Chantal Bémeur

Neurological dysfunction is improved after faecal microbiota transplantation in rats with bile duct ligated-induced chronic liver disease.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, André Marette, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). HE manifests with symptoms such as poor memory, impairment in motor coordination, lethargy and coma. The gut microbiota has been shown to influence neurological functions via various mediators such as cytokines or bacterial metabolites, many studies have demonstrated the gut-brain axis is altered in liver disease. Faecal matter transplantation (FMT) in patients with cirrhosis has revealed beneficial effects yet many limitations of these studies render the results inconclusive. Purpose: The aim of this study is to explore the impact of FMT on gut microbiota and the beneficial effects on neuro behaviour in bile-duct ligated (BDL) rats. Method: Male Sprague-Dawley rats were randomly assigned to one of three groups; SHAM, BDL-VEH (vehicle) and BDL-FMT (who received FMT daily from pooled faeces from SHAM rats). After five weeks, behaviour tests were performed to evaluate short- and long-term memory (Novel Object Recognition), anxiety (Open Field and Elevated Plus Maze) and motor coordination (Rotarod). Plasmatic parameters such as cytokines, short chain fatty acids (SCFA) and liver impairment markers were measured by ELISA, LC-MS/MS and using Cobas respectively. Finally, faeces were collected for bacterial sequencing and SCFA analysis. Results: FMT did not alter degree of liver disease in BDL rats. BDL-VEH developed a loss of short/long term memory and motor coordination compared to SHAM rats. However, alterations in neurological dysfunction were prevented in the BDL-FMT group. FMT did not impact microbiota α-diversity in BDL rats and β-diversity of microbiota was significantly different between all groups. The genera Provotellaceae UCO-001 significantly increased only in SHAM and BDL-FMT rats and Clostridium Senso Stricto 1 significantly increased only in BDL-VEH compared to SHAMs. Finally, Rombustia was only present in SHAM. Plasma pro-inflammatory cytokines (TNF-α & IL-1β) increase in both BDL groups compared to the control group and no difference for the anti-inflammatory cytokine IL-10 was noted. Analysis of short-chain fatty acids in faeces and plasma showed a variation in propionate and butyrate between both BDL groups. Plasma propionate significantly positively correlated with behavioural results. Conclusion: Our results demonstrate that FMT leads to improvement in memory and motor coordination in BDL rats. The microbiota profile was different between BDL-VEH and SHAM, and FMT lead to further alterations on microbiota. The fact that FMT did not normalize microbiota profile compared to SHAM, suggests BDL-FMT leads to a novel specific microbiota profile which in turn protects the brain. The protective effect of plasma propionate needs to be further explored to define its impact on the brain and possible therapeutic application.

La transplantation de microbiote fécal améliore les troubles neurologiques chez les rats avec une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Kraine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

OpenAccess

Nutritional education strategies for patients with cirrhosis: A narrative review.

Manila Sophasath, Alexandre Brisset, Christopher F. Rose, Chantal Bémeur.

Patients with cirrhosis suffer from many complications, including malnutrition, which must be managed promptly and effectively by the healthcare team. Educating patients about their medical condition, the risk of malnutrition and other complications of cirrhosis, could contribute to optimal nutritional status, quality of life and general health. This review provides an overview of the literature on a variety of nutritional education strategies used with patients suffering from cirrhosis. This review also identifies barriers and facilitators which impact the adherence in using these strategies. A patient-partner contributed to this review by providing insights on different issues and concerns that patients with cirrhosis might ask themselves regarding nutritional education strategies. The patient-partner was also involved in the overall revision of the review. Articles published between the years 2000-2023 focusing on nutritional education strategies in patients living with cirrhosis were identified using Google Scholar and PubMed and were screened for inclusion in the study. All selected studies were intervention studies. A quality assessment of the included studies was conducted using the Mixed Methods Appraisal Tool (MMAT). Only a few nutritional education strategies in patients with cirrhosis were documented in the literature. The strategies ranged from using traditional printed materials to advanced technologies. These strategies may prove beneficial in complementing routine interventions provided by health professionals, such as registered dietitians, in their clinical practice. This narrative review clearly highlights the need for further research to elaborate and evaluate nutritional education strategies for people living with cirrhosis. Elaborating and evaluating educational strategies in nutrition for patients living with cirrhosis will be an adjuvant to health professionals and dietitians in their clinical practice by providing them, and the patients, with targeted education resources.

Oral

La transplantation de microbiote fécal améliore les troubles neurologiques chez les rats avec une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Kraine Dubois, Mélanie Tremblay, Chantal Bémeur, F. Rose Christopher.

Oral

Étude transversale : Dépistage à long terme de la malnutrition, de la sarcopénie et de la fragilité physique chez les receveurs d’une transplantation hépatique.

Amal Trigui, Mélanie Tremblay, C. F. Rose, Chantal Bémeur.

Neurological impairment in rats with bile duct ligated-induced chronic liver disease are improved after faecal microbiota transplantation.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). HE manifests with symptoms such as poor memory, impairment in motor coordination, lethargy and coma. The gut microbiota has been shown to influence neurological functions via various mediators such as cytokines or bacterial metabolites, many studies have demonstrated the gut-brain axis is altered in liver disease. Faecal matter transplantation (FMT) in patients with cirrhosis has revealed beneficial effects yet many limitations of these studies render the results inconclusive. Purpose: The aim of this study is to explore the impact of FMT on gut microbiota and the beneficial effects on neuro behaviour in bile-duct ligated (BDL) rats. Method: Male Sprague-Dawley rats were randomly assigned to one of three groups; SHAM, BDL-VEH (vehicle) and BDL- FMT (who received FMT daily from pooled faeces from SHAM rats). After five weeks, behaviour tests were performed to evaluate short- and long-term memory (Novel Object Recognition), anxiety (Open Field and Elevated Plus Maze) and motor coordination (Rotarod). Plasmatic parameters such as cytokines, short chain fatty acids (SCFA) and liver impairment markers were measured by ELISA, LC-MS/MS and using Cobas respectively. Finally, faeces were collected for bacterial sequencing and SCFA analysis. Result(s): FMT did not alter degree of liver disease in BDL rats. BDL-VEH developed a loss of short/long term memory and motor coordination compared to SHAM rats. However, alterations in neurological dysfunction were prevented in the BDL-FMT group. FMT did not impact microbiota α-diversity in BDL rats and β-diversity of microbiota was significantly different between all groups. The genera Bifidobacterium, Lactobacillus and Akkermansia significantly increased in both BDL groups, while Provotellaceae UCO-001 significantly increased only in SHAM and BDL-FMT rats and Clostridium Senso Stricto 1 significantly increased only in BDL-VEH compared to SHAMs. Finally, Rombustia was only present in SHAM. Plasma pro-inflammatory cytokines (TNF-α & IL-1β) increase in both BDL groups compared to the control group and no difference for the anti-inflammatory cytokine IL-10 was noted. Analysis of short-chain fatty acids in faeces and plasma showed a variation in propionate and butyrate between both BDL groups. Plasma propionate significantly positively correlated with behavioural results.

Oral

Le guide la nutrition pour la cirrhose : est-ce une ressource éducative adaptée aux patients atteints de maladie hépatique chronique?

Manila Sophasath, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Prevalence of overweight and obesity in patients on the liver transplant waiting list: Experience of a referral center, Centre hospitalier de l’Université de Montréal (CHUM).

Isaac Ruiz, Mélanie Tremblay, Crystèle Hogue, Amal Trigui, Geneviève Huard, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Background. The global obesity epidemic continues to progress at an alarming rate. Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is becoming the most common cause of end-stage liver disease (ESLD) and indication for liver transplantation (LT). Documenting the prevalence of overweight and obesity in patients on the waiting list for LT is imperative to make recommendations and improve management. Objective. The aim of this study was to evaluate the prevalence of overweight and obesity in patients on the waiting list at the moment of LT. Methodology. This is a retrospective analysis including all consecutive patients who underwent LT at the Centre hospitalier de l'Université de Montréal (CHUM) between 2019 and 2021. Only patients with biological, clinical and or radiological confirmed cirrhosis were included. Overweight and obesity was defined as body mass index (BMI) equal or superior to 25.0 and 30.0, respectively. Results. During the study period, 181 patients were transplanted at the CHUM. 155 patients with cirrhosis were included in this study. Among them, 104/155 (67.1%) were men, mean age was 52 years old (range 18-69). At the moment of transplantation, overall median BMI was 27.7 (range 16.9 – 44.5, mean 28.1). Overweight was present in 58/155 (37.4%), and obesity was present in 47/155 (30.3%). Results of BMI corrected by the presence of ascites and/or oedema will be presented. Figure 1 shows the prevalence of overweight and obesity overall (panel A), and according to the main etiology of chronic liver disease (panel B). Table 1 shows the median BMI in groups divided by the main etiology of cirrhosis. Discussion / Conclusion. At the moment of LT, almost 1/3 of patients display overweight and nearby 1/3 obesity. This study demonstrates the high prevalence of overweight and obesity in cirrhotic patients on the LT waiting list. Therapeutic and management strategies pre- and post-LT are mandatory using a multidisciplinary team, including nutritional intervention, while emphasizing weight stigma awareness.

Oral

La transplantation de microbiote fécal améliore l’atteinte neurologique chez les rats ayant subi une la ligature du canal biliaire induisant une maladie hépatique chronique.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, F. Rose Christopher.

Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique causé par une maladie du foie. Il a été démontré que le microbiote intestinal influence les fonctions neurologiques via divers médiateurs (cytokines/métabolites bactériens), tandis que l'association entre l'altération du microbiote et les maladies hépatiques ressort dans de nombreuses études. Objectif: Explorer l'impact de la transplantation de microbiote fécal (FMT) sur le développement de l’EH de rats ayant subi une ligature du canal biliaire (BDL). Méthodologie: Des rats mâles ont été randomisés en trois groupes : Contrôle (SHAM), BDL-véhicule (VEH) et BDL-FMT qui ont reçu quotidiennement la FMT provenant des rats contrôles. Après cinq semaines, des tests comportementaux ont été effectués pour évaluer la mémoire à court/long terme, l'anxiété et la coordination motrice. Des paramètres cliniques et paracliniques ont été mesurés et les fèces collectées pour séquençage bactérien. Résultats: Les rats BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice comparativement aux rats contrôles. Cependant, les altérations neurologiques ont été prévenues chez les rats BDL-FMT. Le genre Provotellaceae UCO-001 est présent uniquement chez les rats SHAM et BDL-FMT. A l’inverse, le genre Clostridium SS 1 est uniquement présent chez les rats BDL-VEH. L’analyse plasmatique des cytokines ne montre aucune différence entre les rats BDL. Les concentrations d’acides gras à chaines courtes butyrate et propionate au niveau des fèces et du plasma varie entre les rats BDL. Le propionate plasmatique ressort de par les corrélations positives avec les scores de comportement. Discussion et perspectives : Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT n'a pas normalisé le profil du microbiote comparé aux rats SHAM, ce qui suggère qu’elle conduit à un nouveau profil spécifique du microbiote semblant protéger le cerveau. La présence de propionate plasmatique doit être explorée pour définir son impact sur le cerveau.

Oral

Dépistage à long terme de la malnutrition, de la sarcopénie et de la fragilité physique chez les receveurs d’une transplantation hépatique : étude transversale.

Amal Trigui, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Étude longitudinale: Suivi de l’état nutritionnel, de la qualité de vie et de la fonction musculaire des patients sur la liste d'attente pour une greffe de foie.

Amal Trigui, Joann Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

La malnutrition est la complication la plus fréquente chez les patients atteints de maladies hépatiques chroniques (cirrhose) en attente d’une transplantation hépatique (TH) et elle pourrait mener à l’apparition d’autres complications avant et après la TH, incluant la sarcopénie (perte de masse et fonction musculaire). Objectifs: Chez les patients cirrhotiques en attente d’une TH : 1) Évaluer les changements longitudinaux du risque nutritionnel, de la fonction musculaire et de la qualité de vie. 2) Identifier les facteurs pouvant entraîner une détérioration des trois variables évaluées. Méthode: Les patients atteints d'une cirrhose et en attente d’une TH au CHUM sont inclus. Le risque nutritionnel (Liver Disease Undernutrition Screening Tool), la fonction musculaire (Chair Stand Test), et la qualité de vie (SF-36) sont évalués tous les 3 mois avant la TH. Résultats: Actuellement, 36 patients en attente d’une TH ont été inclus. L'âge moyen est de 51,3 ± 11,6 ans. L'étiologie la plus fréquente est l'alcoolisme (47 %) suivie par la cholangite sclérosante primitive (25%). 86 % (31/36) des patients sont à risque de malnutrition, situation qui demeure inchangée jusqu'à 18 mois sur la liste d’attente. Parmi les 5 patients qui n'étaient pas à risque de malnutrition, 60% sont devenus à risque. À l'inclusion, 73 % (26/36) des patients présentaient une faible force musculaire (score moyen de 18,9 ± 7,8 s vs 12,6 s chez les patients sains ; p < 0,001) qui diminuait avec le temps d’attente pour une TH. En ce qui concerne la qualité de vie, les scores moyens de santé physique (44,6% ± 20,4) et de santé mentale (53,5% ± 26,1) étaient inférieurs aux scores des Canadiens du même âge considérés en bonne santé. Le score de santé physique avait tendance à diminuer davantage avec le temps. Conclusion: La majorité des patients en attente d'une TH sont à risque de malnutrition, présentent une fonction musculaire altérée qui se détériore avec le temps. La qualité de vie est également diminuée tandis que le score de santé physique a tendance à diminuer avec le temps.

Oral

La transplantation de microbiote fécal améliore la déficience neurologique chez les rats atteints d'une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique causé par une maladie du foie. Il a été démontré que le microbiote intestinal influence les fonctions neurologiques via divers médiateurs (cytokines/métabolites bactériens), tandis que l'association entre l'altération du microbiote et les maladies hépatiques ressort dans de nombreuses études. Objectif: Explorer l'impact de la transplantation de microbiote fécal (FMT) sur le développement de l’EH de rats ayant subi une ligature du canal biliaire (BDL). Méthodologie: Des rats mâles ont été randomisés en trois groupes : Contrôle (SHAM), BDL-véhicule (VEH) et BDL-FMT qui ont reçu quotidiennement la FMT provenant des rats contrôles. Après cinq semaines, des tests comportementaux ont été effectués pour évaluer la mémoire à court/long terme, l'anxiété et la coordination motrice. Des paramètres cliniques et paracliniques ont été mesurés et les fèces collectées pour séquençage bactérien. Résultats: Les rats BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice comparativement aux rats contrôles. Cependant, les altérations neurologiques ont été prévenues chez les rats BDL-FMT. Le genre Provotellaceae UCO-001 est présent uniquement chez les rats SHAM et BDL-FMT. A l’inverse, le genre Clostridium SS 1 est uniquement présent chez les rats BDL-VEH. L’analyse plasmatique des cytokines ne montre aucune différence entre les rats BDL. Les concentrations d’acides gras à chaines courtes butyrate et propionate au niveau des fèces et du plasma varie entre les rats BDL. Le propionate plasmatique ressort de par les corrélations positives avec les scores de comportement. Discussion et perspectives : Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT n'a pas normalisé le profil du microbiote comparé aux rats SHAM, ce qui suggère qu’elle conduit à un nouveau profil spécifique du microbiote semblant protéger le cerveau. La présence de propionate plasmatique doit être explorée pour définir son impact sur le cerveau.

Le guide La nutrition pour la cirrhose : une ressource éducative adéquate pour nos patients ?

Manila Sophasath, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Long-term screening for malnutrition, sarcopenia, and physical frailty in liver transplant recipients: a cross-sectional study.

Amal Trigui, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Background: The liver is the second most transplanted organ worldwide. Despite the high survival rate after liver transplant (LT), malnutrition, sarcopenia and frailty are present in 47%, 80% and 59%, respectively, of patients 3 months after surgery. These three complications are associated with adverse clinical outcomes and decreased quality of life after LT. However, there are no data regarding malnutrition, sarcopenia, and frailty in the long term after LT. Purpose: The primary objective is to determine the prevalence of malnutrition, sarcopenia, and frailty starting from 1 year after LT. The secondary objectives aim to describe muscle function, quality of life and employment status in LT recipients. Methods: Cross-sectional observational study is conducted including 80 patients transplanted between 2019 and 2021. A single virtual meeting is performed with each patient during which nutritional risk (Canadian Nutrition Screening Tool), sarcopenia (SARC-F questionnaire), frailty (FRAIL questionnaire), muscle function (chair stand test), quality of life (SF36) and employment status are assessed. Results: To date, 57 (29 in 2019, 12 in 2020 and 16 in 2021) patients have completed the study (34 men and 23 women). The mean age is 58.9 ± 10.5 years and 10.5% of patients were at risk of malnutrition, 19.3% of patients were at risk of sarcopenia whereas 43.9% and 19.3% were prefrail and frail. The prevalence of the risk of malnutrition, sarcopenia, and frailty (prefrail and frail) remained unchanged until 3 years after LT. Muscle function was impaired after LT (15.8 ± 5.5 s vs. 12.6 s in healthy people). Regarding quality of life, the score of physical heath (62.6% ± 22.1) is slightly below normal and the scores remain unchanged until 3 years after LT. 68.4% of patients are unemployed of which 46.2% are in early retirement for a liver disease-related cause. Conclusion: Up to 3 years after LT, patients are still at risk of malnutrition, sarcopenia, and frailty. The physical component score of their quality-of-life score is below the score of the general population. The results of this project may help identify appropriate interventions in the long term after LT.

Nutritional education strategies for patients with cirrhosis: Evaluation of the Nutrition in cirrhosis guide.

Manila Sophasath, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Background: Liver disease affects 1 in 4 Canadians. One of the most common complications of chronic liver disease is malnutrition, associated with decreased quality of life. Very few studies have focused on nutritional education resources for this population rendering their development and evaluation essential. Purpose: The general objective is to assess the potential impact of the evidence-based Nutrition in Cirrhosis Guide on cirrhotic patients at the CHUM’s liver outpatient clinic. The first specific objective is to quantitatively assess nutritional knowledge, quality of life and nutritional status. The second is to qualitatively assess the patients’ satisfaction of the Guide. Methods: A randomized controlled study including 100 cirrhotic patients in 2 groups: Guide+ (n = 50) and Guide− (n = 50), is on-going. Patients are assessed for nutrition knowledge, quality of life and presence of malnutrition at baseline, 3 and 6 months. The Guide is taught to Guide+ patients for 6 months. Guide− patients do not use the Guide. The qualitative part evaluates patients’ satisfaction of the Guide through 5 focus groups (3 patients) to assess appreciation, complexity and applicability. A patient-partner participates in focus groups. Results: To date, 21 patients have completed the study: Guide+ (n = 10) and Guide− (n = 11). The preliminary results show a trend of improvement of nutrition knowledge for Guide+ patients (from 76.0% to 80.4%) after 3 months, not maintained at 6 months (down to 76.4%; p > 0.05). The Guide− patients’ knowledge remains unchanged throughout the study. There is a trend of improvement in malnutrition in the group Guide+ (50% of patients initially malnourished, 40% at 3 months and 20% at 6 months; p > 0.05), which worsened in the group Guide− (from 36.4% to 56.5% at 3 months, to 45.5% at 6 months). Preliminary results from focus groups suggest an overall satisfaction towards the content, but a need to lighten and better divide the concepts. Conclusion: A trend of improvement is denoted in patients’ nutritional knowledge over 3 months, not maintained at 6 months, and a decrease in the presence of malnutrition after 6 months. The results of this project will help optimize the cirrhotic patients’ quality of care.

Neurological dysfunction is improved after faecal microbiota transplantation in rats with bile duct ligated-induced chronic liver disease.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, André Marette, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). The gut microbiota has been shown to influence neurological functions via various mediators such as cytokines or bacterial metabolites. Faecal matter transplantation (FMT) in patients with cirrhosis has revealed beneficial effects on behaviour yet many limitations of these studies render the results inconclusive. Purpose: The aim of this study was to explore the impact of FMT on gut microbiota and neuro behaviour in bile-duct ligated (BDL) rats. Method: Male SpragueDawley rats were randomly assigned to one of three groups; SHAM, BDL-VEH (vehicle) and BDL-FMT (who received FMT daily from pooled faeces from SHAM rats). After five weeks, behaviour tests were performed to evaluate short- and longterm memory, anxiety and motor coordination. Plasmatic parameters including cytokines, short chain fatty acids (SCFA) and liver biomarkers were measured. Finally, faeces were collected for bacterial sequencing, SCFA and tissues for analysis after the sacrifice. Results: BDL-VEH developed a loss of short- and long-term memory and motor coordination compared to SHAM rats. However, neurological dysfunction was prevented in the BDL-FMT group. FMT impacted microbiota composition as the genera Bifidobacterium, Lactobacillus and Akkermansia significantly increased in both BDL groups, while Provotellaceae UCO-001 significantly increased only in SHAM and BDL-FMT rats. Clostridium Senso Stricto 1 significantly increased only in BDL-VEH compared to SHAMs. Plasma pro-inflammatory cytokines (TNF-α & IL-1β) increase in both BDL groups compared to SHAM and no difference in anti-inflammatory cytokine IL-10 was noted. Analysis of SCFA in plasma and faeces showed a variation in propionate and butyrate between both BDL groups. Conclusion: Our results demonstrate that FMT leads to improvement in memory and motor coordination in BDL rats. The microbiota profile was different between BDL-VEH and SHAM whereas FMT led to further microbiota alterations. BDL-FMT led to a novel specific microbiota profile which in turn protected the brain.

