Geert Peeters

A Multilevel Modeling Framework to Study Hepatic Perfusion Characteristics in Case of Liver Cirrhosis

Liver cirrhosis represents the end-stage of different liver disorders, progressively affecting hepatic architecture, hemodynamics, and function. Morphologically, cirrhosis is characterized by diffuse fibrosis, the conversion of normal liver architecture into structurally abnormal regenerative nodules and the formation of an abundant vascular network. To date, the vascular remodeling and altered hemodynamics due to cirrhosis are still poorly understood, even though they seem to play a pivotal role in cirrhogenesis. This study aims to determine the perfusion characteristics of the cirrhotic circulation using a multilevel modeling approach including computational fluid dynamics (CFD) simulations. Vascular corrosion casting and multilevel micro-CT imaging of a single human cirrhotic liver generated detailed datasets of the hepatic circulation, including typical pathological characteristics of cirrhosis such as shunt vessels and dilated sinusoids. Image processing resulted in anatomically correct 3D reconstructions of the microvasculature up to a diameter of about 500 μm. Subsequently, two cubic samples (150 × 150 × 150 μm³) were virtually dissected from vascularized zones in between regenerative nodules and applied for CFD simulations to study the altered cirrhotic microperfusion and permeability. Additionally, a conceptual 3D model of the cirrhotic macrocirculation was developed to reveal the hemodynamic impact of regenerative nodules. Our results illustrate that the cirrhotic microcirculation is characterized by an anisotropic permeability showing the highest value in the direction parallel to the central vein (kd,zz = 1.68 × 10-13 m² and kd,zz = 7.79 × 10⁻¹³ m² for sample 1 and 2, respectively) and lower values in the circumferential (kd,ϑϑ = 5.78 × 10⁻¹⁴ m² and kd,ϑϑ = 5.65 × 10⁻¹³ m² for sample 1 and 2, respectively) and radial (kd,rr = 9.87 × 10⁻¹⁴ m² and kd,rr = 5.13 × 10⁻¹³ m² for sample 1 and 2, respectively) direction. Overall, the observed permeabilities are markedly higher compared to a normal liver, implying a locally decreased intrahepatic vascular resistance (IVR) probably due to local compensation mechanisms (dilated sinusoids and shunt vessels). These counteract the IVR increase caused by the presence of regenerative nodules and dynamic contraction mechanisms (e.g., stellate cells, NO-concentration, etc.). Our conceptual 3D model of the cirrhotic macrocirculation indicates that regenerative nodules severely increase the IVR beyond about 65 vol. % of regenerative nodules. Numerical modeling allows quantifying perfusion characteristics of the cirrhotic macro- and microcirculation, i.e., the effect of regenerative nodules and compensation mechanisms such as dilated sinusoids and shunt vessels. Future research will focus on the development of models to study time-dependent degenerative adaptation of the cirrhotic macro- and microcirculation.

Quantitative analysis of hepatic macro- and microvascular alterations during cirrhogenesis in the rat

Cirrhosis represents the end‐stage of any persistent chronically active liver disease. It is characterized by the complete replacement of normal liver tissue by fibrosis, regenerative nodules, and complete fibrotic vascularized septa. The resulting angioarchitectural distortion contributes to an increasing intrahepatic vascular resistance, impeding liver perfusion and leading to portal hypertension. To date, knowledge on the dynamically evolving pathological changes of the hepatic vasculature during cirrhogenesis remains limited. More specifically, detailed anatomical data on the vascular adaptations during disease development is lacking. To address this need, we studied the 3D architecture of the hepatic vasculature during induction of cirrhogenesis in a rat model. Cirrhosis was chemically induced with thioacetamide (TAA). At predefined time points, the hepatic vasculature was fixed and visualized using a combination of vascular corrosion casting and deep tissue microscopy. Three‐dimensional reconstruction and data‐fitting enabled cirrhogenic features to extracted at multiple scales, portraying the impact of cirrhosis on the hepatic vasculature. At the macrolevel, we noticed that regenerative nodules severely compressed pliant venous vessels from 12 weeks of TAA intoxication onwards. Especially hepatic veins were highly affected by this compression, with collapsed vessel segments severely reducing perfusion capabilities. At the microlevel, we discovered zone‐specific sinusoidal degeneration, with sinusoids located near the surface being more affected than those in the middle of a liver lobe. Our data shed light on and quantify the evolving angioarchitecture during cirrhogenesis. These findings may prove helpful for future targeted invasive interventions.

Vascular morphology alterations during liver cirrhogenesis in rats

Authors: Geert Peeters, Charlotte Debbaut, Winnok H. De Vos, Pieter Cornillie, Thomas De Schryver, Diethard Monbaliu, Wim Laleman, Patrick Segers 1 IBiTech – bioMMeda, Dept. Electronics and Information Systems, Ghent University, Belgium 2 Lab. Cell Biology and Histology, Dept. Veterinary Sciences, University of Antwerp, Belgium 3 Cell Systems and Imaging, Dept. Molecular Biotechnology, University of Ghent, Belgium 4 Dept. Morphology, Faculty of Veterinary Medicine, Ghent University, Belgium 5 Centre for X-Ray Tomography, Dept. Physics and Astronomy, Ghent University, Belgium 6 Abdominal Transplant Surgery, University Hospitals Leuven, Belgium 7 Dept. Microbiology and Immunology, KU Leuven, Belgium 8 Gastroenterology & Hepatology, University Hospitals Leuven, Belgium 9 Jessa Hospital, Hasselt, Belgium 10 Dept. Clinical and Experimental Medicine, KU Leuven, Belgium

A multilevel framework to reconstruct anatomical 3D models of the hepatic vasculature in rat livers (vol 230, pg 471, 2017) (corrigendum)

Geert Peeters, Charlotte Debbaut, Wim Laleman, Adrian Friebel, Diethard Monbaliu, Ingrid Vander Elst, Jan R. Detrez, Tim Vandecasteele, Tim Johann, Thomas De Schryver, Luc Van Hoorebeke, Kasper Favere, Jonas Verbeke, Dirk Drasdo, Stefan Hoehme, Patrick Segers, Pieter Cornillie, Winnok H. De Vos IBiTech – bioMMeda, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany Institute of Computer Science, University of Leipzig, Leipzig, Germany (Present address) Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium INRIA Paris & Sorbonne Universit es UPMC Univ Paris 6, LJLL, France (Permanent address) Centre for X-Ray Tomography, Department of Physics and Astronomy, Ghent University, Ghent, Belgium Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany Cell Systems and Imaging, Department of Molecular Biotechnology, Ghent University, Ghent, Belgium *Shared senior co-authorship

P22 NUMERICAL SIMULATIONS TO CHARACTERIZE THE HEPATIC MICROCIRCULATION IN HUMAN CIRRHOSIS

Background and aim: Liver cirrhosis is a chronic liver disease, comprising a wide spectrum of pathological characteristics affecting liver micro-architecture, structure and perfusion (e.g. shunt vessels, fibrosis, regenerative nodules). This degenerative disease deteriorates liver function and may lead to an elevated intrahepatic vascular resistance. The hemodynamic consequences of cirrhosis, especially at microcirculation level, are not yet fully understood. To this end, we performed numerical simulations to assess the perfusion characteristics of the dysregulated microcirculation.