摘要:目的 分析美羅培南相關(guān)肝損傷(MRLI)的影響因素,探討其臨床預(yù)測(cè)價(jià)值。方法 采用回顧性病例對(duì)照研究,使用中國(guó)醫(yī)院藥物警戒系統(tǒng)(CHPS)建立檢索方案,收集2018年1月—2022年12月于十堰市人民醫(yī)院就診并使用美羅培南的住院患者1 625例。根據(jù)是否發(fā)生肝損傷分為病例組(n=62)和對(duì)照組(n=1 563),收集并分析兩組患者的臨床資料和實(shí)驗(yàn)室指標(biāo)。符合正態(tài)分布的計(jì)量資料兩組間比較采用t檢驗(yàn),不符合正態(tài)分布的計(jì)量資料兩組間比較采用Mann-Whitney U檢驗(yàn);計(jì)數(shù)資料兩組間比較采用 χ 2 檢驗(yàn)。采用多因素Logistic回歸分析MRLI的影響因素。建立邏輯回歸方程,利用受試者操作特征曲線(ROC曲線)分析其預(yù)測(cè)價(jià)值。結(jié)果 單因素分析結(jié)果顯示,病例組男性、低蛋白血癥、休克、入住ICU、合并膿毒癥和合并肝、膽、心血管疾病比率,以及ALT、ALP、GGT、AST、CREA、PCT水平和住院天數(shù)均高于對(duì)照組,PLT水平低于對(duì)照組,差異均具有統(tǒng)計(jì)學(xué)意義(P值均lt;0.05);多因素Logistic回歸結(jié)果顯示,男性(OR=2.080,95%CI:1.050~4.123,P=0.036)、入住ICU(OR=8.207,95%CI:4.094~16.453,Plt;0.001)、合并膽疾?。∣R=8.240,95%CI:3.605~18.832,Plt;0.001)、ALP(OR=1.012,95%CI:1.004~1.019,P=0.004)、GGT(OR=1.010,95%CI:1.005~1.015,Plt;0.001)、PLT(OR=0.997,95%CI:0.994~0.999,P=0.020)是 MRLI的獨(dú)立影響因素。ROC曲線分析顯示,ALP、GGT、PLT單獨(dú)預(yù)測(cè)的 ROC曲線下面積(AUC)分別為 0.589、0.637和0.595,聯(lián)合預(yù)測(cè)的AUC為0.837。結(jié)論 男性、入住ICU、合并膽疾病、ALP升高、GGT升高、PLT降低是MRLI的影響因素,聯(lián)合預(yù)測(cè)對(duì)MRLI發(fā)生風(fēng)險(xiǎn)具有較好的預(yù)測(cè)價(jià)值。
關(guān)鍵詞:美羅培南;肝損傷;影響因素
基金項(xiàng)目:湖北省自然科學(xué)基金(2023AFB925);“十四五”湖北省高等學(xué)校優(yōu)勢(shì)特色學(xué)科群(生物與醫(yī)藥)項(xiàng)目(2023BMXKQT5);武當(dāng)特色中藥研究湖北省重點(diǎn)實(shí)驗(yàn)室(湖北醫(yī)藥學(xué)院)開放課題(WDCM2023013)
Influencing factors for meropenem-related liver injury and their predictive value
HE Yan 1,2 ,KE Hongqin 3 ,LI Hongliang 1,2 ,ZHU Jianyong 4 ,ZHAO Lijun 1,2 ,YU Huibin 1,2
1. Department of Pharmacy of Renmin Hospital,Hubei Key Laboratory of Wudang Local Chinese Medicine Research,Hubei University of Medicine,Shiyan,Hubei 442000,China;2. School of Pharmaceutical Sciences,Hubei University of Medicine,Shiyan,Hubei 442000,China;3. Department of Pharmacy,Taihe Hospital,Hubei University of Medicine,Shiyan,Hubei 442000,China;4. Department of Respiratory Medicine,Renmin Hospital,Hubei University of Medicine,Shiyan,Hubei 442000,China