Longitudinal analysis of nutritional risk, muscle function and quality of life of patients with end stage liver disease waiting for liver transplantation.

Amal Trigui, Joann Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

In Canada, more than 400 liver transplantation (LT) are performed every year. However, organ availability continues to be a major issue in LT, as the waiting time for a deceased liver donor ranges from months to years. In patients with end-stage liver disease waiting for LT, protein-energy malnutrition is the most common complication (> 80%) and one of the main risk factors for the onset and progression of sarcopenia (loss of muscle mass and function or quality). Previous clinical studies have shown that sarcopenia and malnutrition are associated with a prolonged hospital stay, increased mortality and higher rate of infections as well as a decrease in quality of life. Pre-operative malnutrition could also impact negatively on the post-transplant outcomes. Screening for the nutritional risk for patients waiting for LT is the first step to address adequate nutritional therapy. However, since the delay to receive a new liver could be long, following the patients longitudinally could help to detect the deterioration in nutritional status and muscle function at an advanced stage as well as to identify factors that could lead to this deterioration. Purpose: In patients with cirrhosis waiting for LT: 1) Assess longitudinal changes in nutritional risk, muscle function and quality of life. 2) Identify factors that could lead to deterioration of nutritional status, muscle function and quality of life. Method: Patients with end-stage liver disease waiting for LT at the CHUM were included. Muscle function (Chair Stand Test), nutritional risk (Liver Disease Undernutrition Screening Tool), and quality of life (SF-36) are assessed every 3 months prior to LT. Biochemical and anthropometric data, medications as well as complications are collected at each follow-up. Results: Currently, 36 patients awaiting LT have been included. The mean age is 51.3 ± 11,6 years. The most common etiology is alcohol (33 %). At enrollment, 86 % (31/36) of patients are at risk of malnutrition, which remain unchanged with follow-ups ranging to 18 months while on the LT waiting list. Among the 5 patients who were not at risk of malnutrition and enrollment, 60% were defined at risk with follow-ups. Based on the EWGSOP-2 diagnostic criteria, at enrollment, 73% (26/36) of patients had a low muscle strength with a mean score of 18,9s ± 7,8 s (vs 12,6 s in healthy patients; p < 0,001) which decreased with time while waiting for an LT. Regarding quality of life, the mean score of physical heath (44,6% ± 20,4) and mental health (53,5% ± 26,1) were below normal scores for healthy Canadian in the same age. The physical health score tended to further decrease over time. Conclusion: A majority of patients with cirrhosis placed on the LT list are at risk of malnutrition, have an impaired muscle function which decreases with time. Moreover, quality of life is impacted, and the physical health component tended to decrease with time.

Nutritional education strategies for cirrhotic patients : Evaluation of a nutrition guide.

Manila Sophasath, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

BACKGROUND: In Canada, liver disease affects 1 in 4 persons. One of the most common complications of cirrhosis is malnutrition, associated with an increased risk of mortality and a decrease in the quality of life of patients. Adherence to nutrition guidelines appears to be difficult. Very few studies have focused on the development and evaluation of nutritional education resources adapted to this population. Thus, the development and evaluation of such strategies is essential. PURPOSE: The general objective of the study is to assess the potential impact of the evidence-based Nutrition in Cirrhosis Guide on cirrhotic patients followed at the CHUM’s liver outpatient clinic through a mixed-design study. The first specific objective is to quantitatively assess nutritional knowledge, quality of life and nutritional status and the second specific objective is to qualitatively assess the patients’ satisfaction of the Guide. METHOD: A randomized controlled study including 100 cirrhotic patients divided in 2 groups: Intervention (Guide+, n=50) and Control (Guide-, n=50), is on-going. All patients are assessed for nutrition knowledge (literacy questionnaire), quality of life (Chronic Liver Disease Questionnaire) and presence of malnutrition (Liver Disease Undernutrition Screen Tool). The Guide is taught to Guide+ patients for 6 months. Guide- patients do not use the Guide. At times T=0, 3 and 6 months, the same evaluations are carried out. The qualitative part evaluates patients’ satisfaction of the Guide through 5 focus groups of 3 patients each to assess general appreciation, complexity and applicability of the Guide. A patient-partner participates in focus groups. RESULT(S): 42 patients are included in the study so far: Guide+ (n=21) and Guide- (n=21). The groups are comparable in age (mean = 59.0 and 55.0 in Guide+ and Guide-, respectively; p=0.28). To date, 21 patients have completed the study: Guide+ (n=10) and Guide- (n=11). The preliminary results show a trend of improvement of nutrition knowledge for Guide+ patients (from 76.0% to 80.4%) after 3 months, which is not maintained at 6 months (down to 76.4%; p>0.05). The Guide- patients’ knowledge remains unchanged throughout the study (from 74.2% to 74.5% after 3 months, to 77.8% after 6 months; p>0.05). As for the presence of malnutrition, a trend of improvement is denoted in the group Guide+ (50% of patients were initially malnourished, 40% at 3 months and 20% at 6 months; p>0.05). Presence of malnutrition worsened in the group Guide- (from 36.4% to 56.5% at 3 months, to 45.5% at 6 months). Preliminary results from focus groups suggest an overall satisfaction towards the content, but a need to lighten and better divide the concepts. CONCLUSION(S): The preliminary results demonstrate a trend of improvement in patients’ nutritional knowledge over 3 months, which is not maintained at 6 months, and a decrease in the presence of malnutrition after 6 months. The results of this project will help optimize the quality of care for people suffering from cirrhosis.

Neurological impairment in rats with bile duct ligated-induced chronic liver disease are improved after faecal microbiota transplantation.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). HE manifests with symptoms such as poor memory, impairment in motor coordination, lethargy and coma. The gut microbiota has been shown to influence neurological function and many studies have demonstrated the association between altered microbiota and liver disease. Fecal matter transplantation (FMT) has revealed beneficial effects in clinical studies yet many limitations of these studies render the results inconclusive. Purpose: The aim of this study is to explore the impact of FMT on gut microbiota and the beneficial effects on neuro behaviour in bile-duct ligated (BDL) rats. Method: Male Sprague-Dawley rats were randomly assigned to one of three groups; SHAM (N=10), BDL-VEH (vehicle) (N=9) and BDL-FMT (who received FMT daily from pooled feces from SHAM rats). After five weeks, behaviour analysis was performed to evaluate short and long-term memory (Novel Object Recognition), anxiety (Open Field and Elevated Plus Maze) and motor coordination (Rotarod). Other parameters such as body weight and composition, ascites, gastrocnemius muscle weight and markers of liver function (ALT, AST, bilirubin and NH3) were also measured. Finally, the feces were collected and 16S RNA was sequenced for all groups. Result(s): FMT did not alter body composition (weight, composition, ascites and gastrocnemius muscle weight as well as and degree of liver disease (liver damage markers) in BDL-FMT vs BDL-Vehicle. BDL-VEH developed a loss of short/longterm memory and motor coordination compared to Sham rats. However, alterations in neurological dysfunction were prevented in the BDL-FMT group. The microbiota -diversity was not significantly different between BDL-VEH and SHAM and furthermore, FMT did not impact -diversity in BDL rats. In contrast, -diversity of microbiota did significantly differ between all groups (p < 0.05). The relative abundance also was significantly different between all three groups. In the BDL-FMT group, the phylum Firmicutes was found decreased while the Bacteroidetes were increased compared to BDLVEH and SHAM. The genera Bifidobacterium and Lactobacillus significantly increased in both BDL groups, while Akkermansia and Provotellaceae UCO-001 increased only in BDL-FMT rats and Clostridium Senso Stricto increased only in BDL-VEH compared to Shams. Finally, the genus Rombustia was only present in SHAM. Conclusion(s): Our results demonstrate that FMT lead to improvement in memory and motor coordination in BDL rats. The microbiota profile was different between BDL-VEH and SHAM, and FMT lead to further alterations. The fact that FMT did not normalize microbiota profile, suggests BDL-FMT leads to a novel specific microbiota profile which in turn protects the brain. The FMT-induced increase in Akkermansia and Provotellaceae UCO-001 merits to be further investigated in regards to their beneficial neurological effect in CLD.

Évolution du risque nutritionnel, de la qualité de vie et de la fonction musculaire des patients en attente d’une transplantation hépatique : Étude longitudinale.

Amal Trigui, Joann Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

La malnutrition est la complication la plus fréquente chez les patients atteints de maladies hépatiques chroniques (cirrhose) en attente d’une transplantation hépatique (TH) et elle pourrait mener à l’apparition d’autres complications avant et après la TH, incluant la sarcopénie (perte de masse et fonction musculaire). Objectifs: Chez les patients cirrhotiques en attente d’une TH : 1) Évaluer les changements longitudinaux du risque nutritionnel, de la fonction musculaire et de la qualité de vie. 2) Identifier les facteurs pouvant entraîner une détérioration des trois variables évaluées. Méthode: Les patients atteints d'une cirrhose et en attente d’une TH au CHUM sont inclus. Le risque nutritionnel (Liver Disease Undernutrition Screening Tool), la fonction musculaire (Chair Stand Test), et la qualité de vie (SF-36) sont évalués tous les 3 mois avant la TH. Résultats: Actuellement, 36 patients en attente d’une TH ont été inclus. L'âge moyen est de 51,3 ± 11,6 ans. L'étiologie la plus fréquente est l'alcoolisme (47 %) suivie par la cholangite sclérosante primitive (25%). 86 % (31/36) des patients sont à risque de malnutrition, situation qui demeure inchangée jusqu'à 18 mois sur la liste d’attente. Parmi les 5 patients qui n'étaient pas à risque de malnutrition, 60% sont devenus à risque. À l'inclusion, 73 % (26/36) des patients présentaient une faible force musculaire (score moyen de 18,9 ± 7,8 s vs 12,6 s chez les patients sains ; p < 0,001) qui diminuait avec le temps d’attente pour une TH. En ce qui concerne la qualité de vie, les scores moyens de santé physique (44,6% ± 20,4) et de santé mentale (53,5% ± 26,1) étaient inférieurs aux scores des Canadiens du même âge considérés en bonne santé. Le score de santé physique avait tendance à diminuer davantage avec le temps. Conclusion: La majorité des patients en attente d'une TH sont à risque de malnutrition, présentent une fonction musculaire altérée qui se détériore avec le temps. La qualité de vie est également diminuée tandis que le score de santé physique a tendance à diminuer avec le temps.

La transplantation de microbiote fécal améliore l’atteinte neurologique chez les rats avec une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique causé par une maladie du foie. Il a été démontré que le microbiote intestinal influence les fonctions neurologiques via divers médiateurs (cytokines/métabolites bactériens), tandis que l'association entre l'altération du microbiote et les maladies hépatiques ressort dans de nombreuses études. Objectif: Explorer l'impact de la transplantation de microbiote fécal (FMT) sur le développement de l’EH de rats ayant subi une ligature du canal biliaire (BDL). Méthodologie: Des rats mâles ont été randomisés en trois groupes : Contrôle (SHAM), BDL-véhicule (VEH) et BDL-FMT qui ont reçu quotidiennement la FMT provenant des rats contrôles. Après cinq semaines, des tests comportementaux ont été effectués pour évaluer la mémoire à court/long terme, l'anxiété et la coordination motrice. Des paramètres cliniques et paracliniques ont été mesurés et les fèces collectées pour séquençage bactérien. Résultats: Les rats BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice comparativement aux rats contrôles. Cependant, les altérations neurologiques ont été prévenues chez les rats BDL-FMT. Le genre Provotellaceae UCO-001 est présent uniquement chez les rats SHAM et BDL-FMT. A l’inverse, le genre Clostridium SS 1 est uniquement présent chez les rats BDL-VEH. L’analyse plasmatique des cytokines ne montre aucune différence entre les rats BDL. Les concentrations d’acides gras à chaines courtes butyrate et propionate au niveau des fèces et du plasma varie entre les rats BDL. Le propionate plasmatique ressort de par les corrélations positives avec les scores de comportement. Discussion et perspectives : Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT n'a pas normalisé le profil du microbiote comparé aux rats SHAM, ce qui suggère qu’elle conduit à un nouveau profil spécifique du microbiote semblant protéger le cerveau. La présence de propionate plasmatique doit être explorée pour définir son impact sur le cerveau.

OpenAccess

Nutritional Strategies to Manage Malnutrition and Sarcopenia following Liver Transplantation: A Narrative Review.

Amal Trigui, Christopher F. Rose, Chantal Bémeur.

Oral

Longitudinal evolution of nutritional risk and muscle function of patients waiting for liver transplantation and the effect of early nutritional intervention following the transplantation

Amal Trigui, Joan Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

In patients living with cirrhosis and waiting for liver transplantation (LT), protein-energy malnutrition is the most common complication (> 80%). After LT, nutritional status can worsen rapidly leading to sarcopenia (loss of muscle mass and function). Objectives: 1) Assess longitudinal changes in nutritional risk, muscle function and quality of life in cirrhotic patients awaiting LT. 2) Evaluate the effect of early nutritional supplementation rich in protein, beta-hydroxy-beta-methylbutyrate (HMB) and energy, after LT, on muscle mass and function, nutritional risk and quality of life. Method: A randomized controlled pilot study is conducted including 30 patients going through LT. Muscle mass (CT scan), muscle function (chair stand test), nutritional risk (liver disease undernutrition screening tool) and quality of life (SF-36) are assessed every 3 months before LT, immediately after discharge from hospital and 12 weeks post-LT. At LT, participants are randomized in: (1) intervention group (n=15) receiving standard nutritional care as well as supplements rich in protein, HMB and energy for 12 weeks and (2) control group (n=15) receiving standard nutritional care. Results: Currently, 26 patients awaiting LT are included. One participant was transplanted. The mean age is 51.3 ± 12.9 years. The most common etiology is alcohol (33 %). 84 % of patients are at risk of malnutrition which remain unchanged within up to one year on the waitlist. Muscle function is impaired (18.1 ± 11.0 s vs. 12.6 s in healthy patients; p < 0,001) and decreased with time on waitlist. Regarding quality of life, the score of physical heath (41.8% ± 18.6) and mental health (52.1% ± 25) are below normal. The quality of life tended to decrease over time before LT. Conclusion: The majority of patients waiting for a LT are at risk of malnutrition, display altered muscle function, and a tendency of decreased quality of life. These preliminary data support the need for early nutritional support after LT.

Faecal microbiota transplantation improves neurological impairment in rats with chronic liver disease.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). HE manifests with symptoms such as poor memory, impairment in motor coordination, lethargy and coma. The gut microbiota has been shown to influence neurological function and many studies have demonstrated the association between altered microbiota and liver disease. Fecal matter transplantation (FMT) has revealed beneficial effects in clinical studies yet many limitations of these studies render the results inconclusive. Purpose: The aim of this study is to explore the impact of FMT on gut microbiota and the beneficial effects on neuro behaviour in bile-duct ligated (BDL) rats. Method: Male Sprague-Dawley rats were randomly assigned to one of three groups; SHAM (N=10), BDL-VEH (vehicle) (N=9) and BDL-FMT (who received FMT daily from pooled feces from SHAM rats). After five weeks, behaviour analysis was performed to evaluate short and long-term memory (Novel Object Recognition), anxiety (Open Field and Elevated Plus Maze) and motor coordination (Rotarod). Other parameters such as body weight and composition, ascites, gastrocnemius muscle weight and markers of liver function (ALT, AST, bilirubin and NH3) were also measured. Finally, the feces were collected and 16S RNA was sequenced for all groups. Result(s): FMT did not alter body composition (weight, composition, ascites and gastrocnemius muscle weight as well as and degree of liver disease (liver damage markers) in BDL-FMT vs BDL-Vehicle. BDL-VEH developed a loss of short/longterm memory and motor coordination compared to Sham rats. However, alterations in neurological dysfunction were prevented in the BDL-FMT group. The microbiota -diversity was not significantly different between BDL-VEH and SHAM and furthermore, FMT did not impact α-diversity in BDL rats. In contrast, β-diversity of microbiota did significantly differ between all groups (p < 0.05). The relative abundance also was significantly different between all three groups. In the BDL-FMT group, the phylum Firmicutes was found decreased while the Bacteroidetes were increased compared to BDLVEH and SHAM. The genera Bifidobacterium and Lactobacillus significantly increased in both BDL groups, while Akkermansia and Provotellaceae UCO-001 increased only in BDL-FMT rats and Clostridium Senso Stricto increased only in BDL-VEH compared to Shams. Finally, the genus Rombustia was only present in SHAM. Conclusion(s): Our results demonstrate that FMT lead to improvement in memory and motor coordination in BDL rats. The microbiota profile was different between BDL-VEH and SHAM, and FMT lead to further alterations. The fact that FMT did not normalize microbiota profile, suggests BDL-FMT leads to a novel specific microbiota profile which in turn protects the brain. The FMT-induced increase in Akkermansia and Provotellaceae UCO-001 merits to be further investigated in regards to their beneficial neurological effect in CLD.

Oral

Évolution de l’état nutritionnel, de la qualité de vie et de la fonction musculaire des patients en attente d’une transplantation hépatique.

Amal Trigui, Joan Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Oral

La transplantation de microbiote fécal améliore la déficience neurologique chez les rats atteints d'une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher Rose.

Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique résultant d'une maladie du foie. Il a été démontré que le microbiote intestinal influence les fonctions neurologiques et l'association entre l'altération du microbiote et les maladies hépatiques ressort dans de nombreuses études. Objectif : Explorer l'impact de la transplantation de microbiote fécal (FMT) sur le développement de l’EH de rats ayant subi une ligature du canal biliaire (BDL). Méthodologie: Des rats Sprague-Dawley mâles ont été randomisés en trois groupes : Contrôle (N=10), BDL-VEH (véhicule) (N=9) et BDL-FMT et ont reçu quotidiennement la FMT provenant des rats contrôles. Après cinq semaines, des tests comportementaux sont effectués pour évaluer la mémoire à court et long terme, l'anxiété et la coordination motrice. Le poids, la composition corporelle, la masse musculaire et les marqueurs hépatiques (ALT, AST, bilirubine). Enfin, les fèces ont été collectées et l’ADN bactérien a été séquencé. Résultats: La FMT n'a pas modifié la composition corporelle et la fonction hépatique chez les BDL-FMT par rapport aux BDL-VEH. Les BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice par rapport aux rats contrôles. Cependant, les altérations neurologiques ont été prévenues dans le groupe BDL-FMT. Concernant le microbiote, l’α-diversité n'était pas significativement différente entre tous les groupes contrairement à la β-diversité. Les genres Bifidobacterium et Lactobacillus sont augmentés de manière significative dans les groupes BDL, tandis que Akkermansia et Provotellaceae UCO-001 sont augmentés uniquement dans les rats BDL-FMT. Discussion: Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT n'a pas normalisé le profil du microbiote dans le groupe BDL-FMT, ce qui suggère qu’elle conduit à un nouveau profil spécifique du microbiote qui, à son tour, semble protéger en partie le cerveau. L'augmentation d’Akkermansia et de Provotellaceae dans le groupe BDL-FMT mérite d'être étudiée plus en détails.

Oral

Évolution de l’état nutritionnel, de la qualité de vie et de la fonction musculaire des patients en attente d’une transplantation hépatique et l'effet d'une intervention nutritionnelle précoce après la transplantation sur ces paramètres.

Amal Trigui, Joan Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Evolution of nutritional risk, muscle function and quality of life of cirrhotic patients waiting for liver transplantation.

Amal Trigui, Joan Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Faecal microbiota transplantation improves neurological impairment in rats with bile-duct ligated induced chronic liver disease.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). HE manifests with symptoms such as poor memory, impairment in motor coordination, lethargy and coma. The gut microbiota has been shown to influence neurological function and many studies have demonstrated the association between altered microbiota and liver disease. Fecal matter transplantation (FMT) has revealed beneficial effects in clinical studies yet many limitations of these studies render the results inconclusive. Purpose: The aim of this study is to explore the impact of FMT on gut microbiota and the beneficial effects on neuro behaviour in bile-duct ligated (BDL) rats. Method: Male Sprague-Dawley rats were randomly assigned to one of three groups; SHAM (N=10), BDL-VEH (vehicle) (N=9) and BDL-FMT (who received FMT daily from pooled feces from SHAM rats). After five weeks, behaviour analysis was performed to evaluate short and long-term memory (Novel Object Recognition), anxiety (Open Field and Elevated Plus Maze) and motor coordination (Rotarod). Other parameters such as body weight and composition, ascites, gastrocnemius muscle weight and markers of liver function (ALT, AST, bilirubin and NH3) were also measured. Finally, the feces were collected and 16S RNA was sequenced for all groups. Result(s): FMT did not alter body composition (weight, composition, ascites and gastrocnemius muscle weight as well as and degree of liver disease (liver damage markers) in BDL-FMT vs BDL-Vehicle. BDL-VEH developed a loss of short/longterm memory and motor coordination compared to Sham rats. However, alterations in neurological dysfunction were prevented in the BDL-FMT group. The microbiota -diversity was not significantly different between BDL-VEH and SHAM and furthermore, FMT did not impact -diversity in BDL rats. In contrast, -diversity of microbiota did significantly differ between all groups (p < 0.05). The relative abundance also was significantly different between all three groups. In the BDL-FMT group, the phylum Firmicutes was found decreased while the Bacteroidetes were increased compared to BDLVEH and SHAM. The genera Bifidobacterium and Lactobacillus significantly increased in both BDL groups, while Akkermansia and Provotellaceae UCO-001 increased only in BDL-FMT rats and Clostridium Senso Stricto increased only in BDL-VEH compared to Shams. Finally, the genus Rombustia was only present in SHAM. Conclusion(s): Our results demonstrate that FMT lead to improvement in memory and motor coordination in BDL rats. The microbiota profile was different between BDL-VEH and SHAM, and FMT lead to further alterations. The fact that FMT did not normalize microbiota profile, suggests BDL-FMT leads to a novel specific microbiota profile which in turn protects the brain. The FMT-induced increase in Akkermansia and Provotellaceae UCO-001 merits to be further investigated in regards to their beneficial neurological effect in CLD.

