【作者】 刘波；

【导师】 蔡金华；

【作者基本信息】 重庆医科大学 ， 影像医学与核医学， 2025， 博士

【摘要】 第一部分多参数MR I与血液生化指标对新生儿及婴儿胆道闭锁的诊断价值目的:胆道闭锁(biliary atresia,BA)的术前诊断目前主要依赖于术中胆管造影和肝脏活检等有创检查方法。虽然超声和肝胆核素显影等无创技术已被报道具有诊断BA的潜力,但其准确性和可靠性仍需进一步提高。本研究旨在评估多参数磁共振成像(magnetic resonance imaging,MRI)特征以及血液生化指标在新生儿和婴儿BA诊断中的应用价值。方法:本研究共纳入79例疑诊为BA的新生儿及婴儿,以术中胆管造影、肝脏活检和临床治疗结果作为诊断金标准,将患儿分为BA组(n=53)与非BA组(n=26)。所有患儿均接受了 MRI和血液生化检查。MRI检查包括三维磁共振胰胆管成像(three-dimensional magnetic resonance cholangiopancreatography,3D-MRCP)和弥散张量成像(diffusion tensor imaging,DTI):其中,3D-MRCP 用于评估肝外胆管和胆囊的发育情况,DTI则用于测量肝右叶、尾状叶及左叶的平均表观扩散系数(apparent diffusion coefficient,ADC)值和分数各向异性(fractional anisotropy,FA)值。血液生化检查包括γ-谷氨酰转肽酶(gamma-glutamyl transpeptidase,GGT)、总胆红素、直接胆红素、间接胆红素、天冬氨酸转氨酶及丙氨酸转氨酶水平和血小板计数的测定。定量数据和定性资料分别采用Mann-Whitney U检验和卡方检验进行组间比较。P<0.05被认为差异具有统计学意义。选择BA组和非BA组间有显著差异的特征,采用二元逻辑回归模型预测BA的存在。诊断性能通过准确性、敏感性、特异性、阳性预测值、阴性预测值及受试者工作特征曲线下面积(area under the receiver operating characteristic curve,AUC)进行评估。结果:BA组肝右叶和尾状叶的平均ADC值显著低于非BA组(分别为P=0.02和P=0.04);BA组3D-MRCP显示肝外胆管和胆囊发育异常的病例数均显著高于非BA组(分别为P≤0.001和P=0.02);BA组的平均血清GGT水平显著高于非BA组(P<0.001)。在这五项指标中,GGT对BA的诊断性能最佳,其准确性、敏感性、特异性、阳性预测值、阴性预测值及AUC分别为75.95%(60/79)、84.91%(45/53)、57.69%(15/26)、80.36%(45/56)、65.22%(15/23)和0.81(P<0.001)。其余四项指标的诊断性能依次为:3D-MRCP显示胆囊发育异常(78.48%、81.13%、73.08%、86%、65.52%和 0.77,P<0.001);肝右叶平均 ADC 值(69.62%、96.23%、15.38%、69.86%、66.67%和 0.66,P=0.03);肝尾状叶平均 ADC 值(64.56%、96.23%、0%、66.23%、0%和 0.64,P=0.04);3D-MRCP 显示肝外胆管发育异常(74.68%、98.11%、26.92%、73.24%、87.5%和 0.63,P=0.07)。结论:血清GGT水平升高、肝右叶和尾状叶平均ADC值降低以及3D-MRCP显示的胆囊和肝外胆管发育异常在新生儿及婴儿BA的诊断中展现出潜在的临床应用价值。第二部分基于多参数MRI和血液生化指标的胆道闭锁诊断评分系统构建及验证目的:构建一个基于多参数MRI和血液生化指标的BA诊断评分系统,并评估其在新生儿和婴儿BA诊断中的应用价值。方法:本研究共纳入79例确诊为BA或非BA的新生儿和婴儿,所有参与者均进行了 MRI和血液生化检查。MRI检查包括DTI和3D-MRCP;其中,3D-MRCP用于评估肝外胆管和胆囊的发育情况,DTI则用于测量肝右叶、尾状叶及左叶的平均ADC值以及FA值。血液生化检查包括GGT、总胆红素、直接胆红素、间接胆红素、天冬氨酸转氨酶、丙氨酸转氨酶水平以及血小板计数的测定。以3D-MRCP显示的肝外胆管和胆囊发育异常、DTI测量的肝右叶和尾状叶的平均ADC值以及血清GGT水平作为特征参数,使用二元逻辑回归分类器构建BA的诊断模型。对模型参数进行加权融合,并对预测值进行logit转换,生成一个单一的诊断指数(范围为0至1),用于预测个体患儿是否患有BA。当该指数大于0.5时,则提示为BA。以术中胆管造影、肝脏活检及临床治疗结果作为诊断金标准,评估融合诊断指数的诊断性能,包括准确性、敏感性、特异性、阳性预测值、阴性预测值及AUC。结果:基于多参数MRI和血液生化指标建立的评分系统预测BA的性能如下:准确性为86.08%,敏感性为90.57%,特异性为76.92%,阳性预测值为88.89%,阴性预测值为80%,AUC为0.9(P<0.001)。结论:根据MRI数据和血液生化指标,开发了一种相对无创的BA评分系统。该评分系统展现出良好的诊断性能,有潜力作为新生儿和婴儿BA诊断的有效手段。第三部分多参数MR I与血液生化指标对胆道闭锁患儿肝纤维化分级评估的价值目的:目前肝脏活检仍然是评估肝纤维化分级的主要参考标准。尽管一些无创方法已显示出评估肝纤维化分级的潜力,但其分级准确性和可靠性仍然不足。本研究旨在探讨多参数MRI和血液生化指标在评估BA患儿肝纤维化分级中的诊断价值。方法:本研究纳入了 53例BA患儿,所有参与者均接受了 MRI和血液生化检查。MRI检查包括3D-MRCP和DTI:其中,3D-MRCP用于评估肝外胆管和胆囊的发育情况,DTI则用于测量肝右叶、尾状叶及左叶的平均ADC值和FA值。血液生化检查包括血清GGT、总胆红素、直接胆红素、间接胆红素、天冬氨酸转氨酶、丙氨酸转氨酶水平以及血小板计数的测定。此外,根据年龄、天冬氨酸转氨酶、丙氨酸转氨酶及血小板计数,计算了相应的纤维化评分4和天冬氨酸转氨酶血小板比率指数,这两者均为相对无创评估肝纤维化的方法。以肝脏活检评估肝纤维化分级的结果作为参考标准,将BA患儿分为五个等级:F0(n=3)、F1(n=18)、F2(n=8)、F3(n=16)与 F4(n=8)。为了评估上述指标与肝纤维化分级之间的相关性,采用Spearman相关系数检验(r)进行分析。对于定量数据和定性资料,分别采用Mann-Whitney U检验和卡方检验,对不同肝纤维化分级之间(F0与≥F1,≤F1与≥F2,≤F2与≥F3,≤F3与F4)进行统计比较。P<0.05被认为具有统计学意义。最后,采用二元逻辑回归模型预测肝纤维化分级,诊断性能通过准确性、敏感性、特异性、阳性预测值、阴性预测值以及AUC进行评估。