Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Hypovitaminosis D is common in obesity and insulin-resistant states. Increased fat mass in patients with non-alcoholic fatty liver disease (NAFLD) may contribute to hypovitaminosis D. To determine the relation among plasma vitamin D concentration, severity of disease and body composition in NAFLD. METHODS: Plasma vitamin D concentration was quantified in 148 consecutive biopsy-proven patients with NAFLD (non-alcoholic steatohepatitis - NASH: n = 81; and hepatic steatosis: n = 67) and healthy controls (n = 39). NAFLD was scored using the NASH CRN criteria. Body composition was quantified by bioelectrical impedance analysis and abdominal CT image analysis. RESULTS: Plasma vitamin D concentration was significantly lower in NAFLD (21.2 ± 10.4 ng/ml) compared with healthy controls (35.7 ± 6.0 ng/ml). Higher NAFLD activity scores were associated with lower plasma concentration of vitamin D (r(2)  = 0.29; P < 0.001). Subgroup analysis among patients with NAFLD showed that patients with NASH had significantly lower (P < 0.01) vitamin D levels than those with steatosis alone (18.1 ± 8.4 vs. 25.0 ± 11.3 ng/ml). Low concentrations of vitamin D were associated with greater severity of steatosis, hepatocyte ballooning and fibrosis (P < 0.05).On multivariate regression analysis, only severity of hepatocyte ballooning was independently associated (P = 0.02) with low vitamin D concentrations. Plasma vitamin D (P = 0.004) and insulin concentrations (P = 0.03) were independent predictors of the NAFLD activity score on biopsy. Patients with NAFLD had higher fat mass that correlated with low vitamin D (r(2)  = 0.26; P = 0.008). CONCLUSIONS: Low plasma vitamin D concentration is an independent predictor of the severity of NAFLD. Further prospective studies demonstrating the impact of vitamin D replacement in NAFLD patients are required.

Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses.

Malnutrition is the most common, reversible complication of cirrhosis that adversely affects survival, response to other complications, and quality of life. Sarcopenia, or loss of skeletal muscle mass, and loss of adipose tissue and altered substrate use as a source of energy are the 2 major components of malnutrition in cirrhosis. Current therapies include high protein supplementation especially as a late evening snack. Exercise protocols have the potential of aggravating hyperammonemia and portal hypertension. Recent advances in understanding the molecular regulation of muscle mass has helped identify potential novel therapeutic targets including myostatin antagonists, and mTOR resistance.

Glycine transporter type 1 blockade changes NMDA receptor-mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels.

Long-term potentiation (LTP) in the hippocampal CA1 region requires the activation of NMDA receptors (NMDARs). NMDAR activation in turn requires membrane depolarization as well as the binding of glutamate and its coagonist glycine. Previous pharmacological studies suggest that the glycine transporter type 1 (GlyT1) maintains subsaturating concentrations of glycine at synaptic NMDARs. Antagonists of GlyT1 increase levels of glycine in the synaptic cleft and, like direct glycine site agonists, can augment NMDAR currents and NMDAR-mediated functions such as LTP. In addition, stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. We have used a new potent GlyT1 antagonist, CP-802,079, with whole-cell patch-clamp recordings in acute rat hippocampal slices to determine the effect of GlyT1 blockade on LTP. Reverse microdialysis experiments in the hippocampus of awake, freely moving rats, showed that this drug elevated only the extracellular concentration of glycine. We found that CP-802,079, sarcosine and glycine significantly increased the amplitude of the NMDAR currents and LTP. In contrast, application of higher concentrations of CP-802,079 and glycine slightly reduced NMDAR currents and did not increase LTP. Overall, these data suggest that the level of glycine present in the synaptic cleft tightly regulates the NMDAR activity. This level is kept below the 'set point' of the NMDAR internalization priming mechanism by the presence of GlyT1-dependent uptake.