Corresponding author:YU Huibin,qingyun125@163.com (ORCID:0009-0009-0901-5632)
Abstract:Objective To analyze the factors influencing meropenem-related liver injury (MRLI) and to explore their clinical predictive value. Methods A retrospective case-control study was conducted,and the Chinese Hospital Pharmacovigilance System (CHPS) was used to establish a retrieval scheme. A total of 1 625 hospitalized cases using meropenem from January 2018 to December 2022 were collected. Patients were divided into case group (n=62) and control group (n=1 563) based on the presence or absence of liver injury. Clinical data and laboratory indicators from both groups were collected and analyzed. The t-test was used for comparison of normally distributed continuous data between the two groups,while the Mann-Whitney U test was used for comparison of continuous data not conforming to a normal distribution. The chi-square test was used for comparison of categorical data between the two groups. A multivariate Logistic regression analysis was performed to identify the influencing factors for MRLI.A Logistic regression equation was established,and the predictive value of these factors was assessed using the receiver operating characteristic (ROC) curve. Results The results of univariate analysis indicated that the rates of male patients,hypoproteinemia,shock,intensive care unit (ICU) admissions,sepsis,and liver,gallbladder,and cardiovascular diseases,the levels of alanine aminotransferase (ALT),alkaline phosphatase (ALP),gamma-glutamyl transpeptidase (GGT),aspartate aminotransferase (AST),creatinine (CREA),and procalcitonin (PCT),and the number of hospitalization days were significantly higher in the case group than in the control group (Plt;0.05),and that the platelet levels in the case group were significantly lower than those in the control group (Plt;0.05). The multivariate Logistic regression analysis showed that male sex (odds ratio [OR]=2.080,95% confidence