Encéphalopathie hépatique | EPFL Graph Search

L'encéphalopathie hépatique est un syndrome neuropsychiatrique complexe secondaire à une insuffisance hépato-cellulaire. Elle est caractérisée par des modifications de l’état de conscience et du comportement, des changements de personnalité, des signes neurologiques et des changements à l’électroencéphalogramme (EEG). Il peut être aigu et réversible (insuffisance hépatique aiguë) ou chronique et irréversible. Elle complique chaque année une cirrhose sur cinq et est associée avec un pronostic altéré. Elle peut être classée en trois types selon sa cause : type A, secondaire à une insuffisance hépatique aiguë ; type B, secondaire à un shunt porto-cave (i.e. un court-circuit du système porte hépatique vers la veine cave) ; type C, post cirrhotique. La cause première de l'encéphalopathie hépatique est l'association d'une insuffisance hépato-cellulaire et d'un shunt porto-systémique causé par l'hypertension portale. Une relation certaine existe entre l'encéphalopathie hépatique et l'augmentation de l’ammonium sérique, due à l'accumulation de son précurseur, la glutamine, qui aurait un effet toxique direct sur le cerveau. La glutamine est théoriquement transformée en glutamate et en ammonium puis en urée par le foie. En cas de défaillance de cet organe, le taux sanguin de ces métabolites augmente fortement. Par ailleurs, l'ammonium est également métabolisé dans les cellules musculaires, l'atrophie musculaire pouvant donc aggraver la situation. Un syndrome inflammatoire peut en aggraver les symptômes. D'autres métabolites comme les mercaptans seraient aussi neurotoxiques. D'autre part, certains neurotransmetteurs dégradés dans le foie, comme le GABA, pourraient se trouver en excès dans le cerveau et participer à l'altération du niveau de vigilance. Enfin, certains arguments plaident en faveur d'un rôle possible du manganèse ; en effet, l'IRM encéphalique montre des images traduisant des dépôts de cet élément dans le globus pallidus. Le microbiote intestinal pourrait également jouer un rôle.

Advanced metabolite mapping at ultra-high field using 1H-MRS, 1H-MRSI and macromolecules: applications in a rat model of type C hepatic encephalopathy

Dunja Simicic

Magnetic Resonance Spectroscopy (MRS) is the only technique capable of measuring a large number of metabolites simultaneously in vivo. Ultra-high magnetic fields (UHF) combined with ultra-short echo time (TE) sequences allow the detection of high-quality 1H MR spectra and the quantification of 20 different metabolites in the brain (markers of energy metabolism, osmoregulation etc.).In vivo brain localized 1H MR spectra at short TEs contain the contribution of mobile macromolecules (MM). Reliable detection and fitting of MM are crucial for accurate quantification. Higher spectral resolution at UHF led to increased interest in using a parametrized MM spectrum and flexible spline baselines to address unpredicted spectroscopic components.In this thesis the MM spectra (from the rat brain at 9.4T) were characterized using an improved methodological approach for their post-processing, fitting and quantification. This method provided an efficient tool for parametrization of the MM spectrum into individual components and estimation of their T2app relaxation times. An extensive assessment on how the MM spectrum and spline baseline stiffness affect the metabolite and MM quantification is also reported Type C hepatic encephalopathy (HE) is a complication of chronic liver disease (CLD). Children and adults respond differently to CLD and its related toxic accumulation of molecules (i.e. ammonium (NH4+), glutamine (Gln)). Children with CLD may grow up with significant neurocognitive deficits even after liver transplantation. Despite considerable advances in understanding the pathogenesis of type C HE, the exact metabolic mechanisms and their regional variations are not fully understood.The advantages of UHF short TE 1H MRS were used herein to describe the regional distribution of metabolites in the developing and adult brain using the bile duct ligated model (BDL) of type C HE (adult and postnatal day 21 rats). Three brain regions were assessed (hippocampus, cerebellum and striatum) pointing towards cerebellum as a region with the heaviest burden of Gln and unique metabolic response. Changes in cell morphology were followed longitudinally and related to the metabolic alterations. Elevated oxidative stress is reported using electron paramagnetic resonance, together with the decreased antioxidants (1H MRS) emphasizing its important role in HE. The brain regional measurements confirmed the higher susceptibility of developing brain to the disease and the increased vulnerability of cerebellum. Finally, the beneficial effect of Cr supplementation on the neurometabolic profile is described using 1H MRS and 31P MRS in CLD pups (BDL at postnatal day 15) suggesting that an appropriate treatment may have significant public health impact.MRSI is a powerful tool to non-invasively and spatially map the brain regional distribution of metabolites in vivo. While MRSI in human brain is increasingly used, preclinical MRSI is not widely applied mainly due to the small rodent brain, long acquisition times and low signal to noise ratio. The implementation of a novel approach: free induction decay (FID) MRSI on the 14.1T preclinical scanner is described herein. This method offers a fast and robust data acquisition with high spatial resolution resulting in high quality spectroscopic maps. Finally, preliminary assessment of the effect of two noise reduction techniques (MP-PCA and TGV reconstruction) on the spectra from preclinical MRSI datasets is briefly presented.

