doi:10.3760/cma.j.cn371439-20250312-00082

Abstract

Figures/Tables 8

药物种类		发生率（%）						代表药物
药物种类		任何级别 ALT或AST升高	≥3级ALT或 AST升高	任何级别胆红素升高	≥3级胆红素升高	任何级别 ALP升高	≥3级ALP 升高	代表药物
化疗药物^[31]	烷化剂	10^a	0~11^a	3.3	0			卡司莫汀、环磷酰胺
	烷化剂	3.3^b	0~5^b	3.3	0			卡司莫汀、环磷酰胺
	铂类	6~57^a	1~3^a					顺铂、奥沙利铂
	铂类	17~51^b	1~3^b					顺铂、奥沙利铂
	二氢叶酸还原酶抑制剂	10~71^a	3~12^a					培美曲塞、甲氨蝶呤
	二氢叶酸还原酶抑制剂	8~53^b	<2~6^b					培美曲塞、甲氨蝶呤
	胸腺核苷合成酶抑制剂	19.5^a	0.2^a	11.9	0.7	14.4		卡培他滨
	胸腺核苷合成酶抑制剂	19.0^b	0.2^b	11.9	0.7	14.4		卡培他滨
	DNA多聚酶抑制剂	68^a	10^a	13	<3	55	7	吉西他滨、地西他滨、阿糖胞苷
	DNA多聚酶抑制剂	67^b	8^b	13	<3	55	7	吉西他滨、地西他滨、阿糖胞苷
	作用于核酸转录的药物	17.1^a		9.8	0			多柔比星
	作用于核酸转录的药物	29.3^b		9.8	0			多柔比星
	DNA拓扑异构酶Ⅰ抑制剂	19	2.4^a	14.3	0			伊立替康、拓扑替康
	DNA拓扑异构酶Ⅰ抑制剂	21.4^b	2.4^b	14.3	0			伊立替康、拓扑替康
	干扰微管蛋白合成的药物	23.3^a	2.3^a	11.6	0			紫杉醇、长春碱类
	干扰微管蛋白合成的药物	30.2^b	4.7^b	11.6	0			紫杉醇、长春碱类
TKI^{[10-11,32-41]}	EGFR抑制剂	5~55^a	1~27^a	0~38.9	2.6		2.6	吉非替尼、厄洛替尼
	EGFR抑制剂	6.3~34.5^b	0.2~0.5^b	0~38.9	2.6		2.6	吉非替尼、厄洛替尼
	抗血管多激酶抑制剂	6~73^a	0~17^a	0~45	0~13	0~60.4	0~9.3	瑞戈非尼、帕唑帕尼、舒尼替尼
	抗血管多激酶抑制剂	4.3~86.4^b	1.0~5.9^b	0~45	0~13	0~60.4	0~9.3	瑞戈非尼、帕唑帕尼、舒尼替尼
	HER2抑制剂	9~46^a	2~13^a	6.2~30.8	0.3~1.1			拉帕替尼、图卡替尼
	HER2抑制剂	2.0~7.4^b	0.3~0.7^b	6.2~30.8	0.3~1.1			拉帕替尼、图卡替尼
	ALK抑制剂	8.3~60.0^a	0~31^a	5.6~15.0	2	10~29	4.5~7.0	色瑞替尼、克唑替尼、阿来替尼
	ALK抑制剂	17~68^b	2.1~6.9^b	5.6~15.0	2	10~29	4.5~7.0	色瑞替尼、克唑替尼、阿来替尼
	JAK抑制剂	25~53^a	1~3^a			19	4.8	菲达替尼、芦可替尼
	JAK抑制剂	31.5~59.0^b	0~2^b			19	4.8	菲达替尼、芦可替尼
	CDK4/6抑制剂	30~48^a	2~14^a					阿贝西利、瑞博西利
	BTK抑制剂	4.5~30^a	0.9~1.9^a	11.1	0			阿卡替尼、泽布替尼
	Bcr-Abl抑制剂	4~59^a	1~19^a	6.9~20.6	1.9	3.4~12.1		博舒替尼、达沙替尼、普纳替尼
	Bcr-Abl抑制剂	5.0~22.3^b	0~6.7^b	6.9~20.6	1.9	3.4~12.1		博舒替尼、达沙替尼、普纳替尼
	PI3K抑制剂	11~50^a	0~14^a	42	4		22	艾德拉尼、阿培利司
	PI3K抑制剂	9.2~16.8^b	0~14^a	42	4		22	艾德拉尼、阿培利司
	FGFR抑制剂	41~51^a	1~6^a	18.6	5.1	83.1	16.9	英菲格拉替尼、培美替尼
	PARP抑制剂	10						卢卡帕利
ICI^[42-47]	CTLA-4抑制剂	1.5~14.6^a	0~5.7^a	11	1.5	17	0.6	替西木单抗、伊匹木单抗
	CTLA-4抑制剂	0.8~13.2^b	0~4.2^b	11	1.5	17	0.6	替西木单抗、伊匹木单抗
	PD-L1抑制剂	30~39^a	2.3~3.3^a	1.04~49.00	0~0.63	1.64~29.00	0~0.74	度伐利尤单抗、阿替利珠单抗
	PD-L1抑制剂	34~36^b	2.5~2.8^b	1.04~49.00	0~0.63	1.64~29.00	0~0.74	度伐利尤单抗、阿替利珠单抗
	PD-1抑制剂	1.4~14.0^a	0~3^a	1.36~16.00	0.63~2.00	3.89~21.00	0.92~2.10	帕博利珠单抗、纳武利尤单抗
	PD-1抑制剂	2.2~16.0^b	0~3^b	1.36~16.00	0.63~2.00	3.89~21.00	0.92~2.10	帕博利珠单抗、纳武利尤单抗
	CTLA-4抑制剂+ PD-1抑制剂/ PD-L1抑制剂	9.4~56.0^a	2~18^a	16~55	0.9~11.0	28~41	3.4~8.0	纳武利尤单抗+伊匹木单抗、度伐利尤单抗+替西木单抗
	CTLA-4抑制剂+ PD-1抑制剂/ PD-L1抑制剂	10.4~63.0^b	0~27^b	16~55	0.9~11.0	28~41	3.4~8.0	纳武利尤单抗+伊匹木单抗、度伐利尤单抗+替西木单抗
ADC^[16,48]		8~82^a	0.4~9.0^a	10.3~36.0	0~7	22~57	0~8	恩美曲妥珠单抗、莫妥尤单抗、德曲妥珠单抗、奥加伊妥珠单抗
ADC^[16,48]		8~98^b	0.8~9.0^b	10.3~36.0	0~7	22~57	0~8	恩美曲妥珠单抗、莫妥尤单抗、德曲妥珠单抗、奥加伊妥珠单抗

