瞬时超声弹性成像联合GGT

∗基金项目:江苏省医学会介入医学科研专项基金资助项目[苏医会科便函(2021)020号]
作者单位:226600江苏省海安市南通大学附属海安医院超声科(刘爱华,符建);第二附属医院超声科(陈小红)
第一作者:刘爱华,女,40岁,大学本科,主治医师㊂研究方向:心脏超声和腹部超声诊断研究㊂E-mail:liuaihua15851@ ㊃病毒性肝炎㊃
瞬时超声弹性成像联合GGT/PLT比值预测慢性乙型肝炎患者肝纤维化价值研究∗
刘爱华,符建,陈小红
㊀㊀ʌ摘要ɔ㊀目的㊀研究应用肝脏硬度检测(LSM)联合血清谷氨酰转肽酶(GGT)/血小板计数(PLT)比值(GPR)预测
慢性乙型肝炎(CHB)患者肝纤维化的价值㊂方法㊀2019年2月~2021年2月我院诊治的175例CHB患者,均接受核苷(酸)类抗病毒治疗,行肝活检了解肝纤维化情况,常规检测血清层粘连蛋白(LN)㊁透明质酸酶(HA)㊁Ⅲ型前胶原(PCⅢ)和Ⅳ型胶原(Ⅳ-C),检测血生化指标和血常规,计算GPR㊂使用Fibroscan行LSM检测㊂应用Logistic回归分析影响肝纤维化发生的因素,应用受试者工作特征(ROC)及曲线下面积(AUC)评估LSM联合GPR预测显著性肝纤维化的价值㊂结果㊀在175例CHB患者中,组织病理学检查发现显著性肝纤维化者25例(F2期10例,F3期9例,F4期6例),无或轻微肝纤维化者150例(F0期138例,F1期12例);F1期㊁F2期㊁F3期和F4期CHB患者LSM分别为(5.3ʃ1.1)kPa㊁(10.6ʃ2.3) kPa㊁(14.1ʃ3.4)kPa和(19.3ʃ4.1)kPa,GPR分别为(0.2ʃ0.1)㊁(0.3ʃ0.1)㊁(0.4ʃ0.1)和(0.5ʃ0.1),组间差异显著(P<
0.05);显著性肝纤维化组血清天冬氨酸氨基转移酶㊁丙氨酸氨基转移酶㊁PCⅢ㊁Ⅳ-C㊁HA水平及LSM和GPR分别为
(69.3ʃ6.4)U/L㊁(87.4ʃ7.1)U/L㊁(17.6ʃ3.2)ng/ml㊁(19.2ʃ3.4)ng/ml㊁(96.2ʃ9.9)ng/ml㊁(14.9ʃ3.7)kPa㊁(0.4ʃ
0.1),均显著高于非显著性肝纤维化组ʌ分别为(31.2ʃ5.4)U/L㊁(31.1ʃ4.5)U/L㊁(10.2ʃ2.0)ng/ml㊁(13.4ʃ2.4)ng/ml㊁
(52.8ʃ8.9)ng/ml㊁(5.9ʃ1.1)kPa和(0.2ʃ0.1),P<0.05ɔ;经Logistic回归分析,结果表明Ⅳ-C㊁HA及LSM和GPR均为
发生显著性肝纤维化的影响因素(P<0.05);经ROC分析显示,LSM和GPR预测显著性肝纤维化截断点分别为10.4kPa 和0.3,两组联合预测的AUC为0.975,其灵敏度为76.0%,特异度为98.0%㊂结论㊀对于接受抗病毒治疗的CHB患者,检测LSM和计算GPR能够预测肝纤维化程度,值得进一步研究㊂
㊀㊀ʌ关键词ɔ㊀慢性乙型肝炎;肝纤维化;肝脏硬度检测;谷氨酰转肽酶/血小板计数比值;诊断
㊀㊀DOI:10.3969/j.issn.1672-5069.2023.05.008
㊀㊀Predicting performance of liver stiffness measurement and GGT/PLT ratio combination in judging liver fibrosis in patients with chronic hepatitis B㊀Liu Aihua,Fu Jian,Chen Xiaohong.Department of Ultrasound,Hai'an Hospital Affiliated to Nantong University,Hai'an226600,Jiangsu Province,China
㊀㊀ʌAbstractɔ㊀Objective㊀The aim of this study was to investigate the predicting performance of liver stiffness measurement (LSM)and serum glutamyl transpeptidase(GGT)/platelet(PLT)ratio combination in judging liver fibrosis(LF)in patients with chronic hepatitis B(CHB).Methods㊀A total of one hundred and seventy-five patients with CHB were encountered in our hospital between February2019and February2021,and