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Article(id=1208862367367164127, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208862365714616539, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.09.14, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1608998400000, receivedDateStr=2020-12-27, revisedDate=1624291200000, revisedDateStr=2021-06-22, acceptedDate=null, acceptedDateStr=null, onlineDate=1766144847956, onlineDateStr=2025-12-19, pubDate=1632758400000, pubDateStr=2021-09-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766144847956, onlineIssueDateStr=2025-12-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766144847956, creator=13701087609, updateTime=1766144847956, updator=13701087609, issue=Issue{id=1208862365714616539, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='9', pageStart='849', pageEnd='953', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766144847562, creator=13701087609, updateTime=1766144914151, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208862645055254758, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208862365714616539, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208862645055254759, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208862365714616539, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=928, endPage=934, ext={EN=ArticleExt(id=1208862367673348321, articleId=1208862367367164127, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=High risk factors associated with relapse of chronic drug-induced liver injury, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the high-risk factors associated with relapse of chronic drug-induced liver injury(DILI) to provide a basis for accurate prediction and treatment. Methods The clinical data of 1660 patients with chronic DILI patients, who were hospitalized from January 2012 to June 2017, were retrospectively collected. The average age of the patients was(43.9±12.3) years old and 970 were females. And they were divided into relapse group (n=196) and non-relapse group (n=1464).Spearman rank correlation was used to analyze the association of inflammation degree and fibrosis stage with relapse, while the high-risk factors associated with relapse were analyzed by univariable and multivariable logistic regression. Results With the increase in the degree of inflammation and fibrosis, the proportion of patients with relapse increased [inflammation grade (G0: 0%, G1: 0.9%, G2:5.8%, G3: 50.7%, G4: 72.7%), fibrosis stage (S0: 2.8%, S1: 5.0%, S2: 17.1%, S3: 22.4%, S4: 42.7%), P<0.001]. Spearman rank correlation analysis showed inflammation grade (r=0.463) and fibrosis stage (r=0.275) had a positive correlation with relapse. Especially,inflammation grade ≥G3 (OR=5.75, 95%CI 3.83-8.64, P<0.001) is a high-risk factor associated with relapse in chronic DILI patients. Biochemically, multivariable logistic regression analysis showed that age >60 years (OR=2.14, 95%CI 1.17-3.90, P=0.014),AST >2×ULN (OR=3.62, 95%CI 1.64-7.79, P=0.001), TBIL >2×ULN (OR=2.19, 95%CI 1.39-3.44, P=0.001), CHE <1×ULN(OR=3.42, 95%CI 2.34-5.01, P<00.01), PLT <100×109/L (OR=2.09, 95%CI 1.24-3.54, P=0.006) were independent high-risk predictors associated with relapse. Conclusion Older age, high AST and TBIL, low CHE and PLT, inflammation grade ≥G3 are high risk factors for relapse, which are of great clinical significance for early prediction and effective improvement of chronic DILI outcome.

, correspAuthors=Dong Ji, authorNote=null, correspAuthorsNote=
*E-mail:
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目的 探讨慢性药物性肝损伤(DILI)复发的高危因素。方法 回顾性分析2012年1月—2017年6月在解放军总医院第五医学中心经病理组织学证实的1660例慢性DILI患者的临床资料。患者年龄(43.9±12.3)岁，其中女970例，男690例，按照是否复发分为复发组(n=196)与无复发组(n=1464)。采用Spearman等级相关分析炎症程度及纤维化分期与复发的相关性；采用logistic单因素及多因素回归分析复发的高危因素。结果 随着炎症程度及纤维化程度的升高，患者复发比例增高[炎症(G0：0%，G1：0.9%，G2：5.8%，G3：50.7%，G4：72.7%)，纤维化(S0：2.8%，S1：5.0%，S2：17.1%，S3：22.4%，S4：42.7%)，P<0.001]，Spearman等级相关分析结果显示，炎症程度及纤维化分期与复发呈正相关(r=0.463，r=0.275)。炎症程度分级G3及以上(OR=5.75，95%CI 3.83~8.64，P<0.001)为慢性DILI复发的高危因素。多因素logistic回归分析结果显示，年龄>60岁(OR=2.14，95%CI 1.17~3.90，P=0.014)、AST >2×正常值上限(ULN)(OR=3.62，95%CI 1.64~7.79，P=0.001)、TBIL >2×ULN(OR=2.19，95%CI 1.39~3.44，P=0.001)、CHE<1×ULN(OR=3.42，95%CI 2.34~5.01，P<00.01)、PLT <100×109/L(OR=2.09，95%CI 1.24~3.54，P=0.006)是慢性DILI复发的独立危险因素。结论 高龄、高AST或TBIL、低CHE或PLT、炎症程度分级G3及以上是慢性DILI复发的高危因素，对早期预测和有效改善慢性DILI患者的预后具有重要的临床意义。