药物： ___________ 初始ALT：___________ 初始ALP：___________ R值=[ALT/ULN]÷[ALP/ULN]=
肝损伤类型：肝细胞型（R≥5.0），胆汁淤积型（R≤2.0），混合型（2.0<R<5.0）
肝细胞损伤型胆汁淤积型或混合型评价
1.用药至发病的时间
初次用药		再次用药	初次用药	再次用药	计分
○从用药开始
●提示	5~90 d	1~15 d	5~90 d	1~90 d	+2
●可疑	<5 d或>90 d	>15 d	<5 d或>90 d	>90 d	+1
○从停药开始	<5 d或>90 d	>15 d	<5 d或>90 d	>90 d	+1
●可疑	≤15 d	≤15 d	≤30 d	≤30 d	+1
注：若肝损伤反应出现在开始服药前，或停药后>15 d（肝细胞损伤型）或>30 d（胆汁淤积型），则应考虑肝损伤与药物无关，不应继续进行RUCAM评分。
2.病程		ALT在峰值和ULN之间的变化	ALP（或TBil）在峰值与ULN之间的变化
○停药后
●高度提示		8 d内下降≥50%	不适用		+3
●提示		30 d内下降≥50%	180 d内下降≥50%		+2
●可疑		不适用	180 d内下降<50%		+1
●无结论		无资料或30 d后下降≥ 50%	不变、上升或无资料		0
●与药物作用相反		30 d后下降<50%或再次升高	不适用		-2
○若继续用药
●无结论		所有情况	所有情况		0
3.危险因素		酒精（乙醇）	酒精或妊娠（任意1种）
○饮酒或妊娠		有	有		+1
		无	无		0
○年龄		≥55岁	≥55岁		+1
		<55岁	< 55 岁		0
4.伴随用药
○无伴随用药，或无资料，或伴随用药至发病时间不相符					0
○伴随用药至发病时间相符					-1
○伴随用药已知有肝毒性，且至发病时间提示或相符					-2
○伴随用药的肝损伤证据明确（再刺激反应呈阳性，或与肝损伤明确相关并有典型的警示标志）					-3
5.除外其他肝损伤原因
第Ⅰ组（6种病因）
○急性甲型肝炎[抗-HAV（-）IgM（+）]或		●	排除组Ⅰ和组Ⅱ中的所有病因		+2
HBV感染[HBsAg和（或）抗-HBc（-）IgM（+）]或		●	排除组Ⅰ中的所有病因		+1
HCV感染[抗-HCV（+）和（或）HCV RNA（+），伴有相应的临床病史]		●	排除组Ⅰ中的5或4种病因		0
○胆道梗阻（影像检查证实）		●	排除组Ⅰ中的少于4种病因		-2
○酒精（乙醇）中毒（有过量饮酒史且AST/ALT≥2）
○近期有低血压、休克或肝脏缺血史（发作2周以内）
第Ⅱ组（2类病因）
○合并自身免疫性肝炎、脓毒症、慢性乙型或丙型肝炎、原发性胆汁性胆管炎（PBC）或原发性硬化性胆管炎（PSC）等基础疾病		●	非药物性因素高度可能		-3
○临床特征及血清学和病毒学检测提示急性CMV、EBV或HSV感染
6.药物既往肝损伤信息
○肝损伤反应已在说明书中标明					+2
○肝损伤反应未在说明书中标明，但曾有报道					+1
○肝损伤反应未知					0
7.再用药反应
○阳性		再次单用该药后ALT升高2倍	再次单用该药后ALP（或TBil）升高2倍		+3
○可疑		再次和首次发生肝损伤时使用的另一药物联合应用，ALT升高2倍	再次和首次发生肝损伤时使用的另一药物联合应用，ALP（或TBil）升高2倍		+1
○阴性		再次单用该药后ALT升高，但低于ULN	再次单用该药后ALP（或TBil）升高，但低于ULN		-2
○未再用药或无法判断		其他情况	其他情况		0

