抗核抗体阳性程度与药物性肝损伤临床特征及预后的相关性研究

肝脏 ›› 2021, Vol. 26 ›› Issue (3): 237-242.

抗核抗体阳性程度与药物性肝损伤临床特征及预后的相关性研究

王艳, 王昱, 王岚, 田秋菊, 杨瑞园, 李柯鑫, 刘立伟, 鲁一达, 王晓明, 王宇, 欧晓娟, 贾继东, 赵新颜

1000050 首都医科大学附属北京友谊医院肝病中心,国家消化系统疾病临床医学研究中心(王艳,王昱,李柯鑫,刘立伟,王晓明,王宇,欧晓娟,贾继东,赵新颜);清华大学附属北京市垂杨柳医院消化内科(田秋菊);青岛大学附属医院肝脏病中心(田秋菊);中国医学论坛报社(杨瑞园);首都医科大学第二临床医学院(鲁一达)

收稿日期:2021-01-07 发布日期:2021-04-21
通讯作者: 赵新颜, Email: zhao_xinyan@ccmu.edu.cn
基金资助:
国家自然科学基金青年基金项目(81900526);首都医科大学本科生科研创新项目(XSKY2020143)

The association between antinuclear antibody titers with the clinical features and prognosis of drug induced liver injury

WANG Yan¹, WANG Yu¹, WANG Lan², TIAN Qiu-ju³, YANG Rui-yuan⁴, LI Ke-xin¹, LIU Li-wei¹, LU Yi-da⁵, WANG Xiao-ming¹, WANG Yu¹, OU Xiao-juan¹, JIA Ji-dong¹, ZHAO Xin-yan¹

1. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases,Beijing 100050, China;
2. Department of gastroenterology, Affiliated Chuiyangliu Hospital of Tsinghua University;
3. Liver Research Center, the Affiliated Hospital of Qingdao University;
4. China Medical Tribune;
5. The Second Clinical Medical College, Capital Medical University

Received:2021-01-07 Published:2021-04-21
Contact: ZHAO Xin-yan, Email: zhao_xinyan@ccmu.edu.cn

摘要/Abstract

摘要： 目的探讨抗核抗体阳性程度(antinuclear antibodies, ANA)对药物性肝损伤(drug-induced liver injury, DILI)临床特征及预后的影响。方法收集2009年1月至2019年1月在北京友谊医院肝病中心住院的DILI患者临床及预后资料,根据ANA状态将患者分为ANA阴性组、ANA 1:80阳性组、ANA 1:160阳性组、ANA≥1:320阳性组,比较各组间临床表现、实验室检查、预后的异同。连续变量采用ANOVA检验或Kruskal-Wallis H检验;分类变量采用卡方检验;多重比较采用Bonferroni校正。结果共纳入602例患者,ANA阴性组177例,ANA 1:80阳性组281例,ANA 1:160阳性组99例, ANA≥1:320阳性组 45例,4组均以女性为主(76.8%~87.9%),中位数年龄为56.0岁。4组ALT、AST、碱性磷酸酶(alkaline phosphatase, ALP)、谷氨酰转肽酶(glutamyl transpeptidase, GGT)、总胆红素(total bilirubin,TBil)差异均无统计学意义;血清白蛋白(albumin, Alb)显著降低:(37.2±5.5)g/L、(36.5±5.0)g/L、(36.2±5.1)g/L、(34.6±4.9)g/L,(P=0.030);凝血酶原活动度(prothrombin activity, PTA)显著降低:(86.1±22.9)%、(82.5±23.5)%、(78.6±24.1)%、(75.7±27.4)%,(P=0.016);血清球蛋白(globulin, GLB)显著升高(27.5±4.6)g/L、(29.5±5.2)g/L、(29.2±5.8)g/L、(32.3±6.4)g/L,(P<0.01)、免疫球蛋白G(Immunoglobulin G, IgG)显著升高[1240.0(1080.0,1420.0)mg/dL、1380.0(1140.0,1670.0)mg/dL、1440.0(1180.0,1840.0)mg/dL、1740.0(1380.0,2110.0)mg/dL,P=0.001]。患结缔组织病比例随ANA阳性程度增高而显著升高:0.6%、2.8%、5.0%、13.3%, P<0.01;随ANA滴度升高,4组患者住院时间显著延长:11.0 (8.0,14.0) d、11.0 (8.0,14.0) d、12.0 (9.0,15.0) d、15.0 (10.0,20.0) d(P<0.01)。肝生化复常的比例依次降低,慢性化、肝硬化、死亡或肝移植比例增加,临床结局组间比较差异有统计学意义(P=0.006)。结论随ANA阳性程度增高,DILI患者合并结缔组织病比例增高、住院时间延长,肝脏合成功能减退、免疫紊乱程度加重,患者肝生化复常比例下降,慢性化、肝硬化、死亡或肝移植比例升高。