, correspAuthors=纪冬, authorNote=null, correspAuthorsNote=
纪冬，E-mail：
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邓亚，硕士研究生，主要从事传染病的临床及基础研究工作

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邓亚，硕士研究生，主要从事传染病的临床及基础研究工作

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Clinical and histologic features of azithromycin-induced liver injury[J]. Clin Gastroenterol Hepatol, 2015, 13(2): 369-376.e3., articleTitle=Clinical and histologic features of azithromycin-induced liver injury, refAbstract=null)], funds=[Fund(id=1209154191931601705, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, awardId=Z181100001718034, language=EN, fundingSource=Capital Characteristic Clinic Project of Beijing Municipal Science and Technology Commission(Z181100001718034), fundOrder=null, country=null), Fund(id=1209154192019682090, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, awardId=Z181100001718034, language=CN, fundingSource=首都临床特色应用研究特色课题(Z181100001718034), fundOrder=null, country=null), Fund(id=1209154192090985259, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, awardId=2018JM12603003, language=EN, fundingSource=Key Project of Jumei Special Fund for Hepatobiliary Disease Prevention and Treatment(2018JM12603003), fundOrder=null, country=null), Fund(id=1209154192174871340, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, awardId=2018JM12603003, language=CN, fundingSource=菊梅肝胆病防治能力建设专项基金重点项目(2018JM12603003), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1209154187271729898, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, xref=1, ext=[AuthorCompanyExt(id=1209154187280118507, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, companyId=1209154187271729898, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China), AuthorCompanyExt(id=1209154187288507116, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, companyId=1209154187271729898, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1南方医科大学第二临床医学院，广州 510515)]), AuthorCompany(id=1209154187359810285, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, xref=2, ext=[AuthorCompanyExt(id=1209154187368198894, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, companyId=1209154187359810285, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China), AuthorCompanyExt(id=1209154187502416624, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, companyId=1209154187359810285, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2解放军总医院第五医学中心肝病医学部，北京 100039)])], figs=[ArticleFig(id=1209154190157411107, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, language=EN, label=Fig.1, caption=Histological features of chronic drug-induced liver injury relapse, figureFileSmall=UIZ6WNyasx0UP4ZhiAVdxw==, figureFileBig=bGz2T+kFm8NpQPdneDHiaQ==, tableContent=null), ArticleFig(id=1209154191365370660, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, language=CN, label=图1, caption=慢性药物性肝损伤复发的组织学特征, figureFileSmall=UIZ6WNyasx0UP4ZhiAVdxw==, figureFileBig=bGz2T+kFm8NpQPdneDHiaQ==, tableContent=null), ArticleFig(id=1209154191466033957, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, language=EN, label=Tab.1, caption=

Comparison of demographic and basic data of drug-induced liver injury patients between relapse group and non-relapse group [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
项目总数(n=1660)未复发(n=1464)复发(n=196)χ2/ZP
女性970(58.4)840(57.4)130(66.3)5.340.021
年龄(岁)   11.950.003
 ≤44809(48.7)733(50.1)76(38.8)
 44~60723(43.6)627(42.8)96(49.0)
 >60128(7.7)104(7.1)24(12.2)
体重指数(kg/m2)   2.580.276
 <24856(53.4)745(52.8)111(57.8)
 24~28593(37.0)532(37.7)61(31.8)
 ≥28153(9.6)133(9.5)20(10.4)
合并症   12.040.007
 无1431(86.2)1275(87.1)156(79.6)
 糖尿病58(3.5)47(3.2)11(5.6)
 高血压151(9.1)128(8.7)23(11.7)
 糖尿病+高血压20(1.2)14(1.0)6(3.1)
肝损伤分型   0.170.918
 胆汁淤积型885(53.3)782(53.4)103(52.6)
 肝细胞型304(18.3)266(18.2)38(19.4)
 混合型471(28.4)416(28.4)55(28.0)
用药史   2.670.263
 中药657(39.6)587(40.1)70(36.0)
 西药571(34.4)505(34.5)66(33.6)
 混合药432(26.0)372(25.4)60(30.4)
PT(s)   39.27<0.001
 ≥14.375(4.6)49(3.4)26(13.3)
 <14.31585(95.4)1415(96.6)170(86.7)
PLT(×109/L)   31.74<0.001
 ≥1001526(91.9)1366(93.3)160(81.6)
 <100134(8.1)98(6.7)36(18.4)
CHE   175.78<0.001
 ≥1×ULN1267(76.3)1192(81.4)75(38.3)
 <1×ULN393(23.7)272(18.6)121(61.7)
TBIL   98.65<0.001
 ≤1×ULN931(56.1)879(60.0)52(26.5)
 1~2×ULN315(19.0)272(18.6)43(22.0)
 <2×ULN414(24.9)313(21.4)101(51.5)
ALT   4.710.095
 ≤1×ULN552(33.2)500(34.2)52(26.5)
 1~2×ULN886(53.4)769(52.5)117(59.7)
 >2×ULN222(13.4)195(13.3)27(13.8)
AST   55.98<0.001
 ≤1×ULN630(38.0)599(41.0)31(15.8)
 1~2×ULN918(55.3)781(53.3)137(69.9)
 >2×ULN112(6.7)84(5.7)28(14.3)
GGT   14.320.001
 ≤1×ULN467(28.1)434(29.6)33(16.8)
 1~2×ULN394(23.7)343(23.4)51(26.0)
 >2×ULN799(48.2)687(47.0)112(57.2)
ALP   15.72<0.001
 ≤1×ULN1112(67.0)1001(68.4)111(56.6)
 1~2×ULN448(27.0)385(26.3)63(32.2)
 >2×ULN100(6.0)78(5.3)22(11.2)
炎症程度分级(G)   577.57<0.001
 G0136(8.2)136(9.3)0(0.0)
 G1645(38.8)639(43.6)6(3.1)
 G2574(34.6)541(37.0)33(16.8)
 G3294(17.7)145(9.9)149(76.0)
 G411(0.7)3(0.2)8(4.1)
纤维化分期(S)151.96<0.001
 S0211(12.7)205(14.0)6(3.1)
 S1734(44.2)697(47.6)37(18.9)
 S2421(25.4)349(23.8)72(36.7)
 S3219(13.2)170(11.6)49(25.0)
 S475(4.5)43(3.0)32(16.3)
), ArticleFig(id=1209154191558308646, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, language=CN, label=表1, caption=