EPFL2022

Overview of oxidative stress findings in hepatic encephalopathy: From cellular and ammonium-based animal models to human data

Cristina Ramona Cudalbu

Oxidative stress is a natural phenomenon in the body. Under physiological conditions intracellular reactive oxygen species (ROS) are normal components of signal transduction cascades, and their levels are maintained by a complex antioxidants systems participating in the in-vivo redox homeostasis. Increased oxidative stress is present in several chronic diseases and interferes with phagocytic and nervous cell functions, causing an up -regulation of cytokines and inflammation. Hepatic encephalopathy (HE) occurs in both acute liver failure (ALF) and chronic liver disease. Increased blood and brain ammonium has been considered as an important factor in pathogenesis of HE and has been associated with inflammation, neurotoxicity, and oxidative stress. The relationship between ROS and the pathophysiology of HE is still poorly understood. Therefore, sensing ROS production for a better understanding of the relationship between oxidative stress and functional outcome in HE pathophysiology is critical for determining the disease mechanisms, as well as to improve the management of patients.This review is emphasizing the important role of oxidative stress in HE development and documents the changes occurring as a consequence of oxidative stress augmentation based on cellular and ammonium-based animal models to human data.

ACADEMIC PRESS INC ELSEVIER SCIENCE2022

Development and applications of hyperpolarized 13C and 1H MR spectroscopy of cerebral metabolism at ultra-high field

Emmanuelle Ines Flatt

This thesis is composed of four studies centered on investigating cerebral metabolism using magnetic resonance spectroscopy (MRS) of hyperpolarized and non-hyperpolarized compounds at ultra-high field. In the first two chapters, we studied longitudinally the effects of different treatments for hepatic encephalopathy (HE) on the neurometabolic changes associated with chronic HE using a rat model of type C HE and a multimodal approach including 1H MRS. The effects of the antibiotic rifaximin administered at different doses as well as its combination with probiotics were studied in the established model of bile duct ligated (BDL) rats. We showed for the first time the beneficial effects of the combined rifaximin and the probiotic Vivomixx® on the neurometabolic changes in vivo and longitudinally in a rat model of type C HE. The longitudinal changes of some brain metabolites concentration (glutamine, glutamate, creatine), as well as gut bifidobacteria concentration, were significantly less pronounced in the group of rats treated with rifaximin and probiotics compared to non-treated rats. We also showed that rifaximin treatment alone had limited efficacy. When administered at human dose in rats, its effects appeared only at the early stages of the disease, whereas at a higher dose some neurometabolic changes associated with HE were attenuated but the general condition of the rats was worse. In the third study, we used dissolution dynamic nuclear polarization (DNP) to hyperpolarize [2H7, U-13C6]-D-glucose, which enabled us to monitor real-time glycolysis in the healthy mouse brain. Given that glucose metabolism is tightly linked to neuronal activity, we first investigated how the change in anesthesia impacts the cerebral metabolism of hyperpolarized glucose. Anesthetics are known to influence brain activity, and in this study we showed for the first time that switching from isoflurane anesthesia to a combination of lower doses of isoflurane and medetomidine had a high impact on cerebral glucose uptake and glycolytic flow, as reflected by the increased labelling of downstream [1-13C] lactate. The second part of this study aimed at evaluating the feasibility of quantifying cerebral glucose metabolism kinetics by evaluating two different mathematical models, where kinetic rate constants were determined by fitting the models on 13C curves by non-linear regression using the Levenberg-Marquardt algorithm. We showed that a 3-compartment model is more stable and reliable than a 4-compartment model. Finally, since lithium salts are widely used for treating bipolar disorder but its mechanism of action is still not clearly understood, we evaluated the potential of hyperpolarized 6Li injected at pharmacological doses to assess its real-time bio-distribution and pharmacokinetic in the rat brain. We demonstrated first that hyperpolarized 6Li can be detected at pharmacological concentration in the rat head with high signal-to-noise ratio (SNR). We also showed that the transport of lithium through the intact blood-brain barrier brain is a limiting factor and demonstrated a striking difference between apparent 6Li T1 values in a brain with normal or disrupted blood-brain barrier.

EPFL2021