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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

引用本文:
Citation:

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
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

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

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:   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。

     

  • 图  1  ANA滴度分级人数分布饼状图

    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
    下载: 导出CSV

    表  2  logistics回归分析结果

    指标 B Wald OR 95%CI P
    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
    下载: 导出CSV

    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
    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
    下载: 导出CSV

    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 P
    基线 1个月 差值 基线 1个月 差值
    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
    下载: 导出CSV

    表  5  ANA滴度多元有序logistic回归分析

    变量 B SE Wald OR 95%CI P
    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
    下载: 导出CSV
  • [1] SHEN T, LIU Y, SHANG J, et al. Incidence and etiology of drug-induced liver injury in mainland China[J]. Gastroenterology, 2019, 156(8): 2230-2241. e11. DOI: 10.1053/j.gastro.2019.02.002.
    [2] ANDRADE RJ, CHALASANI N, BJÖRNSSON ES, et al. Drug-induced liver injury[J]. Nat Rev Dis Primers, 2019, 5(1): 58. DOI: 10.1038/s41572-019-0105-0.
    [3] KE L, LU C, SHEN R, et al. Knowledge mapping of drug-induced liver injury: A scientometric investigation (2010—2019)[J]. Front Pharmacol, 2020, 11: 842. DOI: 10.3389/fphar.2020.00842.
    [4] YU YC, MAO YM, CHEN CW, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury[J]. Hepatol Int, 2017, 11(3): 221-241. DOI: 10.1007/s12072-017-9793-2.
    [5] CHALASANI N, FONTANA RJ, BONKOVSKY HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States[J]. Gastroenterology, 2008, 135(6): 1924-1934, 1934. e1-4. DOI: 10.1053/j.gastro.2008.09.011.
    [6] FONTANA RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives[J]. Gastroenterology, 2014, 146(4): 914-928. DOI: 10.1053/j.gastro.2013.12.032.
    [7] YOKOI T, ODA S. Models of idiosyncratic drug-induced liver injury[J]. Annu Rev Pharmacol Toxicol, 2021, 61: 247-268. DOI: 10.1146/annurev-pharmtox-030220-015007.
    [8] STRAVITZ RT, LEE WM. Acute liver failure[J]. Lancet, 2019, 394(10201): 869-881. DOI: 10.1016/S0140-6736(19)31894-X.
    [9] CHEN QQ, LU HH, SUN FF, et al. Analysis on chronic factors of patients with drug-induced liver injury[J/CD]. Chin J Liver Dis(Electronic Version), 2020, 12(1): 68-75. DOI: 10.3969/j.issn.1674-7380.2020.01.012.

    陈琦琪, 陆慧慧, 孙芳芳, 等. 药物性肝损伤慢性化相关因素分析[J/CD]. 中国肝脏病杂志(电子版), 2020, 12(1): 68-75. DOI: 10.3969/j.issn.1674-7380.2020.01.012.
    [10] HASSAN A, FONTANA RJ. The diagnosis and management of idiosyncratic drug-induced liver injury[J]. Liver Int, 2019, 39(1): 31-41. DOI: 10.1111/liv.13931.
    [11] MADDUKURI VC, BONKOVSKY HL. Herbal and dietary supplement hepatotoxicity[J]. Clin Liver Dis (Hoboken), 2014, 4(1): 1-3. DOI: 10.1002/cld.364.
    [12] CHOW HC, SO TH, CHOI H, et al. Literature review of traditional Chinese medicine herbs-induced liver injury from an oncological perspective with RUCAM[J]. Integr Cancer Ther, 2019, 18: 1534735419869479. DOI: 10.1177/1534735419869479.
    [13] MANNS MP, LOHSE AW, VERGANI D. Autoimmune hepatitis—Update 2015[J]. J Hepatol, 2015, 62(1 Suppl): S100-S111. DOI: 10.1016/j.jhep.2015.03.005.
    [14] CHRISTEN U, HINTERMANN E. Pathogens and autoimmune hepatitis[J]. Clin Exp Immunol, 2019, 195(1): 35-51. DOI: 10.1111/cei.13203.
    [15] LIU X, DENG GY, YANG SF, et al. Microorganism infection and autoimmune diseases[J]. Chin J Immunol, 2020, 36(17): 2169-2173, the cover 4. DOI: 10.3969/j.issn.1000-484X.2020.17.025.