两组药物性肝损伤患者人口统计学及基础资料比较[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
项目总数(n=1660)未复发(n=1464)复发(n=196)χ2/ZP
女性970(58.4)840(57.4)130(66.3)5.340.021
年龄(岁)   11.950.003
 ≤44809(48.7)733(50.1)76(38.8)
 44~60723(43.6)627(42.8)96(49.0)
 >60128(7.7)104(7.1)24(12.2)
体重指数(kg/m2)   2.580.276
 <24856(53.4)745(52.8)111(57.8)
 24~28593(37.0)532(37.7)61(31.8)
 ≥28153(9.6)133(9.5)20(10.4)
合并症   12.040.007
 无1431(86.2)1275(87.1)156(79.6)
 糖尿病58(3.5)47(3.2)11(5.6)
 高血压151(9.1)128(8.7)23(11.7)
 糖尿病+高血压20(1.2)14(1.0)6(3.1)
肝损伤分型   0.170.918
 胆汁淤积型885(53.3)782(53.4)103(52.6)
 肝细胞型304(18.3)266(18.2)38(19.4)
 混合型471(28.4)416(28.4)55(28.0)
用药史   2.670.263
 中药657(39.6)587(40.1)70(36.0)
 西药571(34.4)505(34.5)66(33.6)
 混合药432(26.0)372(25.4)60(30.4)
PT(s)   39.27<0.001
 ≥14.375(4.6)49(3.4)26(13.3)
 <14.31585(95.4)1415(96.6)170(86.7)
PLT(×109/L)   31.74<0.001
 ≥1001526(91.9)1366(93.3)160(81.6)
 <100134(8.1)98(6.7)36(18.4)
CHE   175.78<0.001
 ≥1×ULN1267(76.3)1192(81.4)75(38.3)
 <1×ULN393(23.7)272(18.6)121(61.7)
TBIL   98.65<0.001
 ≤1×ULN931(56.1)879(60.0)52(26.5)
 1~2×ULN315(19.0)272(18.6)43(22.0)
 <2×ULN414(24.9)313(21.4)101(51.5)
ALT   4.710.095
 ≤1×ULN552(33.2)500(34.2)52(26.5)
 1~2×ULN886(53.4)769(52.5)117(59.7)
 >2×ULN222(13.4)195(13.3)27(13.8)
AST   55.98<0.001
 ≤1×ULN630(38.0)599(41.0)31(15.8)
 1~2×ULN918(55.3)781(53.3)137(69.9)
 >2×ULN112(6.7)84(5.7)28(14.3)
GGT   14.320.001
 ≤1×ULN467(28.1)434(29.6)33(16.8)
 1~2×ULN394(23.7)343(23.4)51(26.0)
 >2×ULN799(48.2)687(47.0)112(57.2)
ALP   15.72<0.001
 ≤1×ULN1112(67.0)1001(68.4)111(56.6)
 1~2×ULN448(27.0)385(26.3)63(32.2)
 >2×ULN100(6.0)78(5.3)22(11.2)
炎症程度分级(G)   577.57<0.001
 G0136(8.2)136(9.3)0(0.0)
 G1645(38.8)639(43.6)6(3.1)
 G2574(34.6)541(37.0)33(16.8)
 G3294(17.7)145(9.9)149(76.0)
 G411(0.7)3(0.2)8(4.1)
纤维化分期(S)151.96<0.001
 S0211(12.7)205(14.0)6(3.1)
 S1734(44.2)697(47.6)37(18.9)
 S2421(25.4)349(23.8)72(36.7)
 S3219(13.2)170(11.6)49(25.0)
 S475(4.5)43(3.0)32(16.3)
), ArticleFig(id=1209154191675749159, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, language=EN, label=Tab.2, caption=

