Rheological determinants for simultaneous staging of hepatic fibrosis and inflammation in patients with chronic liver disease

Abstract

The purpose of this study is to investigate the use of fundamental rheological parameters as quantified by MR elastography (MRE) to measure liver fibrosis and inflammation simultaneously in humans. MRE was performed on 45 patients at 3 T using a vibration frequency of 56 Hz. Fibrosis and inflammation scores were obtained from liver biopsies. Biomechanical properties were quantified in terms of complex shear modulus G^* as well as shear wave phase velocity c and shear wave attenuation α. A rheological fractional derivative order model was used to investigate the linear dependence of the free model parameters (dispersion slope y, intrinsic speed c₀ , and intrinsic relaxation time τ) on histopathology. Leave-one-out cross-validation was then utilized to demonstrate the effectiveness of the model. The intrinsic speed c₀ increases with hepatic fibrosis, while an increased relaxation time τ is reflective of more inflammation of the liver parenchyma. The dispersion slope y does not depend either on fibrosis or on inflammation. The proposed rheological model, given this specific parameterization, establishes the functional dependences of biomechanical parameters on histological fibrosis and inflammation. The leave-one-out cross-validation demonstrates that the model allows identification, from the MRE measurements, of the histology scores when grouped into low-/high-grade fibrosis and low-/high-grade inflammation with significance levels of P = 0.0004 (fibrosis) and P = 0.035 (inflammation). The functional dependences of intrinsic speed and relaxation time on fibrosis and inflammation, respectively, shed new light onto the impact hepatic pathological changes on liver tissue biomechanics in humans. The dispersion slope y appears to represent a structural parameter of liver parenchyma not impacted by the severity of fibrosis/inflammation present in this patient cohort. This specific parametrization of the well-established rheological fractional order model is valuable for the clinical assessment of both fibrosis and inflammation scores, going beyond the capability of the plain shear modulus measurement commonly used for MRE.

Keywords: MR elastography; chronic liver disease; fibrosis; hepatitis; inflammation; liver biopsy; rheological model; viscosity.

Figure 1

A: patient population in the HAI fibrosis/inflammation plane. B–F: results of the MRE acquisition for a selected patient depicting anatomy, shear waves, wave speed c_s, attenuation α, viscosity Gl and dispersion slope 2 − 2y of the shear modulus.

Figure 2

Dependence of the damping ratio Q (Eqn.(6)) on fibrosis and inflammation, respectively (A,B). Shown are the mean and corresponding errors on mean values (which are very small). Data suggest that Q is a generic parameter that is not impacted by the histopathology environment. A mean value for the power-law slope of y=0.89±0.003 is found (error on mean C). This corresponds to an average power-law exponent for the shear modulus of 0.22 = 2 − 2y, which is what is seen in Fig.1G.

Figure 3

Dependence of viscoelastic parameters as quantified by MRE on HAI fibrosis and inflammation scores. Shear speed rises linearly with fibrosis (A), while there is almost no dependency on inflammation (B). Attenuation drops only mildly with inflammation (C) while viscosity is rising notably with inflammation (D).

Figure 4

Resulting viscoelastic parameter estimates (blue triangle) when using the established model with the corresponding values found for the four free parameters (Eq.11,12). While the shear speed can be reproduced with high accuracy, as expected, the functional dependencies on inflammation have larger variations.

Figure 5

Estimated HAI scores versus true HAI scores (A, B) for fibrosis and inflammation, respectively. Regrouping the datasets into low/high grade fibrosis/inflammation (C, D) demonstrates ability of the model to differentiate groups with statistically significant P-values of 0.0004 and 0.0351, respectively.