    刘欣, 邓国英, 杨淑凤, 等. 病原微生物感染与自身免疫病[J]. 中国免疫学杂志, 2020, 36(17): 2169-2173, 封4. DOI: 10.3969/j.issn.1000-484X.2020.17.025.
    [16] Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and management of autoimmune hepatitis(2015)[J]. J Clin Hepatol, 2016, 32(1): 9-22. DOI: 10.3969/j.issn.1001-5256.2016.01.002.

    中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 自身免疫性肝炎诊断和治疗共识(2015)[J]. 临床肝胆病杂志, 2016, 32(1): 9-22. DOI: 10.3969/j.issn.1001-5256.2016.01.002.
    [17] SEBODE M, SCHULZ L, LOHSE AW. "Autoimmune(-Like)" drug and herb induced liver Injury: New insights into molecular pathogenesis[J]. Int J Mol Sci, 2017, 18(9): 1954. DOI: 10.3390/ijms18091954.
    [18] WEBER S, BENESIC A, BUCHHOLTZ ML, et al. Antimitochondrial rather than antinuclear antibodies correlate with severe drug-induced liver injury[J]. Dig Dis, 2021, 39(3): 275-282. DOI: 10.1159/000511635.
    [19] ALVAREZ F, BERG PA, BIANCHI FB, et al. International Autoimmune Hepatitis Group Report: Review of criteria for diagnosis of autoimmune hepatitis[J]. J Hepatol, 1999, 31(5): 929-938. DOI: 10.1016/s0168-8278(99)80297-9.
    [20] WEBER S, BENESIC A, ROTTER I, et al. Early ALT response to corticosteroid treatment distinguishes idiosyncratic drug-induced liver injury from autoimmune hepatitis[J]. Liver Int, 2019, 39(10): 1906-1917. DOI: 10.1111/liv.14195.
    [21] HISAMOCHI A, KAGE M, IDE T, et al. An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis[J]. J Gastroenterol, 2016, 51(6): 597-607. DOI: 10.1007/s00535-015-1131-7.
    [22] DEVARBHAVI H, SINGH R, PATIL M, et al. Outcome and determinants of mortality in 269 patients with combination anti-tuberculosis drug-induced liver injury[J]. J Gastroenterol Hepatol, 2013, 28(1): 161-167. DOI: 10.1111/j.1440-1746.2012.07279.x.
    [23] STEPHENS C, ROBLES-DIAZ M, MEDINA-CALIZ I, et al. Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry[J]. J Hepatol, 2021, 75(1): 86-97. DOI: 10.1016/j.jhep.2021.01.029.
    [24] NORMAN BH. Drug Induced Liver Injury (DILI). Mechanisms and medicinal chemistry avoidance/mitigation strategies[J]. J Med Chem, 2020, 63(20): 11397-11419. DOI: 10.1021/acs.jmedchem.0c00524.
    [25] LUCENA MI, SANABRIA J, GARCÍA-CORTES M, et al. Drug-induced liver injury in older people[J]. Lancet Gastroenterol Hepatol, 2020, 5(9): 862-874. DOI: 10.1016/S2468-1253(20)30006-6.
    [26] SUTTI S, TACKE F. Liver inflammation and regeneration in drug-induced liver injury: Sex matters![J]. Clin Sci (Lond), 2018, 132(5): 609-613. DOI: 10.1042/CS20171313.
    [27] CIRULLI ET, NICOLETTI P, ABRAMSON K, et al. A missense variant in PTPN22 is a risk factor for drug-Induced liver injury[J]. Gastroenterology, 2019, 156(6): 1707-1716. e2. DOI: 10.1053/j.gastro.2019.01.034.
    [28] WILLIAMS DP, LAZIC SE, FOSTER AJ, et al. Predicting drug-induced liver injury with bayesian machine learning[J]. Chem Res Toxicol, 2020, 33(1): 239-248. DOI: 10.1021/acs.chemrestox.9b00264.
    [29] LIU A, WALTER M, WRIGHT P, et al. Prediction and mechanistic analysis of drug-induced liver injury (DILI) based on chemical structure[J]. Biol Direct, 2021, 16(1): 6. DOI: 10.1186/s13062-020-00285-0.
    [30] CHEN Z, MENG X, ZOU L, et al. A dual-emissive phosphorescent polymeric probe for exploring drug-induced liver injury via imaging of peroxynitrite elevation in vivo[J]. ACS Appl Mater Interfaces, 2020, 12(11): 12383-12394. DOI: 10.1021/acsami.9b18135.
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