Oral

La transplantation de microbiote fécal améliore la déficience neurologique chez les rats atteints d'une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher Rose.

Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique résultant d'une maladie du foie. Il a été démontré que le microbiote intestinal influence les fonctions neurologiques et l'association entre l'altération du microbiote et les maladies hépatiques ressort dans de nombreuses études. Objectif : Explorer l'impact de la transplantation de microbiote fécal (FMT) sur le développement de l’EH de rats ayant subi une ligature du canal biliaire (BDL). Méthodologie: Des rats Sprague-Dawley mâles ont été randomisés en trois groupes : Contrôle (N=10), BDL-VEH (véhicule) (N=9) et BDL-FMT et ont reçu quotidiennement la FMT provenant des rats contrôles. Après cinq semaines, des tests comportementaux sont effectués pour évaluer la mémoire à court et long terme, l'anxiété et la coordination motrice. Le poids, la composition corporelle, la masse musculaire et les marqueurs hépatiques (ALT, AST, bilirubine). Enfin, les fèces ont été collectées et l’ADN bactérien a été séquencé. Résultats: La FMT n'a pas modifié la composition corporelle et la fonction hépatique chez les BDL-FMT par rapport aux BDL-VEH. Les BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice par rapport aux rats contrôles. Cependant, les altérations neurologiques ont été prévenues dans le groupe BDL-FMT. Concernant le microbiote, l’α-diversité n'était pas significativement différente entre tous les groupes contrairement à la β-diversité. Les genres Bifidobacterium et Lactobacillus sont augmentés de manière significative dans les groupes BDL, tandis que Akkermansia et Provotellaceae UCO-001 sont augmentés uniquement dans les rats BDL-FMT. Discussion: Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT n'a pas normalisé le profil du microbiote dans le groupe BDL-FMT, ce qui suggère qu’elle conduit à un nouveau profil spécifique du microbiote qui, à son tour, semble protéger en partie le cerveau. L'augmentation d’Akkermansia et de Provotellaceae dans le groupe BDL-FMT mérite d'être étudiée plus en détails.

Oral

La transplantation de microbiote fécal améliore la déficience neurologique chez les rats atteints d'une maladie hépatique chronique induite par la ligature du canal biliaire.

Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Karine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher Rose.

Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique résultant d'une maladie du foie. Il a été démontré que le microbiote intestinal influence les fonctions neurologiques et l'association entre l'altération du microbiote et les maladies hépatiques ressort dans de nombreuses études. Objectif : Explorer l'impact de la transplantation de microbiote fécal (FMT) sur le développement de l’EH de rats ayant subi une ligature du canal biliaire (BDL). Méthodologie: Des rats Sprague-Dawley mâles ont été randomisés en trois groupes : Contrôle (N=10), BDL-VEH (véhicule) (N=9) et BDL-FMT et ont reçu quotidiennement la FMT provenant des rats contrôles. Après cinq semaines, des tests comportementaux sont effectués pour évaluer la mémoire à court et long terme, l'anxiété et la coordination motrice. Le poids, la composition corporelle, la masse musculaire et les marqueurs hépatiques (ALT, AST, bilirubine). Enfin, les fèces ont été collectées et l’ADN bactérien a été séquencé. Résultats: La FMT n'a pas modifié la composition corporelle et la fonction hépatique chez les BDL-FMT par rapport aux BDL-VEH. Les BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice par rapport aux rats contrôles. Cependant, les altérations neurologiques ont été prévenues dans le groupe BDL-FMT. Concernant le microbiote, l’α-diversité n'était pas significativement différente entre tous les groupes contrairement à la β-diversité. Les genres Bifidobacterium et Lactobacillus sont augmentés de manière significative dans les groupes BDL, tandis que Akkermansia et Provotellaceae UCO-001 sont augmentés uniquement dans les rats BDL-FMT. Discussion: Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT n'a pas normalisé le profil du microbiote dans le groupe BDL-FMT, ce qui suggère qu’elle conduit à un nouveau profil spécifique du microbiote qui, à son tour, semble protéger en partie le cerveau. L'augmentation d’Akkermansia et de Provotellaceae dans le groupe BDL-FMT mérite d'être étudiée plus en détails.

Évaluation de ressources éducatives en nutrition destinées aux patients atteints de cirrhose : Un projet en quatre volets.

Manila Sophasath, Yvette Mukaneza, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Problématique: La malnutrition est l’une des complications les plus prévalentes de la cirrhose et affecte la qualité de vie des patients et des proches aidants. Objectifs: Le projet vise l’évaluation de ressources éducatives nutritionnelles auprès de patients cirrhotiques, en plusieurs volets. 1)Évaluer le Guide de nutrition pour la cirrhose sur les connaissances en nutrition, qualité de vie et état nutritionnel sur 6 mois. 2)Évaluer l’impact du Guide sur la qualité de vie et perception de fardeau des proches aidants sur 6 mois. 3)Évaluer la satisfaction du Guide des patients. 4)Évaluer la réceptivité des patients à une éducation nutritionnelle via les plateformes technologiques. Méthodologie: 1)100 patients de la clinique d’hépatologie du CHUM divisés en deux groupes (n=50/groupe): Intervention (Guide) et Contrôle (sans Guide). Les évaluations de l’état nutritionnel, les connaissances en nutrition, la qualité de vie et la fonction hépatique sont réalisées à 0, 3 et 6 mois. 2)La qualité de vie et perception de fardeau des proches aidants sont évaluées à 0 et 6 mois. 3)5 groupes de discussion (4 patients/groupe) permettront d’évaluer leur appréciation du Guide. 4)100 patients qui rempliront des questionnaires (transversal) sur leur utilisation, compétences et préférences en matière de technologies. Résultats préliminaires (volet 1): 31 patients ont complété l’évaluation de 3 mois à ce jour : intervention (n=16) et contrôle (n=15). Ces résultats démontrent une tendance d’amélioration des connaissances (4,2%; de 75,4% à 79,6%) pour le groupe intervention, versus 0,9% pour le groupe contrôle (de 73,7% à 74,6%), (p=0.212). Maintenant, 18 patients ont complété l’évaluation de 6 mois: intervention (n=9) et contrôle (n=9). Les résultats préliminaires démontrent que la tendance d’amélioration de connaissances dénotée après 3 mois n’est pas maintenue après 6 mois (groupe intervention): de 75,4% à 79,6% (3 mois), à 74.4% (6 mois). Discussion: Les résultats de cette étude devraient permettre d’optimiser la qualité des soins chez les gens souffrant de cirrhose.

Évolution de l’état nutritionnel, de la qualité de vie et de la fonction musculaire des patients en attente d’une transplantation hépatique.

Amal Trigui, Yvette Mukaneza, Mélanie Tremblay, Joann Maxwell, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Problématique : La malnutrition est la complication la plus fréquente chez les patients atteints de maladies hépatiques chroniques (cirrhose) en attente d’une transplantation hépatique (TH) et elle pourrait avoir un impact négatif sur les issues cliniques avant et après la TH. La malnutrition peut également entraîner la sarcopénie (perte de masse et fonction musculaires). L’objectif est d’évaluer les changements longitudinaux de l'état nutritionnel, de la qualité de vie et de la fonction musculaire des patients cirrhotiques en attente d’une TH. Après la TH, notre objectif est d’évaluer l’effet de la supplémentation précoce, riche en protéines, en bêta-hydroxy-bêta-méthylbutyrate et en énergie sur les mêmes paramètres qu’avant la TH. Méthodologie : Une étude pilote randomisée est menée auprès de 30 patients ayant reçu une TH, (1) groupe intervention (n=15) qui reçoit des suppléments nutritionnels pendant 12 semaines et (2) un groupe témoin (n=15) qui reçoit les soins nutritionnels standards. La masse musculaire (CT-scan), la fonction musculaire (Test d'élévation de la chaise), l'état nutritionnel (Liver Disease Undernutrition Screening Tool) et la qualité de vie (SF-36) sont évalués avant la TH, à la sortie de l'hôpital et après 12 semaines. Résultats et discussion : 24 patients en attente de TH sont présentement inclus. L’âge moyen des patients est 54,7 ± 8,0 ans. Avant la TH, 83.3% des patients souffrent de malnutrition. Les scores de la santé physique (43,5% ± 20,4) et mentale (53,8% ± 25,6) du SF-36 sont inférieurs aux scores des patients en bonne santé (81,60% et 78,58 %; p < 0,001). La fonction musculaire est altérée chez ces patients (19,3 ± 7,5 s vs 12,6 s chez des patients en bonne santé) (p < 0,001). La qualité de vie a légèrement diminué avec le temps (p>0,05). Conclusion : Ces données préliminaires appuient la nécessité d’un soutien nutritionnel précoce après la TH.

Oral

The effect of early nutritional intervention on muscle mass following liver transplantation.

Amal Trigui, Joann Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

After liver transplantation (LT), nutritional status can worsen rapidly leading to sarcopenia (loss of muscle mass and function) and altered quality of life. Few studies have focused on preventing malnutrition and sarcopenia after LT whereas guidelines for the management of sarcopenia after LT are lacking. The objectives of our study are to evaluate the effect of early nutritional supplementation, after LT, rich in protein, beta-hydroxy-beta-methylbutyrate (HMB, active metabolite of leucine) and energy on muscle mass and function, nutritional status, quality of life and development of complications. Method: A randomized controlled pilot study is conducted including 30 patients who have undergone LT: (1) intervention group (n=15) receiving, in addition to the standard nutritional care, supplements rich in protein, HMB and energy for 12 weeks and (2) control group (n=15) receiving standard nutritional care. Muscle mass (computed tomography scan), muscle function (chair stand test), nutritional status (liver disease undernutrition screening tool) and quality of life (SF-36) are assessed every 3 months before LT, after LT on discharge from hospital and after 12 weeks. Dietary protein intake and physical activity are assessed once a month. Adherence to treatment is monitored by phone calls, by a logbook and by measuring urinary HMB once a month. Preliminary results: Currently, 23 patients awaiting liver transplantation are included. Once transplanted, the patient is randomized into one of the two groups. The mean age of the patients is 53.9 ± 12.0 years. Before LT, 82 % of patients were classified as malnourished. Regarding quality of life, the score of physical (47.4% ± 28.6) and mental (51.1% ± 28.8) health of the SF-36 are significantly lower than the scores of healthy patients of the same age (81.60% and 78.58%, respectively) (p < 0,001). Muscle function is also impaired in those patients (25.1 ± 11.0 s vs. 12.6 s in healthy patients) (p < 0,001). Conclusion: These preliminary data support the need for early nutritional support after LT. Our study could significantly improve the health and quality of life of patients after LT through the primary and secondary prevention of malnutrition and sarcopenia.

OpenAccess

Renal dysfunction independently predicts muscle mass loss in patients following liver transplantation.

Mimosa Nguyen, Yvette Mukaneza, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

OpenAccess

Amino acids, ammonia, and hepatic encephalopathy.

Katerina Kroupina, Chantal Bémeur, Christopher F. Rose.

Optimisation de la masse musculaire grâce à une intervention nutritionnelle précoce chez les patients ayant reçu une transplantation hépatique.

Amal Trigui, Yvette Mukaneza, Mélanie Tremblay, Joan Maxwell, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Après la transplantation hépatique (TH), l'état nutritionnel d'un patient peut s’aggraver rapidement conduisant à une sarcopénie (perte de masse et fonction musculaire). L’objectif de notre étude est d’évaluer l’effet de la supplémentation précoce, après la TH, riche en protéines, en bêta-hydroxy-bêta-méthylbutyrate (HMB, métabolite actif de la leucine) et en énergie en sur (1) la masse et la fonction musculaire, (2) l'état nutritionnel, (3) la qualité de vie et (4) le développement de complications. Méthode : Une étude pilote randomisée contrôlée est menée auprès de 30 patients ayant subi une TH, (1) groupe intervention (n=15) qui reçoit des suppléments riches en protéines, en HMB et en énergie (60 ml 4 fois/jour pendant 12 semaines) et (2) un groupe témoin (n=15) qui reçoit les soins nutritionnels standards. La masse musculaire (CT-scan), la fonction musculaire (Test d'élévation de la chaise), l'état nutritionnel (Liver Disease Undernutrition Screening Tool) et la qualité de vie (SF-36) sont évalués avant la TH, après la transplantation à la sortie de l'hôpital et après 12 semaines. L'apport en protéines alimentaires et l'activité physique sont évalués une fois par mois. Résultats préliminaires et discussion : Présentement, 21 patients en attente de greffe hépatique sont inclus. L’âge moyen des patients est 53,9 ± 12,0 ans. Avant la TF, la majorité des patients (82%) souffrent de malnutrition. Concernant la qualité de vie, le score de la santé physique (47,4% ± 28,6) et mentale (51,1% ± 28,8) du SF-36 sont inférieurs aux scores des patients du même âge en bonne santé (81,60% et 78,58 %, respectivement). La fonction musculaire est altérée chez les patients (25,1 ± 11,0 s vs 12,6 s chez des patients en bonne santé). Conclusion : Ces données préliminaires appuient la nécessité d’un soutien nutritionnel précoce après la TF. Notre étude pourrait contribuer à améliorer de façon importante la santé et la qualité de vie des gens ayant reçu une TF en plus de diminuer les coûts hospitaliers, via la prévention primaire et secondaire de la malnutrition et de la sarcopénie.

Effectuer la diète FODMAP via une plateforme web : impact sur la qualité de vie et les symptômes des gens atteints du syndrome de l’intestin irritable

Sandrine Laforce, Mélanie Tremblay, Yvette Mukaneza, Benoît Lamarche, Cécile Delawarde-Saïs, Mickael Bouin, Chantal Bémeur.

Le syndrome de l’intestin irritable (SII) est un désordre gastro-intestinal qui atteint environ 15% de la population mondiale. La diète FODMAP (Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols) a été développée pour établir une tolérance personnelle aux nutriments qui accentuent les symptômes gastro-intestinaux. Cette diète, durant en moyenne douze semaines, est fractionnée en trois phases : élimination, réintroduction et personnalisation. Une approche a été développée avec la plateforme web SOSCuisine.com® afin de permettre aux gens atteints du SII de suivre le protocole FODMAP dans un contexte de libre-service. Cela consiste à utiliser un service en ligne de menus hebdomadaires personnalisés faibles en FODMAP avec des instructions pour chaque étape de la diète en combinaison avec l'accès à un groupe de soutien par pairs modéré par une nutritionniste spécialisée. L’objectif est d’évaluer l’impact de ce nouveau service sur la qualité de vie et le contrôle des symptômes physiologiques et psychologiques des gens atteints du SII. Une étude prospective observationnelle, visant le recrutement de 118 participants qui effectuent la diète FODMAP via la plateforme web, est présentement en cours. Plusieurs variables (qualité de vie, symptômes physiques, anxiété, apport alimentaire) sont évaluées, via des questionnaires administrés en ligne, avant le début de la diète, et après la première et la deuxième phase. Jusqu’à maintenant, 26 personnes ont été incluses dans l’étude (81% femmes, 44,7±12,5 ans). À l’évaluation initiale, il est observé que la plupart des participants souffrent d’un SII d’intensité modérée ou sévère, que leur qualité de vie est sous-optimale et que leur niveau d’anxiété est majoritairement élevé. Notre étude devrait permettre l’identification d’éléments facilitateurs pour l’accès à la diète FODMAP et éventuellement améliorer la qualité de vie de cette population.

Effectuer la diète FODMAP via une plateforme web : impact sur la qualité de vie et les symptômes physiques et psychologiques des gens atteints du syndrome de l’intestin irritable

Sandrine Laforce, Mélanie Tremblay, Yvette Mukaneza, Benoît Lamarche, Cécile Delawarde-Saïas, Mickael Bouin, Chantal Bémeur.

La diète FODMAP via une plateforme web : impact sur la qualité de vie et les symptômes des gens atteints du syndrome de l’intestin irritable

Sandrine Laforce, Yvette Mukaneza, Mélanie Tremblay, Benoît Lamarche, Cécile Delawarde-Saïas, Mickael Bouin, Chantal Bémeur.

PROBLÉMATIQUE : Le syndrome de l’intestin irritable (SII) est un désordre gastro-intestinal qui atteint environ 15% de la population mondiale. Il se caractérise par des douleurs abdominales récurrentes, un changement dans les habitudes de défécations et des symptômes gastro-intestinaux. Ce syndrome diminue de façon significative la qualité de vie et impose un fardeau économique au système de santé. La diète FODMAP (Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols) a été développée pour établir une tolérance personnelle aux nutriments qui accentuent les symptômes. Cette diète, durant en moyenne douze semaines, est fractionnée en trois phases : élimination, réintroduction et personnalisation. Une approche a été développée avec la plateforme web SOSCuisine.com® afin de permettre aux gens atteints du SII de suivre le protocole FODMAP dans un contexte de libre-service. Cela consiste à utiliser un service en ligne de menus hebdomadaires personnalisés faibles en FODMAP avec des instructions pour chaque étape de la diète en combinaison avec l'accès à un groupe de soutien par pairs modéré par une nutritionniste spécialisée. OBJECTIF : Évaluer l’impact de ce nouveau service sur la qualité de vie et le contrôle des symptômes physiologiques et psychologiques des gens atteints du SII. MÉTHODOLOGIE : Une étude prospective observationnelle, visant le recrutement de 118 participants qui effectuent la diète FODMAP via la plateforme web, est présentement en cours. La qualité de vie, la sévérité des symptômes, l’anxiété, le stress et l’apport alimentaire sont évalués, via des questionnaires administrés en ligne, avant le début de la diète, et après la première et la deuxième phase. RÉSULTATS : Quatre participants effectuent présentement la première phase, un effectue la deuxième phase et quatre ont terminé l’étude. DISCUSSION: Notre étude devrait permettre l’identification d’éléments facilitateurs pour l’accès à la diète FODMAP et éventuellement potentiellement améliorer la qualité de vie des gens souffrant de SII.

L’effet d’une intervention nutritionnelle précoce sur la masse musculaire chez les patients ayant reçu une transplantation hépatique.

Amal Trigui, Yvette Mukaneza, Mélanie Tremblay, Joann Maxwell, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

La malnutrition protéino-énergétique est la complication la plus courante (> 80%) chez les patients en attente d’une transplantation hépatique (TH). Après une TH, l'état nutritionnel d'un patient peut s'aggraver conduisant à une sarcopénie (perte de masse musculaire), fortement corrélée à la morbidité et la mortalité après la TH. Objectifs : Évaluer l’effet de la supplémentation en protéines et en bêta-hydroxy-bêta-méthylbutyrate (HMB, métabolite actif de la leucine) en post-TH sur (1) la masse et la fonction musculaire, (2) l'état nutritionnel, (3) la qualité de vie et (4) le développement de complications. Méthode : Une étude pilote randomisée contrôlée, dont le recrutement est en cours, est menée auprès de 30 patients ayant subi une TH, (1) groupe intervention (n=15) qui reçoit des suppléments riches en protéines et en HMB (60 ml 4 fois/jour pendant 12 semaines), en plus de recevoir les conseils nutritionnels habituels et (2) un groupe témoin (n=15) qui reçoit les soins nutritionnels standards. La masse musculaire (CT-scan), la fonction musculaire (force de préhension), l'état nutritionnel (tableau de l’identification de la malnutrition) et la qualité de vie (SF-36) sont évalués : avant la TH, après la transplantation à la sortie de l'hôpital et au terme de 12 semaines d’intervention. L'apport en protéines alimentaires et l'activité physique sont contrôlés une fois par mois. Après la sortie de l'hôpital, l’adhérence est vérifiée par un suivi téléphonique toutes les deux semaines ainsi que par la mesure du HMB urinaire une fois par mois. Résultats attendus et impact potentiel : L’intervention nutritionnelle riche en protéines et en HMB pourrait améliorer la masse musculaire, l’état nutritionnel et la qualité de vie durant la période postopératoire et ainsi prévenir l’apparition des complications par rapport au groupe contrôle. Notre étude pourrait contribuer à améliorer la santé et la qualité de vie des gens ayant reçu une TH en plus de diminuer les coûts hospitaliers.

Le guide de nutrition pour la cirrhose : quel est son effet chez les gens atteints de maladie hépatique chronique et leurs proches aidants?

