569 ENDOCANNABINOIDS AND CIRRHOSIS: HAVE WE PICKED THE RIGHT ONE?

Background and Aims: Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most studied endocannabinoids (ECs), but other related molecules have been more recently identified, including N-palmitoyl-ethanolamine (PEA) and Noleoyl-ethanolamine (OEA). In advanced cirrhosis, research has been mostly focused on AEA as it appears to contribute to the pathogenesis of hyperdynamic circulation and cirrhotic cardiomiopathy. However, we have recently shown that circulating OEA and PEA are even more elevated than AEA in cirrhosis although in a small number of patients. Thus, we assessed: 1. whether the circulating levels AEA, OEA, and PEA are elevated in a larger sample of hospitalized cirrhotic patients; and 2. whether these levels correlate with disease severity or clinical features, including the major complications of cirrhosis. Methods: Blood samples of 101 cirrhotic hospitalized patients without HCC exceeding the Milan criteria (Child-Pugh A/B/C:21/58/22) and 101 age- and sex-matched controls were witdrawn at admission to measure AEA, PEA and OEA by LC/MS/MS. Clinical and laboratory data were collected and the patients followed until discharge. Results: Circulating ECs were significantly higher in cirrhotics than healthy controls (AEA: 1.42±0.06 vs 1.07±0.03 pmol/ml; OEA: 10.9±0.5 vs 5.1±0.2 pmol/ml; PEA: 26.1±0.8 vs 16.3±0.4 pmol/ml, all p < 0.0001). No correlation was found between AEA and disease severity. In contrast, Child-Pugh and MELD scores were positively correlated with OEA (p < 0.01) and PEA (p < 0.05). Compared to those in Child-PughA/B, Child-Pugh C patients showed significantly higher OEA and PEA. An inverse relation close to the statistical significance was observed between OEA and PEA and mean arterial pressure. ECs did not differ when patients were divided according the presence of ascites, gastrointestinal bleeding, hepatic encephalopathy, and renal failure. In contrast, compared to noninfected patients (n = 80), those with bacterial infection (n = 21) presented higher OEA (10.2±0.5 vs 13.0±1.4 pmol/ml; p < 0.05) and PEA levels (24.9±0.8 vs 29.9±2.6 pmol/ml; p < 0.05). Conclusions: The EC system is up-regulated in patients with cirrhosis. However, rather than AEA, the more recent discovered OEA and PEA, with no activity at the CB-receptor sites, but capable to activate PPAR-a and TRPV1 receptors, correlate with disease severity and are affected by bacterial infections. These data prompt further investigations to explore the biological and clinical role of these novel compounds in cirrhosis.