肝硬化胆管三维结构动态演变及对门脉高压症预测价值的研究

Portal hypertension is the central driver of complications in patients with liver cirrhosis. It is characterized by collagen deposition, vascular neovascularization, as well as bile duct proliferation. However, the dynamic morphogenesis of intrahepatic bile ducts has not been performed, and it is unclear whether the characteristic of bile ducts is a predictor of portal hypertension. In the previous study, we successfully reconstructed the three-dimensional image of microvascular with X-ray phase contrast CT technology, and suggested that the microvascular density could be a surrogate marker for predicting the clinical significant portal hypertension. In this proposal, we will first establish three-dimensional morphogenesis of intrahepatic bile ducts in two models of liver fibrosis using the X-ray phase contrast CT technology, observing the surface structure, the ductular ramification, and the microstructures of bile ductular lumen in details. Second, we will analyze the volume ratio, area ratio and bile ductule density through three-dimensional CT images and two-dimensional images, to acquire the quantitative features of bile ducts during the fibrosis process. Finally, we will observe the relationship between the bile duct and portal pressure, to further explain the role of bile ducts in portal hypertension and evaluate whether bile ductule density could be used for predicting portal hypertension in clinic. The study findings will help to understand the role of bile ducts in portal hypertension. Importantly, the information of the bile ducts is a supplementation to the morphological study and provides a new way for diagnosis in the fields of pathology and clinic.

门脉高压症是肝硬化患者最主要的并发症，其病理特点不仅为胶原沉积、血管新生，还伴有胆管增生。但肝内胆管结构的动态演变规律及胆管改变在预测门脉高压症中的价值尚不明确。前期我们应用X线相衬CT技术重建了肝脏微血管三维图像，并提出肝脏微血管密度是预测临床显著门脉高压症的形态学指标。本研究首先运用X线相衬CT技术，获得大鼠肝纤维化模型肝内胆管三维图像，分析胆管表面结构、分支模式及胆道内微观结构，阐述胆管形态的动态演变；其次，通过三维CT图像及二维病理图像，量化胆管增生体积比、面积比及胆管密度，探索胆管数量的变化规律；最后，分析胆管形态及数量改变与门脉压力之间的关系，阐释胆管改变在预测门脉高压症中的价值，评估胆管数量能否成为预测门脉高压症的形态学指标。本研究从胆管增生角度，旨在探讨胆管系统在门脉高压症中的作用，这是对门脉高压症病理形态学特点的补充，并为门脉高压症的诊断提供新的思路。

背景：肝硬化过程中伴有胆管增生，但胆管压力变化尚不清楚。方法：四氯化碳（CCl4）诱导大鼠肝硬化模型，测量不同阶段大鼠门脉压力及胆管压力。观察胆管形态及数量变化，分析肝硬化不同阶段胆管压力变化趋势，探索胆管压力与病理学指标、门脉压力之间的相关性。结果：对照组CK19阳性区域仅位于汇管区胆管壁上；肝硬化时，汇管区以及纤维间隔见大量被CK19标记的新生胆管。对照组，胆管密度、胆管面积分别为5.57±1.73number/mm2、0.64%（0.38%-0.97%）。肝硬化时，胆管密度、胆管面积较对照组分别增加3.73倍、3.58倍，较对照组均有统计学差异。随着胆管数量的增加，胆管压力也明显升高，肝硬化组胆管压力高至19.61mmHg（18.52-21.91mmHg）。将相关指标与胆管压力之间进行相关性分析，结果显示，胆管压力与门脉压力、胶原面积、血管密度、胆管密度、胆管面积均呈正相关，其中与门脉压力之间相关性最好（r=0.778，P＜0.001）。将上述指标纳入多元线性回归分析，胆管压力与门脉压力仍有良好相关性（R=0.781，P＜0.001，调整后的R2=0.599）。逐步建模表明，确定胆管压力值的主要影响因素是门脉压力，胆管压力的推导公式如下：胆管压力=0.631×门脉压力+9.412。结论：在肝硬化形成过程中，随着胆管数量的增加，胆管压力升高，并且胆管压力与门脉压力相关，通过门脉压力可以计算胆管压力。临床意义：本研究第一次对肝硬化不同阶段大鼠胆管压力进行了系统测量，发现了胆管压力与门脉压力的相关性，使肝硬化过程胆管结构变化与压力变化联系在一起，为研究肝硬化与胆管病变提供了新的依据，并为测量胆管压力提供了方法。