治疗不太可能诱导结节性再生性增生。结节性再生性增生的诱导似乎与6-硫鸟嘌呤剂量或6-硫鸟嘌呤核苷酸水平有关。
