肝脏剪切波弹性成像联合GGT_

∗基金项目:湖南省卫生健康委科研计划项目(编号: C2019118)
作者单位:410006长沙市湖南师范大学附属长沙医院超声医学科
第一作者:赵景,男,43岁,医学硕士,主治医师㊂研究方向:从事介入超声诊治研究㊂E-mail:zhaochinajing@ ㊃病毒性肝炎㊃
肝脏剪切波弹性成像联合GGT/PLT比值诊断
慢性乙型肝炎患者肝纤维化价值研究∗
赵景,何秀波,谌瑾寰
㊀㊀ʌ摘要ɔ㊀目的㊀探讨肝脏超声剪切波弹性成像(SWE)联合γ-谷氨酰转肽酶(GGT)/血小板(PLT)比值(GPR)诊断慢性乙型肝炎(CHB)患者肝纤维化的效能㊂方法㊀2021年2月~2022年12月我院收治的CHB患者130例,均接受肝穿刺活组织检查㊂使用超声检测肝脏杨氏模量值,常规检测血清GGT和全血PLT计数,计算GGT/PLT比值㊂采用Kappa 检验分析各诊断方法与病理学诊断CHB患者肝纤维化结果的一致性,应用受试者工作特征曲线下面积(AUROCs)评估各指标诊断CHB患者肝纤维化的效能㊂结果㊀在130例CHB患者中,经肝组织学检查,诊断F0㊁F1㊁F2㊁F3和F4期肝纤维化分别93例㊁14例㊁8例㊁12例和3例,其中显著性肝纤维化23例;F3期肝纤维化患者GGT/PLT比值和杨氏模量值分别为0.5(0.4,0.7)和(10.4ʃ1.5)kPa,F2期分别为0.4(0.3,0.6)和(8.9ʃ1.6)kPa,均显著大于F1期[分别为0.4(0.3, 0.5)和(7.3ʃ1.2)kPa,P<0.05];经AUROCs分析结果显示,GGT/PLT比值㊁杨氏模量值或两者联合诊断CHB患者肝纤
维化与组织病理学诊断结果一致性较好(Kappa=0.42,Kappa=0.50和Kappa=0.63,P<0.05);应用GGT/PLT比值联合杨氏模量值诊断CHB患者显著性肝纤维化的AUC为0.83(95%CI:0.76~0.94),其灵敏度和特异度分别为83.8%和83.9%,显著优于两指标单一诊断(P<0.05)㊂结论㊀应用GGT/PLT比值和SWE检测辅助诊断CHB患者肝纤维化有一
定的临床价值,值得进一步探讨㊂
㊀㊀ʌ关键词ɔ㊀慢性乙型肝炎;肝纤维化;肝脏超声剪切波弹性成像;γ-谷氨酰转肽酶/血小板比值;诊断
㊀㊀DOI:10.3969/j.issn.1672-5069.2023.03.008
㊀㊀Early diagnosis of significant liver fibrosis by liver shear wave elastography and GGT/PLT ratio in patients with chronic hepatitis B㊀Zhao Jing,He Xiubo,Chen Jinhuan.Department of Ultrasound,Changsha Hospital Affiliated to Hunan Normal University,Changsha410006,Hunan Province,China
㊀㊀ʌAbstractɔ㊀Objective㊀The aim of this study was to investigate the diagnostic efficacy of significant liver fibrosis(SLF)by two-dimensional shear wave elastography(SWE)andγ-glutamyltransferase(GGT)/platelet(PLT)ratio(GPR)in patients with chronic hepatitis B(CHB).Methods㊀130patients with CHB were encountered in our hospital between February2021and December2022,and all underwent liver biopsy.The Young's modulus of livers was detected by SWE of ultrasonography,serum GGT levels and whole blood PLT counts were detected routinely,and the GPR was calculated.The consistency between the Young' s modulus and GPR and the pathological diagnosis was evaluated by Kappa test,and the diagnostic efficacy was assessed by the area under the receiver operating characteristic curve(AUROCs).Results㊀Out of the130patients with CHB,the liver histopathological examination showed F0,F1,F2,F3and F4in93cases,14cases,8cases,12cases and3cases,with SLF in 23cases;the GPR and the Young's modulus in patients with stage F3liver fibrosis were0.5(0.4,0.7)and(10.4ʃ1.5)kPa, and in patients with F2were0.4(0.3,0.6)and(8.9ʃ1.6)kPa,all significantly greater than[0.4(0.3,0.5)and(7.3ʃ1.2) kPa,respectively,P<0.05]in patients with F1;the AUROCs analysis showed the good consistency between the Young's modulus, GPR or the combination of the two parameters,and the pathological diagnosis(Kappa=0.42,Kappa=0.50and Kappa=0.63, respectively,P<0.05);the AUC was0.83(95%CI:0.76-0.94),with the sensitivity and the specificity of83.8%and83.9%
by the combination of GPR and Young's modulus in predicting
SLF in patients with CHB,much superior to that by any one of
the two alone(P<0.05).Conclusion㊀The GPR and the SWE
by ultrasonography might be applied to predict the SLF in
patients with CHB clinically,and warrants further investigation.
