Circulating and hepatic endocannabinoids and endocannabinoid-related molecules in patients with cirrhosis.
OBJECTIVE
Endocannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid-related molecules like oleoyl-ethanolamine (OEA) and palmitoyl-ethanolamine (PEA) have also been identified. AEA contributes to the pathogenesis of cardiovascular alterations in experimental cirrhosis, but data on the endocannabinoid system in human cirrhosis are lacking. Thus, we aimed to assess whether circulating and hepatic endocannabinoids are upregulated in cirrhotic patients and whether their levels correlate with systemic haemodynamics and liver function.


METHODS
The endocannabinoid levels were measured in peripheral and hepatic veins and liver tissue by isotope-dilution liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. Systemic haemodynamics were assessed by the transthoracic electrical bioimpedance technique. Portal pressure was evaluated by hepatic venous pressure gradient.


RESULTS
Circulating AEA and, to a greater extent, PEA and OEA were significantly higher in cirrhotic patients than in controls. PEA and OEA were also increased in the cirrhotic liver tissue. AEA, OEA and PEA levels were significantly higher in peripheral than in the hepatic veins of cirrhotic patients, while the opposite occurred for 2-AG. Finally, circulating AEA, OEA and PEA correlated with parameters of liver function, such as serum bilirubin and international normalized ratio. No correlations were found with systemic haemodynamics.


CONCLUSIONS
The endocannabinoid system is upregulated in human cirrhosis. Peripheral AEA is increased in patients with a high model of end-stage liver disease score and may reflect the extent of liver dysfunction. In contrast, the 2-AG levels, the other major endocannabinoid, are not affected by cirrhosis. The upregulation of the endocannabinoid-related molecules, OEA and PEA, is even greater than that of AEA, prompting pharmacological studies on these compounds.
Dipartimento di Medicina Clinica, Alma Mater Studiorum University of Bologna, Bologna, Italy.
Paolo
P
Caraceni
Antonella
A
Viola
Fabiana
F
Piscitelli
Ferdinando
F
Giannone
Annalisa
A
Berzigotti
Matteo
M
Cescon
Marco
M
Domenicali
Stefania
S
Petrosino
Emanuela
E
Giampalma
Anna
A
Riili
Gianluca
G
Grazi
Rita
R
Golfieri
Marco
M
Zoli
Mauro
M
Bernardi
Vincenzo
V
Di Marzo
D000328:Adult; D000577:Amides; D001095:Arachidonic Acids / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D063385:Cannabinoid Receptor Modulators / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D017097:Electric Impedance; D063388:Endocannabinoids; D004983:Ethanolamines / Q000378:metabolism; D005260:Female; D005989:Glycerides / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D019934:International Normalized Ratio; D007558:Italy; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009829:Oleic Acids; D010169:Palmitic Acids / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011865:Radioisotope Dilution Technique; D012720:Severity of Illness Index; D015854:Up-Regulation
D000577:Amides; D001095:Arachidonic Acids; D015415:Biomarkers; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; C033595:N-oleoylethanolamine; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D001663:Bilirubin; C078814:anandamide