结果:肝右叶的平均FA值和年龄与肝纤维化分级之间存在显著的正相关性(分别为P=0.01和P=0.04),而肝右叶的平均ADC值则与肝纤维化分级呈显著的负相关性(P=0.04)。在肝纤维化分级≥F2组中,肝右叶的平均ADC值显著低于肝纤维化分级≤F1组(P=0.02)。该值在预测BA患儿肝纤维化分级≥F2时的准确性为64.15%(34/53),敏感性为84.38%(27/32),特异性为33.33%(7/21),阳性预测值为 65.85%(27/41),阴性预测值为 58.33%(7/12),AUC 为 0.69(P=0.02)。同时,肝纤维化分级≥F2和≥F3组的肝右叶平均FA值分别显著高于肝纤维化分级≤F1和≤F2组(分别为P=0.04和P=0.03)。在预测BA患儿肝纤维化分级≥F2和≥F3时,其准确性均为62.26%(33/53),敏感性分别为 81.25%(26/32)和 37.5%(9/24),特异性分别为33.33%(7/21)和82.76%(24/29),阳性预测值分别为65%(26/40)和 64.29%(9/14),阴性预测值分别为 53.85%(7/13)和61.54%(24/39),AUC 分别为 0.67(P=0.04)和 0.68(P=0.03)。结论:DTI测量肝右叶的平均ADC值和FA值在预测BA患儿的肝纤维化分级方面展现出一定的价值,但整体诊断性能仍有待提高。第四部分基于多参数MRI和血液生化指标的胆道闭锁患儿肝纤维化评分系统构建及验证目的:构建并验证一种基于多参数MRI和血液生化指标的BA患儿肝纤维化无创评分系统,并评估其在肝纤维化分级预测中的临床应用价值。方法:本研究纳入了 53例BA患儿,所有参与者均接受了 MRI和血液生化检查。MRI检查包括3D-MRCP和DTI:其中,3D-MRCP用于评估肝外胆管和胆囊的发育情况,DTI则用于测量肝右叶、尾状叶及左叶的平均ADC值和FA值。血液生化检查包括血清GGT、总胆红素、直接胆红素、间接胆红素、天冬氨酸转氨酶、丙氨酸转氨酶水平以及血小板计数的测定。此外,根据年龄、天冬氨酸转氨酶、丙氨酸转氨酶及血小板计数,计算了相应的纤维化评分4和天冬氨酸转氨酶血小板比率指数,这两者均为相对无创评估肝纤维化的方法。以DTI测量肝右叶的平均ADC值、平均FA值、年龄及血清总胆红素水平作为特征参数,使用K最近邻分类器构建BA患儿肝纤维化分级的诊断模型(F0与≥F1,≤F1与≥F2,≤F2与≥F3,≤F3与F4)。对模型参数进行加权融合,并对预测值进行logit转换,生成一个单一的诊断指数(范围为0至1),用于预测个体BA患儿的肝纤维化分级是否≥F1、≥F2、≥F3及F4。当该指数大于0.5时,提示BA患儿的肝纤维化分级为≥F1、≥F2、≥F3或F4;反之,如果该指数小于或等于0.5,则提示肝纤维化分级为F0、≤F1、≤F2或≤F3。以肝脏活检结果作为诊断金标准,采用AUC评估融合诊断指数的整体诊断性能。结果:肝纤维化评分系统在预测BA患儿肝纤维化分级为F4时表现最佳,AUC为0.71(P=0.01)。其次,肝纤维化分级≥F3的AUC为0.57(P=0.04),肝纤维化分级≥F2的AUC为0.56(P=0.03),而肝纤维化分级≥F1的AUC为0.41(P=0.27)。结论:根据MRI数据和血液生化指标,开发了一种相对无创的BA患儿肝纤维化评分系统。该评分系统对评估BA患儿肝纤维化分级有一定价值,特别是在区分重度肝纤维化方面表现良好,这有助于判断BA患儿Kasai手术前是否存在重度肝纤维化,对手术时机选择及预后判断具有重要指导意义。更多还原

【Abstract】 PART I THE DIAGNOSTIC VALUE OF MULTIPARA METRIC MRI AND BLOOD BIOCHEMICAL INDICA TORS FOR BILIARY ATRESIA IN NEONATES AND INFANTSObjective:The preoperative diagnosis of biliary atresia(BA)currently relies mainly on invasive examination methods such as intraoperative cholangiography and liver biopsy.Although non-invasive techniques like ultrasound and hepatobiliary scintigraphy have been reported to have potential for diagnosing BA,their accuracy and reliability still need to be improved.This study aims to assess the application value of multiparametric magnetic resonance imaging(MRI)features and blood biochemical indicators in diagnosing BA in neonates and infants.Methods:A total of 79 neonates and infants suspected of having BA were enrolled in this study.Using intraoperative cholangiography,liver biopsy,and clinical treatment outcomes as the diagnostic gold standard,patients were divided into the BA group(n=53)and the non-BA group(n=26).All patients underwent MRI and blood biochemical examinations.MRI examinations included three-dimensional magnetic resonance cholangiopancreatography(3D-MRCP)and diffusion tensor imaging(DTI).3D-MRCP was used to evaluate the development of the extrahepatic bile ducts and gallbladder,while DTI was used to measure the average apparent diffusion coefficient(ADC)values