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肝脏生物化学检查指标	意义
ALT	肝细胞损伤标志之一，是严重DILI的敏感信号，特异性优于AST。主要分布于肝细胞的细胞质中，肝脏病变较轻时肝细胞膜发生损伤而线粒体膜保持完整，ALT升高程度大于AST。
AST	大部分存在于线粒体内，敏感性和特异性均低于ALT，可作为ALT的补充。通常需与其他指标联合应用，当病变持续或严重时，线粒体膜受到破坏，大量AST从线粒体中释出，导致AST升高。
ALP	对胆汁淤积型肝损伤和重症DILI具有较好的特异性指示作用，由于恶性肿瘤本身、骨骼疾病和妊娠等也会导致ALP升高，需注意鉴别，通常与ALT和AST联合应用。
GGT	在多数情况下与ALP的变化一致，但骨病时可出现ALP升高而GGT正常的情况。急性肝炎时GGT升高，在病变恢复期GGT下降至正常较转氨酶晚，当其他肝功能指标均已恢复正常而GGT尚未恢复正常时，提示肝内残存病变，肝炎尚未痊愈。如反复波动或长时间维持较高水平，则应考虑肝炎有转为慢性趋势。
TBil/DBil	作为肝损伤指标前，需排除红细胞溶血、胆红素结合功能障碍等血液学疾病和其他能够引起胆红素升高的情况。由于机体对胆红素的清除完全依赖肝脏，因而TBil较ALT、AST和ALP更能直接反映肝脏功能，同时也是评估预后和进行分型的重要参考指标。DBil用于判断黄疸类型及程度，其升高表示肝功能有一定损害，在肝细胞性黄疸和阻塞性黄疸时升高明显。

排除疾病类型	实验室检查指标
甲型、乙型、丙型、戊型病毒性肝炎	抗-HAV（IgM）；HBsAg，抗-HBc，HBV DNA；抗-HCV，HCV RNA；抗-HEV（IgM和IgG），HEV RNA
CMV、HSV、EBV感染	抗-CMV（IgM和IgG），抗-HSV（IgM和IgG），抗-EBV（IgM和IgG）
自身免疫性肝炎	ANA和ASMA滴度、IgG、IgA、IgM
原发性胆汁性胆管炎	AMA（尤其AMA-M2）滴度、IgG、IgA、IgM
酒精性肝病	饮酒史、GGT、MCV
非酒精性脂肪性肝病	超声或MRI
缺氧/缺血性肝病	超声或MRI
胆道疾病	超声或MRI、内镜逆行胰胆管造影术（视情况而定）
Wilson病	铜蓝蛋白
血色素沉着症	铁蛋白、转铁蛋白饱和度
α1-抗胰蛋白酶缺乏症	α1-抗胰蛋白酶