interval [CI]:1.050 — 4.123,P=0.036),admission to the ICU (OR=8.207,95%CI:4.094 — 16.453,Plt;0.001),comorbidity with gallbladder disease (OR=8.240,95%CI:3.605 — 18.832,Plt;0.001),ALP (OR=1.012,95%CI:1.004 — 1.019,P=0.004),GGT(OR=1.010,95%CI:1.005 — 1.015,Plt;0.001),and PLT (OR=0.997,95%CI:0.994 — 0.999,P=0.020) were the influential factors for MRLI. The areas under the ROC curve of ALP,GGT,and PLT were 0.589,0.637,and 0.595,respectively,and the AUC of them combined was 0.837. Conclusion Male sex,ICU admission,comorbidity with gallbladder disease,increased ALP,increased GGT,and decreased PLT were influencing factors for MRLI,and a combination of factors has a better predictive value for the occurrence of MRLI.
Key words:Meropenem;Liver Injury;Influencing Factors
Research funding:Natural Science Foundation of Hubei Provincial (2023AFB925);the Advantages Discipline Group (Biology and Medicine) Project in Higher Education of Hubei Province (2021-2025) (2023BMXKQT5);the Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (WDCM2023013)
美羅培南為廣譜的碳青霉烯類抗菌藥物,對(duì)革蘭陽(yáng)性菌和革蘭陰性菌有較好的治療效果,主要用于中重度細(xì)菌感染、混合性感染、多重耐藥菌感染等[1]。隨著美羅培南在臨床上的廣泛應(yīng)用,相關(guān)肝損傷的報(bào)道日益增加[2]。藥物性肝損傷(drug-induced liver injury,DILI)是臨床上常見的嚴(yán)重藥物不良反應(yīng)之一[3],嚴(yán)重者可導(dǎo)致肝衰竭甚至死亡。因此,本研究通過(guò)回顧性病例對(duì)照研究探討美羅培南相關(guān)肝損傷(meropenem-related liver injury,MRLI)的影響因素,盡早評(píng)估用藥風(fēng)險(xiǎn),優(yōu)化美羅培南抗感染治療方案,提高用藥的安全性。
1 資料與方法
1.1 研究對(duì)象 選取2018年1月—2022年12月于十堰市人民醫(yī)院就診并使用美羅培南的住院患者。納入標(biāo)準(zhǔn):(1)年齡≥18歲;(2)用藥前后有完整的肝臟生化檢查;(3)用藥前未發(fā)生DILI。排除標(biāo)準(zhǔn):(1)其他引起肝功能異常的疾病,如脂肪肝、肝癌、病毒性肝炎、缺血/自身免疫性肝炎、酒精性肝病、惡性腫瘤等[4];(2)死亡病例;(3)臨床資料不完整病例。
1.2 研究方法
1.2.1 DILI的判定標(biāo)準(zhǔn) 根據(jù)《中國(guó)藥物性肝損傷診治指南(2023年版)》[4]中DILI的判定標(biāo)準(zhǔn),肝生化指標(biāo)滿足以下之一:(1)ALT≥5倍正常值上限(ULN);(2)ALP≥2×ULN;(3)ALT≥3×ULN且TBil≥2×ULN。
1.2.2 分組 對(duì)于滿足 DILI 判定標(biāo)準(zhǔn)的病例,采用RUCAM(Roussel Uclaf Causality Assessment Scale)評(píng)分系統(tǒng)評(píng)估肝損傷和美羅培南的因果關(guān)系。將RUCAM評(píng)分≥3分[5],因果關(guān)系評(píng)價(jià)結(jié)果為可能、很可能、極可能的病例作為病例組[6];未發(fā)生肝損傷的病例作為對(duì)照組。