and fractional anisotropy values in the right liver lobe,caudate lobe,and left lobe.Blood biochemical examinations included measurements of gammaglutamyl transpeptidase(GGT),total bilirubin,direct bilirubin,indirect bilirubin,aspartate aminotransferase,alanine aminotransferase levels,and platelet count.Quantitative data and qualitative data were compared between groups using the Mann-Whitney U test and chi-squared test,respectively.P<0.05 was considered statistically significant.Features with significant differences between the BA and non-BA groups were selected,and a binary logistic regression model was used to predict the presence or absence of BA.Diagnostic performance was assessed through accuracy,sensitivity,specificity,positive predictive value,negative predictive value,and the area under the receiver operating characteristic curve(AUC).Results:The average ADC values of the right liver lobe and caudate lobe in the BA group were significantly lower than those in the non-BA group(P=0.02 and P=0.04,respectively);the number of cases with developmental abnormalities of the extrahepatic bile duct and gallbladder detected by 3D-MRCP in the BA group was significantly higher than that in the non-BA group(P<0.001 and P=0.02,respectively);and the average serum GGT level in the BA group was significantly higher than that of the non-BA group(P<0.001).Among these five indicators,GGT demonstrated the best diagnostic performance in diagnosing BA,with an accuracy,sensitivity,specificity,positive predictive value,negative predictive value,and AUC of 75.95%(60/79),84.91%(45/53),57.69%(15/26),80.36%(45/56),65.22%(15/23),and 0.81(P<0.001),respectively.The diagnostic performance of the other four indicators,in order,was as follows:3D-MRCP showing abnormalities in the gallbladder(78.48%,81.13%,73.08%,86%,65.52%,and 0.77,P<0.001);average ADC value of the right liver lobe(69.62%,96.23%,15.38%,69.86%,66.67%,and 0.66,P=0.03);average ADC value of the caudate lobe(64.56%,96.23%,0%,66.23%,0%,and 0.64,P=0.04);and 3D-MRCP showing abnormalities in the extrahepatic bile ducts(74.68%,98.11%,26.92%,73.24%,87.5%,and 0.63,P=0.07).Conclusion:The elevated serum GGT levels,the reduced average ADC values of the right liver lobe and caudate lobe,and the developmental abnormalities of the gallbladder and extrahepatic bile ducts shown by 3D-MRCP all exhibit potential clinical application value in the diagnosis of BA in neonates and infants.PART Ⅱ CONSTRUCTION AND VALIDATION OF A SCORING SYSTEM FOR THE DIAGNOSIS OF BILIARY ATRESIA BASED ON MULTIPARAMETRIC MRI AND BLOOD BIOCHEMICAL INDICATORSObjective:To construct a scoring system based on multiparametric magnetic resonance imaging(MRI)and blood biochemical parameters,and to evaluate its value in the diagnosis of biliary atresia(BA).Methods:This study included 79 neonates and infants confirmed with BA or