Univariable and multivariable logistic regression analysis of high risk factors of relapse of chronic drug-induced liver injury

, figureFileSmall=null, figureFileBig=null, tableContent=
变量单因素分析多因素分析
OR(95% CI)POR(95% CI)P
女性0.68(0.50~0.94)0.017
年龄(岁)
 44~601.48(1.07~2.03)0.017
 >602.23(1.35~3.68)0.0022.14(1.17~3.90)0.014
体重指数(kg/m2)
 24~280.77(0.55~1.07)0.122
 >281.01(0.61~1.68)0.972
肝损伤分型
 肝细胞型1.09(0.73~1.61)0.689
 混合型1.00(0.71~1.42)0.983
ALT
 1~2×ULN1.46(1.04~2.07)0.031
 >2×ULN1.33(0.81~2.18)0.256
AST
 1~2×ULN3.39(2.26~5.08)<0.001
 >2×ULN6.44(3.68~11.27)<0.0013.62(1.64~7.79)0.001
TBIL
 1~2×ULN2.67(1.75~4.09)<0.001
 >2×ULN5.46(3.81~7.81)<0.0012.19(1.39~3.44)0.001
CHE <1×ULN7.07(5.15~9.71)<0.0013.42(2.34~5.01)<0.001
PLT <100(×109/L)3.13(2.06~4.74)<0.0012.09(1.24~3.54)0.006
PT >14.3(s)4.41(2.67~7.28)<0.001
ALP
 1~2×ULN1.48(1.06~2.05)0.021
 >2×ULN2.54(1.52~4.25)<0.001
GGT
 1~2×ULN1.96(1.23~3.10)0.004
 >2×ULN2.14(1.43~3.22)<0.001
炎症程度分级G3及以上7.85(5.36~11.48)>0.0015.75(3.83~8.64)<0.001
), ArticleFig(id=1209154191763829544, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367367164127, language=CN, label=表2, caption=

慢性药物性肝损伤复发高危因素的logistic单因素及多因素回归分析

, figureFileSmall=null, figureFileBig=null, tableContent=
变量单因素分析多因素分析
OR(95% CI)POR(95% CI)P
女性0.68(0.50~0.94)0.017
年龄(岁)
 44~601.48(1.07~2.03)0.017
 >602.23(1.35~3.68)0.0022.14(1.17~3.90)0.014
体重指数(kg/m2)
 24~280.77(0.55~1.07)0.122
 >281.01(0.61~1.68)0.972
肝损伤分型
 肝细胞型1.09(0.73~1.61)0.689
 混合型1.00(0.71~1.42)0.983
ALT
 1~2×ULN1.46(1.04~2.07)0.031
 >2×ULN1.33(0.81~2.18)0.256
AST
 1~2×ULN3.39(2.26~5.08)<0.001
 >2×ULN6.44(3.68~11.27)<0.0013.62(1.64~7.79)0.001
TBIL
 1~2×ULN2.67(1.75~4.09)<0.001
 >2×ULN5.46(3.81~7.81)<0.0012.19(1.39~3.44)0.001
CHE <1×ULN7.07(5.15~9.71)<0.0013.42(2.34~5.01)<0.001
PLT <100(×109/L)3.13(2.06~4.74)<0.0012.09(1.24~3.54)0.006
PT >14.3(s)4.41(2.67~7.28)<0.001
ALP
 1~2×ULN1.48(1.06~2.05)0.021
 >2×ULN2.54(1.52~4.25)<0.001
GGT
 1~2×ULN1.96(1.23~3.10)0.004
 >2×ULN2.14(1.43~3.22)<0.001
炎症程度分级G3及以上7.85(5.36~11.48)>0.0015.75(3.83~8.64)<0.001
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慢性药物性肝损伤复发的高危因素分析
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邓亚 1, 2 , 王春艳 2 , 谭文辉 1, 2 , 付懿铭 2 , 陈松海 2 , 李忠斌 2 , 陈国凤 2 , 纪冬 1, 2, *
解放军医学杂志 | 临床研究 2021,46(9): 928-934
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解放军医学杂志 | 临床研究 2021, 46(9): 928-934
慢性药物性肝损伤复发的高危因素分析
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邓亚1, 2, 王春艳2, 谭文辉1, 2, 付懿铭2, 陈松海2, 李忠斌2, 陈国凤2, 纪冬1, 2, *
作者信息
  • 1南方医科大学第二临床医学院，广州 510515
  • 2解放军总医院第五医学中心肝病医学部，北京 100039

