Targeting the muscle for the treatment and prevention of hepatic encephalopathy

Muscle mass loss or sarcopenia is a principle component of malnutrition which prevails in 65–90% of patients with end-stage liver disease [1]. Intuitively, the roots of malnutrition play a precipitating role in muscle catabolism. Undernutrition frequently occurs in cirrhosis since an inadequate diet is compounded by a hypermetabolic energy demand. However, multiple other factors contribute to the pathogenesis of malnutrition including malabsorption of nutrients, metabolic alterations, increased intestinal protein losses, reduced protein synthesis, increased protein catabolism and disturbance of substrate utilization [2,3]

Nutritional strategies to manage malnutrition and sarcopenia following liver transplantation : a narrative review

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

Role of Nutrition in the Management of Hepatic Encephalopathy in End-Stage Liver Failure

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

Brain edema : a valid endpoint for measuring hepatic encephalopathy?

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

Agirs révolutionnaires et décroissance conviviale : recherche sur la notion de « décolonisation de l’imaginaire »

Une des difficultés de mettre sur pied des organisations sociales innovantes et radicalement différentes de la nôtre est de penser un agir révolutionnaire qui ne soit plus une reproduction de nos formes de vie. En étant contraint à ne pouvoir penser qu’à partir de notre imaginaire et de notre paradigme, nous sommes la plupart du temps prisonniers de ce que nous voulons dépasser. La notion de décolonisation de l’imaginaire, souvent mobilisée au sein de la décroissance, offre des outils pour réfléchir à des formes d’agirs émancipateurs. La recherche que j’ai menée suggère que si l’on veut tendre vers des sociétés post-croissance il est important de libérer notre imaginaire. Un imaginaire libéré, c.-à-d. autonome et créatif, permet de confronter l’ordre établi et son perpétuel présent comme seule forme d’existence possible et de miser sur l’ingéniosité pour affronter l’inconnu d’un futur à bâtir. Quatre guides pour l’agir révolutionnaire sont mis de l’avant : l’auto-transformation de nos milieux de vie favorisant l’autonomie, une lutte plurielle et située ancrée dans les territoires, l’utopie concrète comme méthode d’exploration de nouveaux possibles et le maintien des tensions créatrices au sein de notre société

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

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

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

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. METHODS: This retrospective study included 79 cirrhotic patients who underwent LT. Muscle mass was evaluated using the third lumbar spine vertebra skeletal muscle mass index (SMI) and sarcopenia was defined using established cut-off values. Computerized tomography (CT) scans performed within 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. RESULTS: 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 vs 29±10 days, p = 0.002), higher number of infection (3±1 vs 1±2, p = 0.027), and greater number of complications (5±2 vs 3±2, p <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: β = 0.33; 95% CI = 0.04–0.17; p = 0.003; Model 2, Creatinine: β = –0.29; 95% CI = –0.10 to –0.02; p = 0.009). CONCLUSIONS: The present study highlights the potential role of renal dysfunction in the development and persistence of sarcopenia after LT

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

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