non-BA,all of whom underwent MRI and blood biochemical tests.The MRI examinations included three-dimensional magnetic resonance cholangiopancreatography(3D-MRCP)and diffusion tensor imaging(DTI).3D-MRCP assessed the development of the extrahepatic bile ducts and gallbladder,while DTI measured the apparent diffusion coefficient(ADC)and fractional anisotropy values of the right,caudate,and left hepatic lobes.The blood biochemical tests measured levels of total bilirubin,direct bilirubin,indirect bilirubin,aspartate aminotransferase,alanine aminotransferase,gamma-glutamyl transpeptidase(GGT),and platelet count.Abnormal development of the extrahepatic bile ducts and gallbladder displayed by 3D-MRCP,along with the mean ADC values of the right and caudate lobes measured by DTI and the average serum GGT level,were used as feature parameters to construct the diagnostic model for BA using a binary logistic regression classifier.The model parameters were weighted and fused,and the predicted values were subjected to logit transformation to generate a single diagnostic index(ranging from 0 to 1)for predicting whether an individual patient has BA.When this index was greater than 0.5,it indicated the possibility of BA.Intraoperative cholangiography,liver biopsy,and clinical treatment outcomes were used as the gold standards to assess the diagnostic performance of the fused diagnostic index,including accuracy,sensitivity,specificity,positive predictive value,negative predictive value,and the area under the receiver operating characteristic curve(AUC).Results:The performance of the scoring system in predicting BA was as follows:accuracy was 86.08%,sensitivity was 90.57%,specificity was 76.92%,positive predictive value was 88.89%,negative predictive value was 80%,and AUC was 0.9(P<0.001).Conclusion:Based on MRI data and blood biochemical parameters,a relatively non-invasive scoring system for BA was developed.This scoring system demonstrated good diagnostic performance and has the potential to serve as an effective means to distinguish whether neonates and infants have BA.PART Ⅲ THE VALUE OF MULTIPARAMETRIC MRI AND BLOOD BIOCHEMICAL INDICATORS IN ASSESS ING LIVER FIBROSIS GRADING IN PATIENTS WITH BILIARY ATRESIAObjective:Currently,liver biopsy remains the primary reference standard for assessing liver fibrosis grading.Although some non-invasive methods have shown potential for evaluating liver fibrosis grading,their accuracy and reliability are still insufficient.Therefore,this study aims to explore the diagnostic value of multiparametric magnetic resonance imaging(MRI)and blood biochemical indicators in assessing liver fibrosis grading in neonates and infants with biliary atresia(BA).Methods:This study included 53 patients with BA,all of whom underwent MRI and blood biochemical tests.The MRI examinations included diffusion tensor imaging(DTI)and