    • 邓亚，硕士研究生，主要从事传染病的临床及基础研究工作

通讯作者:

纪冬，E-mail：
High risk factors associated with relapse of chronic drug-induced liver injury
Ya Deng1, 2, Chun-Yan Wang2, Wen-Hui Tan1, 2, Yi-Ming Fu2, Song-Hai Chen2, Zhong-Bin Li2, Guo-Feng Chen2, Dong Ji1, 2, *
Affiliations
  • 1Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
  • 2Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
出版时间: 2021-09-28 doi: 10.11855/j.issn.0577-7402.2021.09.14
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摘要
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目的 探讨慢性药物性肝损伤(DILI)复发的高危因素。方法 回顾性分析2012年1月—2017年6月在解放军总医院第五医学中心经病理组织学证实的1660例慢性DILI患者的临床资料。患者年龄(43.9±12.3)岁，其中女970例，男690例，按照是否复发分为复发组(n=196)与无复发组(n=1464)。采用Spearman等级相关分析炎症程度及纤维化分期与复发的相关性；采用logistic单因素及多因素回归分析复发的高危因素。结果 随着炎症程度及纤维化程度的升高，患者复发比例增高[炎症(G0：0%，G1：0.9%，G2：5.8%，G3：50.7%，G4：72.7%)，纤维化(S0：2.8%，S1：5.0%，S2：17.1%，S3：22.4%，S4：42.7%)，P<0.001]，Spearman等级相关分析结果显示，炎症程度及纤维化分期与复发呈正相关(r=0.463，r=0.275)。炎症程度分级G3及以上(OR=5.75，95%CI 3.83~8.64，P<0.001)为慢性DILI复发的高危因素。多因素logistic回归分析结果显示，年龄>60岁(OR=2.14，95%CI 1.17~3.90，P=0.014)、AST >2×正常值上限(ULN)(OR=3.62，95%CI 1.64~7.79，P=0.001)、TBIL >2×ULN(OR=2.19，95%CI 1.39~3.44，P=0.001)、CHE<1×ULN(OR=3.42，95%CI 2.34~5.01，P<00.01)、PLT <100×109/L(OR=2.09，95%CI 1.24~3.54，P=0.006)是慢性DILI复发的独立危险因素。结论 高龄、高AST或TBIL、低CHE或PLT、炎症程度分级G3及以上是慢性DILI复发的高危因素，对早期预测和有效改善慢性DILI患者的预后具有重要的临床意义。

慢性药物性肝损伤  /  复发  /  高危因素

Objective To explore the high-risk factors associated with relapse of chronic drug-induced liver injury(DILI) to provide a basis for accurate prediction and treatment. Methods The clinical data of 1660 patients with chronic DILI patients, who were hospitalized from January 2012 to June 2017, were retrospectively collected. The average age of the patients was(43.9±12.3) years old and 970 were females. And they were divided into relapse group (n=196) and non-relapse group (n=1464).Spearman rank correlation was used to analyze the association of inflammation degree and fibrosis stage with relapse, while the high-risk factors associated with relapse were analyzed by univariable and multivariable logistic regression. Results With the increase in the degree of inflammation and fibrosis, the proportion of patients with relapse increased [inflammation grade (G0: 0%, G1: 0.9%, G2:5.8%, G3: 50.7%, G4: 72.7%), fibrosis stage (S0: 2.8%, S1: 5.0%, S2: 17.1%, S3: 22.4%, S4: 42.7%), P<0.001]. Spearman rank correlation analysis showed inflammation grade (r=0.463) and fibrosis stage (r=0.275) had a positive correlation with relapse. Especially,inflammation grade ≥G3 (OR=5.75, 95%CI 3.83-8.64, P<0.001) is a high-risk factor associated with relapse in chronic DILI patients. Biochemically, multivariable logistic regression analysis showed that age >60 years (OR=2.14, 95%CI 1.17-3.90, P=0.014),AST >2×ULN (OR=3.62, 95%CI 1.64-7.79, P=0.001), TBIL >2×ULN (OR=2.19, 95%CI 1.39-3.44, P=0.001), CHE <1×ULN(OR=3.42, 95%CI 2.34-5.01, P<00.01), PLT <100×109/L (OR=2.09, 95%CI 1.24-3.54, P=0.006) were independent high-risk predictors associated with relapse. Conclusion Older age, high AST and TBIL, low CHE and PLT, inflammation grade ≥G3 are high risk factors for relapse, which are of great clinical significance for early prediction and effective improvement of chronic DILI outcome.

