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 c , 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 c 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.

Nonlinear viscoelastic constitutive model for bovine liver tissue

“…Although the range of frequencies investigated here is small (0.5-2Hz), the models presented in this study are applicable for other frequencies as well. The fractional order is related to the frequency response, and the value identified in this study ( = 0.2 ) is in good agreement with literature findings (Liu and Bilston 2000;Jordan et al 2011;Sinkus et al 2018;Asbach et al 2008). Thus, by choosing the nonlinear parameters presented in Fig.…”

“…For diagnosis purposes, elastography is a technique that depends on the underlying tissue properties in order to assess the presence of disease (Fovargue et al 2018). In vivo magnetic resonance elastography (MRE) has shown that the existence of liver inflammation and fibrosis gives higher stiffness measurements (Huwart et al 2006;Sinkus et al 2018). However, coexisting diseases (Mueller et al 2010) and the bias introduced by large deformations on elastography measurements (Capilnasiu et al 2019) can further complicate the diagnosis.…”

“…Multifrequency soft tissue measurements of the shear modulus G * indicate a fractional-order dependence on the angular frequency in the form of G * ∝ (Holm and Sinkus 2010), with ∈ [0.2, 0.35] [e.g. ≈ 0.23 (Liu and Bilston 2000), ≈ 0.26 (Jordan et al 2011;Sinkus et al 2018), ≈ 0.32 (Asbach et al 2008)]. Other biomechanical properties of the liver have also been investigated, such as relaxation (Liu and Bilston 2006;Chatelin et al 2011) and creep (Wang et al 1992).…”

Editorial for “Dual‐Frequency MR Elastography to Differentiate Between Inflammation and Fibrosis of the Liver: Comparison With Histopathology”

“…These findings support earlier work that on a physical level it untangles the effects of inflammation and fibrosis. Indeed, by modifying the rheological model used to derive biomechanical properties from the raw data, Sinkus et al in that article showed how fibrosis and inflammation act on specific and different components of the model . The current article's confirmation of these effects is a promising development, as the noninvasive estimation of inflammatory activity takes a further step towards clinical application.…”

Spring–damper equivalents of the fractional, poroelastic, and poroviscoelastic models for elastography

“…That seems often to be the case for elastography data. 20,21 Publications report observed values for the compliance of both models also follows a Mittag-Leffler function. That means that the creep time-and frequency-spectral functions of the two models will also be similar.…”