Dr Chantal Bémeur is associate professor at Nutrition department of Université de Montréal and researcher at CRCHUM.
Associate professor, Department of nutrition, Université de Montréal
2012 - now
Social media profiles :
Career
- (2011-2012) Post-doctoral fellowship. Dr Yan Burelle, Pharmacy Faculty, Université de Montréal
- (2001-2003) Post-doctoral fellowship. Dr Roger Butterworth, Neuroscience Research Unit, Université de Montréal (CRCHUM)
- (2000) Ph.D. Dr Jane Montgomery, Université de Montréal (CRCHUM)
Research interests
- Nutrition
- Factors and mechanisms associated with acidosis lactic crisis of children suffering of French canadian Leigh Syndrome (Lactic acidosis of Saguenay-Lac-Saint-Jean)
- Impact of the genic mutation (LRPPRC) on mitochondrial function and vulnerability to inflammatory stress in vitro et in vivo
- Links between oxidative stress, inflammation and cerebral function and antioxidant interventions to decrease toxicity of reactives species and inflammatory modulators.
Related Publications
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.
Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Kraine Dubois, Mélanie Tremblay, Chantal Bémeur, Christopher F. 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 le cerveau 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 mâles ont été randomisés en trois groupes : SHAM, BDL-VEH et BDL-FMT recevant quotidiennement la FMT provenant des rats SHAM. Après cinq semaines, des tests comportementaux sont effectués pour évaluer la mémoire à court/long terme, l'anxiété et la coordination motrice. Les fèces et plasma ont été collectés pour séquençage bactérien et analyses. Résultats: Les BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice comparée aux rats SHAM. Cependant, les altérations neurologiques sont prévenues dans le groupe BDL-FMT. Une modulation du microbiote a été constatée pour les rats BDL-FMT comparé aux BDL-VEH. Les cytokines (TNF-α et IL-1β) ne varient entre les groupes BDL. L'analyse des acides gras à chaîne courte dans les fèces et le plasma a montré une variation du propionate et du butyrate entre les groupes BDL. Le propionate plasmatique est positivement corrélé aux scores de comportement. Discussion: Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT conduit à un nouveau profil spécifique du microbiote avec la présence du propionate comme métabolite à explorer.
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.
Alexandre Bourgeois, Felix Veillette, Mariana Oliveira, Kraine Dubois, Mélanie Tremblay, Chantal Bémeur, F. Rose Christopher.
Problématique: L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique résultant d'une maladie du foie. Il a été démontré que le microbiote intestinal influence le cerveau 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 mâles ont été randomisés en trois groupes : SHAM, BDL-VEH et BDL-FMT recevant quotidiennement la FMT provenant des rats SHAM. Après cinq semaines, des tests comportementaux sont effectués pour évaluer la mémoire à court/long terme, l'anxiété et la coordination motrice. Les fèces et plasma ont été collectés pour séquençage bactérien et analyses. Résultats: Les BDL-VEH ont développé une perte de mémoire à court/long terme et une perte de coordination motrice comparée aux rats SHAM. Cependant, les altérations neurologiques sont prévenues dans le groupe BDL-FMT. Une modulation du microbiote a été constatée pour les rats BDL-FMT comparé aux BDL-VEH. Les cytokines (TNF-α et IL-1β) ne varient entre les groupes BDL. L'analyse des acides gras à chaîne courte dans les fèces et le plasma a montré une variation du propionate et du butyrate entre les groupes BDL. Le propionate plasmatique est positivement corrélé aux scores de comportement. Discussion: Nos résultats démontrent que la FMT améliore la mémoire et la coordination motrice chez les rats BDL. La FMT conduit à un nouveau profil spécifique du microbiote avec la présence du propionate comme métabolite à explorer.
Amal Trigui, Mélanie Tremblay, C. F. Rose, Chantal Bémeur.
Après la transplantation hépatique (TH), la malnutrition, la sarcopénie et la fragilité physique sont associées à des résultats cliniques défavorables et à une diminution de la qualité de vie. Objectif : Déterminer la prévalence de la malnutrition, de la sarcopénie et de la fragilité physique à un an, deux ans et trois ans après la TH et décrire la fonction musculaire, la qualité de vie chez ces patients. Méthodologie : Étude transversale incluant 65 patients transplantés entre 2019 et 2021. Une seule rencontre est réalisée avec chaque patient afin d’évaluer le risque nutritionnel (outil canadien de dépistage nutritionnel), la sarcopénie (SARC-F), la fragilité (FRAIL), la fonction musculaire (test d’élévation de la chaise) et la qualité de vie (SF-36). Résultats : 64 (24 en 2019, 13 en 2020 et 27 en 2021) patients ont terminé l'étude. 12,5 % des patients sont à risque de malnutrition, 8,3 % sont à risque de sarcopénie tandis que 50 % et 12,5 % sont pré-fragiles et fragiles. Ces prévalences sont restées inchangées jusqu'à 3 ans après la transplantation. La fonction musculaire est altérée après la TH (13,6s contre 12,6 s chez les personnes en bonne santé). Le score de la santé physique (63%) est significativement inférieur au score normal et ce score reste inchangé jusqu'à 3 ans après la transplantation. Conclusion: Jusqu'à 3 ans après la TH, les patients sont toujours à risque de malnutrition, de sarcopénie et de fragilité. Le score de la composante physique de leur qualité de vie est inférieur à celui de la population générale.
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.
Manila Sophasath, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.
Le guide La nutrition pour la cirrhose a été élaboré par une équipe nationale d’experts et de patients. Objectifs: 1)Évaluer l’impact chez les patients cirrhotiques du Guide sur: i) le risque nutritionnel; ii) les connaissances en nutrition; iii) la qualité de vie. 2) Sonder l’appréciation du Guide. Méthodologie: Une étude randomisée contrôlée incluant 100 patients cirrhotiques du CHUM divisés en 2 groupes: Intervention (Guide+) et Contrôle (Guide-). Le risque nutritionnel, les connaissances en nutrition et la qualité de vie sont évalués à 0, 3 et 6 mois. Cinq groupes de discussion de 3 patients sont constitués afin d’évaluer l’appréciation générale du Guide. Résultats préliminaires: 42 patients sont inclus dans l'étude à ce jour: Guide+ (n=21) et Guide- (n=21). À ce jour, 21 patients ont complété l'étude: Guide+ (n=10) et Guide- (n=11). Une tendance d’amélioration des connaissances des patients Guide+ (76,0 % à 80,4 %) après 3 mois n’est pas maintenue à 6 mois (76,4 % ; p>0,05). Le risque nutritionnel a tendance à s’améliorer dans le groupe Guide+ (50% des patients initialement dénutris, 40% à 3 mois et 20% à 6 mois; p>0,05). Le risque nutritionnel est plus élevé dans le groupe Guide- (de 36,4% à 56,5% à 3 mois, à 45,5% à 6 mois; p>0,05). Les résultats préliminaires des groupes de discussion suggèrent une satisfaction globale du contenu, mais un besoin d'alléger et mieux diviser les concepts. Discussion: Ces résultats préliminaires démontrent une tendance positive d’amélioration des connaissances nutritionnelles des patients utilisant le Guide sur 3 mois non maintenue à 6 mois. Une amélioration du risque nutritionnel à 6 mois est observée. Les résultats de ce projet permettront d'optimiser la qualité des soins et de l’éducation nutritionnelle prodiguées aux patients atteints de cirrhose.
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.
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.
Amal Trigui, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.
Après la transplantation hépatique (TH), la malnutrition, la sarcopénie et la fragilité sont associées à des résultats cliniques défavorables et à une diminution de la qualité de vie. Objectif : Déterminer la prévalence de la malnutrition, de la sarcopénie et de la fragilité à un an, deux ans et trois ans après la TF et décrire la fonction musculaire, la qualité de vie et le statut de l'emploi chez ces patients. Méthodologie : Une étude transversale incluant 80 patients transplantés entre 2019 et 2021. Une seule rencontre virtuelle est réalisée avec chaque patient afin évalués le risque nutritionnel (outil canadien de dépistage nutritionnel), la sarcopénie (questionnaire SARC-F), la fragilité (questionnaire FRAIL), la fonction musculaire (test d’élévation de la chaise), la qualité de vie (SF-36) et le statut d’emploi. Résultats : 57 (29 en 2019, 12 en 2020 et 16 en 2021) patients ont terminé l'étude. 10,5 % des patients sont à risque de malnutrition, 19,3 % sont à risque de sarcopénie tandis que 43,9 % et 19,3 % sont pré-fragiles et fragiles. Ces prévalences sont restées inchangées jusqu'à 3 ans après la transplantation. La fonction musculaire est altérée après la TH (15,8 ± 5,5 s contre 12,6 s chez les personnes en bonne santé). En ce qui concerne la qualité de vie, le score de santé physique (62,6 % ± 22,1) est légèrement inférieur au score normale et ce score reste inchangé jusqu'à 3 ans après la transplantation. 68,4% des patients sont au chômage dont 46,2% sont en retraite anticipée pour une cause liée à la maladie du foie. Discussion: Jusqu'à 3 ans après la TH, les patients sont toujours à risque de malnutrition, de sarcopénie et de fragilité. Le score de la composante physique de leur qualité de vie est inférieur à celui de la population générale.
