Two posters and an oral presentation will be offered by our team during AASLD.
American Association for the Study of Liver Diseases' congress is beginning today at Boston, USA (November 6th-11th). Two posters will be presented and an oral presentation will be given by Dr 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.
Background: Brain edema is a serious complication associated with hepatic encephalopathy (HE) due to chronic liver disease (CLD). An increase in blood brain barrier (BBB) ion permeability can occur across an intact BBB through alterations in transport mechanisms. NH4+ has very similar ionic properties to K+ and can be transported through K+ channels and cotransporters, implying that hyperammonemia could result in BBB hyperpermeability. An increase in BBB permeability via transport Na+-K+-2Cl- (NKCC1) has shown to promote brain edema and astrocyte swelling under pathophysiological conditions such as ischemia. Aim: To study the BBB integrity (vasogenic vs cytotoxic) and the role of NKCC1 in the pathogenesis of brain edema in cirrhotic rats. Methods: Two distinct animal models of HE are used in the present study; 1) biliary cirrhosis model (6 weeks bile duct ligation (BDL)). 2) portacaval shunt model (4 weeks portacaval anastomosis (PCA)). Both models develop hyperammonemia however brain edema is only observed in BDL. BBB breakdown was assessed by measuring brain extravasation of Evans blue and sodium fluorescein (injected i.v). Expression of BBB tight junction proteins (occludin, claudin-5, ZO-1 and ZO-2) were assessed by Western blot. Bumetanide was administered (i.p) for 10 days in BDL and SHAM animals. Brain water content was measured in the frontal cortex using the specific gravimetric method. Levels of brain NKCC1 mRNA were evaluated by RT-PCR in cerebral microvessels. Results: Extravasation of Evans blue and sodium fluorescein was not detected and no significant change in all tight junction protein was observed in both BDL and PCA models. Brain water content was reduced in bumetanide-treated BDL rats compared to control (77.66±0.15% vs 78.12±0.21%). In brain microvessels, NKCC mRNA increased in BDL rats compared to BDL SHAM (0.78±0.09 vs. 1.92±0.42) whereas no change was found in PCA compared to PCA SHAM (1.72±0.52 vs. 1.53±0.23). Conclusions: BDL rats did not demonstrate a change in BBB integrity or expression of tight junction proteins concluding brain edema in BDL is not of vasogenic origin. Furthermore, since brain edema was only observed in BDL rats (vs PCA), this implies additional factors aside ammonia, are involved in the pathogenesis of brain edema. Moreover, an increase of NKCC1 mRNA and an attenuation of brain edema following bumetanide treatment were demonstrated in BDL rats suggesting NKCC1 plays a role in the development of brain edema in CLD. These results demonstrate the potential therapeutic use of bumetanide for the treatment of HE.
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 “myosteatosis”. 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 (Figure 1 & 2). 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 5 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 1.04-2.40, P=0.03), and myosteatosis (OR 1.97, 95% CI 1.32-2.99, P=0.001) were significantly associated with hepatic encephalopathy. Conclusions: Cir-rhotic 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.