整合证据链、Roussel Uclaf因果关系评价法、结构化专家观点程序对药物性肝损伤的诊断效用分析

何婷婷; 梁庆升; 王丽苹; 梁龙鑫; 李筱涵; 崔延飞; 景婧; 柏兆方; 宫嫚; 王睿林

doi:10.3969/j.issn.1001-5256.2022.01.022

整合证据链、Roussel Uclaf因果关系评价法、结构化专家观点程序对药物性肝损伤的诊断效用分析

DOI: 10.3969/j.issn.1001-5256.2022.01.022

何婷婷^1a,
梁庆升^1b,
王丽苹^1a,
梁龙鑫^{1c, 2},
李筱涵^1d,
崔延飞^1a,
景婧^1a,
柏兆方^{1c, 3},
宫嫚^1a, ,,
王睿林^1a, ,

1a.
解放军总医院第五医学中心肝病医学部中医肝病科，北京100039
1b.
解放军总医院第五医学中心肝病医学部肝病五病区，北京100039
1c.
解放军总医院第五医学中心肝病研究所，北京100039
1d.
解放军总医院第五医学中心检验科，北京100039
2.
江西中医药大学药学院, 江西 330004
3.
全军中医药研究所，北京 100039

基金项目:

重大科学攻关问题和医药技术难题科研课题 (2020KTY001);

国家科技重大专项 (2018ZX10303502-002-019);

国家科技重大专项 (2018ZX10725506-002);

国家中医药管理局中医药创新团队及人才支持计划项目 (ZYYCXTD-C-202005)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及公开研究成果有关的利益冲充。

作者贡献声明：何婷婷、梁庆升负责提出研究选题，实施研究过程，起草论文，修订论文，终审论文；王丽苹、梁龙鑫负责统计分析，设计论文框架；李筱涵、崔延飞、景婧、柏兆方负责调研整理文献，采集整理数据；宫嫚、王睿林负责设计研究方案，指导性支持。

详细信息

通信作者:
宫嫚，gongman302@163.com

王睿林，wrl7905@163.com

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出版历程
- 收稿日期: 2021-06-13
- 录用日期: 2021-09-06
- 出版日期: 2022-01-20

Diagnostic values of integrated evidence chain, Roussel Uclaf Causality Assessment Method, and Structured Expert Opinion Process method for drug-induced liver injury

Tingting HE^1a,
Qingsheng LIANG^1b,
Liping WANG^1a,
Longxin LIANG^{1c, 2},
Xiaohan LI^1d,
Yanfei CUI^1a,
Jing JING^1a,
Zhaofang BAI^{1c, 3},
Man GONG^{1a
, ,},
Ruilin WANG^{1a
, ,}

1a.
Department of Traditional Chinese Medicine Hepatology of Department of Liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
1b.
The Fifth Ward of Department of Liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
1c.
Institute of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
1d.
Department of Clinical Laboratory, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
2.
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
3.
PLA Institute of Traditional Chinese Medicine, Beijing 100039, China

Research funding:

Major Scientific Research and Difficult Medical Technology Research Project (2020KTY001);

National Science and Technology Major Project (2018ZX10303502-002-019);

National Science and Technology Major Project (2018ZX10725506-002);

Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202005)