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.
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.
Problématique: La malnutrition est l’une des complications les plus prévalentes de la cirrhose (maladie du foie chronique) et affecte la qualité de vie des patients. Objectifs: Le projet vise l’évaluation d’un Guide éducatif en nutrition pour patients avec une cirrhose en 2 volets: 1)Évaluer le guide La nutrition pour la cirrhose sur les connaissances en nutrition, qualité de vie et état nutritionnel sur 6 mois. 2)Évaluer la satisfaction du Guide par les patients. Méthode: 1)100 patients suivis au CHUM randomisés en deux groupes égaux: Intervention (Guide+) et Contrôle (Guide-). Les évaluations de l’état nutritionnel, connaissances en nutrition et qualité de vie sont réalisées à 0, 3 et 6 mois. 2)5 groupes de discussion (3 patients/groupe) pour évaluer l’appréciation du Guide. Résultats prélim. (volet 1): À ce jour, 31 patients (Guide+; n=16 et Guide-; n=15) ont complété l’évaluation à 3 mois. Les résultats démontrent une tendance d’amélioration des connaissances (de 75,4% à 79,6%) pour le groupe Guide+ vs Guide-(de 73,7% à 74,6%), (p=0.212). L’évaluation à 6 mois a été complétée par 21 patients (Guide+; n=10 et Guide-; n=11). Les résultats préliminaires démontrent que la tendance d’amélioration de connaissances du groupe Guide+ après 3 mois n’est pas maintenue après 6 mois : de 80,4% (3 mois) à 76.4% (6 mois). Discussion: Le Guide ne semble pas permettre une rétention de l’information à long terme. Élaborer une ressource éducative plus adaptée serait envisageable.
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.
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.
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.
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.
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.
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.
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.
Amal Trigui, Christopher F. Rose, Chantal Bémeur.
Persisting or newly developed malnutrition and sarcopenia after liver transplant (LT) are correlated with adverse health outcomes. This narrative review aims to examine the literature regarding nutrition strategies to manage malnutrition and sarcopenia after LT. The secondary aims are to provide an overview of the effect of nutrition strategies on the incidence of infections, hospital length of stay (LOS), acute cellular rejection (ACR), and mortality after LT. Four databases were searched. A total of 25 studies, mostly of mid-high quality, were included. Six studies found a beneficial effect on nutritional parameters using branched-chain amino acids (BCAA), immunomodulating diet (IMD), or enteral nutrition (EN) whereas two studies using beta-hydroxy-beta-methylbutyrate (HMB) found a beneficial effect on muscle mass and function. Fourteen studies using pre- or pro-biotics, IMD, and EN were effective in lowering infection and six studies using IMD, BCAA or HMB reported reduced hospital LOS. Finally, four studies using HMB and vitamin D were effective in reducing ACR and one study reported reduced mortality using vitamin D after LT. In conclusion, nutritional intervention after LT has different beneficial effects on malnutrition, sarcopenia, and other advert outcomes. Additional large and well-constructed RCTs using validated tools to assess nutritional status and sarcopenia are warranted to ensure more robust conclusions.
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.
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.
Amal Trigui, Joan 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 cliniques avant et après la TH, incluant la sarcopénie (perte de masse et fonction musculaire). Objectifs: 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. Méthode: 30 patients cirrhotique en attente d’une TH sont inclus dans cette étude. 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 chaque 3 mois avant la TH jusqu’à la transplantation. Résultats: 29 patients en attente de TH sont inclus. L'âge moyen des patients est 51,1 ± 11,6 ans. L'étiologie la plus fréquente est l’alcoolisme (41 %). 83 % des patients sont à risque de malnutrition. La fonction musculaire est altérée (18,9 ± 7,8 s vs 12,6 s chez les patients sains ; p < 0,001) et diminue avec le temps d’attente. Concernant la qualité de vie, les scores de la santé physique (44,6% ± 20,4) et de santé mentale (53,5% ± 26,1) sont inférieurs aux scores normaux des patients en bonne santé (p < 0,001). La qualité de vie avait tendance à diminuer avec le temps d’attente. Conclusion: La majorité des patients en attente d'une TH sont à risque de malnutrition, présentent une fonction musculaire altérée qui diminue avec le temps d’attente et des scores de qualité de vie diminués.
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.
Amal Trigui, Joan Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.
La malnutrition est la complication la plus fréquente chez les patients atteints de cirrhose de foie et en attente d’une transplantation hépatique (TH) et elle pourrait mener à une perte de masse et de fonction musculaire (sarcopénie). Objectifs: 1) 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. 2) Évaluer l’effet de la supplémentation précoce après la TH, riche en protéines et en énergie sur les mêmes paramètres. Méthode: Une étude pilote randomisée est menée auprès de 30 patients en attente d’une TH randomisés entre (1) un groupe intervention (n=15) qui reçoit des suppléments nutritionnels pendant 12 semaines et (2) un groupe contrôle (n=15) qui reçoit les soins nutritionnels standards. La fonction musculaire, l'état nutritionnel et la qualité de vie sont évalués chaque 3 mois avant la TH, à la sortie de l'hôpital et après 12 semaines. Résultats: 26 patients en attente de TH sont inclus dont un participant est transplanté. L'âge moyen des patients est 51,3 ± 12,9 ans. L'étiologie la plus fréquente est l’alcoolisme (33 %). 84 % des patients sont à risque de malnutrition. La fonction musculaire est altérée (18,1 ± 11,0 s vs 12,6 s chez les patients sains ; p < 0,001) et diminue avec le temps d’attente. Concernant la qualité de vie, les scores de la santé physique (41,8% ± 18,6) et de santé mentale (52,1% ± 25,0) sont inférieurs aux scores normaux des patients en bonne santé (p < 0,001). La qualité de vie avait tendance à diminuer avec le temps d’attente. Conclusion: La majorité des patients en attente d'une TH sont à risque de malnutrition, présentent une fonction musculaire altérée et des scores de qualité de vie diminués. Ces données préliminaires confirment la nécessité d'un soutien nutritionnel précoce après la TH.
Amal Trigui, Joan Maxwell, Geneviève Huard, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur.
Introduction: In cirrhosis patients awaiting liver transplantation (LT), protein-energy malnutrition is the most common complication (> 80%) and one of the main risk factors for the onset and progression of sarcopenia, defined as a loss of muscle mass, quality, and function. Previous clinical studies have shown that malnutrition and sarcopenia are associated with negative outcomes, such as increased infections and mortality, as well as decreased quality of life. Objectives: Assess longitudinal changes in nutritional risk, muscle function and quality of life in cirrhotic patients awaiting LT. Method: A randomized controlled pilot study is conducted including 30 cirrhotic patients on the waiting list for LT. Nutritional risk (Liver Disease Undernutrition Screening Tool), muscle function (chair stand test), and quality of life (SF-36) are assessed every 3 months before and until LT. Results: Currently, 25 patients awaiting LT are included. The mean age of the patients is 51.3 ± 12.9 years. The most common etiology is alcoholism (33 %). 84 % of patients were at risk of malnutrition and with follow-ups up to a year on the waitlist, the percentage has not changed. Muscle function is impaired in those patients (18.1 ± 11.0 s vs. 12.6 s in healthy patients) (p < 0,001) and it decreased with the follow-ups (p < 0,05). Regarding quality of life, the score of physical heath was 41.8% ± 18.6 and mental health was 52.1% ± 25. With the follow-ups, the quality of life tended to decrease. 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.
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.
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.
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.
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.
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.
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.
Mimosa Nguyen, Yvette Mukaneza, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.
Liver transplantation (LT) is the only curative treatment for cirrhosis. However, the presence of complications can impact outcomes following LT. Sarcopenia, or muscle mass loss, is highly prevalent in patients with cirrhosis and is associated with longer hospitalization stays and a higher infection rate post-surgery. We aimed to identify patients at higher risk of early sarcopenia post-LT. This retrospective study included 79 cirrhotic patients who underwent LT. Muscle mass was evaluated using the third lumbar spine vertebra skeletal muscle index (SMI) and sarcopenia was defined using established cut-off values. Computerized tomography (CT) scans performed within a six-month peri-operative period (three months pre- and post-LT) were included in the study. Complications and comorbidities were collected and correlated to SMI post-LT and predictive models for SMI post-LT were constructed. The overall prevalence of sarcopenia was 46% and 62% before and after LT, respectively. Newly developed sarcopenia was found in 42% of patients. Post-LT sarcopenia was associated with longer hospital stays (54±37 versus 29±10 days, = 0.002), higher number of infection (3±1 versus 1±2, = 0.027), and greater number of complications (5±2 versus 3±2, < 0.001) compared to absence of sarcopenia. Multivariate analyses showed that the SMI post-LT was independently associated with pre-LT renal function markers, the glomerular filtration rate (GFR) and creatinine (Model 1, GFR: = 0.33; 95% CI 0.04-0.17; = 0.003; Model 2, Creatinine: = -0.29; 95% CI -0.10 to -0.02; = 0.009). The present study highlights the potential role of renal dysfunction in the development and persistence of sarcopenia after LT.