1.2.3 資料收集 根據(jù)納入、排除標(biāo)準(zhǔn),建立中國(guó)醫(yī)院藥物警戒系統(tǒng)(China hospital pharmacovigilance system,CHPS)檢索方案[7],收集住院患者一般資料,包括性別、年齡、基礎(chǔ)疾病、既往史、聯(lián)合用藥、住院時(shí)長(zhǎng)等;實(shí)驗(yàn)室檢查資料,包括 ALT、AST、ALP、TBil、GGT、白蛋白、肌酐(CREA)、血小板計(jì)數(shù)(PLT)、白細(xì)胞計(jì)數(shù)(WBC)、C反應(yīng)蛋白(CRP)、降鈣素原(PCT)、血紅蛋白(HGB)、凝血酶原時(shí)間(PT)、國(guó)際標(biāo)準(zhǔn)化比值(INR)等。
1.3 統(tǒng)計(jì)學(xué)方法 使用SPSS 26.0進(jìn)行統(tǒng)計(jì)分析,非正態(tài)分布的計(jì)量資料以 M(P 25 ~P 75 )表示,兩組間比較采用Mann-Whitney U檢驗(yàn)。計(jì)數(shù)資料兩組間比較采用χ 2檢驗(yàn)。多因素分析采用二元Logistic回歸分析,利用受試者操作特征曲線(ROC曲線)對(duì)預(yù)測(cè)因子的敏感度、特異度以及最佳臨界值進(jìn)行分析。Plt;0.05為差異有統(tǒng)計(jì)學(xué)意義。
2 結(jié)果
2.1 CHPS 檢索病例 根據(jù)研究對(duì)象的納入和排除標(biāo)準(zhǔn),使用 CHPS建立檢索方案進(jìn)行初步檢索和篩選,對(duì)CHPS初步篩檢的4 456例患者進(jìn)行人工二次篩選,共納入研究對(duì)象1 625例,發(fā)生MRLI病例62例,作為病例組;未發(fā)生肝損傷的病例1 563例,作為對(duì)照組,詳見圖1。
2.2 單因素分析 病例組男性、低蛋白血癥、休克、入住ICU、合并膿毒癥和合并肝、膽、心血管疾病比率,以及ALT、ALP、GGT、AST、CREA、PCT水平和住院天數(shù)均高于對(duì)照組,PLT水平低于對(duì)照組,差異均有統(tǒng)計(jì)學(xué)意義(P值均lt;0.05)(表1)。其他指標(biāo)如年齡、飲酒史、過(guò)敏史、WBC等在兩組間差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值均gt;0.05)。
2.3 多因素Logistic回歸分析 以是否發(fā)生肝損傷為因變量,單因素分析中具有顯著性的變量作為自變量,納入多因素Logistic回歸分析,男性(OR=2.080,95%CI:1.050~4.123)、入住 ICU(OR=8.207,95%CI:4.094~16.453)、合并膽疾?。∣R=8.240,95%CI:3.605~18.832)、ALP(OR=1.012,95%CI:1.004~1.019)、GGT(OR=1.010,95%CI:1.005~1.015)、PLT(OR=0.997,95%CI:0.994~0.999)為肝損傷的獨(dú)立影響因素(P值均lt;0.05)(表2)。
2.4 建立 Logistic回歸方程 根據(jù)多因素 Logistic回歸分析結(jié)果,以性別、入住 ICU、合并膽疾病、ALP、GGT、PLT 6 個(gè)因素,建立邏輯回歸方程:Logit (P)=0.732X 1 +2.105X 2 +2.109X 3 +0.011X 4 +0.010X 5 -0.003X 6 -5.896,其中X 1 為性別;X 2 為入住ICU;X 3 為合并膽疾??;X 4 為ALP;X 5 為GGT;X 6 為PLT。對(duì)Logistic方程進(jìn)行等式變換,使X 1 的回歸系數(shù)為1,可得到聯(lián)合預(yù)測(cè)因子表達(dá)式,Y 聯(lián)合 =X 1 +2.876X 2 +2.881X 3 +0.015X 4 +0.014X 5 -0.004X 6 。
