Mechanical properties are promising surrogates for monitoring and characterizing various pathophysiologic conditions of cells and tissues. For example, we have pioneered the development of liver MR elastography (MRE), a noninvasive imaging technology for measuring liver stiffness, which is beginning to see widespread clinical use for assessing hepatic fibrosis as an alternative to biopsy. Despite this progress, there is a need to further develop hepatic MRE so that it can have the precision necessary to track disease progression and response to therapy. Several intrinsic pathologic conditions of the liver (e.g., inflammation) compromise the positive predictive value of liver stiffness for characterizing hepatic fibrosis alone. These factors cause similar amounts of stiffness augmentation but have different pathophysiological origins and correspond to different architectural changes. Therefore, the major goal of this proposal is to develop advanced hepatic MRE techniques, including poroviscoelastic (PVE) mechanical models, capable of differentiating inflammation and fibrosis while considering the effects of steatosis in the liver tissue. Our basic assumption is that liver tissue can reasonably be modeled using biphasic PVE theory consisting of an intrinsically isotropic incompressible viscoelastic solid matrix phase and an incompressible saturated fluid phase. The hypothesis is that analysis of time-harmonic hepatic MRE data based on such a PVE model will enable the separation of the steatosis- and fibrosis-related solid matrix mechanical responses from that of the inflammation-related pore fluid behavior.
In Aim 1, we will implement a PVE analysis method to determine PVE parameters and evaluate the key assumptions of the model in phantom studies.
In Aim 2, we will use an acute hepatic inflammation mouse model to evaluate the potential for a PVE model to differentiate and quantify inflammation extent by testing whether noninvasively calculated PVE pore pressure significantly correlates with invasively measured interstitial fluid pressure (IFP), indicating tha it could be used as a surrogate for histology-proven inflammation extent.
In Aim 3, we will further evaluate the potential for PVE hepatic MRE to differentiate and quantify coexisting inflammation and fibrosis in mouse models with chronic liver disease (NAFLD/NASH mouse model). We hypothesize that significant correlations can be found among MRE-assessed PVE parameters (elasticity, viscosity &pore pressure) and hepatic histology (fibrosis, steatosis &inflammation).
In Aim 4, we will perform a translational human study using existing patient data to determine if there is at least one or a combination of several PVE parameters that can distinguish and quantify progressive steatosis, early onset and ongoing inflammation and subsequently developed hepatic fibrosis in the liver. The success of this proposed study will maximize the clinically relevant information provided by hepatic MRE to substantially advance our understanding and ability to diagnose disease progress in the broad pathophysiologic spectrum of chronic liver diseases.
We will develop techniques to differentiate and quantify steatosis, fibrosis and inflammation in liver disease using a biphasic poroviscoelastic model and hepatic MR elastography (MRE) data from in vivo mouse models and biopsy-proven patients with chronic liver diseases. The success of this proposed study will maximize the clinically relevant information provided by hepatic MRE to substantially advance our understanding and ability to diagnose disease progress in the broad pathophysiologic spectrum of chronic liver diseases.