㊀㊀ʌKey wordsɔ㊀Hepatitis B;Liver fibrosis;Shear wave
elastography;γ-glutamyltransferase/platelet ratio;Diagnosis
㊀㊀慢性乙型肝炎(chronic hepatitis B,CHB)是影响全球公共卫生安全的肝病之一,发病率仍较高[1,2]㊂CHB患者反复或长期存在慢性肝实质性炎症,激活机体过度修复反应,诱导肝纤维组织增生,导致CHB 发展为肝纤维化和肝硬化㊂早期识别㊁监测和干预是改善患者预后的积极的研究方向㊂目前,经皮肝穿刺活检是诊断肝纤维化的金标准,但患者依从性差,反复进行有一定的困难[3,4]㊂γ-谷氨酰转肽酶(γ-glutamyltransferase,GGT)/血小板(platelet,PLT)比值(GPR)是评估肝功能的常用指标,可反映肝区病变进展状态,尤其在肝纤维组织增生修复过程中肝内合成功能亢进或胆汁排除受阻阶段,血清GGT 水平可呈现明显的升高状态㊂在CHB向肝硬化进展阶段,肝内门静脉压力逐渐升高,可引起脾脏充血肿大,导致脾功能亢进和血小板计数下降,进而导致GGT/PLT比值水平升高,但应用血液指标评估肝实质病变的准确性较差[5,6]㊂肝脏剪切波弹性成像(shear wave elastography,SWE)是无创性评估肝组织病变的影像学诊断方法,可有效反映肝实质性病变状态,但无法评估肝组织细胞损伤的微观状态㊂SWE与GGT/PLT比值可协同互补,用于临床诊断[7,8]㊂本研究以组织病理学检查为金标准,分析了SWE联合GGT/PLT比值诊断CHB患者肝纤维化的价值,现报道如下㊂
1㊀资料与方法
1.1一般资料㊀2021年2月~2022年12月我院收治的CHB患者130例,女性45例,男性85例;年龄为32~62岁,平均年龄为(37.13ʃ5.79)岁㊂诊断符合中华医学会感染病学分会和肝病学分会修订的‘慢性乙型肝炎防治指南(2019年版)“[9]的标准㊂排除标准:(1)酒精性肝病㊁药物性肝损伤㊁自身免疫性肝病或遗传代谢性肝病;(2)肝硬化;(3)肝脏恶性肿瘤;(4)妊娠或哺乳期妇女;(5)合并心脑血管疾病㊂本研究经我院医学伦理委员会审核㊁通过,患者签署知情同意书㊂
1.2血清和血液指标检查㊀使用美国贝克曼库尔特公司生产的AU5800型全自动生化分析仪检测血清GGT(上海艾博生物科技有限公司);常规检测全血PLT计数(上海钦诚生物科技有限公司),计算GGT/ PLT比值=(GGT/正常参考值上限U/L)ˑ100/PLT 计数(ˑ109/L)[10]㊂
1.3SWE检查㊀使用上海寰熙医疗器械有限公司生产的LOGIQ型超声诊断仪及其配套设备完成SWE 检查,探头频率为1~6MHz㊂患者取仰卧位,上肢抬高至头部,充分暴露肝区㊂常规使用二维超声检查确定肝脏病变,切换SWE模式㊂嘱患者屏气3s,完成检查㊂选择感兴趣区(region of interest,ROI),测量评估肝组织硬度的杨氏模量值,有效测量5次,取中位测量值㊂
1.4肝活检㊀常规皮肤消毒㊁局部麻醉,在超声定位后,远离大血管位置,在超声引导下行经皮肝脏穿刺活检术,采集长度约2cm的肝组织,在10%中型甲醛溶液中固定,送病理科检查㊂常规行石蜡包埋㊁HE染色和网状纤维染色㊂诊断符合‘肝纤维化中西医结合诊疗指南(2019年版)“[11]的标准㊂
