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长期使用低剂量甲氨蝶呤治疗良性疾病导致的肝毒性

Author
Joel M Kremer, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD
Translators
李蕴铷, 主任医师

引言

使用针对风湿性疾病[尤其是类风湿关节炎(rheumatoid arthritis, RA)]的常规剂量时，甲氨蝶呤(methotrexate, MTX)最常引起的不良反应都不会威胁生命。但某些并发症可能非常严重，尤其是肝毒性。幸运的是，仔细实施适当的患者监测可使这种风险降至最低，并使甲氨蝶呤继续在风湿性疾病的治疗发挥重要作用。 (参见“Major side effects of low-dose methotrexate”和“甲氨蝶呤诱发性肺损伤”)

肝毒性

甲氨蝶呤可以诱导一系列组织学变化，包括脂肪变性、星状细胞肥大、细胞核大小不一和肝纤维化(图片 1)。甲氨蝶呤损伤肝脏的机制尚不清楚。用于治疗RA的剂量可耗竭肝脏内的叶酸储备，而这可通过短期口服亚叶酸得到补充[1]。尚未发现叶酸耗竭和肝毒性之间具有相关性。但每日补充1mg叶酸或每周补充2.5mg亚叶酸都能降低血清转氨酶升高的几率[2,3]。因此，补充叶酸可能有助于为甲氨蝶呤使用者预防肝毒性，但不能替代转氨酶升高时的持续监测和甲氨蝶呤剂量的适当调整。

使用甲氨蝶呤治疗肿瘤和肝脏生化检测结果异常有关。据报道，甲氨蝶呤诱导性血清丙氨酸氨转移酶(alanine aminotransferase, ALT)升高的发生率大约为14%，天冬氨酸氨基转移酶(aspartate aminotransferase, AST)升高至异常范围的发生率为8%[4]。任何甲氨蝶呤疗程中都可发生肝酶升高，而且每日治疗患者的酶水平高于间断治疗患者[5]。肝酶异常通常在停药后1个月之内恢复。 (参见“肝病患者的化疗肝毒性和剂量调整”，关于‘甲氨蝶呤’一节)

对于甲氨蝶呤的潜在肝毒性，我们了解的大部分资料都来自良性疾病患者，如银屑病和RA。银屑病患者的甲氨蝶呤肝毒性似乎随总剂量积累上升而增加[6]。在每日使用甲氨蝶呤的患者中，肝硬化和肝纤维化的发生率是甲氨蝶呤间断使用者的2倍多[7,8]。

来自皮肤科文献的早期研究描述了银屑病患者使用甲氨蝶呤治疗时的严重肝脏疾病，包括肝硬化[9-11]。这些研究的作者也发现肝功能检测不能预测急性肝毒性。因此，皮肤病学界曾推荐在甲氨蝶呤总累积量达到1.5g时行肝活检，以后每累积1g就重复一次肝活检，以便监测肝脏疾病[6]。但作为该推荐依据的研究可能存在一些缺陷：仅在肝活检当天取血样，以及没有对其他肝毒素暴露进行控制，包括饮酒和砷。

     

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Literature review current through: 2017-06 . | This topic last updated: 2017-05-11.
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