419例药物性肝损伤患者临床特点与自身抗体特征分析

陈凤欣; 曾湛; 孙芳芳; 胡蕾苹; 路遥; 张璐; 李明慧; 谢尧

doi:10.3969/j.issn.1001-5256.2022.01.023

419例药物性肝损伤患者临床特点与自身抗体特征分析

DOI: 10.3969/j.issn.1001-5256.2022.01.023

陈凤欣¹,
曾湛²,
孙芳芳¹,
胡蕾苹¹,
路遥¹,
张璐¹,
李明慧^{1, 2},
谢尧^{1, 2, ,}

1.
首都医科大学附属北京地坛医院肝病二科，北京 100015
2.
北京大学地坛医院教学医院肝病二科，北京 100015

基金项目:

国家科技重大专项 (2018ZX10715-005-003-005);

首都临床特色专项资助项目 (Z151100004015122);

北京市医管中心临床专项项目 (XMLX201706);

北京市医管中心临床专项项目 (XMLX202127);

北京市医管中心消化协同中心资助项目 (XXT28);

北京市医管中心消化协同中心资助项目 (XXZ0302);

北京市科委课题 (D161100002716002)

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

作者贡献声明：陈凤欣、曾湛负责课题设计，资料分析，撰写论文；孙芳芳、胡蕾萍、路遥、张璐参与收集数据，修改论文；李明慧负责拟定写作思路；谢尧指导撰写文章并最后定稿。

详细信息

通信作者:
谢尧，xieyao00120184@sina.com

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出版历程
- 收稿日期: 2021-05-27
- 录用日期: 2021-08-09
- 出版日期: 2022-01-20

Clinical features and autoantibody characteristics of patients with drug-induced liver injury: An analysis of 419 cases

Fengxin CHEN¹,
Zhan ZENG²,
Fangfang SUN¹,
Leiping HU¹,
Yao LU¹,
Lu ZHANG¹,
Minghui LI^{1, 2},
XIE Yao^{1, 2
, ,}

1.
Second Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
2.
Second Department of Hepatology, Peking University Ditan Teaching Hospital, Beijing 100015, China

Research funding:

National Science and Technology Major Project of China (2018ZX10715-005-003-005);

Beijing Municipal Science & Technology Commission (Z151100004015122);

Beijing Hospitals Authority Clinical medicine Development of special funding (XMLX201706);

Beijing Hospitals Authority Clinical medicine Development of special funding (XMLX202127);

The Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXT28);

The Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0302);

Beijing Science and Technology Commission (D161100002716002)