Amino acids, ammonia, and hepatic encephalopathy.
Katerina Kroupina, Chantal Bémeur, Christopher F. Rose.
Hepatic encephalopathy (HE) is a decline in brain function arising due to liver insufficiency. The liver's diminished capacity to clear ammonia, and the subsequent accumulation of it, is highly implicated in pathogenesis of HE. Ammonia is endogenously generated from the catabolism of amino acids derived from dietary protein intake. Therefore, a conflict arises in cirrhosis where dietary protein intake may increase ammonia and precipitate HE, and at the same time, cirrhotic patients require high daily protein intake due to altered nutrient metabolism. A nutritional solution is needed to deliver sufficient doses of protein to patients without increasing the risk of HE. In order to address this issue, this review will discuss the catabolism of individual amino acids with a special focus on ammonia-generating steps and highlight a subset of amino acids that have the potential to generate multiple equivalents of ammonia. Following, studies investigating the effects of individual amino acids in cirrhosis on blood ammonia levels as well as development of HE will be reviewed.
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.
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.
Sandrine Laforce, Mélanie Tremblay, Yvette Mukaneza, Benoît Lamarche, Cécile Delawarde-Saïas, Mickael Bouin, Chantal Bémeur.
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.
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.
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.
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.
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.
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.
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.
Marc-André Clément, Cristina R. Bosoi, Mariana M. Oliveira, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.
Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied with various perioperative factors such as blood loss and hypotension which could influence outcomes post-LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension-induced neuronal cell death. Six-week bile duct-ligated (BDL) rats with MHE and respective SHAM-controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90mmHg) were induced via blood withdrawal from the femoral artery and maintained for 120 minutes. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60mmHg (not 90mmHg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM-operated controls as well as non-hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase-3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonemia, improved anxiety and activity, and protected the brain against hypotension-induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk.
Outcomes of sarcopenic obesity and metabolic syndrome in liver transplant patients.
Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher Rose, Chantal Bémeur.
Background: Sarcopenia is associated with a worst prognosis in cirrhotic patients after liver transplantation (LT). As patients gain weight and sarcopenia remains after LT, sarcopenic obesity (SO) develops. Metabolic syndrome (MS), a cluster of factors that increase the risk of heart disease and diabetes, is caused by weight gain. There are limited data about the influence of SO and MS in LT recipients. Purpose: The goal of this study was to examine the impact of SO and MS on outcome after LT. Method: In total, 94 cirrhotic patients who underwent LT at the CHUM – Liver Unit were included. Sarcopenia was assessed at the third lumbar level vertebrae using a CT-scan. Obesity was determined using BMI whereas MS was diagnosed using the presence of ³3 modified NCEP ATP III criteria. The prognostic factors were collected 6 months before and during 1 year after LT through medical records and included number of complications, episodes of infections, length of stay, and frequency of readmissions. Result(s): Most of the patients ( 70%) were not obese before LT. Approximately 20% of the patients developed obesity after LT. Among patients who were obese before LT, 40% of the patients remained obese after LT. SO affected 10% and less of the patients before and after LT. Among patients with MS before LT (64%), 40% of them was still affected after LT. Among patients who were not affected by MS before LT, 38% developed MS after LT and one patient remained not affected after LT. Prognostic factors were worst in patients with SO and MS before and after LT. Conclusion(s): SO affected a small proportion of patients while MS was prevalent before and after LT. Nevertheless, these conditions were associated with worst prognosis. Strategies to manage SO and MS could help to improve recovery in patients who have undergone LT.
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.
Hepatic encephalopathy (HE), sarcopenia, and frailty are serious complications of chronic liver disease that may negatively affect quality of life and survival. HE is a complex neuropsychiatric multifactorial syndrome for which ammonia is believed to play a key role. Sarcopenia, which is nearly universal in chronic liver disease, is a muscle disease characterized by low muscle strength, low muscle quantity or quality, and low physical performance. Physical frailty is described as a multidimensional syndrome of decreased reserve, functional impairment, and resistance to stressors, resulting from cumulative declines across multiple systems, whereas cognitive frailty is characterized by reduced neurophysiological reserve. Pathophysiology of sarcopenia and frailty in the setting of HE and chronic liver disease remains to be elucidated. Therapeutic strategies of HE aim at reducing blood ammonia concentrations. In that context, muscle may play a vital compensatory role in reducing ammonia levels since it contains an ammonia-removing enzyme. Assessing HE, sarcopenia, and frailty during chronic liver disease is the cornerstone of optimal intervention.
Mimosa Nguyen, Mélanie Tremblay, Geneviève Huard, An Tang, Christopher F. Rose, Chantal Bémeur.
Introduction: Sarcopenia is associated with a worst prognosis in cirrhotic patients after liver transplantation (LT). As patients gain weight and sarcopenia remains after LT, sarcopenic obesity (SO) develops. Metabolic syndrome (MS), a cluster of factors that increase the risk of heart disease and diabetes, is caused by weight gain. There are limited data about the influence of SO and MS in LT recipients. The goal of this study was to examine the impact of SO and MS on outcomes after LT. Method: In total, 94 cirrhotic patients who underwent LT at the CHUM – Liver Unit were included. Sarcopenia was assessed at the third lumbar level vertebrae using a CT-scan. Obesity was determined using BMI whereas MS was diagnosed using the presence of 3 modified NCEP ATP III criteria. The prognostic factors were collected 6 months before and during 1 year after LT through medical records and included number of complications, episodes of infections, length of stay, and frequency of readmissions. Results: Most of the patients ( 70%) were not obese before LT. Approximately 20% of the patients developed obesity after LT. Among patients who were obese before LT, 40% of the patients remained obese after LT. SO affected 10% and less of the patients before and after LT. Among patients with MS before LT (64%), 40% of them was still affected after LT. Among patients who were not affected by MS before LT, 38% developed MS after LT and one patient remained not affected after LT. Prognostic factors were worst in patients with SO and MS before and after LT. Conclusion: SO affected a small proportion of patients while MS was prevalent before and after LT. Nevertheless, these conditions were associated with worst prognosis. Strategies to manage SO and MS could help to improve recovery in patients who have undergone LT.
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.
Manila Sophasath, Mélanie Tremblay, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.
Problématique : Au Canada, la prévalence de la maladie hépatique connaît une croissance exponentielle. L’une des complications les plus prévalentes y étant associée est la malnutrition, qui affecte la qualité de vie des patients par l’augmentation des risques de nombreuses complications. Objectif : L’objectif général est d’évaluer l’impact bénéfique potentiel du Guide de nutrition pour la cirrhose, un document éducatif basé sur des données probantes et sur l’expérience de patient-partenaire, qui traduit les lignes directrices en matière de nutrition et cirrhose. Les objectifs spécifiques sont d’évaluer l’état nutritionnel, la qualité de vie reliée à la santé et la fonction hépatique en plus de déterminer les connaissances en nutrition des patients cirrhotiques après l’implantation du Guide. Méthodologie : Nous visons l’inclusion de 132 patients visitant la clinique externe d’hépatologie du CHUM. Les patients seront rencontrés par une nutritionniste, qui évaluera l’état nutritionnel, la qualité de vie, la fonction hépatique et leurs connaissances en nutrition. Le Guide leur sera ensuite enseigné et fourni pour 12 semaines, pendant lesquelles un suivi téléphonique sera réalisé à chaque deux semaines. Au terme des 12 semaines, les mêmes évaluations seront réalisées par la nutritionniste. Ces patients seront comparés à un groupe contrôle d’environ 40 sujets cirrhotiques recevant des conseils nutritionnels « habituels », mais n’ayant pas accès au Guide. Résultats attendus : Les patients ayant eu accès au Guide devraient voir une amélioration au niveau des paramètres mesurés. Discussion : Les résultats de cette étude devraient permettre d’optimiser la qualité des soins chez les gens souffrant de maladies chroniques du foie.
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
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.
Luise Aamann, Puneeta Tandon, Chantal Bémeur.
Sarcopenia and malnutrition are common features in patients with hepatic encephalopathy. Ammonia, a factor implicated in the pathophysiology of hepatic encephalopathy, may be cleared by the muscle via the enzyme glutamine synthetase when the liver function is impaired. Hence, optimizing muscle mass in patients suffering from hepatic encephalopathy is a potential strategy to decrease ammonia levels. Exercise could be an efficient therapeutic approach to optimize muscle mass and therefore potentially reduce the risk of hepatic encephalopathy in patients with chronic liver disease. This review reports the current evidence regarding exercise and hepatic encephalopathy from animal and human studies. After defining concepts such as frailty, sarcopenia, and malnutrition, the present knowledge regarding exercise as potential therapy in cirrhotic patients with or without hepatic encephalopathy is discussed. Recommendations and future aspects are also considered.
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.