Manila Sophasath, Yvette Mukaneza, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Problématique: Les maladies hépatiques touchent plus de 9 millions de Canadiens. La malnutrition est l’une des complications les plus prévalentes de la cirrhose (maladie hépatique chronique) et affecte la qualité de vie des patients et des proches aidants. Objectif: L’objectif général est d’évaluer l’impact du Guide de nutrition pour la cirrhose, un document éducatif développé par des experts et patients canadiens, basé sur des données probantes. Spécifiquement, 1)Évaluer l’effet court/moyen-long terme sur i) l’état nutritionnel; ii) les connaissances en nutrition; iii) la qualité de vie; iv) la fonction hépatique et, à long terme, v) les hospitalisations (fréquence/durée). 2)Déterminer l’impact du Guide sur la qualité de vie et perception de fardeau des proches aidants. 3)Évaluer la satisfaction du Guide des patients et des proches aidants. 4)Élaborer les étapes d’implantation du Guide. Méthodologie: 100 patients de la clinique d’hépatologie du CHUM sont divisés en deux groupes (n=50/groupe) : Expérimental (Guide) et Contrôle (sans Guide). Les évaluations de l’état nutritionnel, les connaissances en nutrition, la qualité de vie et la fonction hépatique sont réalisées par une nutritionniste aux temps T=0, 3 et 6 mois. À 6 mois, les hospitalisations sont documentées. La qualité de vie et perception de fardeau des proches aidants sont évaluées à 0 et 6 mois. Finalement, 3 groupes de discussion de 10 patients et proches permettront l’évaluation qualitative de leur appréciation du Guide. Résultats préliminaires: 25 patients ont complété le suivi court terme (67% hommes, âge moyen de 60 ans, étiologies: 30% NASH, 25% alcoolique, 12,5% virale et étiologies mixtes, et 4% autres). Les résultats démontrent que le groupe expérimental (n=20) a tendance à voir une amélioration des connaissances en nutrition de 10% par rapport aux contrôles (n=5) après 3 mois. Discussion: Les résultats de cette étude devraient permettre d’optimiser la qualité des soins chez les gens souffrant de cirrhose.

La diète FODMAP via une plateforme web : impact sur la qualité de vie et les symptômes des gens atteints du syndrome de l'intestin irritable

Sandrine Laforce, Yvette Mukaneza, Mélanie Tremblay, Benoît Lamarche, Cécile Delawarde-Saïas, Mickael Bouin, Chantal Bémeur.

INTRODUCTION : Le syndrome de l’intestin irritable (SII) est un désordre gastro-intestinal qui atteint environ 15% de la population mondiale. Il se caractérise par des douleurs abdominales récurrentes et un changement dans les habitudes de défécations. La diète FODMAP (Fermentable Oligosaccharides Disaccharides Monosaccharides and Polyols) a été développée pour établir une tolérance personnelle aux nutriments qui accentuent les symptômes. Cette diète, durant en moyenne douze semaines, est fractionnée en trois phases : élimination, réintroduction et personnalisation. Une approche a été développée avec la plateforme web SOSCuisine.com® afin de permettre aux gens atteints du SII de suivre le protocole FODMAP dans un contexte de libre-service. Cela consiste à utiliser un service en ligne de menus hebdomadaires personnalisés faibles en FODMAP avec des instructions pour chaque étape de la diète en combinaison avec l'accès à un groupe de soutien par pairs modéré par une nutritionniste spécialisée. MÉTHODES: L’objectif est d’évaluer l’impact de ce nouveau service sur la qualité de vie et le contrôle des symptômes physiologiques et psychologiques des gens atteints du SII. Une étude prospective observationnelle, visant le recrutement de 118 participants qui effectuent la diète FODMAP via la plateforme web, est présentement en cours. Plusieurs variables (qualité de vie, symptômes physiques, anxiété, apport alimentaire) sont évaluées, via des questionnaires administrés en ligne, avant le début de la diète, et après la première et la deuxième phase. RÉSULTATS : Jusqu’à maintenant, 22 personnes ont été incluses dans l’étude (82% femmes, 43,5±12,1 ans). À l’évaluation initiale, il est observé que les participants souffrent d’un SII d’intensité modérée ou sévère, que leur qualité de vie est sous-optimale et que leur niveau d’anxiété est majoritairement élevé. DISCUSSION: Notre étude devrait permettre l’identification d’éléments facilitateurs pour l’accès à la diète FODMAP et éventuellement améliorer la qualité de vie des gens souffrant de SII.

L’effet d’une intervention nutritionnelle précoce sur la masse musculaire chez les patients ayant reçu une transplantation hépatique.

Amal Trigui, Yvette Mukaneza, Mélanie Tremblay, Joann Maxwell, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Introduction : La malnutrition protéino-énergétique est la complication la plus courante (> 80%) chez les patients en attente d’une transplantation hépatique (TH). L'état nutritionnel peut s'aggraver conduisant à une sarcopénie (perte de masse et fonction musculaire), fortement corrélée à la morbidité et la mortalité après la TH. L’objectif de notre étude est d’évaluer l’effet de la supplémentation précoce en protéines, en bêta-hydroxy-bêta-méthylbutyrate (HMB, métabolite actif de la leucine) et en énergie en post-TH sur (1) la masse et la fonction musculaire, (2) l'état nutritionnel, (3) la qualité de vie et (4) le développement de complications. Méthode : Une étude pilote randomisée contrôlée, dont le recrutement est en cours, est menée auprès de 30 patients ayant subi une TH répartis dans un groupe intervention (n=15) qui reçoit des suppléments riches en protéines, HMB et énergie (60 ml 4 fois/jour/12 semaines) et un groupe témoin (n=15) qui reçoit les soins nutritionnels standards. La masse musculaire (CT-scan), la fonction musculaire (Chair Stand Test), l'état nutritionnel (LDUST,Liver Disease Undernutrition Screening Tool) et la qualité de vie (SF-36, Short Form 36) sont évalués avant la TH, après la transplantation à la sortie de l'hôpital et après 12 semaines. L'apport en protéines alimentaires et l'activité physique sont également évalués une fois par mois. Résultats: Six patients sont présélectionnés et sont en attente de greffe. L’âge moyen des patients est 48,3 ±12,4 ans. 100% des patients sont malnutris. Concernant la qualité de vie, le score des composantes physiques est 50,6 ± 8,6 % et le score des composantes mentales est 60,4± 17,9%.[BC1] Conclusion : Notre étude pourrait améliorer considérablement la santé et la qualité de vie des personnes ayant reçu une TH en plus de réduire les coûts hospitaliers, grâce à la prévention primaire et secondaire de la malnutrition et de la sarcopénie.

The Nutrition in Cirrhosis Guide: a useful education tool for in people suffering from chronic liver disease and their caregivers?

Manila Sophasath, Yvette Mukaneza, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Liver disease affects over 9 million Canadians and kills 2 million people annually worldwide. One of the most prevalent complications of chronic liver disease (cirrhosis) is malnutrition, which greatly affects the quality of life of patients and their caregivers. In this context, several nutritional guidelines for cirrhotic patients have been developed. However, the application of these guidelines seems to have important shortcomings, such as the difficulty of achieving certain nutritional goals for the majority of patients. The Nutrition in Cirrhosis guide was developed by a national team of hepatology and nutrition experts. Objectives: 1) To assess the impact in cirrhotic patients, in the short and long term, of the Guide on: i) nutritional status; ii) nutrition knowledge; iii) quality of life; iv) liver function; and, in the long term, v) complications; vi) number and duration of hospitalization. 2) Determine the impact on the quality of life and the perceived burden of caregivers. 3) Survey the appreciation of the Guide by patients and their caregivers. Method: A randomized controlled study targeting 100 cirrhotic patients at the Centre Hospitalier de l’Université de Montréal (CHUM) divided into 2 groups: Intervention (Guide) and Control (without Guide). Nutritional status (Liver Disease Undernutrition Screening Tool), nutrition knowledge (homemade questionnaire), quality of life (Chronic Liver Disease Questionnaire) and liver function (from medical charts) are assessed at t = 0, 3 and 6 months, and hospitalizations after 6 months. For the second objective, the quality of life (Short-Form 36 Questionnaire) and perceived burden (Zarit Burden Interview) of caregivers is evaluated at t = 0 and 6 months. Three focus groups of 10 patients and their caregiver, randomly chosen from the intervention group, will be created to assess their appreciation of the Guide. Preliminary results: 26 patients completed the 3-month pilot study (67% men, mean age = 60 years and etiologies: 30% non-alcoholic hepatic steatosis, 25% alcoholic, 12.5% hepatitis C, hepatitis B and mixed etiologies, and 4% other etiologies). The results show that the patients in the intervention group (n=20) have better knowledge of nutrition than the controls (n=5) (79.5 ± 7.7% vs 68.4 ± 7.9%; p=0.02) after 3 months. The control group also displayed an improvement in their quality of life after 3 months compared to t = 0 (5.10 ± 1.15 vs 5.61 ± 1.08, p<0.0005). Conclusion: The Guide seems to offer a beneficial effect on the quality of life and nutrition knowledge of cirrhotic patients after 3 months. The long-term impact of this resource still needs to be established in order to develop implementation vehicles and eventually include it in cirrhotic patient care.

The Nutrition in Cirrhosis Guide: Potential beneficial effects in cirrhotic patients and caregivers.

Manila Sophasath, Yvette Mukaneza, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Liver disease affects over 9 million Canadians and kills 2 million people annually worldwide. One of the most prevalent complica-tions of chronic liver disease (cirrhosis) is malnutrition, which greatly affects the quality of life of patients and their caregivers.The Nutrition in Cirrhosis guide was developed by a national team of hepatology and nutrition experts. Objectives: 1) To assess theimpact in cirrhotic patients, in the short and long term, of the Guide on: i) nutritional status; ii) nutrition knowledge; iii) qualityof life; iv) liver function; and, in the long term, v) complications; vi)number and duration of hospitalization. 2) Determine the impact on the quality of life and the perceived burden of caregivers. 3) Survey the appreciation of the Guide by patients and their caregivers. Method: A randomized controlled study targeting 100 cirrhoticpatients at the Centre Hospitalier de l’Université de Montréal (CHUM) divided into 2 groups: Intervention (Guide) and Control (without Guide). Nutritional status, nutrition knowledge, quality of life and liver function are assessed at t = 0, 3 and 6 months, and hospitalizations after 6 months. The quality of life and perceived burden of caregivers is evaluated at t=0 and 6 months.Threefocusgroups of 10 patients and their caregiver, randomly chosen from the intervention group, will be created to assess their appreciation of the Guide. Results (pilot study): 26 patients completed the 3-month pilot study (67% men, mean age = 60 years and etiologies: 30% non-alcoholic hepatic steatosis, 25% alcoholic, 12.5% hepatitis C, hepatitis B and mixed etiologies, and 4% other etiologies). The results show that the patients in the intervention group (n=20) have better knowledge ofnutritionthanthecontrols(n=5)(79.5 ±7.7% vs 68.4 ±7.9%; p=0.02) after 3 months. The control group also displayed an improvement in their quality of life after 3 months compared to t = 0 (5.10 ± 1.15 vs 5.61 ± 1.08, p<0.0005). Conclusion: The Guide seems to offer a beneficial effect on the quality of life and nutrition knowledge of cirrhotic patients after 3 months.

Le Guide de nutrition pour la cirrhose : effets potentiellement bénéfiques chez les patients atteints de maladie hépatique chronique et leurs proches aidants.

Manila Sophasath, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

L’une des complications les plus prévalentes de la maladie hépatique chronique (cirrhose) est la malnutrition, qui affecte grandement la qualité de vie. Le Guide de nutrition pour la cirrhose a été élaboré par une équipe nationale d’experts en hépatologie et en nutrition. Objectifs: 1)Évaluer l’impact chez les patients cirrhotiques, à court et long terme, du Guide sur : i) l’état nutritionnel; ii) les connaissances en nutrition; iii) la qualité de vie; iv) la fonction hépatique; et, à long terme uniquement, v) les complications; vi) le nombre et la durée d’hospitalisation. 2)Déterminer l’impact sur la qualité de vie et la perception de fardeau des proches aidants. 3)Sonder l’appréciation du Guide par les patients et leurs proches aidants. Méthode: Une étude randomisée contrôlée visant 100 patients cirrhotiques du CHUM divisés en 2 groupes : intervention (Guide) et contrôle (sans Guide). L’état nutritionnel, connaissances en nutrition, qualité de vie et fonction hépatique sont évalués à t=0, 3 et 6 mois, et les hospitalisations survenues après 6 mois. La qualité de vie et perception de fardeau des proches aidants sera évaluée à t=0 et 6 mois. Trois groupes de discussion de 10 patients et leur proche aidant, aléatoirement choisis dans le groupe intervention, seront créés afin d’évaluer leur appréciation du Guide. Résultats (pilote): 25 patients ont complété l’étude pilote de 3 mois (67% hommes, âge moyen = 60 ans et étiologies : 30% stéatose hépatique non-alcoolique, 25% alcoolique, 12,5% hépatite C, hépatite B et étiologies mixtes, et 4% autres étiologies). Les résultats montrent que les patients du groupe intervention (n=20) ont des connaissances en nutrition supérieures aux contrôles (n=5) (79,5±7,7% vs 68,4±7,9%; p=0,02) après 3 mois. Le groupe contrôle voit aussi une amélioration de leur qualité de vie après 3 mois en comparaison au t=0 (5,10±1,15 vs 5,61 ±1,08, p<0.0005). Conclusion: Le Guide semble démontrer un effet bénéfique sur la qualité de vie et les connaissances des patients cirrhotiques après 3 mois.

Optimisation de la masse musculaire grâce à une intervention nutritionnelle précoce chez les patients ayant reçu une transplantation hépatique.

Amal Trigui, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

OpenAccess

Bile-duct ligation renders the brain susceptible to hypotension induced neuronal degeneration: implications of ammonia.

Marc-André Clément, Cristina R. Bosoi, Mariana M. Oliveira, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

La diète cétogène : bénéfique pour la stéatose hépatique non alcoolique ?

Manila Sophasath, Yvette Mukaneza, Geneviève Huard, Chantal Bémeur.

Outcomes of sarcopenic obesity and metabolic syndrome in liver transplant patients.

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher Rose, Chantal Bémeur.

Diabetes is associated to the development of hepatic encephalopathy in cirrhotic patients.

Cristina R. Bosoi, Corina Cerlat, Mimosa Nguyen, Mélanie Tremblay, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with type II diabetes (T2D) and has become the main cause of cirrhosis. Both NAFLD and T2D are associated with cognitive and neurological impairments. T2D has been established as a risk factor for first-time development of overt hepatic encephalopathy (HE) in cirrhotic patients. The onset of HE in diabetic patients with cirrhosis develops earlier compared to cirrhosis patients without T2D. However it remains unclear whether NAFLD-induced cirrhosis increases the risk for HE. The present study aims to address the association between NAFLD, T2D and HE. Methods: Our retrospective study includes 102 cirrhotic patients on the liver transplant list at the Liver Unit of the Montreal University Hospital Center. Patients were classified by etiology of cirrhosis; 1) NAFLD and 2) non-NAFLD. Demographic data, blood biochemistry, clinical information on T2D-related comorbidities and cirrhosis complications (including number and severity of HE episodes) were collected. These factors were statistically associated with HE episodes. Results: Our cohort comprised 20 (19%) NAFLD and 82 (79%) non-NAFLD patients presenting similar MELD and Child-Pugh scores. The prevalence of T2D was higher in NAFLD vs non-NAFLD cirrhotics (15 (75%) vs 24 (29%) respectively) and was associated to co-morbidities such as cardiac disease, dyslipidemia, hypertension and obesity. Among non-NAFLD cirrhotics, 47 (57%) patients had a history of HE whereas 8 (40%) were found in the NAFLD cirrhotics (p>0.05). Since T2D is already known as a risk factor for HE, we subdivided both NAFLD and non-NAFLD groups into non-T2D and T2D subgroups. HE was significantly more prevalent in patients with T2D: in the NAFLD group, 5 (25%) T2D patients had developed an episode of HE compared to 3 (15%) patients without T2D (p<0.05); in the non-NAFLD group, 16 (67%) patients had T2D and HE compared to 31 (53%) HE patients without T2D (p<0.001). Fasting glycemia levels analysis in the 4 sub-groups of patients revealed increased levels in patients with history of HE and T2D, regardless of NAFLD etiology; in the NAFLD group 8.60 ± 0.84 mmol/l in patients with HE and T2D vs 6.00 ± 1.35 mmol/l in patients with HE without T2D (p<0.01); in the non-NAFLD group: 9.23 ± 0.93 mmol/l in patients with HE and T2D vs 5.82 ± 0.27 mmol/l in patients with HE without T2D (p<0.001). Conclusion: Our results sustain the association between T2D and HE and suggest high glucose might play a pathological role in the development of cognitive decline. NAFLD is not a risk factor for the development of HE. These interesting results provide new insights in the role of T2D in the development of HE and further studies are required to understand the underlying mechanisms. Furthermore, identifying patients who are at higher risk of developing HE is imperative to initiate early treatment strategies to protect neurological decline in patients with cirrhosis.

Diabetes is associated to the development of hepatic encephalopathy in cirrhotic patients.

Corina Cerlat, Cristina R. Bosoi, Mimosa Nguyen, Mélanie Tremblay, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with type II diabetes (T2D) and has become the main cause of cirrhosis. Both NAFLD and T2D are associated with cognitive and neurological impairments. T2D has been established as a risk factor for first-time development of overt hepatic encephalopathy (HE) in cirrhotic patients. The onset of HE in diabetic patients with cirrhosis develops earlier compared to cirrhosis patients without T2D. However it remains unclear whether NAFLD-induced cirrhosis increases the risk for HE. The present study aims to address the association between NAFLD, T2D and HE. Methods: Our retrospective study includes 102 cirrhotic patients on the liver transplant list at the Liver Unit of the Montreal University Hospital Center. Patients were classified by etiology of cirrhosis; 1) NAFLD and 2) non-NAFLD. Demographic data, blood biochemistry, clinical information on T2D-related comorbidities and cirrhosis complications (including number and severity of HE episodes) were collected. These factors were statistically associated with HE episodes. Results: Our cohort comprised 20 (19%) NAFLD and 82 (79%) non-NAFLD patients presenting similar MELD and Child-Pugh scores. The prevalence of T2D was higher in NAFLD vs non-NAFLD cirrhotics (15 (75%) vs 24 (29%) respectively) and was associated to co-morbidities such as cardiac disease, dyslipidemia, hypertension and obesity. Among non-NAFLD cirrhotics, 47 (57%) patients had a history of HE whereas 8 (40%) were found in the NAFLD cirrhotics (p>0.05). Since T2D is already known as a risk factor for HE, we subdivided both NAFLD and non-NAFLD groups into non-T2D and T2D subgroups. HE was significantly more prevalent in patients with T2D: in the NAFLD group, 5 (25%) T2D patients had developed an episode of HE compared to 3 (15%) patients without T2D (p<0.05); in the non-NAFLD group, 16 (67%) patients had T2D and HE compared to 31 (53%) HE patients without T2D (p<0.001). Fasting glycemia levels analysis in the 4 sub-groups of patients revealed increased levels in patients with history of HE and T2D, regardless of NAFLD etiology; in the NAFLD group 8.60 ± 0.84 mmol/l in patients with HE and T2D vs 6.00 ± 1.35 mmol/l in patients with HE without T2D (p<0.01); in the non-NAFLD group: 9.23 ± 0.93 mmol/l in patients with HE and T2D vs 5.82 ± 0.27 mmol/l in patients with HE without T2D (p<0.001). Conclusion: Our results sustain the association between T2D and HE and suggest high glucose might play a pathological role in the development of cognitive decline. NAFLD is not a risk factor for the development of HE. These interesting results provide new insights in the role of T2D in the development of HE and further studies are required to understand the underlying mechanisms. Furthermore, identifying patients who are at higher risk of developing HE is imperative to initiate early treatment strategies to protect neurological decline in patients with cirrhosis.

Frailty and Sarcopenia in Cirrhosis: The Basics, the Challenges, and the Future

Chantal Bémeur, Christopher F. Rose.

Sarcopenic obesity and metabolic syndrome: what is the impact in the context of liver transplantation?

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

Sarcopenia Pre- and Post-liver Transplantation Implication for Hepatic Encephalopathy.