1.5统计学分析㊀应用SPSS Statistics26.0软件行统计学分析,对正态分布的计量资料以(xʃs)表示,采用t检验㊂对偏态分布的计量资料以M(P25, P75)表示,采用Mann-Whitney U检验㊂计数资料以%表示,采用x2检验㊂应用MedCalc15.1统计学软件绘制受试者工作特征曲线,计算曲线下面积(AUROCs),采用Z检验㊂采用Kappa检验分析各诊断方法的一致性(Kappa值ɤ0.400,提示一致性程度低;0.400<Kappa值<0.700,提示一致性程度中等;Kappa值ȡ0.700提示一致性程度高)㊂P<0.05提示差异有统计学意义㊂
2㊀结果
2.1病理学诊断情况㊀在130例CHB患者中,经肝组织学检查,诊断F0㊁F1㊁F2㊁F3和F4期肝纤维化分别93例㊁14例㊁8例㊁12例和3例,其中显著性肝纤维化23例㊂
2.2不同肝纤维化分期的CHB患者GGT/PLT比值和杨氏模量值比较㊀F4/F3/F2期肝纤维化患者GGT/PLT比值和杨氏模量值显著大于F1期或无肝纤维化患者,差异有统计学意义(P<0.05,表1)㊂2.3GGT/PLT比值和杨氏模量值与病理学诊断的一致性分析㊀经AUROCs分析,确定两指标的最佳截断点,结果显示,GGT/PLT比值㊁杨氏模量值或两者联合诊断CHB患者肝纤维化与组织病理学诊断结果一致性较好(Kappa=0.42,Kappa=0.50和Kappa= 0.63,P<0.05)㊂
2.4GGT/PLT比值和杨氏模量值诊断CHB患者肝纤维化的效能情况㊀经AUROCs分析显示,GGT/ PLT比值联合杨氏模量值诊断CHB患者显著性肝纤维化的效能显著优于单一指标诊断(P<0.05,表2㊁图1)㊂
表1㊀不同肝纤维分期患者GGT/PLT比值和杨氏模量值[M(P25,P75),(xʃs)]比较
肝纤维化例数GGT(U/L)PLT(ˑ109/L)GGT/PLT比值杨氏模量值(kPa) F4期393(83,107)①②③④151.2ʃ34.10.6(0.5,0.8)①②③④11.7ʃ1.9①②③④F3期1287(77,92)①②③170.3ʃ34.90.5(0.4,0.7)①②③10.4ʃ1.5①②③F2期863(60,77)①②171.8ʃ35.10.4(0.3,0.6)①②8.9ʃ1.6①②
F1期1467(54,72)①183.7ʃ36.20.4(0.3,0.5)①7.3ʃ1.2①
F0期9362(57,67)196.6ʃ40.10.3(0.2,0.5) 6.1ʃ1.3
㊀㊀与F0期肝纤维化组比,①P<0.05;与F1期比,②P<0.05;与F2期比,③P<0.05;与F3期比,④P<0.05
表2㊀GGT/PLT比值和杨氏模量值诊断CHB患者肝纤维化的效能情况
截断点AUC95%CI灵敏度(%)特异度(%) GGT/PLT比值0.40.740.64~0.8670.375.3杨氏模量值8.7(kPa)0.750.65~0.8568.983.9
两者联合-0.830.76~0.9483.883.