Introduction: Sarcopenia affects up to 70% of patients suffering from chronic liver disease (cirrhosis). The presence of sarcopenia may influence the prognosis of cirrhotic patients before and after liver transplantation (LT). Few studies have assessed the evolution of sarcopenia in LT. The goal of this study was to follow the evolution and assess the impact of sarcopenia on the prognosis of cirrhotic patients before and after LT. Methods: Skeletal muscle index (SMI) was calculated from cross‐sectional muscle area at the third lumbar level (L3) on computed tomography (CT). The following CT‐scans were analysed: before LT + before discharge and/or nearest 1‐year post‐LT. Sarcopenia was defined using previously published cutoffs based on gender. The association of sarcopenia with prognostic factors (mortality, hospital stay, infections, readmissions) was assessed in cirrhotic patients who underwent LT. Results: Thus far, the average SMI before LT of sarcopenic and non‐sarcopenic patients were 40.3±5.3 cm2/m2 and 58.7±13.7 cm2/m2, respectively. The correlation of SMI with length of hospital stay, infections, and readmissions were high (rspearman = −0.714 p = 0.071), moderate (rspearman = −0.598 p = 0.156), and low (rspearman = −0.386 p = 0.393). Conclusions: Preliminary results indicate that low muscle mass before LT tends to be associated with prolonged hospitalization. As we analyse the remaining data, the strength of the relationship between sarcopenia and the prognosis in LT will help better guide patient care.
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
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.
Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remains to be investigated. Bile duct ligated (BDL)-rats develop chronic liver disease, hyperammonemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL-rats. A group of BDL-rats underwent a progressive resistance training program and a group of non-exercise BDL-rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed five days a week during four weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. BDL+exercise rats had significantly larger gastrocnemius circumference compared to non-exercise BDL-rats: ratio 0.082 vs. 0.075 (p<0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs. 0.005 (p<0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (p=0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non-significant reduction in blood ammonia, however a tendency was observed. This article is protected by copyright. All rights reserved.
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.
Problématique: La sarcopénie (perte de masse et de fonction musculaires) affecte 30 à 70% des patients atteints de maladie hépatique chronique (cirrhose). Un Canadien sur 4 souffrirait de maladie hépatique. Chez les patients cirrhotiques, la présence de la sarcopénie avant et après la transplantation hépatique (TH) serait associée à un mauvais pronostic. Objectif : Le but général de cette étude rétrospective en cours est de déterminer, chez les patients cirrhotiques, la prévalence de la sarcopénie avant la TH ainsi que son impact sur le pronostic après la TH. Méthodologie : Notre étude vise l’inclusion de 100 patients cirrhotiques de diverses étiologies. L’évaluation de la masse musculaire avant la TH s’effectue en utilisant l’index musculaire squelettique lequel est basé sur l’analyse de l’examen radiologique de tomodensitométrie (CT-scan) au niveau de la 3e vertèbre lombaire. La durée de l’hospitalisation, la fréquence d’infections et le nombre de réadmissions durant la première année post-TH sont également recueillis par la consultation des dossiers médicaux. Résultats attendus: Nous anticipons que la sarcopénie soit répandue chez les patients cirrhotiques à l’étude. Sa présence pourrait être associée à une durée d’hospitalisation prolongée, à de fréquentes infections et à des réadmissions récurrentes. Discussion : Une prise en charge de la sarcopénie pourrait s’avérer primordiale si sa présence influence le pronostic des patients suite à la TH.
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.
Problématique: La sarcopénie (perte de masse et de fonction musculaires) affecte 30 à 70% des patients atteints de maladie hépatique chronique (cirrhose). Un Canadien sur 4 souffrirait de maladie hépatique. Chez les patients cirrhotiques, la présence de la sarcopénie avant et après la transplantation hépatique (TH) serait associée à un mauvais pronostic. Objectif : Le but général de cette étude rétrospective en cours est de déterminer, chez les patients cirrhotiques, la prévalence de la sarcopénie avant la TH ainsi que son impact sur le pronostic après la TH. Méthodologie : Notre étude vise l’inclusion de 100 patients cirrhotiques de diverses étiologies. L’évaluation de la masse musculaire avant la TH s’effectue en utilisant l’index musculaire squelettique lequel est basé sur l’analyse de l’examen radiologique de tomodensitométrie (CT-scan) au niveau de la 3e vertèbre lombaire. La durée de l’hospitalisation, la fréquence d’infections et le nombre de réadmissions durant la première année post-TH sont également recueillis par la consultation des dossiers médicaux. Résultats attendus: Nous anticipons que la sarcopénie soit répandue chez les patients cirrhotiques à l’étude. Sa présence pourrait être associée à une durée d’hospitalisation prolongée, à de fréquentes infections et à des réadmissions récurrentes. Discussion : Une prise en charge de la sarcopénie pourrait s’avérer primordiale si sa présence influence le pronostic des patients suite à la TH.
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.
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.
La perte de masse musculaire et la malnutrition sont les complications les plus fréquentes de la maladie hépatique chronique (cirrhose). L’encéphalopathie hépatique (EH; désordre neuropsychiatrique) est une autre complication sérieuse observée chez 80% des patients cirrhotiques, qui pourrait être une conséquence de la perte de masse musculaire. Les myokines, dont « Brain-derived neurotrophic factor » (BDNF), sont des cytokines libérées par le muscle lors de la contraction musculaire exerçant plusieurs fonctions physiologiques bénéfiques. Leurs sécrétions impliquent la production d’un co-activateur transcriptionnel, le « Peroxisome proliferator-activated receptor coactivator-1alpha » (PGC-1a). Notre travail s’est donc concentré sur l’étude de l’impact de l’exercice sur la voie de signalisation PGC-1a/BDNF dans la prévention de la perte de masse musculaire et l’EH chez le rat cirrhotique. Matériel et méthode : La cirrhose et l’EH ont été induites chez le rat 6 semaines après la ligature des voies biliaires (BDL). Quatre groupes expérimentaux ont été constitués : 1) Contrôles; 2) BDL; 3) Contrôles + Exercice 4) BDL+ Exercice. Les rats faisant partie du 3e et du 4e groupe sont soumis à un exercice de type aérobique. L’expression génique et protéique musculaire de PGC-1a et BDNF a été évaluée par immunobuvardage Western. Résultats et discussion :L’exercice augmente l’expression de BDNF mature chez les rats sains, ce qui prévient la fonte musculaire typique de la maladie hépatique et le développement de l’EH. Le rôle du PGC-1a reste à clarifier. Conclusion :Une meilleure compréhension de la voie PGC-1a-BDNF pourrait permettre de cibler le muscle comme thérapie effectrice dans le but d’améliorer le pronostic ainsi que la qualité de vie des patients cirrhotiques. Sincères remerciements à PREMIER-FPC-Département de nutrition et à la Fondation Canadienne du foie
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.
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.
Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher F. Rose, Chantal Bémeur.
Introduction: La malnutrition est un facteur pronostic important influençant l’issue clinique des patients souffrant de maladie hépatique chronique (MHC). La malnutrition accroît le risque de développer d'autres complications, incluant l'encéphalopathie hépatique (EH) et peut également affecter la qualité de vie (QV). Objectif: Comparer l’état nutritionnel des patients MHC aux sujets non-cirrhotiques (NC) et son impact sur l’EH et la QV. Méthodes: 33 patients MHC, étiologies et sévérité de maladie (Child-Pugh Score) diverses et 13 sujets NC ont été évalués pour: A) État nutritionnel (ESG); B) EH (CHESS); C) QV (SF-36). Résultats: Cette étude prospective en cours inclut 33 patients MHC (58% hommes) d’étiologies variées (%: 30 Alcool, 33 Virus, 27 NASH et 33 autres), Child-Pugh (13A, 9B, 5C et 6N/D), âgés de 55,7±12,9 ans et 13 sujets NC (46% hommes, 49,4±14,9 ans). L’ESG révèle que 27% des patients MHC souffrent de malnutrition et présentent un score moindre de fonctionnement physique (p = 0,03) et de santé générale (p=0,03), comparativement aux sujets NC. Aussi, les patients MHC malnutris présentent une diminution de la QV par rapport aux sujets MHC bien nourris (p<0,01). L'analyse de CHESS a révélé qu'aucun des patients MHC n'avaient d'EH alors que 21% d'entre eux avaient un diagnostic médical positif, ce qui suggère que le CHESS ne serait pas assez sensible pour dépister l'EH. Discussion : Ces résultats suggèrent que l'état nutritionnel influe sur la QV des sujets MHC sans égard à l’étiologie. D'autres patients sont nécessaires pour confirmer l'impact de l'état nutritionnel chez les patients MHC et ce, afin d’améliorer les soins et guider les recherches futures.
Cassandra Picinbono-Larose, Annie Lamoussenerie, Mélanie Tremblay, Catherine Vincent, Geneviève Huard, Christopher Rose, Chantal Bémeur.