all patients had received nucleos(t)ides for antiviral therapy.The liver biopsies were performed and the LF was determined by METAVIR scoring system,the LSM was obtained by transient ultrasound elastography(FibroScan)and the GGT/PLT ratio was culculated.Serum laminin(LN),hyaluronidase(HA),typeⅢprocollagen(PCⅢ)andⅣ-collagen levels were detected routinely.The multivariate Logistic analysis was applied to reveal the impacting factors for LF,and the area under the receiver operating characteristic curve(AUC)was applied to predict the efficacy of LSM and GGT/PLT ratio for the diagnosis of LF.Results㊀Out the175patients with CHB,the liver histopathological examination showed significant LF in25cases(F2in10cases,F3in9cases and F4in6cases),and non-or minor-LF in150cases(F0in138 cases,F1in12cases);the LSMs in patients with F1,F2,F3and F4were(5.3ʃ1.1)kPa,(10.6ʃ2.3)kPa,(14.1ʃ3.4)kPa
and(19.3ʃ4.1)kPa,and the GPRs were(0.2ʃ0.1),(0.3ʃ
0.1),(0.4ʃ0.1)and(0.5ʃ0.1),significantly different
among them(P<0.05);serum AST,ALT,PCⅢ,Ⅳ-C,HA
levels and LSM and GPR in patients with significant LF were
(69.3ʃ6.4)U/L,(87.4ʃ7.1)U/L,(17.6ʃ3.2)ng/ml,
(19.2ʃ3.4)ng/ml,(96.2ʃ9.9)ng/ml,(14.9ʃ3.7)kPa and
(0.4ʃ0.1),all much higher than[(31.2ʃ5.4)U/L,(31.1ʃ
4.5)U/L,(10.2ʃ2.0)ng/ml,(13.4ʃ2.4)ng/ml,(52.8ʃ8.9)ng/ml,(
5.9ʃ1.1)kPa and(0.2ʃ0.1),respectively,P< 0.05]in patients without significant LF;the multivariate Logistic analysis showed that serumⅣ-C and HA levels as well as the LSM and the GPR were all the independent risk factors for significant LF(P<0.05);the ROC analysis demonstrated that the AUC was0.975,with the sensitivity of7
6.0%and the specificity of98.0%,when the LSM,with the cut-off value of10.4kPa,and the GPR,with the cut-off value of0.3,combination was applied to predict the significant LF.Conclusion㊀As for the patients with CHB receiving nucleos(t)ides therapy,the LSM and GPR combination might predict significant LF,and warrants further clinical validation.
㊀㊀ʌKey wordsɔ㊀Hepatitis B;Liver fibrosis;Liver stiffness measurement;Glutamyl transpeptidase/platelet ratio;Diagnosis
