∗基金项目:广东省科技厅科研基金资助项目(编号: 2021JH03102)作者单位:518052广东省深圳市华中科技大学协和深圳医院超声科第一作者:彭玉静,女,36岁,大学本科,主治医师㊂E-mail: pyj552@ ㊃病毒性肝炎㊃应用超声评分联合STE/STQ定量检测肝脏硬度评估慢性乙型肝炎患者肝纤维化程度价值研究∗彭玉静,郭航,陈俊光㊀㊀ʌ摘要ɔ㊀目的㊀探讨应用声触诊弹性成像(STE)和声触诊弹性测量(STQ)参数联合超声评分评估慢性乙型肝炎(CHB)患者肝纤维化程度的价值㊂方法㊀2020年1月~2022年12月我院诊治的106例CHB患者,均行肝活检病理学检查,以肝组织肝纤维化Metavir分期为F2及以上为显著性肝纤维化㊂分别使用STE和STQ行肝脏硬度测量(LSM),使用二维超声图像评估肝纤维化超声评分㊂应用受试者工作特征(ROC)曲线评估指标诊断显著性肝纤维化的效能㊂结果㊀在106例CHB患者中,肝组织病理学检查ȡF2期肝纤维化者62例,<F2期者44例;显著性肝纤维化者LSM STE㊁LSM STQ和LSM超声分别为(12.7ʃ2.2)kPa㊁(13.3ʃ2.3)kPa和(10.5ʃ2.2)分,均显著大于无显著性肝纤维化者ʌ分别为(9.2ʃ2.1) kPa㊁(8.9ʃ1.7)kPa和(7.2ʃ1.3)分,均P<0.05ɔ;ROC曲线分析显示,LSM STE㊁LSM STQ和LSM超声诊断CHB患者显著性肝纤维化的AUC分别为0.869(95%CI为0.803~0.935)㊁0.809(95%CI为0.728~0.891)和0.767(95%CI为0.679~ 0.855),其截断点分别为11.6kPa㊁11.9kPa和8.7分,而三者联合诊断的效能显著优于单一指标诊断(其AUC为0.949, 95%CI为0.912~0.986,P<0.05)㊂结论㊀应用LSM联合诊断CHB患者显著性肝纤维化的效能较高,作为无创诊断方法,值得临床进一步验证㊂㊀㊀ʌ关键词ɔ㊀慢性乙型肝炎;肝纤维化;超声;声触诊弹性成像;声触诊弹性测量;诊断㊀㊀DOI:10.3969/j.issn.1672-5069.2024.03.007㊀㊀Liver fibrosis assessment by US elastography in patients with chronic hepatitis B㊀Peng Yujing,Guo Hang,Chen Junguang.Department of Ultrasound,Union Hospital,Affiliated to Huazhong University of Science and Technology,Shenzhen 518052,Guangdong Province,China㊀㊀ʌAbstractɔ㊀Objective㊀The aim of this study was to investigate the diagnostic performance of sound touch elastography (STE)and sound touch quantify(STQ)combined with ultrasound(US)score for assessment of liver fibrosis in patients with chronic hepatitis B(CHB).Methods㊀106patients with CHB were enrolled in our hospital between January2020and December 2022,and they all underwent liver biopsies for the assessment of liver fibrosis Metavir staging(ȡF2as significant liver fibrosis). The liver stiffness measurement(LSM)was obtained by STE and STQ.The ultrasound score for liver fibrosis was calculated according to the two-dimensional ultrasonography.The receiver operating characteristic(ROC)curve was applied to assess the diagnostic efficacy of US