Problématique : La malnutrition est un facteur pronostic important influençant l’issue clinique des patients souffrant de maladie hépatique chronique (MHC). La malnutrition accroît le risque de développer d'autres complications, incluant l'encéphalopathie hépatique (EH) et peut également affecter la qualité de vie (QV). Les stratégies thérapeutiques axées sur l'état nutritionnel en relation avec les complications de la cirrhose représentent un besoin clinique urgent. Objectif : Comparer l’état nutritionnel des patients MHC aux contrôles sains et son impact sur l’EH et la QV. Méthodologie : 33 patients MHC d’étiologies et de sévérité de maladie (Child-Pugh Score) diverses et 13 contrôles sains ont été évalués pour : A) État nutritionnel (ESG); B) EH (CHESS); C) QV (SF-36). Résultats : Cette étude prospective en cours inclut 33 patients MHC (58% hommes) d’étiologies variées (% : 30 Alcool, 33 Virus, 27 NASH et 33 autres), Child-Pugh (13A, 9B, 5C et 6N/D), âgés de 55,7±12,9 ans et 13 témoins sains (46% hommes, 49,4±14,9 ans). L’ESG révèle que 27% des sujets MHC souffrent de malnutrition et présentent un score moindre de fonctionnement physique (p = 0,03) et de santé générale (p=0,03), comparativement aux contrôles sains. Aussi, les patients MHC malnutris présentent une diminution de la QV par rapport aux patients MHC bien nourris (p<0,01). Discussion : Les résultats préliminaires suggèrent que l'état nutritionnel influe sur la QV des sujets MHC sans égard à l’étiologie. D'autres patients sont nécessaires pour confirmer l'impact de l'état nutritionnel chez les patients MHC, afin d’améliorer les soins et guider les recherches futures.
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.
Problématique : La malnutrition est un facteur pronostic important influençant l’issue clinique des patients souffrant de maladie hépatique chronique (MHC). La malnutrition accroît le risque de développer d'autres complications, incluant l'encéphalopathie hépatique (EH) et peut également affecter la qualité de vie (QV). Les stratégies thérapeutiques axées sur l'état nutritionnel en relation avec les complications de la cirrhose représentent un besoin clinique urgent. Objectif : Comparer l’état nutritionnel des patients MHC aux contrôles sains et son impact sur l’EH et la QV. Méthodologie : 33 patients MHC d’étiologies et de sévérité de maladie (Child-Pugh Score) diverses et 13 contrôles sains ont été évalués pour : A) État nutritionnel (ESG); B) EH (CHESS); C) QV (SF-36). Résultats : Cette étude prospective en cours inclut 33 patients MHC (58% hommes) d’étiologies variées (% : 30 Alcool, 33 Virus, 27 NASH et 33 autres), Child-Pugh (13A, 9B, 5C et 6N/D), âgés de 55,7±12,9 ans et 13 témoins sains (46% hommes, 49,4±14,9 ans). L’ESG révèle que 27% des sujets MHC souffrent de malnutrition et présentent un score moindre de fonctionnement physique (p = 0,03) et de santé générale (p=0,03), comparativement aux contrôles sains. Aussi, les patients MHC malnutris présentent une diminution de la QV par rapport aux patients MHC bien nourris (p<0,01). Discussion : Les résultats préliminaires suggèrent que l'état nutritionnel influe sur la QV des sujets MHC sans égard à l’étiologie. D'autres patients sont nécessaires pour confirmer l'impact de l'état nutritionnel chez les patients MHC, afin d’améliorer les soins et guider les recherches futures.
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.
Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham-operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss.
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.
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.
Background: Malnutrition is one of the most common complications in the increasing number of patients suffering from chronic liver disease (CLD) and is a leading cause of morbidity and mortality. Traditional tools used to evaluate nutritional status are not reliable in CLD due to limitations related to weight, which may be artificially increased by the presence of ascites, underestimating malnutrition. New strategies to assess nutritional status focusing on early malnutrition detection are an unmet clinical need. The aim of this pilot study is to describe the performance of different measures of nutrition including body mass index (BMI), handgrip strength (HGS), mid-arm muscle circumference (MAMC) in relation to subjective global assessment (SGA). Methods: In this ongoing prospective study, patients with and without CLD are recruited at Centre Hospitalier de l’Université de Montréal (St-Luc Hospital) in Canada. We assess nutritional status via: BMI, HGS as measured with a calibrated dynamometer, MAMC calculated with the mid-arm circumference and the tricipital skinfold and a modified version of the SGA for CLD patients, Spearman correlation coefficient is used to assess correlation between different tools. Results : We recruited 36 and 18 patients with and without CLD and 18 patients, respectively. Conclusions: Our preliminary results indicate that BMI and HGS, but not MAMC tend to decrease according to the nutritional status (no malnutrition, mild or moderate malnutrition) determined by SGA. Further patients are required to statistically identify a reliable tool and be able to evaluate nutritional status in cirrhosis as well as detect malnutrition in its early stage.
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.
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.
Évaluation de l'état nutritionnel lors de cirrhose.
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.
Le bilan hépatique : comment l'interpréter pour une intervention nutritionnelle optimale?
Geneviève Huard, Catherine Vincent, Chantal Bémeur.
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.
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.
Hepatic encephalopathy (HE) is a major complication of liver failure/disease which frequently develops during the progression of end-stage liver disease. This metabolic neuropsychiatric syndrome involves a spectrum of symptoms, including cognition impairment, attention deficits and motor dysfunction which eventually can progress to coma and death. Pathologically, HE is characterized by swelling of the astrocytes which consequently leads to brain edema, a common feature found in patients with acute liver failure (ALF) as well as in cirrhotic patients suffering from HE. The pathogenic factors involved in the onset of astrocyte swelling and brain edema in HE are unresolved. However, the role of astrocyte swelling/brain edema in the development of HE remains ambiguous and therefore measuring brain edema as an endpoint to evaluate HE is questioned. The following review will determine the effect of astrocyte swelling and brain edema on neurological function, discuss the various possible techniques to measure brain edema and lastly to propose a number of neurobehavioral tests to evaluate HE.
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.
Neuroinflammation et activation microgliale chez des rats cirrhotiques soumis à une hypotension.
Maxime Hovington, Marc-André Clément, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.
Introduction: L’encéphalopathie hépatique est une complication neuropsychiatrique causée par les maladies du foie. Ce syndrome devrait être réglé par la transplantation hépatique, mais d es complications neurologiques persistent chez près de 47% des p atients. La transplantation est accompagnée de stress intraopératoires dont l’hypovolémie et l’hypotension. Nous avons démontré qu’un cerveau fragilisé par l’encéphalopathie hépatique minimale (EHM) chez un rat cirrhotique devient plus susceptible à des dommages cérébraux causés par une hypotension, ce qui résulte en un stress cellulaire ainsi que la mort cellulaire neuronale. Ces signaux de stress cellulaire peuvent induire l’activation de la microglie, les cellules immunitaires du système nerveux central. Matériel et méthodes : Une hypotension par hypovolémie de l’artère fémorale a été effectuée pour atteindre une pression artérielle de 30 et 60 mmHg durant 2 heures chez des rats après 6 semaines suite à une cirrhose induite par ligation de la voie biliaire (BDL) et leu rs contrôles respectifs (SHAM). Nous avons évalué la présence de microglie activée dans le cortex frontal en immunobuvardage, avec CD11b, OX-42, CMH-II et COX-2 et en immunofluorescence, avec Iba-1. Résultats et discussion:Il n’y a pas d’activation microgliale chez les modèles SHAM et BDL dans le cortex préfrontal, mais l’insulte hypotensive induite chez le modèle cirrhotiqu e BDL, avec EHM , cause une activation de la microglie. Conclusion: L’activation microgliale chez les patients cirrhotiques soumis à une hypotension donne des outils supplémentaires dans la compréhension des processus pathophysiologiques délétères subséquents à une transplantation hépatique et permettra de suggérer des interventions cliniques afin de prévenir une aggravation des dommages cérébraux. Remerciements auCOPSE pour la bourse du Département de nutrition
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.
Problématique : L’acidose lactique est une maladie mitochondriale rare causée par la mutation du gène LRPPRC (leucine-rich pentatricopeptide repeat motif containing). Elle est caractérisée principalement par une déficience tissu-spécifique (cerveau et foie) en cytochrome c oxydase, 4e complexe de la chaîne respiratoire ainsi que par des crises fatales d'acidose lactique. Il a été rapporté que ces crises, qui entraînent la mort de 80% des enfants atteints avant l’âge de 4 ans, sont déclenchées, entre autres, par une infection/inflammation et une surcharge nutritionnelle. À ce jour, aucun traitement n’existe pour prévenir ces crises. Question de recherche/objectif/hypothèse : Vérifier si la mutation rend les fibroblastes plus susceptibles au stress inflammatoire et nutritionnel. Méthodologie : Évaluer la viabilité des fibroblastes de peau de sujets contrôles (EBS) et de patients (AL), par microscopie à fluorescence, sous stress inflammatoire (TNF-α;100 ng/ml) et nutritionnel (palmitate; 0,5 mM) pour 24h. Les marqueurs Hoechst, caspase-3 et iodure de propidium ont été utilisés pour détecter les cellules viables, apoptotiques et nécrotiques, respectivement. Résultats : Nos résultats préliminaires démontrent qu’en conditions de stress, les taux de mort cellulaire par apoptose et nécrose semblent plus élevés dans les fibroblastes AL que les EBS. Discussion/conclusion/impact potentiel pour la nutrition : La mutation semble rendre les fibroblastes de patients atteints d’acidose lactique plus susceptibles au stress inflammatoire et nutritionnel. À plus long terme, l’appréciation du bienfait potentiel des acides gras oméga 3 dans ce processus pourrait s’avérer intéressante. Financement du projet / étudiant: Le Grand défi Pierre Lavoie.