chronic drug-induced liver injury  /  relapse  /  high-risk factors
邓亚, 王春艳, 谭文辉, 付懿铭, 陈松海, 李忠斌, 陈国凤, 纪冬. 慢性药物性肝损伤复发的高危因素分析. 解放军医学杂志, 2021 , 46 (9) : 928 -934 . DOI: 10.11855/j.issn.0577-7402.2021.09.14
Ya Deng, Chun-Yan Wang, Wen-Hui Tan, Yi-Ming Fu, Song-Hai Chen, Zhong-Bin Li, Guo-Feng Chen, Dong Ji. High risk factors associated with relapse of chronic drug-induced liver injury[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (9) : 928 -934 . DOI: 10.11855/j.issn.0577-7402.2021.09.14
正文
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药物性肝损伤(drug-induced liver injury，DILI)是指由各类处方或非处方的化学药物、生物制剂、传统中药、天然药、保健品、膳食补充剂及其代谢产物甚至辅料等所诱发的肝损伤。DILI发病率逐年上升，已引起医疗界的广泛重视[1]，是肝病领域的研究热点[2-5]。尽管DILI通常表现为急性过程，但有研究发现约20%的患者可发展为慢性DILI[6]。此外，在临床工作中可观察到经治疗肝酶恢复正常的慢性DILI患者仍会反复出现DILI症状的现象，甚至进展为肝硬化或肝衰竭，造成严重的经济负担。准确把握DILI的临床特征以及复发风险因素对早期优化慢性DILI的治疗尤为重要。国内外目前关于DILI的研究主要集中于其发病率、致病药物种类、临床特征、发病机制及动物模型的开发[7-9]。既往有研究发现，女性、高龄和胆红素升高是慢性DILI的危险因素[10-12]，且炎症程度也是慢性DILI的独立危险因素[12]。但是，目前很少有研究关注慢性DILI的复发及其危险因素。此外，肝活检由于有创、取样误差大、不易重复等因素，限制了其在临床上的应用。因此，本文通过回顾性研究，探索非侵入性检验指标中影响慢性DILI复发的高危因素，以期指导临床早期发现有复发风险的高危人群，从而制定个体化、精准化的治疗方案，降低复发率。
1 资料与方法
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1.1 研究对象
选取2012年1月—2017年6月在解放军总医院第五医学中心住院的DILI患者进行回顾性分析。纳入标准：(1)符合《药物性肝损伤诊疗指南(2015版)》中慢性DILI的诊断标准[DILI发生6个月后，谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)及总胆红素(TBIL)仍持续异常，或存在门静脉高压或慢性肝损伤的影像学和组织学证据][13]；(2)肝活检证实为慢性DILI[13]。排除标准：(1)年龄<18岁；(2)病程<6个月；(3)合并其他原因所致肝病。共筛选2155例，排除合并有病毒性肝炎(43例)、自身免疫性肝病(86例)、酒精性肝病(19例)、吉尔伯特综合征(21例)、非酒精性脂肪性肝病(258例)及失访(68例)的患者，最终纳入慢性DILI患者1660例。收集患者的性别、年龄、ALT、AST、TBIL、谷氨酰转肽酶(GGT)、血小板(PLT)、凝血酶原时间(PT)、胆碱酯酶(CHE)等临床资料，按照是否复发分为无复发组(n=1464)与复发组(n=196)。本研究获得解放军总医院第五医学中心伦理委员会批准(批号2019024D)。
1.2 数据采集及试验设计
在患者进行肝穿刺前7 d内清晨空腹抽取静脉血，采用全自动生化分析仪进行生化及血常规检测，收集肝、肾功能及血常规等指标作为基线数据，并计算R值[R=(ALT实测值/40)/(ALP实测值/150)]，根据指南分为胆汁淤积型(R≤2)、肝细胞损伤型(R≥5)、混合型(2<R<5)[13]。所有患者随访超过1年，根据1年之内的肝酶值(ALT、AST、ALP)评价是否复发。
1.3 慢性DILI复发的定义
慢性DILI复发定义为经保肝治疗肝酶恢复正常(1个月内连续两次检测正常)，1年以内再次出现血清ALT或AST>1.5倍正常值上限(ULN)[11]或ALP>1.1×ULN[12]者(排除自身免疫性肝病、病毒性肝炎、酒精性肝病、非酒精性脂肪性肝病等其他原因；若肝酶恢复正常1年后再次异常不判定为复发)。
1.4 肝组织学检查
采用超声引导下经皮肝穿刺活检，使用一次性活检针(16G)采集肝组织，长度>15 mm，10%中性甲醛固定，常规石蜡包埋，连续切片，行HE及网状纤维和(或)Masson染色，根据Scheuer评分系统[14]进行肝脏炎症程度分级及纤维化分期。
1.5 统计学处理