9
图1㊀GGT/PLT比值和杨氏模量值诊断
CHB患者肝纤维化的AUROCs分析
3㊀讨论
肝纤维化是CHB向肝硬化过渡过程中的可逆性病变㊂完善CHB患者肝纤维化的监测诊断对改善患者预后具有重要的价值[12]㊂经皮肝活检作为目前诊断肝纤维化的金标准,虽具有较高的灵敏度和特异度,但患者依从性差㊂因此,开展无创性诊断肝纤维化的方法是近些年研究的热点㊂目前,针对肝纤维的无创性诊断主要集中在血液和影像学相关指标的研究㊂相关研究报道[13,14],虽然血液指标可评估CHB向肝纤维化进展及肝纤维化病变进展的严重程度,但机体其他炎症反应或应激创伤等同样可能引起血液指标的波动,且缺乏对肝脏实质性病变的客观判断㊂影像学检查常用于各类肝病的辅助诊断,能够客观评价肝区实质性病变[15]㊂因此,筛选并联合高敏性的影像学诊断和血液指标检测方法,将有助于提高CHB患者肝纤维化的准确诊断㊂SWE作为影像学诊断的常用方法,运用弹性成像技术,通过发射多点聚焦的声辐射力脉冲,获取肝
脏组织的剪切波图像,以杨氏模量值的形式表述,诊
断方法简便且快速㊂早期研究结果显示,在肝硬化
背景下SWE对肝实质内良恶性结节的辅助鉴别诊
断有帮助[16,17]㊂以肝活检病理学诊断为金标准,应用声辐射力脉冲成像技术诊断肝纤维化有较高的效
能[18]㊂相对于瞬时弹性成像技术,SWE取代了专用设备,弥补了部分基层医院单位设备不全的缺陷,临床应用前景优越㊂GGT/PLT比值则是评估CHB患者病情的血液学指标㊂应用GGT/PLT比值诊断CHB患者肝组织纤维化分期表现最佳,其AUROCs 为0.683[19]㊂本研究选择SWE联合GGT/PLT比值作为诊断CHB患者肝纤维化的影像学和血液指标,结果显示,随着肝纤维化程度的加重(病理学分期F0~F4),患者GGT㊁GGT/PLT比值和杨氏模量值呈升高趋势,表明随着肝纤维化程度的增加,CHB患者这些指标发生了相应的变化,而杨氏模量值升高更为明显㊂研究分析CHB患者经SWE检查获得的杨氏模量值升高可能与肝纤维化后导致肝脏组织性质改变有关㊂随着肝纤维化程度的加重,导致肝组织应力和应变差距增加,从而导致杨氏模量值升高[20]㊂随着肝纤维化程度的加重,可导致肝胆系统功能失衡,胆汁无法正常排除,进而引起GGT水平升高㊂本研究经AUROCs分析结果显示,GGT/PLT 比值和杨氏模量值在CHB患者肝纤维化的诊断效能均较高,且两者联合诊断效能高于单一指标诊断,进一步表明GGT/PLT比值和SWE检查可用于预测CHB患者肝纤维化程度,且联合诊断效能更高㊂此
外,为进一步比较GGT/PLT比值和杨氏模量值诊断CHB患者肝纤维化的结果与病理学诊断的一致性,本研究对各指标诊断CHB患者肝纤维化的Kappa 一致性分析发现,GGT/PLT比值和SWE单一或联合诊断CHB患者肝纤维化与病理学诊断的Kappa值均>0.4,进一步提示GGT/PLT比值和SWE在CHB 患者肝纤维化诊断方面效能良好㊂
本研究存在一些不足之处,本研究为单中心研究,血清GGT水平和血小板计数变异比较大,可能影响了结果分析㊂后续研究仍需完善多中心大样本随机对照试验以佐证本研究结论,完善CHB患者肝纤维化无创诊断方法的可信性㊂
综上所述,应用GGT/PLT比值和SWE可用于辅助诊断CHB患者肝纤维化程度,且联合诊断效能更高,有一定的临床应用前景㊂
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(收稿:2023-02-27)
(本文编辑:陈从新)。