Rafaela Almeida, Mélanie Tremblay, Christopher Rose, Consortium de l'acidose lactique, Chantal Bémeur.
L’acidose lactique est une maladie mitochondriale rare causée par la mutation du gène LRPPRC (leucine-rich pentatricopeptide repeat motif containing). Elle est caractérisée principalement par une déficience tissu-spécifique (cerveau et foie) en cytochrome c oxydase, 4e complexe de la chaîne respiratoire ainsi que par des crises fatales d'acidose lactique. Il a été rapporté que ces crises, qui entraînent la mort de 80% des enfants atteints avant l’âge de 4 ans, sont déclenchées, entre autres, par une infection/inflammation et une surcharge nutritionnelle. À ce jour, aucun traitement n’existe pour prévenir ces crises. Dans ce contexte, nous étudions l'impact d'un stress inflammatoire et nutritionnel en utilisant des fibroblastes de peau de sujets contrôles (EBS) et de patients atteints d’acidose lactique (AL). L’objectif général du projet est de vérifier si la mutation du gène LRPPRC rend les fibroblastes plus susceptibles dans des conditions de stress inflammatoire et nutritionnel. À cet effet, la viabilité des fibroblastes est évaluée par microscopie à fluorescence dans les conditions de stress inflammatoire et nutritionnel telles que « tumor necrosis factor alpha » (TNF-α) à 100ng/ml et palmitate à 1mM, et ce, à différentes périodes d’incubation. Les marqueurs Hoechst, caspase-3 et iodure de propidium ont été utilisés pour détecter les cellules viables, apoptotiques et nécrotiques, respectivement. Nos résultats préliminaires démontrent qu’en conditions de stress, les taux de mort cellulaire par apoptose et nécrose semblent plus élevés dans les fibroblastes AL que les EBS. La mutation semble rendre les fibroblastes de patients atteints d’acidose lactique plus susceptibles au stress inflammatoire et nutritionnel. À plus long terme, l’appréciation du bienfait potentiel des acides gras oméga 3 dans ce processus pourrait s’avérer intéressante.
Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.
Introduction L’encéphalopathie hépatique (EH) est une complication neuropsychiatrique causée par les maladies du foie. Ce syndrome est considéré comme un désordre métabolique réversible, qui devrait être réglé par la transplantation hépatique (TH), cependant les complications neurologiques persistent chez près de 47% des patients. La TH est une procédure accompagnée de stress intra-opératoires dont l’hypovolémie et l’hypotension. Nous supposons que le cerveau fragilisé devient plus susceptible à une hypotension, résultant en un stress ainsi que la mort cellulaire. Méthodologies Une hypotension par hypovolémie de l’artère fémorale est effectuée pour atteindre une pression artérielle de 30mmHg durant 2 heures chez des rats de 6 semaines avec ligation de la voie biliaire (BDL) et leurs contrôles respectifs (SHAM). Les cerveaux sont prélevés pour immunobuvardage et immunohistochimie. Résultats Les rats BDL avec hypotension ont démontré une diminution du compte neuronal dans le cortex préfrontal en utilisant NeuN+DAPI et le Crésyl violet, comparativement aux contrôles SHAM hypotendus. De plus, la protéine de stress cellulaire HSP32 est augmentée chez les groupes BDL hypotendus, tout comme la caspase-3 clivée, suggérant une mort cellulaire par apoptose. Les groupes contrôles sans hypotension ne démontrent aucune perte neuronale avec les marqueurs précédents. Discussion Ces résultats démontrent que les patients atteints d’EH sont plus susceptibles à une insulte hypotensive induisant une mort neuronale, et peuvent expliquer pourquoi certains patients ayant reçu une TH expérimentent des complications neurologiques.
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.
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.
Problématique : L’acidose lactique est une maladie mitochondriale rare causée par la mutation du gène LRPPRC (leucine-rich pentatricopeptide repeat motif containing). Elle est caractérisée principalement par une déficience tissu-spécifique (cerveau et foie) en cytochrome c oxydase, 4e complexe de la chaîne respiratoire ainsi que par des crises fatales d'acidose lactique. Il a été rapporté que ces crises, qui entraînent la mort de 80% des enfants atteints avant l’âge de 4 ans, sont déclenchées, entre autres, par une infection/inflammation et une surcharge nutritionnelle. À ce jour, aucun traitement n’existe pour prévenir ces crises. Question de recherche/objectif/hypothèse : Vérifier si la mutation rend les fibroblastes plus susceptibles au stress inflammatoire et nutritionnel. Méthodologie : Évaluer la viabilité des fibroblastes de peau de sujets contrôles (EBS) et de patients (AL), par microscopie à fluorescence, sous stress inflammatoire (TNF-α;100 ng/ml) et nutritionnel (palmitate; 0,5 mM) pour 24h. Les marqueurs Hoechst, caspase-3 et iodure de propidium ont été utilisés pour détecter les cellules viables, apoptotiques et nécrotiques, respectivement. Résultats : Nos résultats préliminaires démontrent qu’en conditions de stress, les taux de mort cellulaire par apoptose et nécrose semblent plus élevés dans les fibroblastes AL que les EBS. Discussion/conclusion/impact potentiel pour la nutrition : La mutation semble rendre les fibroblastes de patients atteints d’acidose lactique plus susceptibles au stress inflammatoire et nutritionnel. À plus long terme, l’appréciation du bienfait potentiel des acides gras oméga 3 dans ce processus pourrait s’avérer intéressante. Financement du projet / étudiant: Le Grand défi Pierre Lavoie.
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.
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.
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.
Marc-André Clément, Cristina R. Bosoi, Mélanie Tremblay, Chantal Bémeur, Christopher F. Rose.
Introduction L’encéphalopathie hépatique (EH) est une complication neuropsychiatrique causée par les maladies du foie. Ce syndrome est considéré comme un désordre métabolique réversible, qui devrait être réglé par la transplantation hépatique (TH), cependant les complications neurologiques persistent chez près de 47% des patients. La TH est une procédure accompagnée de stress intra-opératoires dont l’hypovolémie et l’hypotension. Nous supposons que le cerveau fragilisé devient plus susceptible à une hypotension, résultant en un stress ainsi que la mort cellulaire. Méthodologies Une hypotension par hypovolémie de l’artère fémorale est effectuée pour atteindre une pression artérielle de 30 mmHg durant 2 heures chez des rats de 6 semaines avec ligation de la voie biliaire (BDL) et leurs contrôles respectifs (SHAM). Les cerveaux sont prélevés pour immunobuvardage et immunohistochimie. Résultats Les rats BDL avec hypotension ont démontré une diminution du compte neuronal dans le cortex préfrontal en utilisant NeuN+DAPI et le Crésyl violet, comparativement aux contrôles SHAM hypotendus. De plus, la protéine de stress cellulaire HSP32 était augmentée chez les groupes BDL hypotendus, tout comme la caspase-3 clivée, suggérant une mort cellulaire par apoptose. Les groupes contrôles SHAM et BDL sans hypotension ne démontrent aucune perte neuronale avec les marqueurs précédents.
Rafaela Almeida, Mélanie Tremblay, Christopher F. Rose, Chantal Bémeur, Consortium de l'acidose lactique.
Introduction: Le Syndrome de Leigh version canadienne française (LSFC) ou «acidose lactique» est une maladie mitochondriale rare causée par la mutation du gène LRPPRC (leucine-rich pentatricopeptide repeat motif containing). Elle est caractérisée principalement par une déficience tissu-spécifique (cerveau et foie) en cytochrome c oxydase de la chaîne respiratoire ainsi que par des crises fatales d'acidose lactique. Celles-ci sont déclenchées, entre autres, par l'infection/inflammation et la surcharge nutritionnelle. À ce jour, aucun traitement n'existe pour les prévenir et l'identification d'un modèle expérimental de stress inflammatoire et nutritionnel est essentiel afin d'élucider les mécanismes par lesquels la mutation affecte les cellules LSFC. Méthodes: Nous avons évalué la viabilité des fibroblastes de peau de sujets contrôles et de patients atteints d'acidose lactique par Resazurin dans différentes conditions de stress inflammatoire et nutritionnel, telles que LPS (2 μg/ml), TNF-α (100 ng/ml) et palmitate (1 mM), et ce, à différentes périodes d'incubation (0, 24, 48 et 72h). Résultats: Une diminution significative (p<0,001) de la viabilité cellulaire a été observée 48h après l'exposition de palmitate ou en combinaison avec TNF-α. De plus, une tendance à une susceptibilité accrue au stress est notée dans les fibroblastes de patients LSFC. Discussion/Conclusion: Le stress inflammatoire et nutritionnel semble influencer la viabilité des fibroblastes de patients LSFC. À plus long terme, la modulation de la réponse cellulaire par des agents «thérapeutiques» incluant les acides gras oméga 3, pourrait s'avérer intéressante.