摘要

摘要: 目的研究药物性肝损伤(DILI)患者的临床特点与自身抗体特征。方法回顾性分析2014年9月—2018年9月首都医科大学附属北京地坛医院收治的肝功能异常且通过RUCAM评分临床诊断为DILI的患者，收集入院时的基线肝功能、肾功能、血常规、免疫五项、自身抗体、肝穿刺活检结果。计量资料满足正态性2组间比较使用t检验；计量资料不满足正态性2组间比较使用Mann-Whitney U检验。采用卡方检验研究不同性别、肝损伤类型之间的自身抗体检出率是否存在差异；用logistic回归方法分析自身抗体与性别、年龄、损伤类型之间是否存在回归关系；以各项基线化验结果做自变量，ANA的滴度分级作为因变量做有序logistic回归分析。结果共入组419例DILI患者，中位年龄47(35~55)岁，其中男性占32.5%(136/419)，女性占67.5%(283/419)；肝细胞型有88例(21.5%)，混合型87例(21.2%)，胆汁淤积型235例(57.3%)。自身抗体检出率为50.6%(212/419)，其中抗核抗体检出率为42.9%(180/419)，抗体滴度以1∶ 100为主(104/180)。不同性别(χ²=2.658，P=0.103)与不同损伤类型(χ²= 0.859，P=0.651)之间的自身抗体检出率差异均无统计学意义。二元logistics回归提示性别、年龄和损伤类型与自身抗体之间均不存在回归关系(P值均＞0.05)。自身抗体阳性组和阴性组患者的PTA和INR存在显著差异(t=2.161，P=0.031；Z=-3.010，P=0.003)。有序logistics回归提示INR和IgG与ANA分级有相关性(OR=3.101，P=0.040; OR=1.043，P=0.014)。结论 DILI患者自身抗体检出率较高，但自身抗体检出率与性别、损伤类型、年龄无关，自身抗体阳性与阴性患者之间的PTA和INR存在差异，INR和IgG水平与ANA抗体滴度有相关性。
- 药物性肝损伤 /
- 自身抗体 /
- 免疫球蛋白G
Abstract: Objective To investigate the clinical features and autoantibody characteristics of patients with drug-induced liver injury (DILI). Methods A retrospective analysis was performed for the patients with abnormal liver function who were admitted to Beijing Ditan Hospital, Capital Medical University, from September 2014 to September 2018 and were diagnosed with DILI based on RUCAM score, and related data on admission were collected, including baseline liver function, renal function, routine blood test results, five immune indices, autoantibody, and liver biopsy results. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used to compare the detection rate of autoantibody between the patients with different sexes or types of liver injury. A logistic regression analysis was used to investigate whether autoantibody had a regression relationship with sex, age, and type of injury, and an ordinal logistic regression analysis was performed with baseline laboratory results as independent variables and anti-nuclear antibody (ANA) titer as the dependent variable. Results A total of 419 patients with DILI were enrolled in the study, with a median age of 47 (35-55) years, among whom male patients accounted for 32.5% (136/419) and female patients accounted for 67.5% (283/419). Among these 419 patients, 88 (21.5%) had hepatocellular-type liver injury, 87 (21.2%) had mixed-type liver injury, and 235 (57.3%) had cholestasis-type liver injury. The detection rate of autoantibodies was 50.6% (212/419), and the detection rate of ANA was 42.9% (180/419), with a titer of mainly 1∶ 100 (104/180). There was no significant difference in the detection rate of autoantibodies between the patients with different sexes (χ²=2.658, P=0.103) or different types of injury (χ²=0.859, P=0.651). The binary logistic regression analysis showed that autoantibody did not have a regression relationship with sex, age, and type of injury (all P > 0.05) There were significant differences in prothrombin time activity (PTA) and international normalized ratio (INR) between the positive autoantibody group and the negative autoantibody group (t=2.161, P=0.031; Z=-3.010, P=0.003). The ordinal logistic regression analysis showed that INR (odds ratio [OR]=3.101, P=0.040) and IgG (OR=1.043, P=0.014) were associated with ANA grade. Conclusion There is a relatively high detection rate of autoantibodies in patients with DILI, and the detection rate of autoantibodies is not associated with sex, age, or type of injury. There are differences in PTA and INR between autoantibody-positive patients and autoantibody-negative patients, and the levels of INR and IgG are correlated with antibody titer.
- Drug-Induced Liver Injury /
- Autoantibodies /
- Immunoglobulin G

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图 1 ANA滴度分级人数分布饼状图

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表 1 自身抗体分布情况

抗体种类	例数	抗体种类	例数
ANA	180	CENP	8
AMA	2	nRNP/Sm	2
ANCA	15	RO-52	36
dsDNA	10	SSA	17
LKM	4	SSB	10
PCNA	5	抗Sm	8
SMA	2

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表 2 logistics回归分析结果

指标	B值		Wald	OR	95%CI	P值
性别	-0.318	0.219	2.098	0.728	0.474~1.119	0.148
年龄	0.002	0.008	0.104	1.002	0.988~1.017	0.747
损伤类型
肝细胞型				Ref
混合型	0.064	0.251	0.064	1.066	0.651~1.744	0.800
胆汁淤积型	0.185	0.255	0.529	1.203	0.731~1.982	0.467

