College of Pharmacy, Gyeongsang National University.
Mokhwa Convalescent Hospital.
J Immunother. 2021 Jan;44(1):16-21. doi: 10.1097/CJI.0000000000000347.
Although hepatotoxicity induced by immune checkpoint inhibitors (ICPIs) can cause severe clinical complications, the risk factors associated with hepatotoxicity have rarely been investigated. The purpose of this study was to determine the potential risk factors for the incidence of hepatotoxicity and for time to ICPI-induced hepatotoxicity. Patients who received ICPIs (atezolizumab, nivolumab, pembrolizumab, and ipilimumab) were included in this retrospective 2-center study. Collected data included sex, age, body weight, body surface area, Eastern Cooperative Oncology Group performance status, underlying disease, liver metastasis, programmed cell death ligand-1 expression, interval from previous chemotherapy, and concomitant drug use. Among the 194 patients, patients who experienced hepatotoxicity after ICPI administration was 64.4% (n=125) in all grade and 10.8% (n=21) in grade III or higher. Multivariate analysis showed that patients aged 30-50 and 50-70 years had increased risks of hepatotoxicity by 4.9-fold (95% confidence interval, 1.3-18.0) and 2.7-fold (95% confidence interval, 1.3-5.5), respectively, compared with those older than 70 years. The use of acetaminophen increased the occurrence of hepatotoxicity by 2.1 times; the attributable risk was 53.2%. Male patients and patients younger than 65 years had around 1.5-fold increased hazard of time to reach hepatotoxicity. Patients treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors had a 4.7-fold higher risk of grade III-IV hepatotoxicity compared with those without HMG-CoA reductase inhibitors; the attributable risk was 78.8%. In conclusion, close monitoring of liver function is recommended, especially in male patients, patients younger than 65 years old, and when there is concomitant use of hepatotoxic drugs including acetaminophen and HMG-CoA reductase inhibitors.
虽然免疫检查点抑制剂（ICPIs）引起的肝毒性可导致严重的临床并发症，但肝毒性相关的风险因素很少被研究。本研究旨在确定发生肝毒性和 ICPIs 引起肝毒性的时间的潜在风险因素。本回顾性 2 中心研究纳入了接受 ICPIs（阿替利珠单抗、纳武利尤单抗、帕博利珠单抗和伊匹单抗）治疗的患者。收集的数据包括性别、年龄、体重、体表面积、东部肿瘤协作组体能状态、基础疾病、肝转移、程序性死亡配体-1 表达、上次化疗的间隔时间和伴随用药。在 194 例患者中，所有级别肝毒性的发生率为 64.4%（n=125），3 级或更高级别的发生率为 10.8%（n=21）。多变量分析显示，年龄在 30-50 岁和 50-70 岁的患者发生肝毒性的风险分别是年龄大于 70 岁的患者的 4.9 倍（95%置信区间，1.3-18.0）和 2.7 倍（95%置信区间，1.3-5.5）。使用对乙酰氨基酚使肝毒性的发生风险增加 2.1 倍；归因风险为 53.2%。男性患者和 65 岁以下的患者发生肝毒性的风险约增加 1.5 倍。与未使用 HMG-CoA 还原酶抑制剂的患者相比，使用 3-羟基-3-甲基戊二酰基辅酶 A（HMG-CoA）还原酶抑制剂的患者发生 3 级-4 级肝毒性的风险增加 4.7 倍；归因风险为 78.8%。总之，建议密切监测肝功能，特别是在男性患者、65 岁以下的患者以及合并使用包括对乙酰氨基酚和 HMG-CoA 还原酶抑制剂在内的肝毒性药物时。