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.
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.
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.
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.
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.
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.
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.
Chantal Bémeur, Cristina Bosoi, Mélanie Tremblay, Christopher F. Rose.
Background: Malnutrition is an important prognostic factor which can influence clinical outcome of patients suffering from chronic liver disease (CLD). Believed to cause hypermetabolism, malnutrition exacerbates hepatic encephalopathy and sarcopenia in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD complications are an unmet clinical need. We hypothesize supplementation with branched-chain amino acid isoleucine (ILE) and exercise (EX) could possibly attenuate muscle mass loss and prevent brain edema 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 post BDL, BDL + EX 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 + EX + ILE demonstrated a significant gain in body weight (BDL + ILE + EX: 112.3 g vs BDL: 33.7 g; p < 0.05), an increase in muscle mass (weight/body weight ratio) (BDL + ILE + EX: 0.0056 vs BDL: 0.0047; p < 0.05) and attenuated hypermetabolic status. Brain water content was decreased in BDL + ILE + EX rats compared to BDL animals. Conclusion: Our results demonstrate that EX and supplemental ILE improve body weight, muscle mass, metabolic activity and attenuate cerebral edema. These findings suggest that strategies aiming at muscle mass optimization and improving nutritional status attenuate complications and therefore improve outcome in patients with CLD. EX and ILE supplementation could rapidly be translated into clinical practice.
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.
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.
Piero Amodio, Chantal Bémeur, Roger Butterworth, Juan Cordoba, Akinobu Kato, Sara Montagnese, Misael Uribe, Hendrik Vilstrup, Marsha Y. Morgan.
Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex-related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35-45 kcal/g and 1.2-1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short-term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE.
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
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.
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.
Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy.
Chantal Bémeur, Paul Desjardins, Roger F. Butterworth.
Hepatic encephalopathy (HE) is a serious complication of liver failure. HE manifests as a series of neuropsychiatric and neuromuscular symptoms including personality changes, sleep abnormalities, asterixis and muscle rigidity progressing through stupor to coma. The pathophysiologic basis of HE remains unclear. There is general agreement that ammonia plays a key role. In recent years, it has been suggested that oxidative/nitrosative stress constitutes part of the pathophysiologic cascade in HE. Direct evidence for oxidative/nitrosative stress in the pathogenesis of HE has been demonstrated in experimental animal models of acute or chronic liver failure. However, evidence from studies in HE patients is limited. This review summarizes this evidence for a role of oxidative/nitrosative stress in relation to ammonia toxicity and to the pathogenesis of HE.
Javier Vaquero, Chantal Bémeur, Paul Desjardins, Roger F. Butterworth.
Previous studies have demonstrated protective effects of mild hypothermia following acetaminophen (APAP)-induced acute liver failure (ALF). However, effects of this treatment in ALF due to other toxins have not yet been fully investigated. In the present study, the effects of mild hypothermia in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines were assessed in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stages of encephalopathy in parallel with AOM mice maintained mildly hypothermic (35 degrees C). AOM treatment led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels, and brain GSH/GSSG ratios as well as selective increases in expression of plasma proinflammatory cytokines. Mild hypothermia resulted in reduced hepatic damage, improvement in neurological function, normalization of glutathione levels, and selective attenuation in expression of circulating proinflammatory cytokines. These findings demonstrate that the beneficial effects of mild hypothermia in experimental AOM-induced ALF involve both antioxidant and anti-inflammatory mechanisms.
Chantal Bémeur, Javier Vaquero, Paul Desjardins, Roger F. Butterworth.
N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2 g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.
Chantal Bémeur, Hong Qu, Paul Desjardins, Roger F. Butterworth.
Previous reports suggested that brain-derived proinflammatory cytokines are involved in the pathogenesis of hepatic encephalopathy (HE) and brain edema in acute liver failure (ALF). To further address this issue, expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were measured in the brains of mice with acute liver failure resulting from exposure to azoxymethane. In addition, time to severe encephalopathy (coma) was assessed in mice lacking genes coding for interferon-gamma, the tumor necrosis factor receptor-1 or the interleukin-1 type 1 receptor. Interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma expression were quantified using RT-PCR. Significant increases in interleukin-1beta and tumor necrosis factor-alpha mRNA were observed in the frontal cortex of azoxymethane-treated wild-type mice at coma stages of encephalopathy. Interferon-gamma, however, could not be detected in the brains of these animals. Onset of severe encephalopathy (coma) and brain edema in ALF mice were significantly delayed in interleukin-1 type 1 receptor or tumor necrosis factor receptor-1 knockout mice. Deletion of the interferon-gamma gene, on the other hand, had no significative effect on the neurological status or brain water content of acute liver failure mice. These results demonstrate that toxic liver injury resulting from exposure to azoxymethane is associated with selective induction of proinflammatory cytokines in the brain and that deletion of tumor necrosis factor receptor-1 or interlukin-1 type 1 receptor delays the onset of coma and brain edema in this model of acute liver failure. These findings further support a role for selective brain-derived cytokines in the pathogenesis of the cerebral complications in acute liver failure and suggest that anti-inflammatory strategies could be beneficial in their prevention.
Increased oxidative stress during hyperglycemic cerebral ischemia.
Chantal Bémeur, Line Ste-Marie, Jane Montgomery.
In this review, we summarize the role of hyperglycemia during cerebral ischemia. Hyperglycemia occurring during experimental and clinical stroke has been associated with increased cerebral damage. Increased oxidative stress resulting from hyperglycemia is believed to contribute to the exacerbated damage. More specifically, superoxide, nitric oxide and peroxynitrite are believed to play an important role in cerebral damage. This also involves increased recruitment of various blood cells to the ischemic zone that contribute to inflammation. We present data from our group and others that demonstrate that free radical production is increased during hyperglycemic stroke in rodents. Recent data suggest that inflammation is an important component of ischemic damage under both normo- and hyperglycemic conditions. We summarize numerous studies that indicate that a variety of antioxidant (inhibition of free radical production, scavenging of free radicals and increasing free radical degradation) and anti-inflammatory strategies decrease cerebral infarction. Finally, we compare the success of some of these strategies in clinical trials compared to the animal models.
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.
Hyperglycemia worsens outcome of stroke either in the clinical setting or in animal models. In the present study, two focal cerebral ischemia models, permanent middle cerebral artery occlusion (MCAO, 3-4 h) and reversible MCAO (1 h ischemia + 3 h reperfusion), under hyperglycemic conditions were compared. Using 2,3,5-triphenyltetrazolium chloride staining to define viable tissue, this resulted in the infarction area being confined primarily to the cerebral cortex in the permanent MCAO group, while it extended to the subcortical area in the reversible MCAO group, and the lesion areas were respectively 27.7 +/- 5.3% and 46.8 +/- 12.0% of the ipsilateral hemisphere (P = 0.012). Hyperglycemia accelerated the cerebral damage compared to normoglycemia and ascorbic acid pre-treatment maintained tissue viability during the acute phase of hyperglycemic MCAO. In conclusion, hyperglycemia combined with either of the two MCAO models resulted in rapid infarction associated with increased oxidative stress. The hyperglycemic models are suitable for pharmaceutical therapeutic studies of antioxidant efficacy.
Chantal Bémeur, Line Ste-Marie, Paul Desjardins, Luc Vachon, Roger F. Butterworth, Alan S. Hazell, Jane Montgomery.
We investigated the effect of dehydroascorbic acid (DHA), the oxidized form of vitamin C which is a superoxide scavenger, on manganese superoxide dismutase (MnSOD), copper-zinc SOD (CuZnSOD), cyclooxygenase-2 (COX-2) and interleukin-1beta (IL-1beta) expression in a rat model of focal cerebral ischemia under normo- and hyperglycemic conditions. Edema formation was also assessed. MnSOD, CuZnSOD, COX-2 and IL-1beta mRNA and protein expression were studied 3 h post-ischemia. No changes were observed in MnSOD and CuZnSOD mRNA expression among the groups. COX-2 and IL-1beta mRNA expression were upregulated by ischemia but were not influenced by the glycemic state. At the protein level, hyperglycemic cerebral ischemia increased MnSOD and CuZnSOD [Bémeur, C., Ste-Marie, L., Desjardins, P., Butterworth, R.F., Vachon, L., Montgomery, J., Hazell, A.S., 2004a. Expression of superoxide dismutase in hyperglycemic focal cerebral ischemia in the rat. Neurochem. Int. 45, 1167-1174] and IL-1beta expression compared to normoglycemic ischemia. COX-2 protein expression was also significantly higher following hyperglycemic ischemia compared to hyperglycemic shams. DHA administration did not change the pattern of COX-2 or IL-1beta mRNA expression, but normalized the increased protein expression following hyperglycemic ischemia. DHA administration also normalized MnSOD and CuZnSOD protein expression to the levels observed in normoglycemic ischemic animals. Edema formation was significantly reduced by DHA administration in hyperglycemic ischemic animals. The DHA-induced post-transcriptional normalization of MnSOD, CuZnSOD, COX-2 and IL-1beta levels and the decreased edema formation suggest that hyperglycemia accelerates superoxide formation and the inflammatory response, thus contributing to early damage in hyperglycemic stroke and strategies to scavenge superoxide should be an important therapeutic avenue.