摘要

摘要: 目的从西药肝损伤和中药肝损伤2个维度对目前诊断药物性肝损伤的3种常用诊断方法进行临床适用性分析，并比较其特征及差异。方法前瞻性队列研究纳入2015年1月—2020年12月入住解放军总医院第五医学中心的非中西药联合应用的急性药物性肝损伤住院患者289例为研究对象，其中，中药肝损伤187例，西药肝损伤102例。分别应用整合证据链(IEC)、Roussel Uclaf因果关系评价法(RUCAM)、结构化专家观点程序(SEOP)3种诊断方法对289例患者进行诊断，收集患者急性起病时的一般资料、潜伏期、详细服药情况、实验室指标ALT、AST、GGT、ALP、TBil等。统计分析3种诊断方法分别对西药肝损伤和中药肝损伤病例诊断结果评定的一致性和各自适用性。计量资料组间比较采用Kruskal-Wallis H检验，计数资料组间比较采用χ²检验。结果西药肝损伤与中药肝损伤的临床肝损伤类型均以肝细胞型为主(81.4%、74.3%)，实验室指标表现为有更高的ALT和AST水平。应用IEC、RUCAM、SEOP分别对西药肝损伤病例进行诊断，临床诊断率依次为65.7%、100%、63.7%；西药肝损伤构成比依次是23.2%、35.3%和22.5%。再依次对中药肝损伤病例进行诊断，临床诊断率分别为47.6%、100%、29.9%；中药肝损伤构成比分别为30.8%、64.7%、19.4%。一致性检验结果显示，在诊断西药肝损伤病例时，除IEC与SEOP评价结果存在一致性外(Kappa=0.785，P＜0.05)，RUCAM vs IEC(Kappa=0.149，P＞0.05)和RUCAM vs SEOP (Kappa=0.117，P＞0.05)的一致性评定结果均较差。在诊断中药肝损伤时，RUCAM vs SEOP(Kappa=0.066，P＞0.05) 的一致性评定结果较差，而RUCAM vs IEC(Kappa=0.026，P＜0.05)和IEC vs SEOP(Kappa=0.437，P＜0.05)评价结果存在一致性。结论 IEC对西药肝损伤和中药肝损伤均有较好的适用性，IEC与SEOP在诊断西药肝损伤时存在一致性，虽然在诊断中药肝损伤病例结果间也存在一致性，但一致性水平较低。RUCAM与另2种诊断方法评定结果的一致性均较差。临床对药物性肝损伤患者进行诊断时，应综合运用IEC、RUCAM和SEOP，以便更准确地判断药物与肝损伤之间因果关系。
- 化学性与药物性肝损伤 /
- 诊断 /
- 疾病特征
Abstract: Objective To investigate the clinical applicability and different characteristics of three commonly used diagnostic methods for drug-induced liver injury from the two aspects of liver injury induced by Western medicine and liver injury induced by traditional Chinese medicine. Methods A prospective cohort study was performed for 289 hospitalized patients with acute drug-induced liver injury who were admitted to The Fifth Medical Center of Chinese PLA General Hospital from January 2015 to December 2020 and did not receive integrated traditional Chinese and Western medicine therapy, among whom 187 patients had herb-induced liver injury and 102 had Western medicine-induced liver injury. The 289 patients were diagnosed by the integrated evidence chain (IEC), Roussel Uclaf Causality Assessment Method (RUCAM), and the Structured Expert Opinion Process (SEOP) method, and related data at acute onset were collected, including general information, latency period, detailed medication, and laboratory markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, and total bilirubin. A statistical analysis was performed to investigate the consistency between IEC, RUCAM, and SEOP in the diagnosis of Western medicine-induced liver injury and herb-induced liver injury and their own applicability. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data; the chi-square was used for comparison of categorical data. Results The hepatocellular type was the main type of clinical liver injury in both Western medicine-induced liver injury and herb-induced liver injury, accounting for 81.4% and 74.3%, respectively, and laboratory examination showed higher levels of ALT and AST. Western medicine-induced liver injury cases were diagnosed by IEC, RUCAM, and SEOP, with a clinical diagnosis rate of 65.7%, 100%, and 63.7%, respectively, and the constituent ratio of Western medicine-induced liver injury was 23.2%, 35.3%, and 22.5%, respectively. Herb-induced liver injury cases were diagnosed by these three methods, with a clinical diagnosis rate of 47.6%, 100%, and 29.9%, respectively, and the constituent ratio of herb-induced liver injury was 30.8%, 64.7%, and 19.4%, respectively. The consistency test of the three diagnostic methods showed that in the diagnosis of Western medicine-induced liver injury cases, there was good consistency between IEC and SEOP (Kappa=0.785, P < 0.05), while there was poor consistency between RUCAM and IEC (Kappa=0.149, P > 0.05) and between RUCAM and SEOP (Kappa=0.117, P > 0.05); in the diagnosis of herb-induced liver injury cases, there was poor consistency between RUCAM and SEOP (Kappa=0.066, P > 0.05), while there was good consistency between RUCAM and IEC (Kappa=0.026, P < 0.05) and between IEC and SEOP (Kappa=0.437, P < 0.05). Conclusion The IEC method shows good applicability for both Western medicine-induced liver injury and herb-induced liver injury, and there is good consistency between IEC and SEOP in the diagnosis of Western medicine-induced liver injury cases, while there is a relatively low level of consistency between IEC and SEOP in the diagnosis of herb-induced liver injury. There is poor consistency between RUCAM and the other two methods. In the clinical diagnosis of Western medicine-induced liver injury, IEC, RUCAM, and SEOP should be used in combination to accurately judge the causal relationship between drugs and liver injury.
- Chemical and Drug Induced Liver Injury /
- Diagnosis /
- Disease Attributes