parameters.Results㊀Among the106patients with CHB,theȡF2liver fibrosis were found in62cases and<F2(no significant liver fibrosis)in44cases;the LSM STE,LSM STQ and LSM U S in patients with significant liver fibrosis were (12.7ʃ2.2)kPa,(13.3ʃ2.3)kPa and(10.5ʃ2.2),all significantly greater than[(9.2ʃ2.1)kPa,(8.9ʃ1.7)kPa and(7.2ʃ1.3),respectively,all P<0.05]in patients without significant liver fibrosis;the ROC analysis showed that the AUCs were0.869 (95%CI:0.803-0.935),0.809(95%CI:0.728-0.891)and0.767(95%CI:0.679-0.855),when the LSM STE,LSM STQ and LSM U S were applied for predicting the significant liver fibrosis,and the diagnostic performance of the three parameter combination was much superior to any one of them(the AUC was0.949,with the95%CI of0.912-0.986,P<0.05).Conclusion㊀The combination of LSM STE,LSM STQ and LSM US is greatly efficacious in predicting significant liver fibrosis in patients with CHB,and as a non-invasive diagnosis,it is worthy of further clinical verification.㊀㊀ʌKey wordsɔ㊀Hepatitis B;Liver fibrosis;Ultrasonography;Sound touch elastography;Sound touchquantify;Diagnosis㊀㊀慢性乙型肝炎(chronic hepatitis B,CHB)可进展为肝硬化和肝细胞癌㊂肝纤维化是肝脏对慢性损伤的病理性修复反应,也是CHB进展为肝硬化过程的重要病理学改变[1]㊂组织学上,肝纤维化具有可逆性,但进一步发展引起肝小叶结构紊乱㊁肝细胞结节性再生,形成肝硬化的假小叶结构,则难以逆转,故明确CHB患者肝纤维化程度是制定诊疗方案的关键[2]㊂病理学检查是诊断肝纤维化程度的金标准,但系创伤性检查,应用受限㊂超声作为无创性诊断工具,常规二维超声也可通过观察肝实质和肝被膜回声等特征,计算超声评分,评估纤维化程度[3]㊂弹性超声成像是评估组织硬度的新技术,其中声触诊弹性测量(sound touch quantify,STQ)可利用剪切波传导信号,定量评估肝组织硬度[4]㊂声触诊弹性成像(sound touch elastography,STE)则是以二维剪切波弹性成像为基础的新成像技术,能形成直观的㊁彩色编码的弹性图像,较STQ技术能采集到更多的数据,检测结果也更稳定[5]㊂本研究使用超声无创性检查,采用超声评分与STE和STQ联合测量评估CHB 患者肝纤维化程度,现将结果报道如下㊂1 资料与方法1.1一般资料㊀2020年1月~2022年12月我院诊治的CHB患者106例,男性77例,女性29例;年龄为27~62岁,平均年龄为(39.7ʃ5.4)岁㊂符合‘慢性乙型肝炎防治指南(2019年版)“[6]诊断标准㊂纳入患者检查前未行抗肝纤维化治疗㊂排除标准:⑴合并其他肝炎病毒或人类免疫缺陷病毒感染;⑵合并自身免疫性肝炎㊁酒精性肝病㊁肝脏肿瘤等其他肝病;⑶合并慢性充血性心力衰竭等引起肝脏淤血性疾病;⑷中度及以上脂肪肝;⑸既往有肝脏介入治疗或手术治疗史㊂1.2超声检查㊀使用迈瑞Renas7彩色多普勒超声诊断仪,探头频率为3.5~5.0MHz㊂检查时,嘱患者仰卧位,右上肢抬至头顶,充分暴露肝区㊂使用二维超声观察肝脏内部回声,接着嘱患者深吸气,将腹部鼓起并屏气以配合扫查㊂参考超声二维图像肝纤维化评分法[7],根据肝脏二维超声特点计分:肝实质回声(光点均匀㊁细腻为1分,回声增强且不均匀㊁粗糙为2分,呈小结节状或斑片状为3分,结节ȡ0.5cm 