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.
This study investigated the possibility that hyperglycemia induces early expression of various superoxide dismutases (SOD) and nitric oxide synthases (NOS) following focal cerebral ischemia in the rat. MnSOD, CuZnSOD, nNOS and eNOS mRNA and protein expression were examined 3 h after permanent middle cerebral artery occlusion under acute hyperglycemic or normoglycemic conditions. 2,3,5-triphenyltetrazolium chloride (TTC) treatment post-mortem revealed a significant area at risk of infarction following ischemia in hyperglycemic compared to normoglycemic rats. Although no changes in MnSOD, CuZnSOD, nNOS and eNOS mRNA expression were detected, Western blots of ischemic cortex revealed an increase in MnSOD and CuZnSOD protein expression in hyperglycemic compared to normoglycemic rats. Pre-treatment of hyperglycemic rats with the NOS inhibitors L-nitroarginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) or dehydroascorbic acid (DHA), a superoxide scavenger, significantly reduced the TTC delineated zone. The hyperglycemia-induced post-transcriptional upregulation of MnSOD and CuZnSOD levels suggest a response to increased superoxide production which, in the presence of increased nitric oxide production, may play a major role in the increased risk of damage following hyperglycemic stroke.
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.
beta-Actin is often used as a housekeeping gene when performing reverse transcription-polymerase chain reaction (RT-PCR) analysis for cerebral ischemia models. In the present study, we tested two different control genes used for RT-PCR experiments, beta-actin and porphobilinogen deaminase (PBG-D), in a rat model of focal cerebral ischemia under normo- or hyperglycemic conditions. A three-vessel occlusion model with permanent middle cerebral artery occlusion was used in the rat. beta-Actin mRNA expression was decreased in hyperglycemic ischemic rats compared to normoglycemic ischemic animals 3 h post-ischemia. beta-Actin protein content was unchanged. As for PBG-D, its mRNA expression remained constant throughout the groups. Our data thus show that, following focal cerebral ischemia in hyperglycemic conditions, beta-actin is an unsuitable housekeeping gene whereas PBG-D is more appropriate. This study clearly demonstrates the importance of selecting a stable housekeeping gene when performing RT-PCR experiments.
Line Ste-Marie, Alan S. Hazell, Chantal Bémeur, Roger Butterworth, Jane Montgomery.
We have characterized the temporal changes in iNOS, MnSOD and nitrotyrosine immune reactivity in a rat model of permanent middle cerebral artery occlusion under acute hyperglycemic or normoglycemic conditions followed by either 3- or 24-h recovery. We found that the macroscopic labeling pattern for all three antibodies colocalized with the ischemic core and penumbra which was determined by cresyl violet histological evaluation in adjacent sections. Hyperglycemia induced prior to ischemia resulted in earlier infarction which correlated with increased immunoreactivity for iNOS, MnSOD and nitrotyrosine. In the penumbral region of the frontal cortex, labeling of specific cell structures was largely limited to cortical neurons near the corpus callosum and was apparent earlier in the hyperglycemic rats. Increased polymorphonuclear leukocyte adhesion in blood vessels was observed at 24 h in the hyperglycemic group. At both of the recovery times studied, we observed only minor vascular staining for nitrotyrosine and none for iNOS. Our results are consistent with hyperglycemia resulting in an early and concomitant increase in both superoxide and nitric oxide production which can lead to peroxynitrite formation that then nitrates tyrosine residues. It would appear that hyperglycemic ischemia contributes to the early induction of key enzymes involved in nitric oxide bioavailability.
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.
Line Ste-Marie, Luc Vachon, Chantal Bémeur, Jean Lambert, Jane Montgomery.
In vivo bilateral microdialysis in the rat striatum was used to investigate hydroxyl radical formation under basal conditions and after intrastriatal administration of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). After a short equilibration period, 4-hydroxybenzoate (4HBZ), which scavenges hydroxyl radicals to produce 3,4-dihydroxybenzoate (34DHB), was injected intraperitoneally 15 min before infusion of MPP+. To evaluate the enzymatic contribution to hydroxyl radical formation, two other series of microdialyses were performed following administration of monoamine oxidase B inhibitors, either 1-deprenyl (selegiline) or MDL 72,974A [(E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride]. Microdialysate samples were analyzed by high-performance liquid chromatography for catecholamines, 3,4-dihydroxyphenylacetate (DOPAC), homovanillate (HVA), along with the hydroxyl radical adduct, 34DHB and its precursor, 4HBZ. MPP+ administration resulted in a massive release of dopamine along with a decrease in DOPAC and HVA in all three groups. A striking effect in all three groups was noted in which MPP+ resulted in a decrease in interstitial 4HBZ to < 50% of the non-MPP+ -treated side. In absolute terms, the amount of 34DHB produced was low but similar in all three groups, even after unilateral MPP+ infusion. When 34DHB was normalized to 4HBZ release to account for differences in precursor availability, there were no significant differences in the 34DHB/4HBZ ratios either with or without MAO inhibitor treatment or after local MPP+ infusion. Systemic 4HBZ administration appears to result predominantly in intra-cellular sampling of hydroxyl radicals which produces different results from local infusion of trapping agents such as salicylate.
The Nutrition in Cirrhosis Guide.
Puneeta Tandon, Vanessa DenHeyer, Kathleen P Ismond, Jan Kowalczewski, Maitreyi Raman, Tannaz Eslamparast, Chantal Bémeur, Christopher Rose.
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.
Éditorial: Les maladies rares, non moins importantes.
Chantal Bémeur, Marie-Eve Lavoie.
Modern nutrition in health and disease.
Chantal Bémeur, Roger F. Butterworth.
Nutrition in the management of cirrhosis and its neurological complications.
Chantal Bémeur, Roger F. Butterworth.
Malnutrition is a common feature of chronic liver diseases that is often associated with a poor prognosis including worsening of clinical outcome, neuropsychiatric complications as well as outcome following liver transplantation. Nutritional assessment in patients with cirrhosis is challenging owing to confounding factors related to liver failure. The objectives of nutritional intervention in cirrhotic patients are the support of liver regeneration, the prevention or correction of specific nutritional deficiencies and the prevention and/or treatment of the complications of liver disease per se and of liver transplantation. Nutritional recommendations target the optimal supply of adequate substrates related to requirements linked to energy, protein, carbohydrates, lipids, vitamins and minerals. Some issues relating to malnutrition in chronic liver disease remain to be addressed including the development of an appropriate well-validated nutritional assessment tool, the identification of mechanistic targets or therapy for sarcopenia, the development of nutritional recommendations for obese cirrhotic patients and liver-transplant recipients and the elucidation of the roles of vitamin A hepatotoxicity, as well as the impact of deficiencies in riboflavin and zinc on clinical outcomes. Early identification and treatment of malnutrition in chronic liver disease has the potential to lead to better disease outcome as well as prevention of the complications of chronic liver disease and improved transplant outcomes.
Neurological complications post-liver transplantation: impact of nutritional status.
Nutritional status is significantly altered in patients with end-stage liver disease (cirrhosis). Malnutrition is a common complication of cirrhosis and is known to be associated with a greater risk of post-operative complications and mortality, especially following liver transplantation. Neurological complications occur frequently after transplant and the nature and extent of these complications may relate to nutritional deficits such as protein-calorie malnutrition as well as vitamin and micronutrient deficiencies. A consensus document from the International Society on Hepatic Encephalopathy and Nitrogen metabolism (ISHEN) has been established in order to address these concerns. Careful assessment of nutritional status followed by prompt treatment of nutritional deficits has the potential to impact on transplant outcome and, in particular, on post-transplant neurological disorders in patients with cirrhosis.
Chantal Bémeur, Roger F. Butterworth.
A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood-brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.
Neurochemical Mechanisms in Disease. Advances in Neurobiology.
Chantal Bémeur, Jane A. Montgomery, Roger F. Butterworth.
Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.
Chantal Bémeur, Paul Desjardins, Roger F. Butterworth.
Malnutrition is common in patients with end-stage liver failure and hepatic encephalopathy, and is considered a significant prognostic factor affecting quality of life, outcome, and survival. The liver plays a crucial role in the regulation of nutrition by trafficking the metabolism of nutrients, their distribution and appropriate use by the body. Nutritional consequences with the potential to cause nervous system dysfunction occur in liver failure, and many factors contribute to malnutrition in hepatic failure. Among them are inadequate dietary intake, malabsorption, increased protein losses, hypermetabolism, insulin resistance, gastrointestinal bleeding, ascites, inflammation/infection, and hyponatremia. Patients at risk of malnutrition are relatively difficult to identify since liver disease may interfere with biomarkers of malnutrition. The supplementation of the diet with amino acids, antioxidants, vitamins as well as probiotics in addition to meeting energy and protein requirements may improve nutritional status, liver function, and hepatic encephalopathy in patients with end-stage liver failure.
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