Abstracts accepted at CASL 2015

Accepted abstract

Dr Rose and Marc-André Clément will attend Canadian Association for Study of Liver meeting, in Banff (Alberta, Canada), hold from February 26th to March 2nd 2015.

They will present 2 abstracts of our most recent results at Banff, Alberta, during CASL congress.

Related Publications

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

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

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 Methods: Using 6-week bile-duct ligated rats and respective controls, blood is withdrawn from the femoral artery (inducing hypovolemia) until an arterial pressure of 30 mmHg (hypotension) and maintained for 150 minutes.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

Sarcopenia and Myosteatosis Increase the Risk of Hepatic Encephalopathy in Cirrhotic Patients.

Aldo J. Montano-Loza, Andres Duarte-Rojo, Christopher F. Rose.

Background: Sarcopenia is one of the most common complications of cirrhosis and it is associated with increased mortality. Muscle depletion is generally characterized by both a reduction in muscle size and increased proportion of inter- and intra-muscular fat denominated ldquomyosteatosisrdquo. Skeletal muscle may serve as an alternative site of ammonia detoxification in patients with cirrhosis. Aims: In this study we aimed to investigate if sarcopenia and myosteatosis are associated with overt hepatic encephalopathy in patients with cirrhosis. Methods: A total of 678 cirrhotic patients undergoing assessment for liver transplantation were studied. Sarcopenia and myosteatosis (characterized as low muscle attenuation) were analyzed using computed tomography (CT) scans at the level of the 3rd lumbar vertebral body. The area of paraspinal skeletal muscle (L3 SMI) at this location, and the muscle attenuation index were calculated. Hepatic encephalopathy was assessed clinically by applying the West-Heaven criteria (grade 0-IV). Results: Of the 678 patients, 457 patients were males (67%). Cirrhosis was caused by HCV in 256 patients (38%), alcohol in 152 (22%), NASH/cryptogenic in 171 (25%), autoimmune liver disease in 53 (8%), HBV in 41 (6%), other etiology in five patients (1%); and 292 patients had concomitant HCC (43%). Sarcopenia was noted in 291 patients (43%), and 353 patients had myosteatosis (52%). A total of 216 patients (32%) had history of hepatic encephalopathy (162 grade I-II, 54 grade III-IV). The prevalence of hepatic encephalopathy was significantly higher in patients with sarcopenia (40 vs. 26%, P<0.001), and myosteatosis (39 vs. 24%). By multivariate regression analysis (adjusted to age, gender, and MELD score), both sarcopenia (OR 1.68 [95% CI 1.04 to 2.40]; P=0.03), and myosteatosis (OR 1.97 [95% CI 1.32 to 2.99]; P=0.001) were significantly associated with hepatic encephalopathy. Conclusions: Cirrhotic patients with sarcopenia and myosteatosis have a higher risk of overt hepatic encephalopathy. Skeletal muscle seems to play a protective role in the pathogenesis of hepatic encephalopathy in cirrhosis, and therapeutic strategies to improve the muscle mass and quality may improve hepatic encephalopathy in cirrhosis. Funding Agency: American College of Gastroenterology.

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.