㊀㊀慢性乙型肝炎(CHB)是由乙型肝炎病毒(HBV)感染所致的慢性肝脏传染性疾病,具有易传染㊁传染途径复杂和病情迁延的特征,临床多采用常规抗病毒治疗,但随着病情的发展,CHB患者容易形成肝纤维化,最终发展为肝硬化,严重威胁患者的生命安全[1,2]㊂因此,准确预测和控制肝纤维化的发生和进展对治疗方案的调整及预后的改善具有重大意义㊂瞬时超声弹性成像(FibroScan)是无创诊断肝纤维化的重要方法,已被2015年中国‘慢性乙型肝炎防治指南“推荐使用[3]㊂有学者研究表明,谷氨酰转肽酶(GGT)/血小板(PLT)计数比值(GPR)对肝纤维化程度的诊断效能已经接近,甚至超过临床广泛关注的血清学无创诊断模型天门冬氨酸氨基转移酶/血小板比值指数(APRI)或基于4因子指数(FIB -4)[4,5]㊂本研究旨在探讨使用FibroScan联合GPR 预测CHB患者肝纤维化程度的效能,现报道如下㊂1㊀资料与方法
1.1病例来源㊀2019年2月~2021年2月我院收治的CHB患者175例,男性101例,女性74例;年龄为25~59岁,平均年龄为(36.9ʃ5.4)岁㊂符合‘慢性乙型肝炎防治指南(2019年版)“的诊断标准[6],纳入患者均常规应用核苷(酸)类抗病毒药物治疗, 1个月内未服用过降酶药㊂排除标准:酒精性肝病㊁其他(甲型㊁丙型)病毒性肝炎或药物性肝损害㊁合并脂肪肝㊁失代偿期肝硬化㊁原发性肝癌或肝转移癌㊁合并自身免疫性疾病或血液系统疾病㊁合并艾滋病㊁妊娠或哺乳期妇女㊁肋间隙狭窄无法进行肝脏弹性检测㊂患者签署知情同意书,本研究经我院医学伦理委员会批准㊂
1.2检测与检查㊀采集空腹静脉血,分离血清㊂采用酶促化学发光免疫分析法检测血清层粘连蛋白(LN)㊁透明质酸酶(HA)㊁Ⅲ型前胶原(PCⅢ)和Ⅳ型胶原(Ⅳ-C);使用美国Beckman全自动生化分析仪检测血生化指标(北京科美生物医学有限公司);使用美国Beckman coulter血细胞分析仪检测血常规,计算GPR=(GGT/ULN)ˑ100/PLT(ˑ109/L);使用美国ABI7300荧光定量PCR仪检测血清HBV DNA(中山大学达安基因股份有限公司);使用法国Echosens公司生产的Fibroscan行肝脏硬度检测(LSM),即选择右侧腋前线至腋中线7~9肋间,测量10次,取均值,成功率>60%㊂
1.3肝活检㊀经凝血功能和腹部超声检查,符合肝穿刺活检条件㊂在超声引导下进行经皮肝穿刺活检,常规消毒,局部麻醉,使用18G活检针穿刺活检㊂将取得的肝组织置于甲醛溶液中固定㊁石蜡包埋, 4μm切片,行HE染色㊂根据Metavir半定量评分系统[7]对肝纤维化分期进行评估,其中F0期为无纤维化;F1期为汇管区纤维化扩大,局限在窦周及小叶内纤维化;F2期为汇管区周围纤维化,形成纤维隔,保留小叶结构;F3期为形成纤维隔,小叶结构紊乱,但无肝硬化;F4期为早期肝硬化㊂
1.4统计学方法㊀应用IBM SPSS Statistics24.0软件行统计学分析,计数资料以n(%)表示,行x2检验;计量资料以(xʃs)表示,组间比较采用独立样本t检验,多组间比较采用单因素方差分析;应用Logistic回归分析影响肝纤维化的因素;应用受试者工作特征(ROC)曲线及曲线下面积(AUC)评估LSM 和GPR联合检测预测肝纤维化的效能㊂P<0.05表示差异有统计学意义㊂
2㊀结果
2.1肝组织学检查情况㊀经肝组织病理学检查显示,在175例CHB患者中未发生肝纤维化者(F0期)138例,F1期12例,F2期10例,F3期9例,F4期6例㊂2.2不同肝纤维化分期的CHB患者LSM和GPR比较㊀随着肝纤维化程度加重,LSM和GPR呈逐渐升高趋势,组间差异显著(P<0.05,表1)㊂
表1㊀不同肝纤维化分期CHB患者LSM和GPR(xʃs)比较例数LSM(kPa)GPR
F0138 5.1ʃ0.60.2ʃ0.1
F112 5.3ʃ1.10.2ʃ0.1
F2期1010.6ʃ2.30.3ʃ0.1
F3期914.1ʃ3.40.4ʃ0.1
F4期619.3ʃ4.10.5ʃ0.1
F65.85747.256
P<0.001<0.0012.3两组一般资料比较㊀显著性肝纤维化组血清AST㊁ALT㊁PCⅢ㊁Ⅳ-C㊁HA㊁LSM和GPR水平均显著高于非显著性肝纤维化组(P<0.05,表2)㊂
2.4影响肝纤维化的多因素分析㊀以血清AST㊁ALT㊁PCⅢ㊁Ⅳ-C㊁HA及LSM和GPR为自变量(均为连续变量),以是否发生显著性肝纤维化为因变量(是=1,否=0),将它们纳入多因素Logistic回归分析,结果表明血清Ⅳ-C㊁HA及LSM和GPR为发生显著性肝纤维化的影响因素(P<0.05,表3)㊂