three-dimensional magnetic resonance cholangiopancreatography(3D-MRCP).Among these,DTI was employed to measure the mean apparent diffusion coefficient(ADC)and fractional anisotropy(FA)values of the right hepatic lobe,caudate lobe,and left hepatic lobe,while 3D-MRCP was used to assess the development of the extrahepatic bile ducts and gallbladder.The blood biochemical tests measured levels of gamma-glutamyl transpeptidase,aspartate aminotransferase,alanine aminotransferase,total bilirubin,direct bilirubin,indirect bilirubin,and platelet count.Additionally,the corresponding fibrosis score 4 and aspartate aminotransferase to platelet ratio index were calculated.Using the results of liver biopsy as a reference standard to assess the grading of liver fibrosis,the BA patients were classified into five grades:FO(n=3),F1(n=18),F2(n=8),F3(n=16),and F4(n=8).To evaluate the correlation between the above indicators and the grading of liver fibrosis,the Spearman correlation coefficient(r)was used for analysis.For quantitative and qualitative data,the MannWhitney U test and chi-square test were respectively employed to statistically compare different liver fibrosis grades(FO vs.≥F1,≤F1 vs.≥F2,≤F2 vs.≥F3,≤F3 vs.F4).P<0.05 was considered statistically significant.Finally,binary logistic regression analysis was used to predict liver fibrosis grading,and the diagnostic performance was evaluated using accuracy,sensitivity,specificity,positive predictive value,negative predictive value,and the area under the receiver operating characteristic curve(AUC).Results:The average FA value of the right hepatic lobe and age showed a significant positive correlation with liver fibrosis grading(P=0.01 and P=0.04,respectively),while the average ADC value of the right hepatic lobe exhibited a significant negative correlation with liver fibrosis grading(P=0.04).In the liver fibrosis grading group ≥F2,the average ADC value of the right hepatic lobe was significantly lower than that of the<F1 grading group(P=0.02).The accuracy of the average ADC value of the right hepatic lobe in predicting liver fibrosis grading>F2 in patients with BA was 64.15%(34/53),with a sensitivity of 84.38%(27/32),specificity of 33.33%(7/21),positive predictive value of 65.85%(27/41),negative predictive value of 58.33%(7/12),and an AUC of 0.69(P=0.02).Meanwhile,the average FA value of the right hepatic lobe in liver fibrosis grading groups>F2 and>F3 was significantly higher than that in the<F1 and<F2 groups,respectively(P=0.04 and P=0.03).In predicting liver fibrosis grading>F2 and>F3 in patients with BA,the accuracy of the average FA value of the right hepatic lobe was 62.26%(33/53),with sensitivities of 81.25%(26/32)and 37.5%(9/24),specificities of 33.33%(7/21)and 82.76%(24/29),positive predictive values of 65%(26/40)and 64.29%(9/14),negative predictive values of 53.85%(7/13)and 