基于分子水平的肝纤维化多模态MR成像新技术及相关影像生物标志物的研究

Liver fibrosis is an inevitable stage to cirrhosis in response to repetitive liver injury from various causes, early and accurate assessment of liver fibrosis plays an important role in clinical work. But until now, there are still no acknowledged noninvasive approaches in fibrosis assessment. Gd-EOB-DTPA-enhanced MRI with T1-mapping sequence, intravoxel incoherent motion imaging, whole-liver perfusion and susceptibility weighted Imaging reflect the states of hepatocellular impairment, liver diffusion and microcirculation, as well as iron deposition respectively. In addition, the enhancement effect of liver parenchyma on hepatobiliary phase by Gd-EOB-DTPA correlates with the expressions of organic anion transporting polypeptide (OATP) and multidrug resistance associated protein (MRP), and liver fibrosis can alter the levels of OATP and MRP, which result in differences in T1 relaxation time of liver parenchyma. Thus, we propose that the MR imaging technologies above will become critical tools for diagnosis and evaluation of liver fibrosis. In this study, we suppose to measure varied imaging biomarkers of the new multiparameter MR imaging technologies above on three different rat fibrosis models as well as pathologically confirmed patients with HBV-related liver fibrosis, so as to assess their values in hierarchical diagnosis and therapeutic evaluation of liver fibrosis and their relationship with the membrane transporters (OATP, MRP), and further investigate the mechanisms of liver fibrosis.

肝纤维化是各种慢性肝病进展至肝硬化的必经阶段，早期、准确评估纤维化程度具有重要临床意义，目前尚缺乏公认可靠的无创评估手段。前期研究表明，Gd-EOB-DTPA增强肝胆特异期T1-mapping成像、双指数弥散成像、全肝动态增强灌注成像和磁敏感成像可分别反映肝细胞功能损伤，肝内微观弥散、微循环灌注，及铁沉积状态；而Gd-EOB-DTPA增强肝胆特异期成像与细胞膜有机转运肽（OATP）和多药耐药蛋白（MRP）密切相关，肝纤维化可引起OATP和MRP表达水平改变，导致肝实质T1弛豫时间的改变。我们认为，上述MR成像新技术有望成为肝纤维化的重要诊断和评估工具。本课题将采用三种大鼠肝纤维化模型及HBV相关肝纤维化患者，对上述多模态MR成像新技术中相关影像生物标志物进行测定比较，并对细胞膜转运蛋白表达水平及活性进行相关性分析，从多层面探讨肝纤维化的发生发展机制及其分级诊断、疗效评估价值，指导临床实践。

肝纤维化是各种慢性肝病进展至肝硬化的必经阶段，早期、准确评估纤维化程度具有重要临床意义，目前尚缺乏公认可靠的无创评估手段。本课题建立大鼠肝纤维化模型并纳入HBV相关肝纤维化患者，对包括Gd-EOB-DTPA增强肝胆特异期T1-mapping成像、DKI成像结合直方图分析、MR细胞外容积成像等在内的多模态MR成像新技术中相关影像生物标志物进行测定比较，并对细胞膜转运蛋白表达进行相关性分析，从多层面探讨肝纤维化的发生发展机制及其分级诊断价值。.本项目通过对Gd-EOB-DTPA增强T1-mapping成像T1弛豫时间定量分析，得出20min-T1弛豫时间、△T1%和△R1%与肝纤维化程度显著相关，相较于炎症活动度及铁沉积含量，纤维化级别是T1弛豫时间的独立决定因素，其中△R1%对肝纤维化的诊断效能高于APRI及FIB-4。与此同时，OATP1表达在mRNA和蛋白水平均与20min-T1和△T1%显著相关。.通过DKI成像可探讨肝细胞外基质微观结构改变，明确微观弥散状态在肝纤维化发生发展中的作用。本研究结果得出，D值、K值及ADC值与纤维化级别显著相关，可作为纤维化分级诊断的有效补充手段，但其诊断效能并不显著优于传统扩散成像技术；结合直方图分析可为肝纤维化提供更多的定量诊断信息。.磁共振细胞外容积成像（MRI-ECV）可反映肝细胞外基质空间大小，ECV与纤维化分级呈显著正相关，与炎症活动度相比，纤维化分级是ECV的独立影响因素。ECV对肝纤维化诊断效能高于血生化指标APRI和FIB-4，与超声弹性成像2D-SWE比较不具有统计学差异。.综上得出，Gd-EOB-DTPA增强肝胆特异期T1-mapping成像、DKI成像结合直方图分析、MRI-ECV等多模态MR成像新技术对肝纤维化分级诊断具有重要价值；同时，我们从分子水平验证了纤维化肝实质T1弛豫时间改变主要由OATP1受体表达决定，Gd-EOB-DTPA增强T1-mapping成像可作为肝细胞膜转运蛋白表达的影像生物标志物。