The current gold standard for evaluating the progression of liver diseases includes a combination of serum testing, liver biopsy, and, as the disease progresses, hepatic venous pressure gradient (HVPG) measurement. Ultrasound provides an opportunity to evaluate two aspects of clinical hepatic disease that are traditionally mea- sured invasively: liver fibrosis and HVPG. The first, ultrasound characterization of liver fibrosis, has been ex- tensively studied with relation to comparing biopsy-based fibrosis stage to noninvasively obtained quantitative estimates of liver stiffness. Specifically, Acoustic Radiation Force Impulse (ARFI) based quantitative estimation of tissue stiffness has successfully distinguished advanced from moderate hepatic fibrosis noninvasively. Recent studies have suggested that ultrasound-based estimates of liver stiffness also increase with hepatic venous pressurization. These changes in stiffness metrics with hepatic interstitial pressure may confound stiffness-based predictions of liver fibrosis stage. The underlying mechanism for this observed stiffening behavior with pressurization is not well understood, and is not explained with commonly used linear elastic mechanical models. The project designed in this proposal combines data collected from ex-vivo liver samples, nonlinear tissue-mimicking materials, and finite element simulations to better understand the observed hepatic pressure-dependent stiffening and evaluate the potential for hepatic pressure characterization in-vivo. A strain-dependent hyperelastic model can provide the basis for understanding observed hepatic stiffening with pressurization. The proposed work involves development and validation of this model using parametric analyses of finite element simulations and calibration to nonlinear tissue-mimicking materials. Preliminary data have been obtained using a custom designed experimental setup that allows pressurization of excised livers under both constrained and unconstrained conditions. Once the model has been validated, ARFI-based experimental ex-vivo hepatic stiffness measures under various pressurization states will be fit to established nonlinear material parameters. The primary goal of the proposed project is to use the nonlinear hepatic model to investigate methods to noninvasively characterize liver pressures using ARFI-based shear stiffness metrics in order to reduce the need for catheter-based HVPG measurements. Nonlinear tissue-mimicking materials will be deformed similarly to the strain state observed with hepatic pressurization and two ultrasound transducers will be used to determine whether ARFI-based stiffness metrics and knowledge of underlying material properties can be used to find the deformation state of the liver. This experimental setup can also be used on ex-vivo hepatic pressurization experiments prior to clinical testing. Imaging compressed nonlinear phantoms with two transducers will test the hypothesis that the nonlinear behavior of the liver under pressure can be exploited to noninvasively estimate HVPG.
The proposed project will investigate a method for noninvasive, ultrasonic hepatic pressure quantification. If successful, this method would obviate the need for invasive, catheter-based hepatic pressure measurements.