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表 3 自身抗体阳性组与阴性组基线情况

指标	所有患者(n=419)	阴性组(n=207)	阳性组(n=212)	统计值	P值
女性(例)	283	132	151	χ²=2.658	0.103
年龄(岁)	47(35~55)	46(35~54)	47(35~56)	Z=-0.871	0.384
ALT (U/L)	365.0(121.0~751.0)	401.0(108.1~802.0)	342.5(133.5~716.3)	Z=-0.478	0.633
AST (U/L)	206.0(93.0~446.4)	200.2(87.4~446.4)	216.9(101.3~445.3)	Z=-0.826	0.409
TBil (μmol/L)	33.2(6.9~109.3)	36.5(18.0~117.0)	28.5(16.0~101.7)	Z=-1.641	0.101
DBil (μmol/L)	21.0(16.0~83.2)	26.0(7.5~88.0)	16.0(6.3~73.2)	Z=-1.241	0.214
ALP (U/L)	129.4(96.0~172.9)	134.4(96.5~177.9)	127.0(95.5~170.0)	Z=-0.749	0.454
BUN (mmol/L)	3.9(3.1~5.0)	4.05(3.05~5.13)	3.72(3.06~4.74)	Z=-1.636	0.102
CREA (μmol/L)	58.7(51.0~67.1)	59.0(51.1~68.8)	58.0(51.0~65.6)	Z=-1.526	0.127
PTA(%)	89.00±21.82	91.35±21.76	86.74±21.69	t=2.161	0.031
INR	1.03(0.97~1.17)	1.02(0.96~1.12)	1.05(0.99~1.19)	Z=-3.010	0.003
WBC (×10⁹/L)	4.92(4.08~6.03)	4.97(4.11~6.15)	4.88(4.07~5.93)	Z=-0.923	0.356
Hb (g/L)	131.0(120.0~237.0)	131.0(121.9~141.0)	131.0(119.0~141.0)	Z=-0.472	0.637
IgG(g/L)	13.8(11.4~18.0)	13.4(11.4~16.7)	14.8(11.2~20.1)	Z=-1.215	0.224
IgA(g/L)	2.49(1.77~3.47)	2.49(1.77~3.65)	2.49(1.78~3.33)	Z=-0.138	0.890
IgM(g/L)	1.03(0.72~1.65)	1.01(0.71~1.62)	1.11(0.72~1.69)	Z=-0.874	0.382
C3(g/L)	0.89(0.69~1.06)	0.93(0.71~1.06)	0.89(0.68~1.06)	Z=-1.452	0.146
C4(g/L)	0.20(0.14~0.23)	0.20(0.15~0.23)	0.19(0.14~0.23)	Z=-0.516	0.606

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表 4 DILI患者随访1个月与基线检查结果差值对比

指标	阳性组(n=207)			阴性组(n=212)			Z值	P值
指标	基线	1个月	差值	基线	1个月	差值	Z值	P值
ALT(U/L)	342.5(133.5~716.3)	74.7(34.4~139.6)	-270.0(-665.3~-26.8)	401.0(108.1~802.0)	74.7(34.4~132.8)	-299.5(-746.05~-1.5)	-0.357	0.721
AST(U/L)	216.9(101.3~445.3)	80.7(39.0~242.0)	-137.0(-383.1~17.8)	200.2(87.4~446.4)	77.6(44.5~235.5)	-87.7(-348.4~46.2)	-0.898	0.369
TBil(μmol/L)	28.5(16.0~101.7)	18.0(13.3~33.6)	-10.3(-84.0~4.9)	36.5(18.0~117.0)	17.0(12.2~29.2)	-13.9(-84.7~5.1)	-0.158	0.874

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表 5 ANA滴度多元有序logistic回归分析

变量	B值	SE	Wald	OR	95%CI	P值
ALT	0.000	0.000	2.464	1.000	0.999~1.001	0.117
TBil	-0.004	0.006	0.353	0.996	0.984~1.009	0.552
DBil	0.003	0.008	0.096	1.003	0.986~1.019	0.756
INR	1.132	0.552	4.206	3.101	1.051~9.145	0.040
IgG	0.042	0.017	6.038	1.043	1.008~1.078	0.014

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