关键词: 药物性肝损伤, 抗核抗体, 预后, 结缔组织病

Abstract: Objective To study the clinical characteristics and outcomes of patients with drug-induced liver injury (DILI) and different titers of antinuclear antibodies (ANA). Methods The clinical and prognostic data of DILI patients who were hospitalized in Liver Research Center, Beijing Friendship Hospital, Capital Medical University from January 2009 to January 2019 were collected. They were divided into ANA negative, titers of 1:80, 1:160 and ≥ 1:320 groups. The clinical manifestations, laboratory indexes, and prognosis among each group were compared. ANOVA test, Kruskal Wallis H test was used for continuous variables. Chi Square test was used for categorical variables. Bonferroni correction was used for multiple comparisons. P<0.05 was statistically significant. Results A total of 602 patients was enrolled, with 177 in ANA negative group, 281 in ANA 1:80 group, 99 in ANA 1:160 group, and 45 cases in ANA ≥ 1:320 group. The majority of patients were female (76.8%-87.9%), and the median age was 56.0 years old. There was no significant difference in the peak value of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), glutamyl transpeptidase (GGT) and total bilirubin (TBIL) among these four groups of patients. However, with the increase of ANA titer, serum albumin (Alb) (37.2 ± 5.5g/L, 36.5 ± 5.0 g/L, 36.2 ± 5.1 g/L, 34.6 ± 4.9 g/L in these four groups, respectively, P=0.030) and prothrombin activity (PTA) (86.1 ± 22.9%, 82.5 ± 23.5%, 78.6 ± 24.1%, 75.7 ± 27.4%, P=0.016) significantly decreased, whereas serum globulin (GLB) (27.5 ± 4.6 g/L, 29.5 ± 5.2 g/L, 29.2 ± 5.8 g/L, 32.3 ± 6.4 g/L, P<0.001) and Immunoglobulin G (IgG) [1240.0 (1080.0, 1420.0)mg/dL, 1380.0 (1140.0, 1670.0) mg/dL, 1440.0 (1180.0, 1840.0) mg/dL, 1740.0 (1380.0, 2110.0) mg/dL, P=0.001] significantly increased. The proportion of connective tissue diseases increased successively along with the increased titers of ANA (0.6%, 2.8%, 5.0%, 13.3%, respectively, P<0.001). The hospitalization time also significantly prolonged, which were 11.0 (8.0, 14.0) days, 11.0 (8.0, 14.0) days, 12.0 (9.0, 15.0) days and 15.0 (10.0, 20.0) days, respectively (P<0.001). The proportion of normalization of liver biochemical indexes decreased, whereas the proportion of progression of chronicity, cirrhosis, death or liver transplantation significantly increased (P=0.006). Conclusion Higher ANA titer in DILI patients is associated with an increase of connective tissue diseases, prolonged hospitalization time, impaired liver synthetic function, worsened immune function, less normalization of liver biochemical indexes. It is also related to significant progression of chronicity, cirrhosis, death or liver transplantation. Our data suggests that the higher titer of ANA, the worse of outcomes of DILI patients, which warrant clinical awareness.

Key words: Drug-induced liver injury (DILI), Antinuclear antibody (ANA), Prognosis, Connective tissue diseases

王艳, 王昱, 王岚, 田秋菊, 杨瑞园, 李柯鑫, 刘立伟, 鲁一达, 王晓明, 王宇, 欧晓娟, 贾继东, 赵新颜. 抗核抗体阳性程度与药物性肝损伤临床特征及预后的相关性研究[J]. 肝脏, 2021, 26(3): 237-242.

WANG Yan, WANG Yu, WANG Lan, TIAN Qiu-ju, YANG Rui-yuan, LI Ke-xin, LIU Li-wei, LU Yi-da, WANG Xiao-ming, WANG Yu, OU Xiao-juan, JIA Ji-dong, ZHAO Xin-yan. The association between antinuclear antibody titers with the clinical features and prognosis of drug induced liver injury[J]. Chinese Hepatolgy, 2021, 26(3): 237-242.

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