2.5 ROC曲線對(duì)MRLI的預(yù)測(cè)分析 分別以ALP、GGT、PLT 和聯(lián)合預(yù)測(cè)因子為檢驗(yàn)變量構(gòu)建 ROC 曲線,計(jì)算ROC曲線下面積(AUC)以評(píng)估其預(yù)測(cè)效能。聯(lián)合預(yù)測(cè)因子以及 ALP、GGT、PLT預(yù)測(cè)的 AUC分別為 0.837、0.589、0.637和0.595(表3)。與單一指標(biāo)相比,聯(lián)合預(yù)測(cè)的假陽(yáng)性值和假陰性值較低,敏感度和特異度較高。因此,聯(lián)合預(yù)測(cè)對(duì)MRLI發(fā)生風(fēng)險(xiǎn)具有較好的預(yù)測(cè)效果(圖2)。
3 討論
本研究通過(guò)多因素Logistic回歸分析得出,男性、入住 ICU、合并膽疾病、ALP 升高、GGT 升高、PLT 降低是MRLI的獨(dú)立影響因素。
性別對(duì)DILI的影響一直存在爭(zhēng)議。林良沫等[8]研究認(rèn)為性別對(duì)伏立康唑引起的相關(guān)肝損傷沒(méi)有顯著性影響;楊雪敏等[9]研究認(rèn)為,女性是抗結(jié)核藥物相關(guān)肝損傷的影響因素。但Zhong等[10]和Lin等 [11]研究認(rèn)為,男性發(fā)生 DILI的風(fēng)險(xiǎn)高于女性,是 DILI發(fā)生的影響因素。本研究發(fā)現(xiàn)男性是MRLI的影響因素。在使用美羅培南的患者中,男性發(fā)生肝損傷的風(fēng)險(xiǎn)是女性的2.08倍。研究顯示疾病嚴(yán)重程度也是 DILI 的危險(xiǎn)因素[12]。Yu等[12]在一項(xiàng)多中心回顧性研究中發(fā)現(xiàn),入住ICU是替加環(huán)素發(fā)生DILI的危險(xiǎn)因素。本研究發(fā)現(xiàn)患者入住ICU是MRLI的影響因素。臨床上,入住ICU的患者病情較嚴(yán)重,更容易出現(xiàn)缺血缺氧再灌注損傷、免疫損傷、全身炎癥反應(yīng)等,這些可增加DILI發(fā)生的風(fēng)險(xiǎn)[13]。多項(xiàng)研究表明,合并膽疾病是DILI的危險(xiǎn)因素。Eder等[14]研究發(fā)現(xiàn),膽囊疾病、膽管結(jié)石會(huì)增加DILI發(fā)生的風(fēng)險(xiǎn)。魏倩等[15]分析DILI的危險(xiǎn)因素,結(jié)果顯示,發(fā)生DILI的風(fēng)險(xiǎn)與膽囊疾病密切相關(guān)。本研究發(fā)現(xiàn),合并膽疾病是MRLI的影響因素,與上述研究結(jié)果一致。美羅培南的膽汁排泄率約為25%[16],該藥物或其代謝物需要通過(guò)膽道排泄,當(dāng)機(jī)體膽管損傷時(shí),可能引發(fā)炎癥反應(yīng),直接波及肝組織,造成膽汁淤積和肝細(xì)胞損傷[17]。MRLI多為膽汁淤積型肝損傷[2,18-19]。膽汁淤積與 ALP、GGT水平升高具有一定的關(guān)聯(lián)性[20]。吳雪嬌等[21]研究表明,ALP水平升高可增加DILI發(fā)生的風(fēng)險(xiǎn)。Lv等[22]研究發(fā)現(xiàn)ALP是他克莫司引起DILI的影響因素。GGT是臨床中常用的評(píng)價(jià)肝損傷程度和肝臟儲(chǔ)備功能的生化指標(biāo),與DILI密切相關(guān)。朱玉菡等[23]和賀毅等[24]研究顯示,GGT水平升高是誘發(fā)DILI的獨(dú)立危險(xiǎn)因素。本研究發(fā)現(xiàn),ALP、GGT水平升高是MRLI的影響因素。ALP在體內(nèi)隨膽汁排泄,ALP水平升高提示患者存在肝膽排泄系統(tǒng)功能障礙[25]。此外,ALP水平升高與氧化應(yīng)激有關(guān)[26]。肝臟在氧化應(yīng)激狀態(tài)下,導(dǎo)致氧自由基水平升高,機(jī)體抗氧化能力降低,體內(nèi)的生物大分子如蛋白質(zhì)、DNA、脂質(zhì)等可能受到不可逆損傷,導(dǎo)致細(xì)胞死亡而引起肝損傷[27]。這些都可能加重DILI發(fā)生的風(fēng)險(xiǎn)。GGT是體內(nèi)氧化應(yīng)激的標(biāo)志物,與體內(nèi)谷胱甘肽(glutathione,GSH)代謝有關(guān)[28]。GSH 是一種主要的抗氧化劑,具有保肝作用。
GGT 對(duì) GSH 的分解代謝可導(dǎo)致活性氧和自由基的產(chǎn)生[28]。因此,GGT水平升高可能導(dǎo)致體內(nèi)GSH水平降低,活性氧和自由基產(chǎn)生增加,增加 DILI發(fā)生的風(fēng)險(xiǎn)。