呈网状或条索状为4分)㊁肝被膜回声(平整㊁光滑为1分,增厚且不平整或见细水纹为2分,小结节状或节段状为3分,波浪状或锯齿状被膜为4分)㊁肝边缘(尖锐为1分,轻度钝化为2分,轻度钝化且形态失常为3分,重度钝化伴形态失常为4分)㊁肝静脉(清晰为1分,变细且清晰为2分,粗细不均或狭窄为3分,纤细或显示不清为4分)㊁脾脏厚度(<4cm 为1分,ȡ4cm且<6cm为2分,ȡ6cm且<8cm为3分,ȡ8cm为4分)㊂以上5项超声特点计分相加为最终超声评分,评分范围为5~20分㊂评分越高,提示肝纤维化程度越严重;在右腋前线第7~9肋间,选择肝右前叶切面,避开肝内大血管㊁肝被膜和胆管等结构,选择直径2.0cm的感兴趣区,切换为STE模式,设置参数:图像深度为8.0cm,弹性量程为30kPa,弹性取样框为4.0cmˑ3.0cm㊂将取样框置于肝被膜下1.0~2.0cm处,嘱患者屏气3~5s,在图像稳定时冻结,记录STE模式下肝脏硬度测量(LSM)值㊂在同一位置测量5次,取中位数;切换为STQ模式,调节取样框为1.5cmˑ1.0cm㊂与STE模式一样,测量肝脏硬度㊂STE测量成功的标准:运动稳定指数ȡ4颗星,且可信度指数>90%(图1A); STQ测量成功的标准:运动稳定指数ȡ4颗星(图1B)㊂图1㊀STE和STQ模式下肝脏硬度检测A:STE模式下检测成功,其运动稳定指数ȡ4颗星,且可信度指数>90%,肝脏弹性测量值为4.79kpa;B:ST Q 模式下检测成功,其运动稳定指数ȡ4颗星,肝脏弹性测量值为6.28kpa1.3肝活检㊀在超声检查后48h内行肝穿刺活检㊂检查前,患者签署知情同意书㊂取肝右叶组织,经10%福尔马林固定㊁石蜡包埋㊁切片㊂应用Metavir 肝纤维化分期标准[8],其中F0为无纤维化,F1为汇管区纤维化㊁无纤维间隔形成,F2为汇管区纤维化伴少量纤维间隔形成,F3为存在明显的纤维间隔, F4为肝硬化㊂ȡF2期为显著性肝纤维化㊂1.4统计学方法㊀应用SPSS26.0软件进行统计学分析,首先应用Shapiro-Wilk进行正态性检验,对符合正态分布的计量资料以(xʃs)表示,采用t检验;计数资料以%表示,采用x2检验或Fisher精确概率计算;应用受试者工作特征(receiver operating char-acteristic,ROC)曲线线性分析,得到曲线下面积(area under the curve,AUC),采用非参数Mann-Whitney U检验比较诊断效能㊂P<0.05为差异有统计学意义㊂2㊀结果2.1两组基线资料比较㊀在106例CHB患者中,肝组织病理学检查发现,Metavir肝纤维化分期为F0期13例,F1期31例,F2期34例,F3期21例和F4期7例,其中ȡF2期显著性肝纤维化者62例,<F2期无显著性肝纤维化者44例;显著性肝纤维化与无显著性肝纤维化者年龄㊁性别㊁体质指数等基线资料比较,差异无统计学意义(P>0.05),而显著性肝纤维化者LSM STE㊁LSM STQ和SM超声均显著大于无显著性肝纤维化者,差异有统计学意义(均P<0.05,表1)㊂2.2STE和STQ参数联合超声评分诊断CHB患者显著性肝纤维化的效能情况㊀经ROC曲线分析显示, LSM STE㊁LSM STQ和LSM超声评估CHB患者显著性肝纤维化具有较高的诊断效能值(均P<0.05),而三者联合诊断的效能显著优于单一指标诊断(P<0.05,表2㊁图2)㊂表1㊀两组基线资料[%,(xʃs)]比较显著性肝纤维化(n=62)无显著性肝纤维化(n=44)年龄(岁)38.0ʃ5.339.3ʃ5.7男性46(74.2)31(70.5)体质指数(kg/m2)23.1ʃ2.222.9ʃ2.0高血压7(11.3)3(6.8)糖尿病4(6.5)2(4.5)白细胞计数(ˑ109/L)7.9ʃ1.77.4ʃ1.5血小板计数(ˑ109/L)189.4ʃ28.2181.3ʃ25.1 HBV DNA(Ig U/mL) 6.7ʃ1.17.0ʃ1.2 ALT(U/L)61.5ʃ5.959.7ʃ5.7 AST(U/L)49.4ʃ5.348.3ʃ5.1 LSM STE(kPa)12.7ʃ2.2①9.2ʃ2.1 LSM STQ(kPa)13.3ʃ2.3①8.9ʃ1.7 LSM超声(分)10.5ʃ2.2①7.2ʃ1.3表2㊀LSM评估CHB患者显著性肝纤维化的效能截断点AUC95%CI敏感度(%)特异度(%)P值LSM