肝脏黏弹性超声定量评估炎症坏死和纤维化程度的实验研究

Liver fibrosis is the pathology characteristic of liver cirrhosis and hepatocellular carcinoma in early stage. Precise assessment on its progression and reversion is crying needs in modern treatment. Ultrasound elastography has been recommended as a noninvasive method for the staging of hepatic fibrosis by the clinical practice guidelines. The ultrasound elastography in clinic only detects tissue elasticity, and ignores tissue viscosity. However, biological tissue is inherently viscoelastic. It is difficult to eliminate the influences of inflammation and necrosis on liver fibrosis judgment. The new technology of ultrasound elastography for quantitative testing hepatic viscoelasticity meets the precision medicine development trend and is the development direction of ultrasound elastography. This project proposes that quantitative measurement of hepatic viscoelasticity can accurately response the mechanical properties of the liver and accurately diagnose liver fibrosis stages. The animal models of liver fibrosis and acute hepatic failure are the research objects. The liver pathological inflammatory and necrosis grading and fibrosis staging are the reference standards. The internal relations between hepatic viscoelasticity and liver pathological changes are analyzed. A joint diagnosis method based on hepatic elasticity and viscosity is built, which could eliminate the influences of inflammation and necrosis on liver fibrosis judgment and accurately diagnose liver fibrosis stages. The project will provide a new method for noninvasive assessment of liver fibrosis and fundamentally improve the diagnostic accuracy. So it has a great clinical significance.

肝纤维化是肝硬化和肝癌的早期病理特征，精准评判其进展-逆转是现代治疗方法的迫切要求。超声弹性成像无创性评估肝纤维化程度已得到临床指南的认可和推荐。然而目前临床上采用的超声弹性成像方法均忽略组织黏性，仅反应组织弹性，不符合生物组织是一种黏弹性材料的特征，难以排除炎症坏死对肝纤维化程度判断的影响。采用超声弹性成像新技术定量检测肝脏黏弹性符合精准医疗发展趋势，是超声弹性成像发展方向。本项目提出，定量检测肝脏黏弹性能更准确反应肝脏的生物力学特性，能够精确诊断肝纤维化分期。以肝纤维化和急性肝衰竭动物模型为研究对象，肝脏病理炎症坏死分级和纤维化分期为参考标准，分析肝脏弹性和黏性与病理改变的内在联系，构建基于弹性和黏性的联合诊断方法，排除炎症坏死对肝纤维化程度判断的影响，实现精确诊断肝纤维化分期。本项目将为无创性评估肝纤维化程度提供新的方法，从根本上提高诊断准确性，具有重要临床意义。

超声弹性成像无创性评估肝纤维化程度已得到临床指南的认可和推荐。然而目前临床上采用的超声弹性成像方法均忽略组织黏性，仅反应组织弹性，不符合生物组织本质上是黏弹性体的特征，并无法区分肝脏纤维化和炎症坏死对弹性测值的影响。本项目分为动物实验和临床研究两部分。动物实验主要内容为采用临床超声设备和实验室设备两种手段检测肝纤维化和急性肝衰竭大鼠的肝脏弹性和黏性测值，分析肝脏弹性和黏性测值与纤维化和炎症坏死程度的关系。临床研究主要内容为分析ALT和TB水平对肝脏弹性测值的影响，以及不同肝病患者肝脏弹性和黏性测值，为超声弹性成像新技术定量检测肝脏黏弹性在临床推广应用提供理论依据。动物实验研究结果显示，临床超声设备检测的肝脏弹性测值在急性肝衰竭组明显高于肝硬化组，证实了肝脏炎症坏死会明显升高弹性测值。大鼠肝脏弹性测值与纤维化和炎症坏死程度均相关，但黏性测值仅与炎症坏死程度相关，且相关性高于弹性测值，并能够区分显著和严重炎症坏死程度。临床研究结果显示，ALT>2×ULN时，相同肝纤维化分期的肝脏弹性测值会显著升高，TB水平同样影响肝脏弹性测值，TB升高导致肝脏弹性测值评估肝纤维化分期的准确性降低，假阳性率升高。健康志愿者和不同慢性肝病患者，肝脏黏性参数各组间比较均有统计学差异，说明黏性参数具有临床使用价值。在慢加急性肝衰竭患者病情转归过程中，黏性参数和弹性参数呈现不同的趋势变化，说明两者反应不同的肝脏病理状态。因此，本项目研究从动物实验到临床研究证实了炎症坏死对肝脏弹性测值的影响，肝脏黏性测值与炎症坏死程度有较好相关性，可用于区分肝脏不同的炎症坏死程度，以避免单一肝脏弹性测值高估肝纤维化分期的问题，实现肝纤维化和炎症坏死程度的超声全面评估，提高诊断准确性，具有较好的临床应用价值和前景。