表2㊀不同肝纤维化的CHB患者一般资料(xʃs)比较
显著性(n=25)非显著性(n=150)t/x2值P值HBV DNA(lg copies/ml) 1.1ʃ0.2 1.0ʃ0.2 1.6700.097 AST(U/L)69.3ʃ6.431.2ʃ5.417.388<0.001 ALT(U/L)87.4ʃ7.131.1ʃ4.513.281<0.001 PCⅢ(ng/ml)17.6ʃ3.210.2ʃ2.017.224<0.001Ⅳ-C(ng/ml)19.2ʃ3.413.4ʃ2.411.869<0.001 LN(ng/ml)92.7ʃ11.586.2ʃ9.1 1.8350.101 HA(ng/ml)96.2ʃ9.952.8ʃ8.97.939<0.001 LSM(kPa)14.9ʃ3.7 5.9ʃ1.117.301<0.001 GPR0.4ʃ0.10.2ʃ0.1 5.402<0.001
表3㊀影响显著性肝纤维化发生的多因素分析
影响因素βSE Wald x2P OR95%CI
Ⅳ-C0.9210.436 4.4620.032 2.512 1.104~5.714 HA 1.1230.31212.955<0.001 3.074 1.351~6.993 LSM 1.2450.35812.094<0.001 3.473 1.527~7.900 GPR 1.1030.29613.886<0.001 3.013 1.325~6.854 2.5LSM和GPR联合检测预测肝纤维化的效能情况
㊀经ROC分析显示,LSM联合GPR预测接受抗病
毒治疗的CHB患者肝纤维化的效能显著优于两指
标单独预测(图1㊁表4)㊂
图1㊀LSM联合GPR检测预测肝纤维化的ROC曲线
表4㊀LSM联合GPR预测CHB患者肝纤维化的效能
截断点AUC95%CI灵敏度(%)特异度(%) LSM10.4kPa0.9450.901~0.97488.0(22/25)92.7(139/150) GPR0.30.9140.863~0.95180.0(20/25)91.3(137/150)联合检测-0.9750.940~0.99376.0(19/25)98.0(147/150)
3㊀讨论
据流行病学调查显示,我国急性乙型肝炎发病率逐渐降低,但慢性乙型肝炎发病一直持续[7]㊂CHB患者肝组织细胞能分泌大量的胶原纤维并沉积
于肝组织内,从而发生早期纤维化,此时尚可逆转㊂随着肝纤维化的不断进展,肝组织内会形成假小叶,则进入肝硬化期,此时则不可逆转[8,9]㊂因此,临床精确评估肝纤维化的发生发展对CHB患者的预后评估具有关键的作用,越早期预测肝硬化的发生,越能够为临床防治提供有利的依据和时间,从而最大可能地维持患者生命健康[10]㊂
近年来,国内外学者均致力于肝纤维化评估系统的研究,其中肝脏硬度是目前受到广泛关注的无创诊断方法[11,12]㊂GPR是最新的肝纤维化预测指标,为血清GGT水平与血PLT计数的比值[13]㊂本研究对两者进行了评估分析,结果显示随着肝纤维
化程度的加重,LSM和GPR呈逐渐升高趋势㊂显著
性肝纤维化组LSM和GPR均显著高于非肝纤维化
组,经Logistic回归分析,结果表明LSM和GPR均为
发生肝纤维化的影响因素(P<0.05)㊂FibroScan是
根据声波传导速率和组织硬度相关性,采用切变弹
性探测仪对慢性肝炎患者进行肝脏瞬时弹性测定,
以LSM表示其测量结果㊂LSM值越大,提示肝纤维
化程度越严重,且具有无创无痛㊁快速客观的优
势[14,15]㊂其中GGT是反映肝功能变化的指标,与肝脏组织的损伤具有一定的关联性,其水平会随着慢
性肝脏疾病炎症和纤维化的加重呈逐渐升高趋
势[16,17]㊂同时,CHB患者肝脏炎症及纤维化程度的加重会导致门静脉高压的发生,而PLT在肿大的脾脏中会遭到破坏,导致PLT数量逐渐降低,与纤维化程度密切相关[18,19]㊂因此,LSM和GGT/PLT比值则会随着肝纤维化分期的加重呈逐渐升高趋势,可作为诊断肝纤维化的指标㊂本研究通过绘制ROC曲线对两者联合预测CHB患者肝纤维化发生进行了评估,结果显示,LSM联合GPR预测显著性肝纤维化的AUC为0.975,其特异度显著高于两指标单独预测㊂临床上,对于正在接受抗病毒治疗的CHB患者,通过联合监测LSM和GPR,可对肝纤维化情况进行早期和连续评估,将有助于临床治疗措施的改进及预防措施的制定,从而控制肝纤维化的进展,有助于促进患者病情的恢复,提高生活质量[20]㊂但本研究仍有一定的不足之处,未调查患者接受抗病毒治疗的时间,不清楚不同抗病毒治疗时间的患者是否影响了获得的研究数据的真实性㊂
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(收稿:2022-08-29)
(本文编辑:陈从新)。