Mimosa Nguyen, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

BACKGROUND: Muscle wasting (sarcopenia) and hepatic encephalopathy affect 30 to 70% of cirrhotic patients. The presence of sarcopenia may be associated with a worst prognosis and complications, including hepatic encephalopathy, in cirrhotic patients awaiting and after liver transplantation (LT). To this day, few studies have evaluated and followed muscle mass (in terms of quantity and quality) after LT. The goal of this study was to assess the association between the evolution of sarcopenia and the prognosis of cirrhotic patients, including hepatic encephalopathy and neurological complications, before and after LT. METHODS: In total, 94 cirrhotic patients who underwent LT at the Montreal University Hospital Center - Liver Unit were included. Sarcopenia was assessed at the third lumbar level vertebrae using a computed tomography scan (CT-scan). The diagnostic of sarcopenia was based on previously established sex-specific cut-off values of skeletal muscle index. Patients were classified into two groups: (1) persistent or newly developed sarcopenia after LT (Sarc+); (2) resolved sarcopenia or absence of sarcopenia before and after LT (Sarc-). Muscle quality (myosteatosis) was assessed by calculating intramuscular adipose tissue content. The prognostic factors were collected 6 months before and during 1 year after LT through medical records and included the number of complications, the presence of hepatic encephalopathy and the episodes of infections, the length of stay, and the frequency of readmissions. RESULTS: Sarcopenia persisted or was newly developed (Sarc+) in 62% of the patients (n = 58). It remained absent or was resolved after LT in 38% of the patients (n = 35). Muscle quality was significantly decreased post-LT (P = 0.034). The group Sarc+ experienced more complications pre-LT (P = 0.012) and post-LT (P < 0.001), infections post-LT (P = 0.006) and readmissions (P = 0.048) compared to the group Sarc-. The length of stay was longer for the group Sarc+ as opposed to the group Sarc- (P < 0.001). Hepatic encephalopathy was present in 83% of patients pre-LT whereas 17% experienced persistent neurological complications post-LT. CONCLUSIONS: Persistent and newly developed sarcopenia after LT appear to have negative outcomes on the prognosis of patients. Interventional strategies to optimize, increase or preserve muscle mass could help to improve post-operative recovery as well as the quality of life in patients who have undergone LT.

Malnutrition in chronic liver disease: Implications for quality of life and hepatic encephalopathy

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher Rose, Chantal Bémeur.

BACKGROUND: Malnutrition is the most common complication in patients with chronic liver disease (CLD) and may increase the risk of developing hepatic encephalopathy (HE) as well as affect pa-tients’ functional status and quality of life (QOL). Management strategies focussing on nutritional status in relation to complications of CLD are an unmet clinical need. PURPOSE: The objectives are to: 1) Assess nutri-tional status and its relationship to QOL; 2) Ascer-tain the presence, severity and history of HE; 3) Inquire the relationship of HE and history of HE on the QOL of CLD subjects. METHOD: Observational and cross-sectional study involving 50 patients (hospitalized and outpatients) from the CHUM’s Liver Unit, Montreal, Canada) and 18 controls (non-cirrhotic). All subjects were assessed for: 1) Nutritional Status: Standardized Questionnaire Subjective Global Assessment (SGA); 2) QOL: General questionnaire SF-36 evalu-ating the QOL as perceived by the patient (8 scales: physical functioning (PF), role limitations due to physical health (RP), due to emotional problems (RE), social functioning (SF), bodily pain (BP), vitality (VT), mental health (MH) and general health (GH)); 3) HE: History and presence of covert HE using EncephalApp Stroop test or overt HE using the Clinical Hepatic Encephalopathy Staging Scale.RESULT(S): 50 CLD patients (72% men) of various etiologies (18% NASH, 12% alcoholic, 8% autoim-mune, 6% viral, 12% others and 44% mixed eti-ologies), Child–Pugh (15A, 7B, 18C and 10 N/A), aged 56±12 years and 18 non-cirrhotic patients (33% male, aged 42±15). SGA revealed that 34% of CLD subjects were malnourished. Among mal-nourished CLD patients, 18% were diagnosed with covert or overt HE. CLD malnourished patients had a lower perception of QOL than well-nour-ished CLD patients for all SF-36 scales (p < 0.01). History of HE was associated with poor QOL as CLD patients with a history of HE (36%) showed decreased PF (p = 0.024) and RP (p < 0.01). Com-pared to controls, CLD patients displayed a lower score in PF (p < 0.05) and GH (p < 0.05).CONCLUSION(S): Our data suggest that a subop-timal nutritional status based on SGA negatively affects 6 scales out of 8 of QOL (RP, RE, SF, VT, MH and GH) but is not associated with presence of HE. However, history of HE does impact two scales of QOL (PF and RP). Identifying malnourished CLD patients is of great importance to improve QOL. Interventions to prevent and treat malnutrition in CLD remain a primary need.

Sarcopenia in the context of liver transplantation: What is the prognosis?

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher Rose, Chantal Bémeur.

BACKGROUND: Muscle wasting (sarcopenia) af-fects 30 to 70% of cirrhotic patients. The presence of sarcopenia may be associated with a worst prog-nosis in cirrhotic patients awaiting and after liver transplantation (LT). To this day, few studies have evaluated and followed muscle mass (in terms of quantity and quality) after LT.PURPOSE: The goal of this study was to assess the association between the evolution of sarcopenia and the prognosis of cirrhotic patients before and after LT.METHOD: In total, 94 cirrhotic patients who un-derwent LT at the Montreal University Hospital Center – Liver Unit were included. Sarcopenia was assessed at the third lumbar level vertebrae using a computed tomography scan (CT-scan). The diag-nostic of sarcopenia was based on previously estab-lished sex-specific cut-off values of skeletal muscle index. Patients were classified into two groups: 1) persistent or newly developed sarcopenia after LT (Sarc+); 2) resolved sarcopenia or absence of sarcope-nia before and after LT (Sarc–). Muscle quality (myo-steatosis) was assessed by calculating intramuscular adipose tissue content. The prognostic factors were collected 6 months before and during 1 year after LT through medical records and included the num-ber of complications, the episodes of infections, the length of stay, and the frequency of readmissions.RESULT(S): Sarcopenia persisted or was newly de-veloped (Sarc+) in 62% of the patients (n = 58). It remained absence or was resolved after LT in 38% of the patients (n = 35). Muscle quality was significantly decreased post-LT (p = 0.034). The group Sarc+ ex-perienced more complications pre-LT (p = 0.012) and post-LT (p < 0 .001), infections post-LT (p = 0.006) and readmissions (p = 0.048) compared to the group Sarc−. The length of stay was longer for the group Sarc+ as opposed to the group Sarc− (p < 0 .001).CONCLUSION(S): Persistent and newly developed sarcopenia after LT appear to have negative out-comes on the prognosis of patients. Interventional strategies to optimize, increase or preserve muscle mass could help to improve post-operative recov-ery as well as the quality of life in patients who have undergone LT.

Évaluation d’un guide éducatif en nutrition destiné aux gens atteints de maladie hépatique chronique.

Manila Sophasath, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Association entre la sarcopénie et le pronostic des patients cirrhotiques dans le contexte de la transplantation hépatique.

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

Introduction : La sarcopénie affecte jusqu’à 70% des patients atteints d’une maladie hépatique chronique (cirrhose). Sa présence a été associée à une qualité de vie détériorée. Par ailleurs, elle pourrait influencer le pronostic des patients cirrhotiques avant et après la transplantation hépatique (TH), seul traitement curatif pour la cirrhose à ce jour. Peu d’études ont étudié l’évolution de la sarcopénie après la TH. Le but de cette étude était d’évaluer l’évolution de la sarcopénie et son association avec le pronostic des patients cirrhotiques pré- et post-TH. Méthodes : L’évaluation de la masse musculaire a été effectuée chez 94 patients du département d’hépatologie du CHUM ayant reçu la TH entre le 5 juin 2012 et le 30 avril 2017. Elle était évaluée en utilisant l’index musculaire squelettique lequel est basé sur l’analyse de l’examen radiologique de tomodensitométrie au niveau de la 3e vertèbre lombaire. Par la consultation des dossiers médicaux, les critères de pronostic étaient évalués durant l’année suivant la TH et comprenaient le nombre de complications, les épisodes d’infection, la durée de l’hospitalisation et la fréquence des réadmissions. Résultats : La sarcopénie a persisté ou est apparue (Sarc+) chez 62% des patients (n=58) alors qu’elle a régressé ou est demeurée absente (Sarc-) chez 38% des patients (n=35). Le groupe Sarc+ a eu davantage de complications avant la TH (p=0,012) et après la TH (p<0,001) et d’infections après la TH (p=0,006) par rapport au groupe Sarc-. La durée de l’hospitalisation était aussi prolongée chez le groupe Sarc+ comparativement au groupe Sarc- (p<0,001). Conclusion : La sarcopénie persistante ou nouvellement développée telle qu’évaluée jusqu’à 1 an après la TH est associée à un mauvais pronostic, particulièrement en période post-TH. La mise en place de stratégies d’intervention pour préserver ou même augmenter la masse musculaire pourrait aider à améliorer le pronostic des patients suite à la TH. Bourses octroyées par le Département de nutrition et la Faculté de médecine de l’Université de Montréal

Sarcopenia is associated with a worst prognosis in cirrhotic patients in the context of liver transplantation.

Mimosa Nguyen, Mélanie Tremblay, An Tang, Christopher F. Rose, Chantal Bémeur.

Background and aims:Musclewasting (sarcopenia) affects 30 to 70%of cirrhotic patients. The presence of sarcopenia may be associatedwith a worst prognosis in cirrhotic patients awaiting and after livertransplantation (LT). To this day, few studies have evaluated andfollowed muscle mass (in terms of quantity and quality) after LT.The goal of this study was to assess the association between theevolution of sarcopenia and the prognosis of cirrhotic patients beforeand after LT.Method:In total, 94 cirrhotic patients who underwent LT at theMontreal University Hospital Center-Liver Unit were included.Sarcopenia was assessed at the third lumbar level vertebrae using acomputed tomography scan (CT-scan). The diagnostic of sarcopeniawas based on previously established sex-specific cut-off values ofskeletal muscle index. Patients were classified into two groups: (1)persistent or newly developed sarcopenia after LT (Sarc+); (2)resolved sarcopenia or absence of sarcopenia before and after LT(Sarc-). Muscle quality (myosteatosis) was assessed by calculatingintramuscular adipose tissue content. The prognostic factors werecollected 6 months before and during 1 year after LT through medicalrecords and included the number of complications, the episodes ofinfections, the length of stay, and the frequency of readmissions.Results:Sarcopenia persisted or was newly developed (Sarc+) in 62%of the patients (n = 58). It remained absence or was resolved after LTin 38% of the patients (n = 35). Muscle quality was significantlydecreased post-LT (p = 0.034). The group Sarc+ experienced morecomplications pre-LT (p = 0.012) and post-LT (p < 0.001), infectionspost-LT (p = 0.006) and readmissions (p = 0.048) compared to thegroup Sarc-. The length of stay was longer for the group Sarc+ asopposed to the group Sarc- (p < 0.001).Conclusion:Persistent and newly developed sarcopenia after LTappear to have negative outcomes on the prognosis of patients.Interventional strategies to optimize, increase or preserve musclemass could help to improve post-operative recovery as well as thequality of life in patients who have undergone LT.

Role of Exercise in the Management of Hepatic Encephalopathy: Experience From Animal and Human Studies.

Luise Aamann, Puneeta Tandon, Chantal Bémeur.

The association between sarcopenia and the prognosis of cirrhotic patients in liver transplantation.

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

Association entre la sarcopénie et le pronostic des patients cirrhotiques dans le contexte de la transplantation hépatique.

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

Introduction : La sarcopénie affecte jusqu’à 70% des patients atteints d’une maladie hépatique chronique (cirrhose). Sa présence a été associée à une qualité de vie détériorée. Par ailleurs, elle pourrait influencer le pronostic des patients cirrhotiques avant et après la transplantation hépatique (TH), seul traitement curatif pour la cirrhose à ce jour. Peu d’études ont étudié l’évolution de la sarcopénie après la TH. Le but de cette étude était d’évaluer l’évolution de la sarcopénie et son association avec le pronostic des patients cirrhotiques pré- et post-TH. Méthodes : L’évaluation de la masse musculaire a été effectuée chez 94 patients du département d’hépatologie du CHUM ayant reçu la TH entre le 5 juin 2012 et le 30 avril 2017. Elle était évaluée en utilisant l’index musculaire squelettique lequel est basé sur l’analyse de l’examen radiologique de tomodensitométrie au niveau de la 3e vertèbre lombaire. Par la consultation des dossiers médicaux, les critères de pronostic étaient évalués durant l’année suivant la TH et comprenaient le nombre de complications, les épisodes d’infection, la durée de l’hospitalisation et la fréquence des réadmissions. Résultats : La sarcopénie a persisté ou est apparue (Sarc+) chez 62% des patients (n=58) alors qu’elle a régressé ou est demeurée absente (Sarc-) chez 38% des patients (n=35). Le groupe Sarc+ a eu davantage de complications avant la TH (p=0,012) et après la TH (p<0,001) et d’infections après la TH (p=0,006) par rapport au groupe Sarc-. La durée de l’hospitalisation était aussi prolongée chez le groupe Sarc+ comparativement au groupe Sarc- (p<0,001). Conclusion : La sarcopénie persistante ou nouvellement développée telle qu’évaluée jusqu’à 1 an après la TH est associée à un mauvais pronostic, particulièrement en période post-TH. La mise en place de stratégies d’intervention pour préserver ou même augmenter la masse musculaire pourrait aider à améliorer le pronostic des patients suite à la TH. Bourses octroyées par le Département de nutrition et la Faculté de médecine de l’Université de Montréal

OpenAccess

Progressive resistance training prevents loss of muscle mass and strength in bile duct ligated rats.

Mariana M. Oliveira, Christopher F. Rose, Luise Aamann, Rafael Ochoa-Sanchez, Mariana Oliveira, Mélanie Tremblay, Chantal Bémeur, Gitte Dam, Hendrik Vilstrup, Niels Kristian Aagaard, Christopher Rose.

Nutritional status in patients with chronic liver disease: Impact on hepatic encephalopathy and health-related quality of life.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Introduction: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (CLD; cirrhosis) and may increase the risk of developing other complications including hepatic encephalopathy (HE). Malnutrition in cirrhosis may also affect patient’s functional status and health-related quality of life (HRQOL). Management strategies focussing on nutritional status in relation to complications of cirrhosis are an unmet clinical need. We hypothesize that sub-optimal nutritional status in cirrhotic patients increases the risk of developing HE and decreases HRQOL. Objectives: The primary goal is to evaluate the impact of nutritional status on health-related quality of life in cirrhotic patients. The secondary goal is to ascertain the presence of HE and examine its relationship with nutritional status and HRQOL. Methods: Hospitalized and outpatients with cirrhosis as well as non-cirrhotic (NC) patients were assessed for 1) Nutritional status (SGA); 2) HE; 3) HRQOL (SF-36). Results: 50 cirrhotic patients (72% men) of various etiologies as well as 18 NC patients (33% men) were included. SGA analysis revealed that 34% of cirrhotic patients were malnourished whereas 12% of cirrhotic patients were diagnosed with HE at time of recruitment and 37% had a history of HE. Among malnourished CLD patients, 18% were diagnosed with HE. CLD malnourished patients showed a decreased HRQOL compared to well-nourished CLD patients (p<0,01). Moreover, HE had an impact on HRQOL as cirrhotic patients with a history of HE episode(s) showed decreased physical functioning (p=0,024) and role limitations due to physical health (p=0,002). Interestingly, when compared to NC patients, CLD patients displayed a lower score in physical functioning (p<0,0001) and general health (p=0,027). Conclusion: Our data suggest that poor nutritional status and history of HE episode(s) do negatively influence HRQOL in cirrhotic patients. Significance: Our study provides important results in order to empower the field of dietitics to actively engage in malnutrition management in cirrhosis.

Impact de la sarcopénie lors de la transplantation hépatique : une étude rétrospective en cours.

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

Impact de la sarcopénie lors de la transplantation hépatique : une étude rétrospective en cours.

Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.

Impact de l'état nutritionnel sur la qualité de vie et l'encéphalopathie hépatique lors de maladies chroniques du foie.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Nutritional status, hepatic encephalopathy and health-related quality of life in patients with chronic liver disease.

Christopher F. *Rose, Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (CLD; cirrhosis) and may increase the risk of developing other complications including hepatic encephalopathy (HE). Malnutrition in cirrhosis may also affect patient’s functional status and health-related quality of life (HRQOL). Management strategies focussing on nutritional status in relation to complications of cirrhosis are an unmet clinical need. We hypothesize that sub-optimal nutritional status in cirrhotic patients increases the risk of developing HE and decreases HRQOL. Purpose: The primary purpose is to evaluate the impact of nutritional status on health-related quality of life in cirrhotic patients. The secondary purpose is to ascertain the presence of hepatic encephalopathy and examine its relationship with nutritional status and HRQOL. Method: Hospitalized and outpatients (CHUM’s Liver Unit, Montreal, Canada) with cirrhosis as well as non-cirrhotic (NC) patients were assessed for 1) Nutritional status (Subjective Global Assessment (SGA)); 2) HE (presence or history); 3) HRQOL (Short-Form-36 (SF-36) questionnaire). Results: 50 cirrhotic patients (72% men) of various etiologies, Child-Pugh (15A, 7B, 18C, 10 unknown), mean age 56±12 as well as 18 NC patients (33% men, mean age 42±15) were included. SGA analysis revealed that 34% of cirrhotic patients were malnourished whereas 12% of cirrhotic patients were diagnosed with HE at time of recruitment and 37% had a history of HE. Among malnourished CLD patients, 18% were diagnosed with HE. CLD malnourished patients showed a decreased HRQOL compared to well-nourished CLD patients (p<0,01). Moreover, HE had an impact on HRQOL as cirrhotic patients with a history of HE episode(s) showed decreased physical functioning (p=0,024) and role limitations due to physical health (p=0,002). Interestingly, when compared to NC patients, CLD patients displayed a lower score in physical functioning (p<0,0001) and general health (p=0,027). Conclusion: Our data suggest that poor nutritional status does negatively influence HRQOL in cirrhotic patients but is not associated with HE. However, history of HE episode(s) does impact on HRQOL among this population. Therefore, identifying malnourished patients is of great importance and interventions for treating malnutrition remains an unmet clinical need.

Caractérisation de la microglie dans un modèle expérimental du syndrome de leigh version canadienne française.

Raluca Ticala, Mélanie Tremblay, Christopher F. Rose, Consortium de l'acidose lactique, Chantal Bémeur.

Introduction : Le Syndrome de Leigh version canadienne française (LSFC) est une maladie rare dont l’incidence est élevée dans la région du Saguenay-Lac-Saint-Jean. Il est causé par une mutation du gène « leucine-rich pentatricopeptide repeat motif containing protein » (LRPPRC), entrainant une déficience tissu-spécifique en cytochrome c oxydase de la chaîne respiratoire mitochondriale. L’activité de l’enzyme est réduite jusqu’à 80% dans le foie et le cerveau. Les atteintes hépatiques semblent avoir des répercussions au niveau cérébral; le phénotype consiste en un retard de développement, de l’hypotonie et un dimorphisme facial. Les enfants atteints sont susceptibles de souffrir d’épisodes aiguës d’acidose métabolique (crises) menant à la mort de 80% d’entre eux avant l’âge de 4 ans. Ces crises sont souvent déclenchées par plusieurs changements, incluant une infection ou un apport nutritionnel riche en matières grasses et sucres. Aucune avenue thérapeutique n’existe. Plusieurs recherches portent sur les atteintes hépatiques de la maladie, mais aucune investigation ne s’est penchée sur la caractérisation cérébrale de la microglie. Matériel et méthodes :L’hypothèse est qu’une activation de la microglie, cellules immunitaires du cerveau, est présente dans un modèle expérimental de souris ayant la mutation du gène LRPPRC au niveau hépatique et l’objectif est de caractériser cette activation. L’expression de marqueurs de cellules microgliales est mesurée par immunobuvardage Western, avec l’utilisation d’anticorps primaires (CD11b, OX-42 et Iba-1) spécifiques aux protéines d’intérêt. Résultats et discussion :Aucun anticorps n’a démontré des résultats valides et plusieurs sources d’erreur peuvent expliquer ces résultats. Conclusion :Ce projet de recherche a tenté de caractériser pour la première fois l’activation de la microglie dans un modèle expérimental de la maladie. Considérant les résultats obtenus, il est nécessaire de reproduire cette étude.

Impact de l’exercice sur la protection du cerveau lors de maladie hépatique chronique expérimentale.

Charlène Blanchette, Luise Aamann, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Nutritional status, hepatic encephalopathy and health-related quality of life in patients with chronic liver disease.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (CLD; cirrhosis) and may increase the risk of developing other complications including hepatic encephalopathy (HE). Malnutrition in cirrhosis may also affect patient’s functional status and health-related quality of life (HRQOL). Management strategies focussing on nutritional status in relation to complications of cirrhosis are an unmet clinical need. We hypothesize that sub-optimal nutritional status in cirrhotic patients increases the risk of developing HE and decreases HRQOL. Purpose: The primary purpose is to compare the nutritional status of adult patients with cirrhosis to non-cirrhotic patients. The secondary purposes is to ascertain hepatic encephalopathy (current and previous history) and quality of life among this population. Method: Hospitalized and outpatients (CHUM’s Liver Unit, Montreal, Canada) with cirrhosis as well as non-cirrhotic (NC) patients were assessed for 1) Nutritional status (Subjective Global Assessment (SGA)); 2) HE (presence or history); 3) HRQOL (Short-Form-36 (SF-36) questionnaire). Results: 50 cirrhotic patients (72% men) of various etiologies, Child-Pugh (15A, 7B, 18C, 10 unknown), mean age 56±12 as well as 18 NC patients (33% men, mean age 42±15) were included. SGA analysis revealed that 34% of cirrhotic patients were malnourished whereas 12% of cirrhotic patients were diagnosed with HE at time of recruitment and 37% had a history of HE. Among malnourished CLD patients, 18% were diagnosed with HE. CLD malnourished patients showed a decreased HRQOL compared to well-nourished CLD patients (p<0,01). Moreover, HE had an impact on HRQOL as cirrhotic patients with a history of HE episode(s) showed decreased physical functioning (p=0,024) and role limitations due to physical health (p=0,002). Interestingly, when compared to NC patients, CLD patients displayed a lower score in physical functioning (p<0,0001) and general health (p=0,027). Conclusion: Our data suggest that poor nutritional status does negatively influence HRQOL in cirrhotic patients but is not associated with HE. However, history of HE episode(s) does impact on HRQOL among this population. Therefore, identifying malnourished patients is of great importance and interventions for treating malnutrition remains an unmet clinical need.