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表 1 西药肝损伤患者一般资料及临床特征

指标	所有患者(n=102)	肝细胞损伤型(n=83)	胆汁淤积型(n=10)	混合型(n=9)	χ²值	P值
女性(%)	73.5	78.3	60.0	44.4	5.771	0.056
年龄(岁)	48(37~56)	48(38~55)	47(36~61)	51(29~58)	0.112	0.946
BMI(kg/m²)	23.18(20.97~26.86)	23.22(21.00~26.81)	22.48(18.33~26.23)	26.00(20.68~28.43)	1.346	0.510
过敏史(%)	14.7	15.7	10.0	11.1	0.327	0.849
饮酒史(%)¹⁾	12.7	12.0	10.0	22.2	0.663	0.663
潜伏期(d)	20(7~60)	21(10~90)	16(7~53)	14(5~30)	3.443	0.179
生化指标
初始ALT(U/L)	396.0(218.0~988.8)	541.0(236.0~1032.0)	217.5(41.0~267.6)	265(188.0~346.5)	15.212	＜0.001
初始AST(U/L)	318.0(153.0~715.8)	428.0(191.0~908.0)	170(52.3~333.5)	118(105.5~162.5)	16.630	＜0.001
初始ALP(U/L)	150.0(110.8~246.8)	142.0(107.0~195.0)	314.5(202.5~506.8)	296(202.0~501.5)	14.177	0.001
初始GGT(U/L)	162.0(66.0~317.0)	137.0(63.0~271.0)	162.5(46.8~688.3)	689(265.0~813.5)	9.980	0.007
初始TBil(μmol/L)	73.9(20.2~148.3)	69.2(15.4~147.0)	125.25(89.6~269.8)	72(22.2~144.0)	5.985	0.050
嗜酸性粒细胞(×10⁹/L)	0.09(0.05~0.17)	0.08(0.05~0.17)	0.11(0.06~0.16)	0.13(0.12~0.23)	2.281	0.320
肌酐(μmol/L)	66.5(55.8~74.0)	65.0(57.0~73.0)	66.0(59.0~76.0)	89.0(64.5~101.5)	5.555	0.062
尿素(mmol/L)	3.7(2.9~4.7)	3.5(2.7~4.6)	3.75(3.15~4.40)	4.7(4.2~5.5)	4.441	0.109
抗核抗体(%)	28.4	28.9	30.0	22.2	0.190	0.909
抗线粒体抗体(%)	3.9	4.8	0.0	0.0	0.944	0.624
抗平滑肌抗体(%)	2.9	3.6	0.0	0.0	0.701	0.704
抗胃壁细胞抗体(%)	5.9	3.6	20.0	11.1	4.768	0.092
抗肝/肾微粒体抗体(%)	0	0	0	0	0	1.000
抗线粒体M2(%)	0.9	1.2	0	0	0.229	0.892
预后(%)
治愈	56.9	59.0	30.0	66.7	3.420	0.181
慢性药物性肝损伤	11.8	12.0	10.0	11.1	0.040	0.980
肝硬化	14.7	15.7	20.0	0	1.818	0.403
死亡	2.9	2.4	10.0	0	2.080	0.354
失访	13.7	10.8	30.0	22.2	3.335	0.189
注：1)既往有饮酒史但未达到酒精性肝病诊断标准，且发病前1个月以内未饮酒。

