药物性肝损伤:2015年文献综述要点
Drug-Induced Liver Injury: Highlights from a Review of the 2015 Literature.
作者信息
Sarges Philip, Steinberg Joshua M, Lewis James H
机构信息
Department of Medicine, Division of Gastroenterology, Hepatology Section, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA.
出版信息
Drug Saf. 2016 Sep;39(9):801-21. doi: 10.1007/s40264-016-0427-8.
Numerous publications contributed to the expanding knowledge base about drug-induced liver injury (DILI) in 2015. New findings from the US Drug Induced Liver Injury Network (DILIN) in their most recently updated registry include a 1- to 3-week delay in the appearance of acute DILI from short-course antibiotics such as cefazolin. They corroborated the finding that acute DILI in patients with underlying liver disease was far more severe and potentially fatal than in patients without liver disease. The only drug that seemed to have an increased risk of hepatotoxicity in these patients was azithromycin. While nearly one in six patients with acute DILI had persistently elevated liver tests at 6 months, and results for 75 % of these patients continued to be abnormal at 12 months, most of these "chronic" injury cases were relatively minor and the result of cholestatic hepatotoxins. Newly described DILI agents include tolvaptan, as well as some new direct-acting antiviral protease inhibitors for chronic hepatitis C. The latter have been associated with serious acute hepatitis, hyperbilirubinemia, and decompensation. Herbal hepatotoxicity continues to be increasingly reported, although applying causality assessment to these cases can, in fact, be more challenging than with prescription drugs. As important as cases with DILI, the class of PCSK9 inhibitors used to lower low-density lipoprotein (LDL) cholesterol have not been associated with significant liver injury, in contrast with other lipid-lowering agents. With respect to pharmacologic DILI risk factors, new data show that drugs metabolized by cytochrome P450 enzymes had a nearly four times higher likelihood of causing DILI. Interestingly, high lipophilicity, which was previously felt to be a risk factor for DILI, was not found to be associated, although more study is needed to confirm this observation. While human leukocyte antigen (HLA) genotypes have been linked to several specific agents, the role of such testing in the general population remains undefined due to the currently low positive and negative predictive values of the available tests. New DILI biomarkers, specifically microRNA-122 and keratin-18, among others, appear to have the necessary predictive value to determine the prognosis and outcome of patients with paracetamol (acetaminophen [AAP])-induced acute liver failure (ALF), and may be of great benefit in deciding who requires N-acetylcysteine (NAC), and for what duration. Treatment options for other forms of DILI remain limited; no firm conclusions can currently be drawn for the use of NAC in non-AAP ALF.
2015年,众多出版物为药物性肝损伤(DILI)不断扩展的知识库做出了贡献。美国药物性肝损伤网络(DILIN)在其最新更新的登记处发布的新发现包括,使用头孢唑林等短期抗生素后,急性DILI的出现会延迟1至3周。这些发现证实,与无肝脏疾病的患者相比,患有基础肝脏疾病的患者发生的急性DILI更为严重,且有潜在致命风险。在这些患者中,唯一似乎有肝毒性风险增加的药物是阿奇霉素。虽然近六分之一的急性DILI患者在6个月时肝功能检查持续升高,且其中75%的患者在12个月时结果仍异常,但这些“慢性”损伤病例大多相对较轻,是胆汁淤积性肝毒素所致。新描述的DILI药物包括托伐普坦,以及一些用于慢性丙型肝炎的新型直接作用抗病毒蛋白酶抑制剂。后者与严重急性肝炎、高胆红素血症和失代偿有关。草药肝毒性的报告越来越多,尽管对这些病例进行因果关系评估实际上可能比对处方药更具挑战性。与DILI病例同样重要的是,与其他降脂药物相比,用于降低低密度脂蛋白(LDL)胆固醇的PCSK9抑制剂类药物与显著的肝损伤无关。关于药物性DILI的危险因素,新数据显示,由细胞色素P450酶代谢的药物导致DILI的可能性几乎高出四倍。有趣的是,尽管此前认为高亲脂性是DILI的一个危险因素,但并未发现两者有关联,不过还需要更多研究来证实这一观察结果。虽然人类白细胞抗原(HLA)基因型与几种特定药物有关,但由于现有检测的阳性和阴性预测值目前较低,此类检测在普通人群中的作用仍不明确。新的DILI生物标志物,特别是微小RNA-122和角蛋白-18等,似乎具有确定对乙酰氨基酚(扑热息痛 [AAP])所致急性肝衰竭(ALF)患者预后和结局的必要预测价值,在决定谁需要N-乙酰半胱氨酸(NAC)以及使用多长时间方面可能有很大帮助。其他形式DILI的治疗选择仍然有限;目前对于在非AAP ALF中使用NAC无法得出明确结论。