Comparison of nutritional assessment tools in cirrhotic patients.

Annie Lamoussenerie, Cassandra Picinbono-Larose, Mélanie Tremblay, Thierry Cresson, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Oral

Hepatic encephalopathy and health-related quality of life among cirrhotic patients: Scope of nutritional status.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher Rose, Chantal Bémeur.

Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (cirrhosis; CLD). Malnutrition may increase the risk of developing other complications including hepatic encephalopathy (HE). Malnutrition in cirrhosis may also affect patient’s functional status and health-related quality of life (HRQOL). Management strategies focussing on nutritional status in relation to complications of cirrhosis are an unmet clinical need. We hypothesize sub-optimal nutritional status in cirrhotic patients increases the risk of developing HE and decreases HRQOL. Hospitalized and outpatients (CHUM’s Liver Unit in Montreal, Canada) with liver cirrhosis of different etiologies and healthy controls were assessed for 1) Nutritional status (Subjective Global Assessment (SGA)); 2) HE (Clinical HE Staging Scale (CHESS)); 3) HRQOL (Short-Form-36 (SF-36) questionnaire). This on-going prospective study included 33 cirrhotic patients (58% men) of various etiologies (% : 30 alcohol, 33 virus, 27 NASH and 33 others), Child-Pugh (13A, 9B, 5C and 6N/A), mean age 55,7±12,9 as well as 13 healthy controls (46% men, mean age 49,4±14,9). SGA analysis revealed that 27% of cirrhotic patients were malnourished. Furthermore, cirrhotic malnourished patients show decreased HRQOL compared to well-nourished cirrhotic patients (p<0.01). Cirrhotic patients, when compared to controls, displayed a lower score in physical functioning (p=0.03) and general health (p=0.03). CHESS analysis revealed none of the cirrhotic patients had HE while 21% of them had an HE diagnosis in medical chart, suggesting CHESS would not be sensible enough to screen HE. Our preliminary results suggest that nutritional status does influence particular domains of HRQOL in cirrhotic patients irrespective of their etiology. Further patients are required to statistically confirm the impact of nutritional status on HE and HRQOL in cirrhotic patients. Identifying factors associated with nutritional status, HRQOL and HE in cirrhotic patients may help improve patient care and guide future research.

Impact de l’état nutritionnel sur l’encéphalopathie hépatique et la qualité de vie chez les patients atteints de maladie chronique du foie : Résultats préliminaires d’une étude prospective.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Comparaison d’outils d’évaluation nutritionnelle lors de cirrhose.

Annie Lamoussenerie, Cassandra Picinbono-Larose, Mélanie Tremblay, Thierry Cresson, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Oral

Impact de l'état nutritionnel sur l'encéphalopathie hépatique et la qualité de vie chez les patients atteints de maladie chronique du foie: résultats préliminaires d'une étude prospective.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher Rose, Chantal Bémeur.

OpenAccess

The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis.

Cristina R. Bosoi, Mariana M. Oliveira, Rafael Ochoa-Sanchez, Mélanie Tremblay, Gabriella A. Ten Have, Nicolaas E. Deutz, Christopher F. Rose, Chantal Bémeur.

Impact of nutritional status on hepatic encephalopathy and quality of life in patients with chronic liver disease: preliminary results of a prospective study.

Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Demers, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (cirrhosis; CLD). Malnutrition may increase the risk of developing other complications including hepatic encephalopathy (HE). Malnutrition in cirrhosis may also affect patient’s functional status and wellbeing or health-related quality of life (HRQOL). Management strategies focussing on nutritional status in relation to complications of cirrhosis are an unmet clinical need. We hypothesize sub-optimal nutritional status in cirrhotic patients increases the risk of developing HE and decreases HRQOL. Methods: 33 patients (outpatients and hospitalized; CHUM’s Liver Unit in Montreal, Canada) with liver cirrhosis of different etiologies and 13 healthy controls were assessed for 1) Nutritional status (Subjective Global Assessment (SGA)); 2) HE (Clinical HE Staging Scale (CHESS)); 3) HRQOL (Short-Form-36 (SF-36) questionnaire). Results: This on-going prospective study included 33 cirrhotic patients (58% men) of various etiologies (30% alcohol, 33 % virus, 27% NASH and 33% others), Child-Pugh A/B/C (13A, 9B, 5C and 6 N/A), mean age 55,7±12,9 as well as 13 healthy controls (46% men, mean age 49,4±14,9). SGA analysis revealed that 27% of cirrhotic patients were malnourished in which 22% of them malnourished showed signs of HE as assessed by CHESS. Cirrhotic patients, when compared to controls, displayed a lower score in physical functioning (p=0.03) and general health (p=0.03), both part of the physical health domain of SF-36. Furthermore, cirrhotic malnourished patients show decreased physical aspects of HRQOL compared to well-nourished cirrhotic patients (p<0.01). Conclusion: Our preliminary results suggest that nutritional status does influence particular domains of HRQOL in cirrhotic patients irrelevant of their etiology. Further patients are required to statistically confirm the impact of nutritional status on HE and HRQOL in cirrhotic patients. Identifying factors associated with nutritional status, HRQOL and HE in cirrhotic patients may help improve patient care and guide future research.

Oral

Effects of anaerobic exercise in muscle mass optimization in bile duct ligated rats.

Mariana Oliveira, Christopher Rose, Luise Aamann, Rafael Ochoa-Sanchez, Mariana M. Oliveira, Mélanie Tremblay, Chantal Bémeur, Gitte Dam, Hendrik Vilstrup, Niels Kristian Aagaard, Christopher F. Rose.

Background/Aims: Skeletal muscle abnormalities, such as sarcopenia and myosteatosis are frequent complications of cirrhosis and are associated with increased morbidity and mortality. Hyperammonemia plays a significant role in the pathogenesis of hepatic encephalopathy (HE). Skeletal muscle have a significant compensatory part in detoxifying ammonia during liver disease since it houses the enzyme glutamine synthetase, an important ammonia-removing pathway during the amination of glutamate to glutamine. Therefore, we aimed to investigate whether reduced quantity and quality of muscle is associated with hyperammonemia, HE and mortality in patients with cirrhosis. Methods: A total of 677 cirrhotic patients were evaluated. Computed tomography (CT) scans were used to analyze the skeletal muscle (transverse CT image at the level of the 3rd. lumbar vertebra (L3) was selected from each scan) and sarcopenia and myosteatosis was evaluated. Overt HE was assessed clinically and ammonia blood levels were performed at the time of the muscularity assessment. Results: Sarcopenia was noted in 292 patients (43%), and 352 patients had myosteatosis (52%). A total of 225 patients (33%) had history of overt HE and 221 (of 267) patients (83%) had hyperammonemia. The prevalence of overt HE was higher in patients with sarcopenia (42% vs. 27%, P<0.001), and myosteatosis (41% vs. 25%, P<0.001). By multivariable regression analysis, sarcopenia and myosteatosis were independently associated with higher risk of overt HE (HR 1.89, P=0.007, HR 1.68, P=0.03) and hyperammonemia (HR 1.71, P=0.006, HR 1.88, P=0.001, respectively). Median survival was worse in patients with overt HE and sarcopenia (18±4 vs. 42±7 months, P=0.01), hyperammonemia and sarcopenia (11±7 vs. 38±16 months, P<0.001), and myosteatosis and hyperammonemia (19±3 vs. 38±20 months, P=0.005) compared to patients without these factors. Conclusions: Cirrhotic patients with sarcopenia and myosteatosis have a higher risk of hyperammonemia and overt HE. Further, skeletal muscle abnormalities present concomitantly with HE and hyperammonemia increase the risk of mortality in these patients.

Nutritional status assessment in patients with chronic liver disease: a pilot study.

Annie Lamoussenerie, Cassandra Picinbono-Larose, Mélanie Tremblay, Catherine Demers, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.

Experimental models of Leigh syndrome French Canadian: impact of inflammatory and nutritional stress.

Chantal *Bémeur, Rafaela Almeida, Mélanie Tremblay, Christopher F. Rose, The LSFC Consortium, Chantal Bémeur.

Evaluation of nutritional status in patients with chronic liver disease: a pilot study.

Annie Lamoussenerie, Mélanie Tremblay, Thierry Cresson, An Tang, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Evaluation of nutritional status in patients with chronic liver disease: a pilot study.

Annie Lamoussenerie, Mélanie Tremblay, Thierry Cresson, An Tang, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is one of the most common complication in the increasing number of patients suffering from chronic liver disease (cirrhosis; CLD) and is a leading cause of morbidity and mortality. Traditional tools used to evaluate nutritional status are not reliable in chronic liver disease due to limitations related to weight, which may be artificially increased by the presence of ascites, underestimating malnutrition. New strategies to assess nutritional status focussing on early malnutrition detection are an unmet clinical need. The aim of this ongoing pilot study is to describe the performance of different measures of nutrition including handgrip strength (HGS), mid-arm circumference (MAC) and subjective global assessment (SGA) in corre- lation to skeletal muscle index (SMI), an objective measure of skeletal muscle mass, among cirrhotic patients. Methods: In this ongoing pro- spective study, patients with and without CLD are recruited at the Centre hospitalier de l’Université de Montréal (St-Luc Hospital) in Can- ada. We assess nutritional status via: HGS as measured in the dominant hand with a calibrated dynamometer, MAC, SGA and SMI, as measured by computed tomography scan at the level of the third lumbar vertebrae. We also assess recommended and achieved calorie and protein intake. Spearman correlation coefficient is used to assess correlation between different tools. Results: To date, we recruited 21 patients with and 6 patients without CLD. Preliminary results indicate that SMI tends to correlate with HGS in both groups. Our prelim- inary results also suggest that SMI varies according to sex and etiology of cirrhosis. Discussion: The impact of age and sex of SMI needs fur- ther assessment. Objective measures of nutrition assessment in cirrhotics have the potential to reduce the dependence on subjective measures and allow accurate risk assessment. This may in turn lead to a change in clinical practice toward ensuring nutritional optimization in this high-risk population and attenuate CLD-related complications.

Évaluation de l'état nutritionnel lors de cirrhose.

Annie Lamoussenerie, Mélanie Tremblay, Thierry Cresson, An Tang, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

Évaluation de l'état nutritionnel lors de cirrhose.

Annie Lamoussenerie, Mélanie Tremblay, Thierry Cresson, An Tang, Catherine Vincent, Christopher F. Rose, Chantal Bémeur.

OpenAccess

Le bilan hépatique : comment l'interpréter pour une intervention nutritionnelle optimale?

Geneviève Huard, Catherine Vincent, Chantal Bémeur.

Oral

Minimal hepatic encephalopathy renders the brain susceptible to hypotension-induced neuronal cell loss in BDL rats.

Marc-André Clément, Cristina Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by liver disease characterized by cognitive and motor dysfunction. Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve following liver transplantation (LT). However, persisting neurological complications remain a common problem affecting as many as 47% of LT recipients. LT is a major surgical procedure accompanied by intraoperative stress, including blood loss and hypotension. Aim : We hypothesize, in the setting of minimal HE (MHE), the compromised brain becomes susceptible to hypotensive insults, resulting in cell injury and death. Methods: Six-week bile-duct ligated (BDL) rats with MHE and respective controls (SHAM) were used. Blood is withdrawn from the femoral artery (inducing hypovolemia) until a mean arterial pressure of 30, 60 and 90 mmHg (hypotension) and maintained for 120 minutes. Cerebral blood flow (BCF) was assessed by injecting fluorescent microspheres through the brachial artery. Upon sacrifice, brains were extracted for apoptotic analysis (western blot) and neuronal cell count (immunohistochemistry). In a separate group, BDL rats were treated for MHE with ornithine phenylacetate (OP; OCR-002), administered orally (1g/kg) for 3 weeks. Results: Both BDL rats and SHAM-operated controls without hypotension did not display any cell injury or neuronal loss. However, BDL rats following hypotension (30 and 60mmHg) demonstrated a significant decrease in neuronal cell count in the frontal cortex (using NeuN+DAPI and Cresyl Violet) compared to hypotensive SHAM-operated controls. In addition, neuronal loss was associated with an increased in cleaved caspase-3, suggesting apoptotic cell death. CBF decreased in BDL rats compared to SHAM and correlated with degree of hypotension insult. BDL rats treated with OP resulted in a decrease in blood ammonia and improvement in behaviour and did not lead to neuronal cell death following hypotension. Discussion: These findings strongly suggest that cirrhotic patients with MHE are more susceptible to hypotension-induced neuronal cell loss. Moreover, these results suggest a patient with HE (even MHE), with a “frail brain”, will fare worse during liver transplantation and consequently result in poor neurological outcome. Combination of MHE and hypotension may account for the persisting neurological complications observed in a number of cirrhotic patients following LT. Therefore, MHE, should not to be ignored and merits to be treated in order to reduce the risk of neurological complications occurring post-LT.

OpenAccess

Targeting the muscle for the treatment and prevention of hepatic encephalopathy.

Krista Rombouts, Chantal Bémeur, Christopher F. Rose.

OpenAccess

Brain edema: a valid endpoint for measuring hepatic encephalopathy?

Chantal Bémeur, Cristina Cudalbu, Gitte Dam, Alexander S. Thrane, Arthur J. L. Cooper, Christopher F. Rose.

Oral

Leucine et exercices : bénéfique lors d'encéphalopathie expérimentale.

Corine Fontaine, Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Introduction : L’encéphalopathie hépatique (EH) est une complication neuropsychiatrique sérieuse de la maladie hépatique chronique (cirrhose). La pathogénèse de l’EH serait attribuable, entre autres à l’ammoniac. L’accumulation de cette neurotoxine jouerait un rôle clé. De plus, la malnutrition est associée à un risque élevé de développer une perte sévère de masse musculaire et à l’EH; ces complications augmentent le risque de mortalité. La déficience en leucine, a été démontrée lors de cirrhose. La leucine sert de substrat énergétique et de précurseur pour d’autres acides aminés en plus de stimuler la synthèse protéique. De plus, l’expression de mammalian target of rapamycin (mTOR) et sa cible p70S6 kinase, deux protéines impliquées dans de nombreuses réactions en lien avec la survie cellulaire, serait altérée dans le muscle lors de maladie hépatique chronique. Une masse musculaire optimale lors d’EH contribuerait à réduire l’ammoniac via l’enzyme glutamine synthase (GS). L’hypothèse de recherche est que l’optimisation de la masse musculaire permet de prévenir/atténuer les épisodes d’EH. Matériel et méthode: Un modèle deligature des voies biliaires (BDL) chez le rat qui récapitule les caractéristiques de la cirrhose et de l’EH est utilisé. Cinq groupes sont évalués: 1) Contrôle avec simulation de la chirurgie (Sham); 2) BDL; 3) BDL+ Leucine; 4) BDL + Exercices; 5) BDL + Leucine + Exercices. Six semaines post-chirurgie, l’EH est vérifiée par des tests comportementaux et phénotypage neurologique. La masse musculaire est évaluée par imagerie par résonance magnétique. Les rats sont ensuite sacrifiés et les muscles sont prélevés. L’expression protéique de mTOR et de p70S6 kinase est mesurée par immunobuvardage. Résultats: Chez le groupe BDL, on remarque une baisse de la masse musculaire et de la synthèse protéique comparativement au groupe Sham. La supplémentation en leucine et l’exercice favorise une augmentation de la masse musculaire chez les rats BDL. La voie de signalisation via mTOR semble moins exprimée dans le muscle du groupe BDL versus Sham. Conclusion: Dans le but d’optimiser le statut nutritionnel et d’améliorer la qualité de vie des patients cirrhotiques atteints d’EH, des recherches plus approfondies devront être effectuées.

Oral

Neuroinflammation et activation microgliale chez des rats cirrhotiques soumis à une hypotension.

Maxime Hovington, Marc-André Clément, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Oral

Minimal hepatic encephalopathy leads to hypotension-induced neuronal cell loss in BDL rats.

Marc-André Clément, Cristina Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by liver disease characterized by cognitive and motor dysfunction. The only curative treatment to date remains liver transplantation (LT). Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve following LT. However, persisting neurological complications remain a common problem affecting as many as 47% of LT recipients. LT is a major surgical procedure accompanied by intraoperative stress and confounding factors, including blood loss and hypotension. We hypothesize, in the setting of minimal HE (MHE), the compromised brain becomes susceptible to hypotensive insults, resulting in cell injury and death. Methods: Six-week bile-duct ligated (BDL) rats with MHE and respective controls (SHAM) were used. Blood is withdrawn from the femoral artery (inducing hypovolemia) until an mean arterial pressure of 30 and 60 mmHg (hypotension) and maintained for 120 minutes. Cerebral blood flow (BCF) was assessed by injecting fluorescent microspheres (1x106 microspheres/ml) through the brachial artery. Upon sacrifice, brains were extracted for apoptotic analysis (western blot) and neuronal cell count (immunohistochemistry). In a separate group, BDL rats were treated for MHE with ornithine phenylacetate (OP; OCR-002) (1g/kg) for 3 weeks. Results: Both BDL rats and SHAM-operated controls without hypotension did not display any cell injury or neuronal loss. However, BDL rats following hypotension (30 and 60mmHg) demonstrated a significant decrease in neuronal cell count in the frontal cortex (using NeuN+DAPI and Cresyl Violet) compared to hypotensive SHAM-operated controls. In addition, neuronal loss was associated with an increased in cellular stress protein, hsp32, hsp70 and caspase-3, suggesting apoptotic cell death. CBF decreased in BDL rats compared to SHAM and correlated with degree of hypotension insult. BDL rats treated with OP did not lead to neuronal cell death following hypotension. Discussion: These findings strongly suggest that cirrhotic patients with MHE are more susceptible to hypotension-induced neuronal cell loss. Moreover, these results suggest a patient with HE (even MHE), with a “frail brain”, will fare worse during liver transplantation and consequently result in poor neurological outcome. Combination of MHE and hypotension may account for the persisting neurological complications observed in a number of cirrhotic patients following LT. Therefore, MHE, i) should not to be ignored and ii) deserves to be treated in order to reduce the risk of neurological complications occurring post-LT.

Impact d'un stress inflammatoire et nutritionnel dans un modèle cellulaire d'acidose lactique.

Rafaela Almeida, Mélanie Tremblay, Christopher Rose, Consortium de l'acidose lactique, Chantal Bémeur.

Diminution du compte neuronal par une insulte hypotensive chez le rat avec ligation de la voie biliaire: implications pour la persistance des complications neurologiques après transplantation hépatique.

Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Impact d’un stress de type inflammatoire et nutritionnel dans un modèle cellulaire d’acidose lactique.

Rafaela Almeida, Mélanie Tremblay, Christopher Rose, Consortium de l'acidose lactique, Chantal Bémeur.

Oral

Impact d'un stress inflammatoire et nutritionnel dans un modèle cellulaire d'acidose lactique.

Rafaela Almeida, Mélanie Tremblay, Christopher Rose, Consortium de l'acidose lactique, Chantal Bémeur.

Oral

Bile-duct ligated rats are susceptible to hypotension-induced neuronal cell loss: Implications for persisting neurological complications following liver transplantation.

Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by liver disease characterized by cognitive and motor dysfunction. The only curative treatment to date remains liver transplantation (LT). Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve following LT. However, even following the implantation of a new liver, persisting neurological complications remain a common problem affecting as many as 47% (8 47%) of liver transplant recipients. LT is a major surgical procedure accompanied by intraoperative stress and confounding factors, including blood loss (hypovolumia) and hypotension. We hypothesize, in the setting of MHE, that the compromised brain becomes predisposed to what would normally be an innocuous hypotensive insult, resulting in cell injury and death. Methods: Six-week bile-duct ligated (BDL) rats with MHE and respective controls will be used. Blood is withdrawn from the femoral artery (inducing hypovolemia) until an arterial pressure of 30 mmHg (hypotension) and maintained for 150 minutes. Upon sacrifice, brains are perfused and extracted for apoptotic analysis (western blot) and neuronal cell count (immunohistochemistry). Results: Both BDL rats and SHAM-operated controls without hypotension do not display any neuronal loss. However, BDL rats following hypotension demonstrated a significant decrease in neuronal cell count in the frontal cortex using NeuN+DAPI and Cresyl Violet compared to hypotensive SHAM-operated controls. In addition, neuronal loss was associated with an increased in cellular stress protein, hsp32, hsp70 and caspase-3, suggesting apoptotic cell death. Discussion: These findings suggest that patients with MHE are more susceptible to hypotension-induced neuronal cell loss. Moreover, these results suggest a patient with HE (even MHE), with a “frail brain”, will fare worse during LT and consequently result in poor neurological outcome. The combination of MHE and hypotension may justify for the persisting neurological complications observed in a number of cirrhotic patients following LT. This implies the impact of MHE on outcome is undervalued. MHE should not to be ignored and patients with MHE merit to be treated pre-LT.