采用R软件对数据进行统计处理及分析。正态分布的计量资料以$\bar{x}±s$表示，两组间比较采用独立样本t检验；非正态分布的计量资料以M(Q1，Q3)表示，组间比较采用Mann-Whitney秩和检验；计数资料以例(%)表示，组间比较采用χ2检验；采用单因素及多因素logistic回归模型进行分析，相关性采用Spearman秩相关进行分析。两等级资料趋势性检验采用Kendall's tau-b等级相关分析。P<0.05为差异有统计学意义。
2 结果
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2.1 两组基线资料比较
最终纳入患者1660例，女970例(58.4%)，男690例(41.6%)，年龄(43.9±12.3)岁，其中胆汁淤积型885例(53.3%)，肝细胞损伤型304例(18.3%)，混合型471例(28.4%)。用药种类分为中药(39.6%、657/1660)、西药(34.4%、571/1660)以及混合药26%(432/1660)三类。229例(13.8%)合并慢性病，包括糖尿病58例(3.5%)，高血压151例(9.1%)，同时合并高血压及糖尿病20例(1.2%)。为进一步分析慢性DILI患者复发的高危因素，将年龄、体重指数、ALT、AST、ALP、GGT、TBIL、CHE、PLT及PT进行分层，结果显示，复发组患者中女性(66.3%)、高龄、高TBIL、高AST、高ALP、高GGT、高PT、低CHE及低PLT占比均高于无复发组，差异有统计学意义(P<0.05)，ALT、体重指数、肝损伤分型、用药史差异无统计学意义(P>0.05)(表1)。
2.2 慢性DILI复发的组织学特征
Spearman等级相关分析结果显示，肝脏炎症程度分级及纤维化分期与复发呈正相关(r=0.463，r=0.275)。肝脏炎症程度分级：随着炎症程度的加重，患者复发的比例增高[G0：0%(0/136)，G1：0.9%(6/645)，G2：5.8%(33/574)，G3：50.7%(149/294)，G4：72.7%(8/11)]。纤维化分期：伴随纤维化程度增加，复发的比例亦增高[S0：2.8%(6/211)，S1：5.0%(37/734)，S2：17.1%(72/421)，S3：22.4%(49/219)，S4：42.7%(32/75)]。尤其是炎症程度分级G3及以上(157/196，80.1%)、纤维化分期S2及以上(153/196，78.1%)在慢性DILI复发患者中占比较高(P<0.001)(图1)。Kendall's tau-b等级相关分析结果显示，DILI患者炎症程度与纤维化程度存在正相关(tau-b=0.501，P<0.001)，即随着炎症程度的增加纤维化程度亦增加。
2.3 慢性DILI复发的高危因素分析
将上述有统计学意义及临床意义的指标纳入多因素分析，结果显示，年龄>60岁(OR=2.14，95%CI 1.17~3.90，P=0.014)、AST >2×ULN(OR=3.62，95%CI 1.64~7.79，P=0.001)、TBIL >2×ULN(OR=2.19，95%CI 1.39~3.44，P=0.001)、CHE <1×ULN(OR=3.42，95%CI 2.34~5.01，P<0.001)、PLT<100×109/L(OR=2.09，95%CI 1.24~3.54，P=0.006)、炎症程度分级G3及以上(OR=5.75，95%CI 3.83~8.64，P<0.001)是慢性DILI复发的独立危险因素(表2)。
3 讨论
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在我国，近年来因传统中药及膳食补充剂的普遍应用，DILI的发生越来越多。一项针对中国内地DILI发病率及病因学的研究发现，DILI的发病率约为23.8/10万，引起DILI的主要药物为中草药及膳食补充剂(26.81%)[15]。本研究中由中药所致的慢性DILI患者占比高达39.6%(657/1660)，与既往研究一致。目前，DILI的临床诊治面临以下难点：诊断难度高，属于排他性诊断，肝活检很重要但接受度差；临床表现多样，复发比例高，重症化风险高，部分患者病情进展快[16]。DILI根据病程可以分为急性和慢性，其中急性占绝大多数，具有自限性，但在停用可疑药物后，仍有6%~20%的患者会进展为慢性DILI[17-18]，此类患者预后不佳，严重者可发生肝衰竭甚至死亡。临床研究表明，基线TBIL、高龄、代谢性疾病(糖尿病、高脂血症等)是DILI慢性化的独立预测指标[19-21]。国内外均有研究表明，TBIL、国际标准化比值(INR)、GGT、总胆汁酸(TBA)等实验室指标有助于评估DILI的严重程度甚至预后[17,22-24]，但关于慢性DILI复发及预测慢性DILI复发高危因素的研究较少，且尚未对慢性DILI复发提出明确的定义。因此，本文对慢性DILI复发的定义及危险因素进行了探索性分析。
本研究结果显示，随着炎症程度及纤维化分期的增高，慢性DILI的复发率升高，其中以肝脏炎症G3及肝纤维化S2期较明显，多因素分析结果显示，炎症程度分级G3及以上是慢性DILI复发的高危因素。此外，本研究还发现，慢性DILI患者的炎症程度与纤维化程度存在正相关关系，表明反复的炎症损伤和修复会加剧疾病的进展，导致发展为肝纤维化甚至肝硬化。因此，对于有复发高风险的慢性DILI患者应进行更积极的治疗，以防止疾病进一步恶化。然而，就诊断金标准的肝活检而言，虽然其对于确诊DILI、明确肝脏炎症程度及纤维化分期至关重要，但因其为有创检查，取样误差大，存在发生各种并发症的潜在危险，且获取病理的时间较长，可能会影响临床决策，延误病情，患者接受度差，用于评估慢性DILI的复发风险存在一定的局限性。