STE11.6kPa0.8690.803~0.93567.790.9<0.001 LSM STQ11.9kPa0.8090.728~0.89175.875.0<0.001 LSM超声8.7分0.7670.679~0.85556.595.5<0.001三项联合-0.9490.912~0.98680.670.5<0.001图2㊀LSM评估CHB患者显著性肝纤维化的ROC曲线3㊀讨论肝纤维化是CHB患者病情进展为肝硬化的重要病理学基础㊂早期肝纤维化具有可逆性,晚期则难以逆转㊂明确肝纤维化程度可为临床制定治疗方案提供指导意见[7-9]㊂肝活检组织病理学检查是诊断肝纤维化的金标准㊂肝纤维化Metavir分期是‘肝纤维化诊断及治疗共识(2019年)“推荐应用的判断肝纤维化程度的标准,具有简单㊁重复性好等优点,但肝穿刺创伤较大,有0.3%患者在穿刺后发生严重并发症,临床难以广泛实施,其应用受限[10]㊂超声作为无创检查手段,是诊断肝纤维化应用最多的工具之一㊂传统二维超声可结合肝脏回声特点㊁肝边缘形态㊁肝静脉特点等评估肝纤维化程度,虽然存在主观性较强等缺陷,但在肝纤维化诊断方面具有一定的应用价值[11]㊂本研究CHB伴有显著性肝纤维化患者超声评分显著高于无显著性肝纤维化患者, LSM超声诊断CHB患者显著性肝纤维化的AUC为0.767(95%CI为0.679~0.855),其截断点为8.7分,提示常规超声检查评分也能初步评估肝纤维化程度㊂肝组织成纤维细胞产生大量的细胞外胶原纤维,导致细胞外基质过度沉积,造成小叶结构紊乱和血流改变,这些改变随肝纤维化程度的加剧而加重,故超声检测肝实质和肝被膜等特征变化也可初步评估肝纤维化程度[12]㊂STE和STQ均是利用声辐射力脉冲诱导形成剪切波,通过声波探测组织力学形变特性,组织硬度越大,其剪切波速度越快[13]㊂STE可结合高质量图像处理技术高分辨和高准确性地形成彩色编码弹性图像,绿色为高质量的剪切波,黄色或红色提示质量差,不仅实时选取图像质量良好的组织硬度值,对于肥胖等弹性成像困难者,还能利用穿透模式提高测量成功率[14,15]㊂STQ技术可定点测量组织硬度,但图像分辨率稍逊于STE技术㊂对于肥胖者,STQ需自行调节图像深度,显示更多的肝实质,且取样框放置需准确,应处于弹性图像中心均匀和稳定的区域,检测失败风险大于STE技术[16,17]㊂另外,考虑到STE和STQ检测均可受呼吸运动等因素的影响,造成测量结果与实际结果之间存在偏差㊂本研究采用同一位置多次测量,取其中位数的方式,避免了测量误差㊂结果显示,STE和STQ检查均成功,LSM STE和LSM STQ诊断CHB患者显著性肝纤维化的截断点分别为11.6kPa和11.9kPa,但LSM STE诊断的AUC 值为0.869(95%CI为0.803~0.935),略高于LSM STQ诊断的AUC值0.809(95%CI为0.728~ 0.891),提示STE技术测量的肝组织硬度更为准确,可能与STE技术具有更好的穿透力,也能减少呼吸运动幅度过大导致的测量值与实际值的偏差,其准确性更高有关[18]㊂此外,本研究经ROC曲线分析发现,LSM STE㊁LSM STQ联合LSM超声诊断CHB患者显著性肝纤维化的AUC值为0.949(95%CI为0.912~0.986),显著优于单一超声参数或评分评估㊂仅采取LSM STE或LSM STQ判断肝纤维化可能过于片面,结合其他超声征象共同判断更有利于提高准确性[19,20]㊂ʌ参考文献ɔ[1]Ozturk A,Olson MC,Samir AE,et al.Liver fibrosis assessment:MR and US elastography.Abdom Radiol(NY),2022,47(9): 3037-3050.[2]Yang M,Wei L.Impact of NAFLD on the outcome of patients withchronic hepatitis B in Asia.Liver Int,2022,42(9):1981-1990.[3]黄平,曾霞,张亚萍,等.肝静脉波形分型联合肝脏超声半定量评分对慢性乙型肝炎患者肝纤维化程度评估价值研究.实用肝脏病杂志,2022,25(2):187-190.[4]丁世兰,朱成诚,肖春华,等.剪切波弹性成像及血清学模型评估慢性肝病纤维化.中国临床研究,2023,36(1):70-75. 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