Bile-ligated rats are susceptible to hypotension-induced neuronal cell loss: implications for persisting neurological complications following liver transplantation.

Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by liver disease characterized by cognitive and motor dysfunction. The only curative treatment to date remains liver transplantation (LT). Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve following LT. However, even following the implantation of a new liver, persisting neurological complications remain a common problem affecting as many as 47% (8 47%) of liver transplant recipients. LT is a major surgical procedure accompanied by intraoperative stress and confounding factors, including blood loss (hypovolumia) and hypotension. We hypothesize, in the setting of MHE, that the compromised brain becomes predisposed to what would normally be an innocuous hypotensive insult, resulting in cell injury and death. Methods: Using 6-week bile-duct ligated rats and respective controls, blood is withdrawn from the femoral artery (inducing hypovolemia) until an arterial pressure of 30 mmHg (hypotension) and maintained for 150 minutes. Upon sacrifice, brains are perfused and extracted for western blotting and immunohistochemistry. Results: Both BDL rats and SHAM-operated controls without hypotension do not display any neuronal loss. However, BDL rats following hypotension demonstrated a significant decrease in neuronal cell count in the frontal cortex using NeuN+DAPI and Cresyl Violet compared to hypotensive SHAM-operated controls. In addition, neuronal loss was associated with an increased in cellular stress protein, hsp32 and caspase-3, suggesting apoptotic cell death. Discussion: These findings suggest that patients with HE are more susceptible to hypotension-induced neuronal cell loss and this may explain why transplanted patients are experiencing persisting neurological complications. Aside from cirrhotic patients having a stroke, these results also suggest a patient with HE (even MHE) with a “frail brain”, fare worse during transplantation leading to poor neurological outcome. This implies MHE should not be ignored and therefore treated pre-LT.

Muscle mass optimization prevents experimental hepatic encephalopathy.

Sara Ghezzal, Marc-André Clément, Cristina R. Bosoi, Roxanne Beauchamp, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (cirrhosis; CLD). Malnutrition exacerbates severe muscle loss and hepatic encephalopathy (HE) in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD-related complications are an unmet clinical need. Aims: We hypothesize supplementation with branched-chain amino acid leucine (LEU) and exercise training (EX) could possibly attenuate muscle mass loss and prevent HE (characterized by brain edema as well as cognitive and psychomotor impairments) in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + LEU; 3) BDL + EX; 4) BDL + LEU + EX; 5) Sham-operated rats. One week following BDL, rats were submitted to 15 min EX (10 cm/s) every other day and BDL rats receiving LEU, were gavaged daily (1.35 mg/kg) for five weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass), cerebral edema (specific gravity method) and cognitive/psychomotor function (open-field test; anxiety-like behavior assessment and novel object recognition test; memory testing) were measured in all groups. Results: BDL rats gained less body weight compared to sham-operated rats (125.0±24.9 g vs 226.0±38.5 g; P<0.05). LEU-treated BDL rats display an improvement in brain edema (78.50±0.03% vs 80.27±0.14%; P<0.05), muscle mass (5.48±0.90 g/kg vs 4.83±0.11 g/kg; P<0.05) and circumference (15.6±0.8 cm/kg vs 13.1±0.7 cm/kg ; P<0.05) and metabolic activity (27.48±1.15 vs 32.99±2.35; P<0.05), which was further ameliorated with EX, compared to BDL animals. In addition, BDL rats receiving LEU and EX exhibited less anxiety-like behavior (4.9±1.2 s vs 2.2±0.9 s passed in the center; P<0.01) as well as better novel object recognition memory (69.6±15.2% vs 25.4±9.6%; P<0.01), in comparison with BDL rats. Conclusions: Our results demonstrate that supplemental LEU along with EX reduces body weight and muscle mass loss, improves metabolic activity, attenuates brain edema and improve cognitive and psychomotor function. These findings suggest that strategies aiming at improving nutritional status will attenuate muscle mass loss, reduce the risk of developing HE and therefore improve quality of life and decrease mortality in CLD. LEU supplementation and EX could rapidly be translated into clinical practice. Funding Agency: CIHR.

OpenAccess

Nutritional status of HIV-infected patients during the first year HAART in two West African cohorts.

Maryline Sicotte, Chantal Bémeur, Assane Diouf, Maria Victoria Zunzunegui, Vinh-Kim Nguyen, ATARAO initiative.

To examine the association between nutritional markers at initiation and during follow up in two different cohorts of HIV-infected adults initiating highly active antiretroviral therapy (HAART) in West Africa. The ATARAO study was a one year prospective study carried in Mali. It consisted of a sample of consecutive patients initiating HAART in one of four participating centers during that period. Data were collected at time of treatment initiation (baseline) and every 3 months thereafter. The ANRS 1290 study followed Senegalese patients recruited in similar conditions. Bivariate analyses were used to identify nutritional and immunological covariates of malnutrition at baseline. Longitudinal trajectories of body mass index, hemoglobin and albumin, and their associated factors, were evaluated using mixed linear models. In ATARAO, 250 participants were retained for analyses; of which, 36% had a BMI < 18.5 kg/m(2), nearly 60% were anemic and 47.4% hypoalbuminemic at time of treatment initiation. At baseline, low hemoglobin, hypoalbuminemia and low CD4 levels were associated with a BMI < 18.5 kg/m(2). Similarly, low BMI, low albumin and low CD4 counts were linked to anemia; while, hypoalbuminemia was associated with low hemoglobin levels and CD4 counts. In ANRS, out of the 372 participants retained for analyses, 31% had a low BMI and almost 70% were anemic. At baseline, low BMI was associated with low hemoglobin levels and CD4 counts, while anemia was associated with low CD4 counts and female sex. While treatment contributed to early gains in BMI, hemoglobin and albumin in the first 6 months of treatment, initial improvements plateaued or subsided thereafter. Despite HAART, malnutrition persisted in both cohorts after one year, especially in those who were anemic, hypoalbuminemic or had a low BMI at baseline. In ATARAO and ANRS, malnutrition was common across all indicators (BMI, hemoglobin, albumin) and persisted despite treatment. Low BMI, anemia and hypoalbuminemia were associated with attrition, and with a deficient nutritional and immunological status at baseline, as well as during treatment. In spite of therapy, malnutrition is associated with negative clinical and treatment outcomes which suggests that HAART may not be sufficient to address co-existing nutritional deficiencies.

Beneficial effects of muscle mass optimization using leucine supplementation and exercise training in the prevention of hepatic encephalopathy in experimental cirrhosis.

Chantal *Bémeur, Sara Ghezzal, Marc-André Clément, Cristina R. Bosoi, Roxanne Beauchamp, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Caractérisation d'un modèle cellulaire de stress de type inflammatoire et nutritionnel lors du syndrome de leigh version canadienne française.

Rafaela Almeida, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur, Consortium de l'acidose lactique.

Diminution du compte neuronal par une insulte hypotensive chez le rat avec ligation de la voie biliaire: implications pour la persistance des complications neurologiques après transplantation hépatique.

Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Oral

Optimizing muscle mass: therapeutic target to prevent experimental hepatic encephalopathy.

Chantal *Bémeur, Sara Ghezzal, Marc-André Clément, Cristina R. Bosoi, Roxanne Beauchamp, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (cirrhosis; CLD). Malnutrition, considered a consequence of metabolic disturbances (hypermetabolism), exacerbates severe muscle loss and hepatic encephalopathy (HE) (complex neuropsychiatric disorder) in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD-related complications are an unmet clinical need. We hypothesize supplementation with branched-chain amino acid leucine (LEU) and exercise training (EX) could possibly attenuate muscle mass loss and prevent HE (characterized by brain edema as well as cognitive and psychomotor impairments) in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + LEU; 3) BDL + EX; 4) BDL + LEU + EX; 5) Sham-operated rats. One week following BDL, rats were gavaged with LEU (1.35 mg/kg) daily and submitted to 15 min EX (10 cm/s) every other day for 5 weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass), cerebral edema (specific gravity method) and cognitive/psychomotor function (open-field test; anxiety-like behavior assessment and novel object recognition test; memory testing) were measured. Results: BDL rats gained less body weight compared to sham-operated rats (125.0g ± 24.9 vs 226.0g ± 38.5; p<0.05). LEU-treated BDL rats display an improvement in brain edema (78.50% ± 0.03 vs 80.27% ± 0.14; p<0.05), muscle mass (5.48g/kg ± 0.90 vs 4.83g/kg ± 0.11; p<0.05) and circumference (15.6cm/kg ± 0.8 vs 13.1cm/kg ± 0.7; p<0.05) and metabolic activity (27.48 ± 1.15 vs 32.99 ± 2.35; p<0.05), which was further ameliorated with EX, compared to BDL animals. In addition, BDL rats receiving LEU and EX exhibited less anxiety-like behavior (4.9s ± 1.2 vs 2.2s ± 0.9 passed in the center; p<0.01) as well as better novel object recognition memory (69.6 ± 15.2% vs 25.4 ± 9.6%; p<0.01), in comparison with BDL rats. Conclusion: Our results demonstrate that supplemental LEU along with EX recovers body weight loss, increases muscle mass, improves metabolic activity, attenuates brain edema and improves cognitive and psychomotor function. These findings suggest that strategies aiming at improving nutritional status will attenuate muscle mass loss and reduce the risk of developing HE. This in turn will improve quality of life, decrease mortality and enhance outcome post-liver transplantation. LEU supplementation and EX could rapidly be translated into clinical practice.

Oral

Bile-duct ligated rats are susceptible to hypotension-induced neuronal cell loss: Implications for persisting neurological complications following liver transplantation.

Marc-André Clément, Cristina Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.

Background: Hepatic encephalopathy (HE) is a major neuropsychiatric complication caused by liver disease characterized by cognitive and motor dysfunction. The only curative treatment to date remains liver transplantation (LT). Historically, HE has always been considered to be a reversible metabolic disorder and has therefore been expected to completely resolve following LT. However, even following the implantation of a new liver, persisting neurological complications remain a common problem affecting as many as 47% (8 47%) of liver transplant recipients. LT is a major surgical procedure accompanied by intraoperative stress and confounding factors, including blood loss (hypovolumia) and hypotension. We hypothesize, in the setting of MHE, that the compromised brain becomes predisposed to what would normally be an innocuous hypotensive insult, resulting in cell injury and death. Methods: Using 6-week bile-duct ligated rats and respective controls, blood is withdrawn from the femoral artery (inducing hypovolemia) until an arterial pressure of 30 mmHg (hypotension) and maintained for 150 minutes. Upon sacrifice, brains are perfused and extracted for western blotting and immunohistochemistry. Results: Both BDL rats and SHAM-operated controls without hypotension do not display any neuronal loss. However, BDL rats following hypotension demonstrated a significant decrease in neuronal cell count in the frontal cortex using NeuN+DAPI and Cresyl Violet compared to hypotensive SHAM-operated controls. In addition, neuronal loss was associated with an increased in cellular stress protein, hsp32, hsp70 and caspase-3, suggesting apoptotic cell death. Discussion: These findings suggest that patients with HE are more susceptible to hypotension-induced neuronal cell loss and this may explain why transplanted patients are experiencing persisting neurological complications. Aside from cirrhotic patients having a stroke, these results also suggest a patient with HE (even MHE) with a “frail brain”, fare worse during transplantation leading to poor neurological outcome. This implies MHE should not be ignored and therefore treated pre-LT.

Beneficial effects of muscle mass optimization using leucine supplementation and exercise training in the prevention of hepatic encephalopathy in experimental cirrhosis.

Chantal *Bémeur, Sara Ghezzal, Marc-André Clément, Cristina R. Bosoi, Roxanne Beauchamp, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (cirrhosis; CLD). Malnutrition, considered a consequence of metabolic disturbances (hypermetabolism), exacerbates severe muscle loss and hepatic encephalopathy (complex neuropsychiatric disorder) in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD-related complications are an unmet clinical need. We hypothesize supplementation with branched-chain amino acid leucine (LEU) and exercise training (EX) could possibly attenuate muscle mass loss and prevent hepatic encephalopathy (characterized by brain edema as well as cognitive and psychomotor impairments) in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + LEU; 3) BDL + EX; 4) BDL + LEU + EX; 5) Sham-operated rats. One week following BDL, rats were submitted to 15 min EX (10 cm/s) every other day and BDL rats receiving LEU, were gavaged daily (1.35 mg/kg) for 5 weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass), cerebral edema (specific gravity method) and cognitive/psychomotor function (open-field test; anxiety-like behavior assessment and novel object recognition test; memory testing) were measured in all groups. Results: BDL rats gained less body weight and muscle mass compared to sham-operated rats. LEU-treated BDL rats display an improvement in brain edema, muscle mass and circumference and metabolic activity, which was further ameliorated with EX. In addition, BDL rats receiving LEU and EX exhibited less anxiety-like behavior as well as better novel object recognition memory. Conclusion: Our results demonstrate that supplemental LEU along with EX reduces body weight and muscle mass loss, improves metabolic activity, attenuates brain edema and improve cognitive and psychomotor function. These findings suggest that strategies aiming at improving nutritional status will attenuate muscle mass loss, reduce the risk of developing hepatic encephalopathy and therefore improve quality of life and decrease mortality in CLD. LEU supplementation and EX could rapidly be translated into clinical practice.

L'impact de l'optimisation de la masse musculaire sur la prévention de l'encéphalopathie hépatique lors de maladie hépatique chronique.

Chantal Bémeur, Cristina R. Bosoi, Mélanie Tremblay, Christopher F. Rose.

Beneficial effects of muscle mass optimization using leucine supplementation and exercise training in the prevention of hepatic encephalopathy in experimental cirrhosis.

Sara Ghezzal, Marc-André Clément, Cristina R. Bosoi, Roxanne Beauchamp, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.

Aims: The pathogenesis of hepatic encephalopathy (HE) is multifactorial. Even though ammonia is the central component in the pathogenesis of HE, oxidative stress is believed to play a role in exacerbating the neuropsychological effects of ammonia in patients with liver disease. With new, highly sensitive imaging techniques, brain edema is observed in HE patients. We previously demonstrated that portacaval shunted hyperammonemic rats do not develop oxidative stress or brain edema. In order to define a synergistic effect between hyperammonemia and systemic oxidative stress, the present study investigates the role of oxidative stress in the pathogenesis of brain edema in PCA rats following glutathione depletion by diethyl maleate (DEM). Methods: In the first set of experiments, we evaluated the effect of DEM in PCA and SHAM-operated control rats by injecting DEM at a dose of 0.4 and 1 mg/kg/day intraperitoneally for 10 days starting at day 18 after surgery. Rats were sacrificed at day 28 and oxidative stress was evaluated by arterial malon-dialdehyde (MDA, commercial kit). In the second set of experiments, 1 mg/kg/day DEM was used to induce oxidative stress. Ammonia (commercial kit) as well as other different oxidative stress markers: reactive oxygen species (DCFDA fluorescence technique), and 4-hydroxy-2-nonenal (HNE, Western blot) were assessed in arterial plasma and frontal cortex tissue. Brain water content was measured in the frontal cortex using a specific gravimetric technique. Results: DEM at 1 mg/kg/day (not 0.4 mg/kg/day) induced a significant increase in MDA levels in PCA rats. No increase in MDA was detected following either dose of DEM in SHAM-operated controls. Ammonia levels in both DEM-treated and non-treated PCA rats were significantly increased vs respective sham-operated controls (p<0.001) and remained unchanged between non-treated and DEM-treated PCA groups (p>0.05). An increase in brain water content was observed in DEM-treated PCA rats vs non-treated PCA rats (PCA+DEM: 78.45 ± 0.13% vs PCA: 77.38 ± 0.11, p< 0.001). Although no significant changes in reactive oxygen species were observed, there was an increase in plasma levels of HNE in DEM-treated PCA rats compared to non-treated PCA rats. No significant changes in any oxidative stress markers were observed in the frontal cortex. Conclusions: DEM treatment in PCA rats induced systemic oxidative stress but not central oxidative stress. This, imposed on hyperammonemia, was accompanied by the onset of brain edema in rats with PCA. Oxidative stress and brain edema were not detected in SHAM-operated rats, which were not hyperammonemic. Our findings suggest a synergistic effect between hyperammonemia and systemic oxidative stress is implicated in the pathogenesis of brain edema in hepatic encephalopathy.

Impact of muscle mass optimization in the prevention of hepatic encephalopathy in experimental cirrhosis.

Chantal Bémeur, Cristina Bosoi, Mélanie Tremblay, Christopher F. Rose.

Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (CLD). Malnutrition, considered a consequence of metabolic disturbances (hypermetabolism), exacerbates sarcopenia (severe muscle loss) and hepatic encephalopathy (complex neuropsychiatric disorder) in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD-related complications are an unmet clinical need. We hypothesize supplementation with branched-chain amino acid isoleucine (ILE) and exercise could possibly attenuate muscle mass loss and prevent brain edema, a common entity of hepatic encephalopathy, in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + ILE; 3) BDL + EX; 4) BDL + ILE + EX; 5) Sham-operated rats. Two weeks following BDL, rats were submitted to 15 min exercise (10 cm/s) every other day and BDL rats receiving ILE, were gavaged daily (1.5 mg/kg) for 4 weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass) and cerebral edema (specific gravity method) were measured in all groups. Results: BDL rats gained less body weight (33.7  6.3 g vs 204.5  26.0 g; p < 0.01) and muscle mass (weight/body weight ratio) (0.0047  0.0002 vs 0.0051  0.0002; p < 0.05) compared to sham-operated rats, respectively. ILE-treated BDL rats submitted to exercise demonstrated an increase in weight gain and an increase in muscle mass (weight/body weight ratio) (0.0056  0.0003 vs 0.0047  0.0003; p < 0.05) and an attenuation in hypermetabolic status, compared to BDL rats respectively. ILE+exercsie also attenuated brain water content in BDL rats. Conclusion: Our results demonstrate that supplemental ILE along with exercise reduces body weight and muscle mass loss, improves metabolic activity and attenuates brain edema. These findings suggest that strategies aiming at improving nutritional status and preventing muscle mass loss will attenuate the onset of sarcopenia and hepatic encephalopathy, and therefore improve outcome in CLD. EX and ILE supplementation could rapidly be translated into clinical practice.

Oral

L'impact de l’isoleucine et de l’exercice physique sur l’état métabolique, la masse musculaire et l’encéphalopathie hépatique chez des rats cirrhotiques.

Cristina R. *Bosoi, Chantal Bémeur, Cristina R. Bosoi, Mélanie Tremblay, Christopher F. Rose.

Introduction: La malnutrition est un important facteur de pronostique qui peut affecter le résultat clinique des patients souffrant d’une maladie hépatique chronique (MHC). Étant une cause du hypermétabolisme, la malnutrition aggrave l’encéphalopathie hépatique et la sarcopénie chez les patients cirrhotiques. Des nouvelles stratégies de traitement visant l’amélioration de l’état nutritionnel et l’atténuation des complications de la MHC sont un besoin clinique à satisfaire. Notre hypothèse était que la supplémentation avec l’acide aminé ramifié isoleucine (ILE) et l’exercice physique (EX) peuvent atténuer la perte de masse musculaire et prévenir l’œdème cérébral dans la MHC. Méthodes : MHC a été induite chez des rats suite à une ligature de la voie biliaire (LVB). 5 groupes expérimentaux ont été étudiés : 1) LVB; 2) LVB + ILE; 3) LVB + EX; 4) LVB + ILE + EX; 5) SHAM opérés. Deux semaines après la LVB, les rats LVB + EX ont subi des sessions d’exercice de 15 min (10 cm/s) à chaque 2 jours et les rats ILE ont été gavés à chaque jour (1.5 mg/kg ILE) pendant 4 semaines. Le poids, la masse musculaire (muscle gastrocnémien), l’état métabolique (la dépense énergétique indépendante de la quantité de nourriture et masse fécale) et l’œdème cérébral (gravimétrie spécifique) ont été mesurés. Résultats : LVB + EX + ILE ont démontré un gain du poids corporel significatif (LVB + ILE + EX: 112.3 g vs LVB: 33.7 g; p < 0.05), une augmentation de la masse musculaire (poids muscle/poids corporel) (LVB + ILE + EX: 0.0056 vs LVB: 0.0047; p < 0.05) et une atténuation de l’état hypermétabolique. Le contenu en eau cérébrale a diminué chez les rats LVB+ ILE + EX comparé aux rats LVB. Conclusion: Nos résultats démontrent que l’EX et l’ILE améliorent le poids corporel, la masse musculaire, le métabolisme et atténuent l’œdème cérébral. Cela suggère que des stratégies visant l’optimisation de la masse musculaire et l’amélioration de l’état nutritionnel pourraient diminuer les complications chez des patients cirrhotiques.

Impact of isoleucine and exercise on metabolic state, muscle mass and hepatic encephalopathy in cirrhotic rats.

Chantal Bémeur, Cristina Bosoi, Mélanie Tremblay, Christopher F. Rose.