本文旨在通过对生化指标与慢性DILI复发的关系进行研究，了解慢性DILI复发的临床特点，并通过生化指标预测慢性DILI患者的复发风险，可极大地提高患者的依从性，且操作性、可重复性强。有研究显示，合并自身免疫表现的DILI患者倾向于晚期复发[25]，但由于本研究是在肝活检基础上进行的，可排除自身免疫性肝病，且肝穿刺病理活检提示门管区/小叶内淋巴-浆细胞浸润、肝细胞“玫瑰花环”样改变及穿入现象等免疫征象的患者也被排除，故未收集自身抗体相关的指标进行分析。一项系统评价研究发现，中草药及膳食补充剂导致的肝损伤较其他类型的DILI更严重，且再次暴露的可能性更大[26]，但也有研究认为不同种类药物导致的DILI预后之间无明显差异[27]。本研究也未发现中药与西药在慢性DILI复发方面的区别。此外，有研究提示，低CHE、PT延长、较高的基于4因子的纤维化指数(FIB-4)、炎症程度分级G3及以上可能是复发的危险预测因素[28]，与本研究结果类似，但该研究入组的病例数少(124例)，多因素分析仅发现CHE这一个独立危险因素。本研究多因素分析结果显示，高龄、高AST、高TBIL、低CHE、低PLT及炎症程度分级G3及以上是复发的危险预测因素。一项多中心研究结果显示，高TBIL与DILI损伤后较长的恢复时间有关[29]，另有多项研究表明TBIL有助于评估DILI的预后[12,23]。本研究结果显示，TBIL>2×ULN的患者慢性DILI复发的风险是TBIL≤1×ULN患者的2.19倍。CHE能够早期反映肝功能储备情况，与肝病严重程度有很好的相关性，且不易受抗凝剂、黄疸、输注白蛋白及临床输血等因素的影响，是判断慢性肝病转归的良好指标[30]。本研究结果显示，CHE<1×ULN的患者慢性DILI复发的风险是CHE≥1×ULN患者的3.42倍。此外，PLT与慢性肝脏疾病的严重程度呈负相关已被广泛接受，美国的一项研究结果表明，低PLT可作为评估DILI预后的重要预测指标[31]。本研究也发现，PLT<100×109/L的患者复发风险是PLT≥100×109/L患者的2.09倍。
本研究属于单中心回顾性研究，有一定的局限性，但由于入组例数多，且全部是基于肝活检的结果，因此弥补了部分不足。总之，高龄、高AST或TBIL、低CHE或PLT、炎症程度分级G3及以上是慢性DILI患者复发的高危因素，可用于指导治疗。对有复发风险的高危人群应提高警惕，采取更加积极的治疗措施，以提高患者的生存质量，改善预后，降低复发率。后期我们将进一步建立预测复发风险的临床模型，为临床决策提供更加准确的参考。
基金
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  • 首都临床特色应用研究特色课题(Z181100001718034)
  • 菊梅肝胆病防治能力建设专项基金重点项目(2018JM12603003)
文献
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2021年第46卷第9期
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doi: 10.11855/j.issn.0577-7402.2021.09.14
  • 接收时间：2020-12-27
  • 首发时间：2025-12-19
  • 出版时间：2021-09-28
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  • 收稿日期：2020-12-27
  • 修回日期：2021-06-22
基金
Capital Characteristic Clinic Project of Beijing Municipal Science and Technology Commission(Z181100001718034)
首都临床特色应用研究特色课题(Z181100001718034)
Key Project of Jumei Special Fund for Hepatobiliary Disease Prevention and Treatment(2018JM12603003)
菊梅肝胆病防治能力建设专项基金重点项目(2018JM12603003)
作者信息
    1南方医科大学第二临床医学院，广州 510515
    2解放军总医院第五医学中心肝病医学部，北京 100039

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2种不同金属材料的力学参数
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Number of
genus		 种数
Number of
species		 占总种数比例
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total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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