此外,根據(jù)ROC曲線中約登指數(shù)最大值計(jì)算得到GGT、ALP的最佳臨界值分別為43.05 U/L、116.5 U/L。高于此臨界值時(shí),發(fā)生MRLI的風(fēng)險(xiǎn)增加。在應(yīng)用美羅培南時(shí),應(yīng)密切監(jiān)測(cè)ALP、GGT等肝功能指標(biāo)。PLT與肝臟疾病的嚴(yán)重程度呈負(fù)相關(guān),可作為評(píng)估DILI的重要指標(biāo)[29]。張昭君等[30]和王巧玲等 [31]指出PLT水平降低是DILI發(fā)生的危險(xiǎn)因素。此外,耿俊玲等[32]報(bào)道,PLT水平升高是抗結(jié)核藥物發(fā)生DILI的保護(hù)因素。本研究發(fā)現(xiàn)PLT水平降低是MRLI的影響因素。肝損傷導(dǎo)致PLT在體內(nèi)合成減少[33],消耗增加 [34]。PLT的產(chǎn)生主要由血小板生成素(thrombopoietin,TPO)調(diào)節(jié),而TPO主要由肝臟分泌。肝損傷時(shí),TPO 分泌減少,導(dǎo)致 PLT 生成減少[33]。
肝損傷繼發(fā)的炎癥反應(yīng)也可以誘導(dǎo)內(nèi)皮細(xì)胞受損消耗PLT[34],進(jìn)一步引起 PLT 減少。因此,PLT 可作為預(yù)測(cè)DILI風(fēng)險(xiǎn)的指標(biāo)。根據(jù)ROC曲線分析,PLT的最佳臨界值為148.5×10 9 /L。低于此臨界值,MRLI發(fā)生的風(fēng)險(xiǎn)增加。在應(yīng)用美羅培南時(shí),密切觀察患者的PLT指標(biāo),及時(shí)采取措施,降低DILI發(fā)生的風(fēng)險(xiǎn)。
此外,一些研究顯示,DILI的危險(xiǎn)因素還有高齡、合并低蛋白血癥、基線ALT水平等[35-36],與本研究結(jié)果有差異,這可能與使用藥物的患者群體、使用藥物的種類、劑型等有關(guān)。
綜上所述,本研究回顧性收集4年內(nèi)使用美羅培南的住院病例數(shù)據(jù),通過(guò)單因素分析和多因素Logistic回歸分析發(fā)現(xiàn)男性、合并膽疾病、入住ICU、ALP升高、GGT升高和PLT降低是MRLI的獨(dú)立影響因素,聯(lián)合預(yù)測(cè)因子對(duì)MRLI發(fā)生風(fēng)險(xiǎn)具有較好的預(yù)測(cè)效果。此外,使用CHPS建立檢索方案,設(shè)置住院患者年齡、入院時(shí)間、出院時(shí)間以及檢查值,排除部分病例,初步篩選所需病例,提高了研究者工作效率。但本研究存在病例組樣本量較少的局限性,結(jié)果可能存在偏倚。因此,研究結(jié)果還需大樣本量以及使用其他醫(yī)院數(shù)據(jù)集進(jìn)行外部驗(yàn)證,以評(píng)估結(jié)果的準(zhǔn)確性。
倫理學(xué)聲明:本研究方案于2024年1月1日經(jīng)由十堰市人民醫(yī)院倫理委員會(huì)審批,批號(hào):SYSRMYY-018。
利益沖突聲明:本研究不存在任何利益沖突。
作者貢獻(xiàn)聲明:賀艷負(fù)責(zé)收集數(shù)據(jù)、資料分析、撰寫論文;柯洪琴負(fù)責(zé)參與收集數(shù)據(jù)、統(tǒng)計(jì)分析;李洪亮、朱建勇、趙利軍負(fù)責(zé)提供寫作建議、指導(dǎo)論文撰寫;于慧斌負(fù)責(zé)擬定寫作思路、指導(dǎo)撰寫、修改文章并最后定稿。
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收稿日期:2024-08-05;錄用日期:2024-10-10
本文編輯:王亞南
引證本文:HE Y, KE HQ, LI HL, et al. Influencing factors for meropenem-related liver injury and their predictive value[J].J Clin Hepatol, 2025, 41(3): 506-512.
賀艷, 柯洪琴, 李洪亮, 等. 美羅培南相關(guān)肝損傷的影響因素及其預(yù)測(cè)價(jià)值[J]. 臨床肝膽病雜志, 2025, 41(3): 506-512.