Attenuation of oxidative stress protects the brain in rats with “acute-on-chronic” liver failure.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Background: Acute-on-chronic liver failure (ACLF) is defined as an acute decompensation of chronic liver disease. Brain edema is frequently observed in hepatic encephalopathy associated with both acute and chronic liver disease. While in acute liver failure, toxic levels of ammonia induce cerebral oxidative stress and brain edema, in chronic liver disease, systemic (not central) oxidative stress and hyperammonemia synergistically cause brain edema. This study investigated the role of both systemic and central oxidative stress and ammonia in relation to brain edema in a rat model of ACLF. Methods: ACLF was induced in male Sprague-Dawley rats by portacaval shunt (PCA), followed 4 weeks later by hepatic artery ligation (HAL). Acute liver failure (ALF) induced by concomitant PCA and HAL, PCA (4 weeks) and SHAM-operated rats were used as controls. ACLF rats were divided into 2 groups that were sacrificed at: 1) coma stage of hepatic encephalopathy (defined as loss of corneal reflex) (ACLF-C) and 2) in parallel with ALF-induced coma (ACLF-P) rats. Brain edema (specific gravimetric technique), ammonia levels (commercial kit) and oxidative stress markers (plasmatic and cerebral reactive oxygen species, fluorescence spectroscopy) were evaluated along with hepatic function (routine biochemistry, haematoxylin-phloxine-saffron histopathology). Results: Coma was delayed by 8h in ACLF compared to ALF rats (p< 0.01). Liver biochemistry markers did not differ between ACLF-C, ACLF-P and ALF rats; liver histopathology showed mild necrosis in ACLF-P, moderate in ALF and severe in ACLF-C. Brain water content was significantly attenuated in both ACLF-C and ACLF-P vs. ALF rats (p< 0.01). Arterial ammonia concentration followed a similar pattern: they were attenuated in ACLF-C: 0.35±0.07 mM and ACLF-P: 0.49±0.14 mM vs. ALF: 1.34±0.09 mM (p< 0.001), but remained high compared to SHAM: 0.06±0.01 mM (p< 0.001). Systemic oxidative stress was present in both ACLF and ALF rats, while cerebral oxidative stress was present only in ALF rats. Conclusion: Brain edema, ammonia levels and oxidative stress are reduced in ACLF rats compared to ALF rats. These findings suggest that during chronic liver failure, compensatory mechanisms that prevent the apparition of brain edema and attenuate oxidative stress during an acute deterioration are developed.

Oral

L'atténuation du stress oxydatif protège le cerveau chez des rats souffrant d’une décompensation hépatique aigue durant une hyperammoniémie chronique.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Attenuation of oxidative stress protects the brain in rats with “acute-on-chronic” liver failure.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Background: Acute-on-chronic liver failure (ACLF) is defined as an acute decompensation of chronic liver disease. Brain edema is frequently observed in hepatic encephalopathy associated with both acute and chronic liver disease. While in acute liver failure, toxic levels of ammonia induce cerebral oxidative stress and brain edema, in chronic liver disease, systemic (not central) oxidative stress and hyperammonemia synergistically cause brain edema. This study investigated the role of both systemic and central oxidative stress and ammonia in relation to brain edema in a rat model of ACLF. Methods: ACLF was induced in male Sprague-Dawley rats by portacaval shunt (PCA), followed 4 weeks later by hepatic artery ligation (HAL). Acute liver failure (ALF) induced by concomitant PCA and HAL, PCA (4 weeks) and SHAM-operated rats were used as controls. ACLF rats were divided into 2 groups that were sacrificed at: 1) coma stage of hepatic encephalopathy (defined as loss of corneal reflex) (ACLF-C) and 2) in parallel with ALF-induced coma (ACLF-P) rats. Brain edema (specific gravimetric technique), ammonia levels (commercial kit) and oxidative stress markers (plasmatic and cerebral reactive oxygen species, fluorescence spectroscopy) were evaluated along with hepatic function (routine biochemistry, haematoxylin-phloxine-saffron histopathology). Results: Coma was delayed by 8h in ACLF compared to ALF rats (p< 0.01). Liver biochemistry markers did not differ between ACLF-C, ACLF-P and ALF rats; liver histopathology showed mild necrosis in ACLF-P, moderate in ALF and severe in ACLF-C. Brain water content was significantly attenuated in both ACLF-C and ACLF-P vs. ALF rats (p< 0.01). Arterial ammonia concentration followed a similar pattern: they were attenuated in ACLF-C: 0.35±0.07 mM and ACLF-P: 0.49±0.14 mM vs. ALF: 1.34±0.09 mM (p< 0.001), but remained high compared to SHAM: 0.06±0.01 mM (p< 0.001). Systemic oxidative stress was present in both ACLF and ALF rats, while cerebral oxidative stress was present only in ALF rats. Conclusion: Brain edema, ammonia levels and oxidative stress are reduced in ACLF rats compared to ALF rats. These findings suggest that during chronic liver failure, compensatory mechanisms that prevent the apparition of brain edema and attenuate oxidative stress during an acute deterioration are developed.

Oral

Chronic hyperammonemia “priming” alleviates the induction of oxidative stress and development of brain edema following an acute liver insult.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Aims: Acute-on-chronic liver failure (ACLF), an acute deterioration of liver function during compensated chronic liver disease, is associated with the development of hepatic encephalopathy (HE). Brain edema is frequently observed in patients with HE induced by either acute liver failure (ALF) or chronic liver disease. We recently demonstrated in a rat model of cirrhosis that hyperammonemia and systemic oxidative stress synergistically lead to brain edema. Therefore, the aim of this study was to develop a rat model of ACLF by inducing an acute liver insult, superimposed onto a chronic hyperammonemia background, and to investigate the role of oxidative stress and ammonia in relation to brain edema. Methods: ACLF was induced in male Sprague-Dawley rats by portacaval shunt (PCA), followed 4 weeks later by hepatic artery ligation (HAL). Liver devascularisation by concomitant PCA and HAL was used to induce ALF. SHAM and PCA (chronic hyperammonemic) rats, sacrificed 4 weeks after surgery, were included as controls. Liver status (routine biochemistry and histopathology), blood ammonia and brain edema (specific gravimetric technique) were assessed. Oxidative stress was evaluated by plasmatic and cerebral levels of reactive oxygen species (DCFDA fluorescence), glutathione (DTNB method), and activities of xanthine oxidase and catalase (Amplex Red method). Results : Coma developed in ALF rats 8h after HAL; it was significantly delayed in ACLF rats, where it occurred after 16h. Liver necrosis markers AST and ALT did not differ between pair-killed ACLF and ALF rats; however, liver histopathology showed more severe necrosis in ACLF than in ALF rats. Brain water content increased in ALF rats and was significantly attenuated in ACLF rats: 80.04±0.13% p<0.01vs ALF (81.39±0.15%), n.s. vs SHAM. The increase in arterial ammonia, as seen in ALF rats, was prevented in ACLF rats: 0.35±0.07 mM, p<0.001vs ALF (1.34±0.09 mM), p<0.01 vs SHAM. Oxidative stress was present in the blood of both ACLF and ALF rats, while signs of oxidative stress in the brain were present only in the ALF rats. Conclusions: The alterations observed in ALF are attenuated in ACLF. In spite of a more severe hepatic necrosis in the ACLF rats, the onset of coma was delayed, and brain edema, ammonia levels and oxidative stress were reduced in comparison to the ALF rats. In conclusion, severe HE is alleviated by compensatory mechanisms comprising oxidative stress, which are developed during chronic hyperammonemia prior to an acute liver deterioration. A better understanding of these mechanisms may help define the pathogenesis of ACLF.

The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.

Piero Amodio, Chantal Bémeur, Roger Butterworth, Juan Cordoba, Akinobu Kato, Sara Montagnese, Misael Uribe, Hendrik Vilstrup, Marsha Y. Morgan.

L'encéphalopathie hépatique sévère est retardée chez des rats souffrant d’une décompensation hépatique aigue durant une hyperammoniémie chronique.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Introduction: Les patients avec une insuffisance hépatique chronique souffrent fréquemment de décompensations aigues de la fonction hépatique (DAH). L’œdème cérébral est une complication de l’insuffisance hépatique aigue ainsi que de celle chronique. Le stress oxydatif et l’ammoniaque contribuent à l’induction de l’œdème cérébral lors d’une insuffisance hépatique chronique. Le but de cette étude est d’investiguer le rôle du stress oxydatif et de l’hyperammoniémie en relation avec l’œdème cérébral dans un modèle de DHA chez le rat. Méthodes: DHA a été induite chez des rats suite à une anastomose portocave (APC) suivie par la ligature de l’artère hépatique (LAH), 4 semaines plus tard. L’insuffisance hépatique aigue (IHA) a été induite par une APC et une HAL effectuées simultanément. Des rats contrôles SHAM et APC ont été sacrifiés 4 semaines après la chirurgie. L’œdème cérébral (gravimétrie spécifique), les espèces réactives d’oxygène et le glutathion (spectrophotométrie) ont été mesurés dans le plasma et dans le cerveau. Résultats: Le début du coma a été significativement retardé chez les rats DHA comparé aux rats IHA. L’examen histopathologique du foie a démontré une nécrose plus sévère chez les rats DHA que chez les rats IHA. Pourtant l’œdème cérébral et l’augmentation de l’ammoniaque ont été prévenus chez ces rats : eau cérébrale 80.04±0.13 % (p<0.01 vs IHA) et ammoniaque plasmatique 0.35±0.07 mM (p<0.001 vs IHA). Chez les rats DHA, le stress oxydatif a été seulement détecté systémiquement tandis que chez les rats IHA, il était présent tant au niveau systémique que cérébral. Conclusions: Les altérations observées dans l’insuffisance hépatique aigue sont améliorées lors d’une DHA survenant sur une hyperammoniémie chronique: l’œdème cérébral, l’ammoniaque et le stress oxydatif sont réduits et le coma est retardé. Cela suggère que des mécanismes compensatoires développés durant une hyperammoniémie chronique préviennent les manifestations sévères d’une insulte hépatique aigue

Onset of severe hepatic encephalopathy is delayed in rats with acute liver insult superimposed on chronic hyperammonemia compared to rats with acute liver failure: a look at underlying mechanisms.

Cristina R. Bosoi, Chantal Bémeur, Bich Nguyen, Mélanie Tremblay, Christopher F. Rose.

Background: Acute-on-chronic liver failure (ACLF) represents an acute decompensation of chronic liver disease. Brain edema is frequently observed in hepatic encephalopathy associated with both acute and chronic liver disease. Since systemic oxidative stress and ammonia are believed to act synergistically in inducing brain edema in chronic liver failure, the objective of this study was to develop a rat model of hepatic encephalopathy following ACLF, and to investigate the role of oxidative stress and ammonia in relation to brain edema. Methods: ACLF was induced in male Sprague-Dawley rats by portacaval shunt (PCA), followed 4 weeks later by hepatic artery ligation (HAL). Liver devascularisation by concomitant PCA and HAL was used to induce acute liver failure (ALF). Body temperature and blood glucose were monitored and maintained throughout the progression to coma. Control SHAM and PCA rats, sacrificed 4 weeks after surgery, were also included. Routine biochemistry and liver histopathology were used to assess liver status. Brain edema (specific gravimetric technique), reactive oxygen species and glutathione levels (spectrophotometry) were measured in plasma and brain tissue of all groups. Results: The onset of coma was significantly delayed in ACLF compared to ALF rats by approximately 8h. Liver necrosis markers AST and ALT did not differ between ACLF and ALF rats; however, liver histopathology showed more severe necrosis in ACLF than in ALF rats. Brain water content was significantly attenuated in acute-on-chronic rats: ACLF: 80.04±0.13 % (ns vs SHAM; p<0.01 vs ALF); SHAM: 80.12±0.09 %; ALF: 81.39±0.15 % (p<0.01 vs SHAM). Increase in arterial ammonia concentration was prevented in ACLF rats: ACLF: 0.35±0.07 mM (p<0.001 vs SHAM; p<0.001 vs ALF); SHAM: 0.06±0.01 mM; ALF: 1.34±0.09 mM (p<0.001 vs SHAM). Evidence of oxidative stress (increased reactive oxygen species and decreased glutathione levels) was systemically present in both ACLF and ALF rats, while signs of oxidative stress in the brain were present only in ALF rats. Conclusions: Our animal model of acute liver insult, superimposed on chronic hyperammonemia, reproduces the alterations observed in acute liver failure; however, the latter were attenuated. In spite of a more severe liver necrosis in ACLF rats, the onset of coma was delayed, and brain edema, ammonia levels and oxidative stress were reduced when compared to ALF rats. These findings therefore suggest that during chronic liver failure, compensatory mechanisms are developed, which in turn prevent the apparition of brain edema and attenuate oxidative stress during acute deterioration.

Oral

Role of oxidative stress in prevention of brain edema during an acute deterioration of chronic liver failure.

Cristina R. *Bosoi, Chantal Bémeur, Cristina R. Bosoi, Mélanie Tremblay, Christopher F. Rose.

Aims: Acute-on-chronic liver failure (ACLF) represents an acute decompensation of liver cirrhosis. End-to-side portacaval anastomosis (PCA) followed by hepatic artery ligation (HAL) performed after 4 weeks represents a model of liver decompensation. In this model, the onset of coma is delayed compared to acute liver failure induced by hepatic devascularisation. As oxidative stress plays a role in brain edema in chronic liver failure, the objective of this study was to investigate the role of oxidative stress in the pathogenesis of brain edema in ACLF. Methods: Male Sprague-Dawley rats were subjected to PCA followed by hepatic artery ligation (HAL) either concomitantly (HAL-0) or 4 weeks (HAL-4W) following shunt surgery or to a SHAM intervention. Body temperature and blood glucose were monitored and maintained throughout the experiments. Brain edema (specific gravimetric technique) and glutathione levels (spectrophotometry) were measured in brain tissue of all groups. Results: Brain water content was significantly attenuated in “acute-on-chronic” rats (SHAM: 80.12±0.09 %; HAL-0: 81.39±0.15 % (p<0.01 vs SHAM); HAL-4W: 80.04±0.13 % (ns vs SHAM; p<0.01 vs HAL-0)). Arterial ammonia concentration followed a similar pattern (control: 0.060±0.007 mM; HAL-0: 1.340±0.090 mM (p<0.001 vs SHAM); HAL-4W: 0.350±0.070 mM (p<0.001 vs SHAM; p<0.001 vs HAL-0)). Glutathione levels did not change in HAL-4W compared to SHAM and were significantly decreased in the brains of HAL-0 rats (by 36% vs SHAM, p<0.05 and by 25% vs HAL-4W). These effects were not due to an improvement in liver function, as liver necrosis markers AST and ALT did not differ between HAL-4W and HAL-0 rats. Conclusions: Brain edema, ammonia levels and oxidative stress are reduced in ACLF rats compared to acute liver failure rats. These findings suggest that during chronic liver failure compensatory mechanisms are developed that prevent the apparition of brain edema and attenuate oxidative stress during an acute deterioration.

IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure.

Chantal Bémeur, Hong Qu, Paul Desjardins, Roger F. Butterworth.

Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy.

Chantal Bémeur, Paul Desjardins, Roger F. Butterworth.

Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse.

Javier Vaquero, Chantal Bémeur, Paul Desjardins, Roger F. Butterworth.

N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms.

Chantal Bémeur, Javier Vaquero, Paul Desjardins, Roger F. Butterworth.

Increased oxidative stress during hyperglycemic cerebral ischemia.

Chantal Bémeur, Line Ste-Marie, Jane Montgomery.

Comparison of two rat models of cerebral ischemia under hyperglycemic conditions.

Longshan Liu, Ziying Wang, Xiang Wang, Lijun Song, Huifang Chen, Chantal Bémeur, Line Ste-Marie, Jane Montgomery.

Dehydroascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat.

Chantal Bémeur, Line Ste-Marie, Paul Desjardins, Luc Vachon, Roger F. Butterworth, Alan S. Hazell, Jane Montgomery.

Expression of superoxide dismutase in hyperglycemic focal cerebral ischemia in the rat.

Chantal Bémeur, Line Ste-Marie, Paul Desjardins, Roger F. Butterworth, Luc Vachon, Jane Montgomery, Alan S. Hazell.

Decreased beta-actin mRNA expression in hyperglycemic focal cerebral ischemia in the rat.

Chantal Bémeur, Line Ste-Marie, Paul Desjardins, Alan S. Hazell, Luc Vachon, Roger Butterworth, Jane Montgomery.

Immunohistochemical detection of inducible nitric oxide synthase, nitrotyrosine and manganese superoxide dismutase following hyperglycemic focal cerebral ischemia.

Line Ste-Marie, Alan S. Hazell, Chantal Bémeur, Roger Butterworth, Jane Montgomery.

Hydroxyl radical production in the cortex and striatum in a rat model of focal cerebral ischemia.

Line Ste-Marie, Pascal Vachon, Luc Vachon, Chantal Bémeur, Marie-Claude Guertin, Jane Montgomery.

Increases in hydroxyl radical production have been used as evidence of oxidative stress in cerebral ischemia/ reperfusion. Ischemia can also induce increased dopamine release from the striatum that may contribute to hydroxyl radical formation. We have compared hydroxyl radical production in the cortex and striatum as an index of oxidative stress in a rat model of focal cerebral ischemia with cortical infarction. Using a three vessel occlusion model of focal cerebral ischemia combined with bilateral microdialysis, hydroxylation of 4-hydroxybenzoate (4HB) was continuously monitored in both hemispheres in either the lateral striatum or frontoparietal cortex. The ischemia protocol consisted of one hour equilibration, 30 min of three vessel occlusion, then release of the contralateral common carotid artery (CCA) for 2.5 h. Induction of ischemia resulted in a 30-fold increase in dopamine release in the lateral striatum. Compared to the nonischemic striatum, the ratio of the hydroxylation product 3,4-dihydroxybenzoate (34DHB) to 4HB (trapping agent) in the ipsilateral striatum increased significantly 30 min after ischemia induction. In contrast, during the 30 min of three vessel occlusion there was no increase in the ratio in the cortex. Following the release of the contralateral CCA, the ratio from the ischemic cortex increased significantly compared to sham-operated animals. However, under all circumstances, the 34DHB/4HB ratio was greater in the striatum than in the cortex. The increase in the 34DHB/4HB ratio in the lateral striatum coincides with the increased dopamine release suggesting a role for dopamine oxidation in the increased production of hydroxyl radicals. The significant increase in the ratio from the ischemic cortex compared to that from the sham-operated animals is consistent with increased oxidative stress induced by ischemia. However, the lower 34DHB/4HB ratio in the cortex which does not receive dopaminergic innervation compared to the striatum suggests a different mechanism for hydroxyl radical production. Such an alternate mechanism may represent a more toxic oxidative insult that contributes to infarction.

Local striatal infusion of MPP+ does not result in increased hydroxylation after systemic administration of 4-hydroxybenzoate.

Line Ste-Marie, Luc Vachon, Chantal Bémeur, Jean Lambert, Jane Montgomery.

The Nutrition in Cirrhosis Guide.

Puneeta Tandon, Vanessa DenHeyer, Kathleen P Ismond, Jan Kowalczewski, Maitreyi Raman, Tannaz Eslamparast, Chantal Bémeur, Christopher Rose.

OpenAccess

Mitochondrial vulnerability and increased susceptibility to nutrient-induced cytotoxicity in fibroblasts from leigh syndrome French canadian patients.

Yan Burelle, Chantal Bémeur, Marie-Eve Rivard, Julie Thompson Legault, Gabrielle Boucher, L. S. F. C. Consortium, Charles Morin, Lise Coderre, Christine Des Rosiers.

Mutations in LRPPRC are responsible for the French Canadian variant of Leigh Syndrome (LSFC), a severe disorder characterized biochemically by a tissue-specific deficiency of cytochrome c oxidase (COX) and clinically by the occurrence of severe and deadly acidotic crises. Factors that precipitate these crises remain unclear. To better understand the physiopathology and identify potential treatments, we performed a comprehensive analysis of mitochondrial function in LSFC and control fibroblasts. Furthermore, we have used this cell-based model to screen for conditions that promote premature cell death in LSFC cells and test the protective effect of ten interventions targeting well-defined aspects of mitochondrial function. We show that, despite maintaining normal ATP levels, LSFC fibroblasts present several mitochondrial functional abnormalities under normal baseline conditions, which likely impair their capacity to respond to stress. This includes mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, lower membrane potential, increased sensitivity to Ca2+-induced permeability transition, but no changes in reactive oxygen species production. We also show that LSFC fibroblasts display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral. Furthermore, we demonstrate that compounds that are known to promote flux through the electron transport chain independent of phosphorylation (methylene blue, dinitrophenol), or modulate fatty acid (L-carnitine) or Krebs cycle metabolism (propionate) are protective, while antioxidants (idebenone, N-acetyl cysteine, resveratrol) exacerbate palmitate plus lactate-induced cell death. Collectively, beyond highlighting multiple alterations in mitochondrial function and increased susceptibility to nutrient-induced cytotoxicity in LSFC fibroblasts, these results raise questions about the nature of the diets, particularly excess fat intake, as well as on the use of antioxidants in patients with LSFC and, possibly, other COX defects.

Studies on Hepatic Disorders

Chantal Bémeur.