分级	实验室检查	临床表现
0级（无肝损伤）	对暴露药物耐受，无肝毒性反应	无症状
1级（轻度肝损伤）	ALT和（或）ALP↑，TBil<2.5×ULN，INR<1.5	无症状或乏力、腹痛、黄疸等轻微症状
2级（中度肝损伤）	ALT和（或）ALP↑，TBil≥2.5×ULN或INR≥1.5	症状加重
3级（重度肝损伤）	ALT和（或）ALP↑，TBil≥5×ULN或INR≥1.5	症状进一步加重，需要住院治疗
4级（急性肝衰竭）	ALT和（或）ALP↑，TBil≥10×ULN或TBil每日升高≥1.0 mg/dl （17.1 μmol/L），INR≥2.0或PTA<40%	可出现腹腔积液或与DILI相关的器官功能衰竭
5级（致命）		因DILI死亡，或需接受肝移植才能存活

分级	CTCAE 4.0版^[67]	CTCAE 5.0版^[68]
G1（轻度）	AST或ALT>（1~3）×ULN；ALP>（1~2.5）×ULN； TBil>（1~1.5）×ULN	AST或ALT>（1~3）×ULN（基线值正常）/（1.5~3）×基线值（基线值异常）； ALP>（1~2.5）×ULN（基线值正常）/（2~2.5）×基线值（基线值异常）； TBil>（1~1.5）×ULN（基线值正常）/>（1~1.5）×基线值（基线值异常）
G2（中度）	AST或ALT （3~5）×ULN；ALP>（2.5~5）×ULN； TBil>（1.5~3）×ULN	AST或ALT>（3~5）×ULN（基线值正常）/>（3~5）×基线值（基线值异常）； ALP>（2.5~5）×ULN（基线值正常）/>（2.5~5）×基线值（基线值异常）； TBil>（1.5~3）×ULN（基线值正常）/>（1.5~3）×基线值（基线值异常）
G3（重度）	AST或ALT（5~20）×ULN；ALP>（5~20）×ULN； TBil>（3~10）×ULN	AST或ALT>（5~20）×ULN（基线值正常）/>（5~20）×基线值（基线值异常）； ALP>（5~20）×ULN（基线值正常）/（5~20）×基线值（基线值异常）； TBil>（3~10）×ULN（基线值正常）/>（3~10）×基线值（基线值异常）
G4（致命）	AST或ALT>20×ULN；ALP>20×ULN； TBil>10×ULN	AST或ALT>20×ULN（基线值正常）/>20×基线值（基线值异常）； ALP>20×ULN（基线值正常）/>10×基线值（基线值异常）； TBil>10×ULN（基线值正常）/>10×基线值（基线值异常）

分级	管理措施
G1	继续ICI治疗
	每周监测1次肝功能
	如肝功能稳定，适当减少监测频率
G2	暂停ICI治疗
	0.5~1 mg/kg泼尼松口服，如肝功能好转，缓慢减量，总疗程至少4周
	泼尼松剂量减至≤10 mg/d，且肝损伤≤1级，可重新ICI治疗
	每3天检测1次肝功能
	可选择进行肝脏活检
G3	建议停用ICI，泼尼松剂量减至<10 mg/d，且肝损伤≤1级，可考虑重新ICI治疗
G4	建议停用ICI治疗
	静脉使用甲泼尼龙，1~2 mg/kg，待肝损伤降至2级后，可等效改换口服的泼尼松并继续缓慢减量，总疗程至少4周
	3 d后如肝功能无好转，考虑加用麦考酚酯（500~1 000 mg，2次/d）
	如麦考酚酯效果仍不佳，应考虑联合免疫抑制治疗，如托珠单抗、他克莫司，硫唑嘌呤、环孢素或抗人胸腺淋巴细胞球蛋白等
	不推荐使用英夫利西单抗
	请肝病专家会诊
	进行肝脏CT、磁共振胰胆管成像或超声检查
	考虑肝脏活检
	每1~2天检测1次肝功能
	考虑住院治疗

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MELD评分	3个月死亡风险
≤9	1.9%
10~19	6.0%
20~29	19.6%
30~39	52.6%
≥40	71.3%