61.54%(24/39),and AUCs of 0.67(P=0.04)and 0.68(P=0.03),respectively.Conclusion:The measurement of the average ADC and average FA values of the right hepatic lobe using DTI has certain values in predicting liver fibrosis grading in patients with BA,but the overall diagnostic performance of these features still needs improvement.PART IV CONSTRUCTION AND VALIDATION OF A LIVER FIBROSIS SCORING SYSTEM FOR PATIENTS WITH BILIARY ATRESIA BASED ON MULTIPARAME TER MRI AND BLOOD BIOCHEMICAL INDICATORSObjective:This study aims to construct and validate a non-invasive liver fibrosis scoring system for biliary atresia(BA)patients based on multiparameter magnetic resonance imaging(MRI)and biochemical blood indicators,and to evaluate its clinical application value.Methods:This study included 53 BA patients,all of whom underwent MRI and blood biochemical tests.The MRI examination used diffusion tensor imaging(DTI)to measured the mean apparent diffusion coefficient(ADC)and fractional anisotropy(FA)values of the right,caudate,and left hepatic lobes.The blood biochemical tests measured levels of total bilirubin,direct bilirubin,indirect bilirubin,aspartate aminotransferase,alanine aminotransferase,gamma-glutamyl transpeptidase,and platelet count.The ADC and FA values of the right hepatic lobe measured by DTI,along with age and serum total bilirubin levels,were used as features to construct a diagnostic model for liver fibrosis grading in BA patients using a K-nearest neighbors classifier(FO vs.≥F1,≤F1 vs.≥F2,≤F2 vs.≥F3,≤F3 vs.F4).The model parameters were weighted and fused,and the predicted values underwent logit transformation to generate a single diagnostic index(ranging from 0 to 1)for predicting whether the liver fibrosis grade of an individual BA patient was ≥F1,≥F2,≥F3,or F4.When this index is greater than 0.5,it indicated that the liver fibrosis grade for BA children was>F1,>F2,>F3,or F4;conversely,if the index is less than or equal to 0.5,it indicated that the liver fibrosis grades was F0,≤F1,≤F2,or ≤F3.Liver biopsy results were used as the gold standard for diagnosis,and the area under the receiver operating characteristic curve(AUC)was utilized to evaluate the overall diagnostic performance of the combined diagnostic index.Results:This scoring system exhibited the best performance in predicting a liver fibrosis grade of F4 in BA patients,with an AUC of 0.71(P=0.01).The AUC for a fibrosis grade of ≥F3 was 0.57(P=0.04),for>F2 was 0.56(P=0.03),and for>F1 was 0.41(P=0.27).Conclusion:Based on MRI data and blood biochemical indicators,a relatively non-invasive liver fibrosis scoring system for BA patients has been developed.This scoring system performs well in distinguishing whether there is severe liver fibrosis in BA patients before Kasai surgery and shows potential as an effective method for classifying liver fibrosis grades in BA patients.更多还原