Comparative Medicine, Pfizer Inc.
Digital Medicine & Translational Imaging, Pfizer Inc.
J Vis Exp. 2021 Apr 20(170). doi: 10.3791/62403.
Nonalcoholic Steatohepatitis (NASH) is a condition within the spectrum of Non-Alcoholic Fatty Liver Disease (NAFLD), which is characterized by liver fat accumulation (steatosis) and inflammation leading to fibrosis. Preclinical models closely recapitulating human NASH/NAFLD are essential in drug development. While liver biopsy is currently the gold standard for measuring NAFLD/NASH progression and diagnosis in the clinic, in the preclinical space, either collection of whole liver samples at multiple timepoints during a study or biopsy of liver is needed for histological analysis to assess the disease stage. Conducting a liver biopsy mid-study is an invasive and labor-intensive procedure, and collecting liver samples to assess disease level increases the number of research animals needed for a study. Thus, there is a need for a reliable, translatable, non-invasive imaging biomarker to detect NASH/NAFLD in these preclinical models. Non-invasive ultrasound-based B-mode images and Shear Wave Elastography (SWE) can be used to measure steatosis as well as liver fibrosis. To assess the utility of SWE in preclinical rodent models of NASH, animals were placed on a pro-NASH diet and underwent non-invasive ultrasound B-mode and shear wave elastography imaging to measure hepatorenal (HR) index and liver elasticity, measuring progression of both liver fat accumulation and tissue stiffness, respectively, at multiple time points over the course of a given NAFLD/NASH study. The HR index and elasticity numbers were compared to histological markers of steatosis and fibrosis. The results showed strong correlation between the HR index and percentage of Oil Red O (ORO) staining, as well as between elasticity and Picro-Sirius Red (PSR) staining of livers. The strong correlation between classic ex vivo methods and in vivo imaging results provides evidence that shear wave elastography/ultrasound-based imaging can be used to assess disease phenotype and progression in a preclinical model of NAFLD/NASH.
非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病（NAFLD）的疾病谱，其特征是肝脏脂肪堆积（脂肪变性）和炎症导致纤维化。临床前模型能够很好地重现人类 NASH/NAFLD，这对于药物开发至关重要。虽然肝活检是目前临床上测量 NAFLD/NASH 进展和诊断的金标准，但在临床前领域，需要在研究过程中的多个时间点收集整个肝脏样本或进行肝活检，以便进行组织学分析以评估疾病阶段。进行中期肝活检是一种侵入性和劳动密集型的程序，并且收集肝脏样本以评估疾病水平会增加研究所需的研究动物数量。因此，需要一种可靠、可转化、非侵入性的成像生物标志物来检测这些临床前模型中的 NASH/NAFLD。基于超声的 B 模式图像和剪切波弹性成像（SWE）可用于测量脂肪变性和肝纤维化。为了评估 SWE 在 NASH 临床前啮齿动物模型中的效用，动物被置于促 NASH 饮食中，并进行非侵入性超声 B 模式和剪切波弹性成像成像，以分别测量肝肾功能（HR）指数和肝脏弹性，在给定的 NAFLD/NASH 研究过程中的多个时间点测量肝脂肪积累和组织硬度的进展。将 HR 指数和弹性数值与脂肪变性和纤维化的组织学标志物进行比较。结果表明，HR 指数与油红 O（ORO）染色的百分比之间以及肝脏弹性与苦味酸-天狼星红（PSR）染色之间具有很强的相关性。经典的离体方法与体内成像结果之间的强相关性提供了证据，表明剪切波弹性成像/基于超声的成像可用于评估 NAFLD/NASH 临床前模型中的疾病表型和进展。
