肝脏特异性磁共振标记物定量评价不同病理类型肝纤维化分期与肝功能

Liver fibrosis serves as the key component during the pathogenesis of a variety of chronic liver diseases developing into hepatic cirrhosis. Early detection and treatment of fibrosis can reverse the process of fibrogenesis by suppression of the fibrotic response, which can significantly improve the prognosis of the patients. Besides, for patients with liver fibrosis or cirrhosis and candidates to hepatectomy, evaluating the reserved hepatic function is an essential procedure for estimation the risk of surgery. However, grading of the hepatic fibrosis requires a biopsy till now, which subjects patients to a risk of serious complications; and current approaches for evaluation of liver function also have their own limitations and cannot meet the clinical requirements.. Gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a liver-specific magnetic resonance imaging (MRI) contrast medium that can be selectively taken up and excreted by hepatocytes, thus its hepatocyte-phase images can provide information of the hepatic function. This study is aimed to establish three kinds of animal models of liver fibrosis with different etiologies and to evaluate hepatic function with Gd-EOB-DTPA contrast enhanced MRI. During this study, quantitatively evaluation of perfusion changes in the process of fibrosis can be obtained by applying dynamic contrast-enhanced (DCE) MRI, the heterogeneity of liver parenchyma which reflect the process of fibrogenesis can also be measured with computer-aided texture analysis technique. By comparing the results of liver biopsy and indocyanine green (ICG) clearance test, the imaging biomarkers for staging liver fibrosis and evaluating hepatic function can be determined respectively. The expression of the transporter proteins in different types and grades of fibrosis models will also be evaluated and correlated with hepatic function, to reveal the pathological changes during the process of liver fibrosis.. The application of this study could be valuable in staging liver fibrosis and evaluating hepatic function. The clinical potential of non-invasive quantitative MRI biomarkers is promising.

肝纤维化是各种慢性肝病向肝硬化发展的关键环节，早期诊治肝纤维化能明显改善患者预后。另一方面，对需行手术的肝纤维化患者，肝脏储备功能的评价决定了治疗策略选择。现有肝纤维化及肝功能评价方法具有各自的局限性，不能满足临床需求。.Gd-EOB-DTPA为新型肝脏特异性MR对比剂，被肝细胞特异性摄取并排泄。本研究通过构建不同病因、时点的肝纤维化动物模型，应用Gd-EOB-DTPA增强MRI扫描，评价肝细胞功能，并结合动态增强序列，定量评价肝纤维化中的血流灌注变化；结合纹理分析后处理技术，评价纤维化进程中结构重塑所引起的分布异质性。本研究分别以病理学及ICG清除实验为对照，实现肝纤维化、肝功能相关的特异性影像学生物标志物的筛选和确立。并分析不同病因、时点中转运蛋白的分布特征，结合肝功能评价，进一步探索肝纤维化进展中的病理变化机制。.本项目的开展，将为肝纤维化和肝储备功能的评价提供重要的临床前研究成果。

肝纤维化的早期诊治是改善慢性肝病预后的关键因素，且对于合并肝纤维化的手术病例，准确评价肝功能决定治疗决策的选择。本研究旨在通过应用新型肝脏特异性对比剂（钆赛酸二钠，Gd-EOB-DTPA），结合新型的图像后处理技术——纹理特征参数分析技术，利用动物模型，探索定量评价肝纤维化及肝功能的影像生物标志物。.本研究成功构建了大鼠肝纤维化模型，建立了基于临床3.0T磁共振仪的小动物专用磁共振（MRI）扫描技术方案，具体包括：（1）基础序列：T2 TSE序列、T1 TSE序列；（2）功能序列：①动态增强序列（DCE-MRI），包括快速动态增强扫描、肝胆期多期扫描，分别获得灌注图像与肝胆期多期图像；②高分辨序列，包括注射对比剂前与注射后肝胆期多期扫描；③T1mapping，包括注射对比剂前后肝胆期多期扫描。以病理学为对照，筛选了肝纤维化相关的特异性影像学生物标志物，以吲哚菁绿（ICG）清除实验为对照，筛选了肝功能评价相关的特异性影像学生物标志物，同时应用纹理分析技术，探索了肝纤维化相关的纹理特征参数。.本研究主要结果显示：（1）对于肝纤维化的定量评价，定量灌注参数如容量转移常量（Ktrans）、血管外细胞外间隙体积百分数（Ve）、初始曲线下面积（iAUC）等、半定量灌注参数如达峰时间（Tmax）对肝纤维化分级具有一定提示意义；通过多期肝胆期信号强度-时间曲线获得的参数如各时间点相对强化率（RE）、RE减半的时间（TRE1/2）、60 min RE下降程度（RE下降=RE3 min-RE60 min）对于肝纤维化分级具有一定提示意义。（2）对于肝功能的定量评价，功能序列T1 mapping多期图像获得的参数如晚期肝胆期的T1值（T150min）、T1减低率（ΔT150min）、T1减低率的减半时间（TΔT1 1/2）与肝功能存在显著相关性；多期肝胆期参数如达峰时间（Tmax）、RE减半时间（TRE1/2）与肝功能存在显著相关性。（3） 增强MRI、T1mapping的特征纹理参数，尤其是打药前T1 mapping图像的entropy对诊断肝纤维化具有一定价值。.综上，Gd-EOB-DTPA增强MRI及多功能成像序列、纹理特征参数对于肝纤维及肝功能的定量诊断具有一定价值，为诊断提供新的可能的选择。