A multiscale-multiparametric metabolic-mechanical model (M5) to enable identification of structural-functional changes of the liver using quantitative MRI and MR elastography

• Applicants: Privatdozent Dr. Nikolaus Berndt; Privatdozent Dr. Rolf Otto Reiter; Professor Dr.-Ing. Tim Ricken; Professor Dr. Ingolf Sack
• Subject Area: Radiology ; Applied Mechanics, Statics and Dynamics ; Biochemistry ; Gastroenterology ; Mechanics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540759292

Background: The early diagnosis of liver diseases is still a major challenge because clinical symptoms often appear only when metabolic dysfunction and structural damage of the liver have progressed to an advanced stage. In clinical practice, different basic techniques are used to diagnose liver disease: Imaging techniques are used to detect and characterize morphological changes in liver tissue; and plasma markers, such as transaminases or bilirubin, can indicate accelerated cell death and decline in central metabolic liver functions. However, liver biopsies and histological gradings remain the gold standard and to date, it has been virtually impossible to translate the macroscale data obtained with non-invasive techniques into structural and metabolic changes at the cellular and tissue level. Objective: This project aims to develop a multiscale-multiparametric metabolic-mechanical model (M5) of the liver, which allows relating patient-specific profiles of plasma markers and imaging data obtained by quantitative magnetic resonance imaging (qMRI) and elastography (MRE) to perturbations of cellular metabolism and microarchitecture. We will study how microstructural changes (e.g., restricted perfusion due to increased cellular fat content and fibrosis) and metabolic changes (e.g., altered expression and hormonal regulation of metabolic pathways) translate into non-invasive clinical data from elastography and plasma profiling. Based on this knowledge, it will be possible to estimate the metabolic reserve capacity of individual livers and to support clinicians in the optimal choice of surgical and pharmacological therapy. Methods: We describe the whole liver as an ensemble of liver lobules represented by homogenized porous continuum models. A single lobule is composed of sinusoidal tissue units consisting of metabolically active hepatocytes, extracellular tissue, and capillaries. Mathematically, the coupling of dynamic processes at different spatial scales results in a large, numerically demanding system of partial and ordinary differential equations describing the biomechanical and metabolic changes, respectively. To parameterize the model, we will use proteomic and histological data from a mouse model of non-alcoholic steatohepatitis (NASH) with defined disease activity scores. Model refinement and validation will be performed by comparing numerical model simulations with qMRI/MRE parameters and metabolic plasma profiles obtained from healthy volunteers exposed to targeted perturbations, such as water intake or breathing exercises, and from patients with biopsy-proven NASH of varying degrees (mild, moderate, severe). By linking microstructure and metabolism with in vivo biomechanical and biophysical imaging data, M5 will for the first time bridge the scale between the cellular, tissue, and whole organ levels to help diagnose diffuse liver disease and predict liver reserve capacity.

• DFG Programme: Research Grants