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表 2 中药肝损伤患者一般资料及临床特征

指标	所有患者(n=187)	肝细胞损伤型(n=139)	胆汁淤积型(n=23)	混合型(n=25)	χ²值	P值
女性(%)	73.3	72.7	69.6	80.0	0.761	0.683
年龄(岁)	50(40~56)	49(40~56)	49(42~54)	53(43~61)	2.581	0.275
BMI	23.43(21.25~25.43)	23.43(21.45~25.40)	24.44(22.18~26.36)	22.76(20.01~24.01)	5.211	0.074
过敏史(%)	12.8	13.7	4.3	16.0	1.782	0.410
饮酒史(%)¹⁾	15.0	18.0	0.0	12.0	5.187	0.075
潜伏期(d)	30(15~90)	30(15~90)	30(15~90)	60(20~90)	0.654	0.721
生化指标
初始ALT(U/L)	625(232~1162)	895(491~1312)	115(62~222)	200(169~234)	84.192	＜0.001
初始AST(U/L)	405(186~855)	629(297~941)	103(54~187)	144(87.5~260.5)	62.618	＜0.001
初始ALP(U/L)	171(139~242)	161(125~200)	347(252~415)	222(167.5~248.0)	41.520	＜0.001
初始GGT(U/L)	166(104~245)	162(105~235)	242(92~545)	171(86.15~321.50)	1.483	0.476
初始TBil(μmol/L)	96.6(33.0~209.9)	95.5(40.8~200.0)	121.0(24.3~224.0)	105.0(14.2~239.0)	0.310	0.856
嗜酸性粒细胞(×10⁹/L)	0.11(0.05~0.19)	0.11(0.05~0.19)	0.15(0.07~0.29)	0.08(0.02~0.14)	5.155	0.076
肌酐(μmol/L)	64(56~75)	63(56~74)	71(58~90)	62(54~78)	2.070	0.355
尿素(mmol/L)	3.6(3.0~4.4)	3.6(2.9~4.2)	3.7(2.8~5.3)	3.5(3.0~4.7)	1.646	0.439
抗核抗体(%)	31.6	31.7	26.1	36.0	0.545	0.762
抗线粒体抗体(%)	3.7	5.0	0	0	2.498	0.287
抗平滑肌抗体(%)	8.6	9.4	8.7	4.0	0.772	0.680
抗胃壁细胞抗体(%)	7.0	7.9	4.3	4.0	1.024	0.599
抗肝/肾微粒体抗体(%)	0	0	0	0	0	1.000
抗线粒体M2(%)	3.2	3.6	0	4.0	0.876	0.645
预后(%)
治愈	58.8	60.4	65.2	44.0	2.790	0.248
慢性化肝炎	16.0	16.5	8.7	20.0	1.232	0.540
肝硬化	15.5	13.7	17.4	24.0	1.787	0.409
死亡	1.6	1.4	0	4.0	1.301	0.522
失访	8.0	7.9	8.7	8.0	0.016	0.992
注：1)既往有饮酒史但未达到酒精性肝病诊断标准，且发病前1个月以内未饮酒。

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表 3 3种诊断方法诊断结果差异

诊断方法	诊断结果	西药肝损伤(n=102)	中药肝损伤(n=187)	临床诊断率(%)		构成比(%)
诊断方法	诊断结果	西药肝损伤(n=102)	中药肝损伤(n=187)	西药肝损伤	中药肝损伤	西药肝损伤/ (西药肝损伤+ 中药肝损伤)	中药肝损伤/ (西药肝损伤+ 中药肝损伤)
IEC				65.7	47.6	23.2	30.8
	疑似诊断	35	98
	临床诊断	67	87
	确定诊断	0	2
RUCAM				100.00	100.00	35.3	64.7
	可能	38	66
	很可能	62	116
	极可能	2	5
SEOP				63.7	29.9	22.5	19.4
	可以诊断	65	56
	不可诊断	37	131

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表 4 3种诊断方法特点对比

特点	IEC	RUCAM	SEOP
评价要素	9条判断依据	7项要素	12个步骤
可疑肝损伤药物识别特点	药物、中药溯源、基源鉴定、代谢物、生物标志物	药物、合并用药、药物说明书、药物再激发	LiverTox网站
药物溯源情况	需要溯源，以及剩余中草药鉴定	不需要	不需要
文献检索	需要明确药物既往文献或说明书有无肝毒性报道	需要明确药物既往文献或说明书有无肝毒性报道	未明确
前瞻/回顾性评估能力	前瞻或回顾性病例均可适用，推荐前瞻性病例	仅适用于前瞻性病例	前瞻或回顾性病例均可适用，推荐前瞻性病例
诊断证据力	诊断证据链提高了诊断力度	相关性因果评估，相对客观，但评分量表可重复性不理想	专家经验性诊断意见，主观性较强
可操作性	依据9条判据逐步诊断，操作方便	依据量表进行评分，操作难易程度与是否能获取表内全面信息有关	需要大量人力，操作步骤多，比较耗时费力
诊断分类/级	分级诊断，包括疑似诊断、临床诊断、确定诊断3个级别	相关性诊断，根据评分结果包括极可能、很可能、有可能、不太可能、可排除5个级别	包括可诊断与不可诊断两类

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参考文献(18)

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