Ruolo del sistema endocannabinoide nella cirrosi biliare primitiva

Endocannabinoid system (EC) has emerged as a crucial mediator in a variety of pathophysiological conditions. A cannabinoid agonist (WIN5521-2) has been shown to increase the pruritus threshold in cholestatic rats. Moreover, in the course of chronic cholangiopaties hepatic progenitor cells are activated constituting a neuroendocrine compartment regulated by different agents including neuropeptides. Aims: 1. To evaluate whether the EC system is activated in PBC; 2. To evaluate if genetic variations in human cannabinoid-specific receptor genes (CB1 and CB2) might cause a different phenotypic expression of the disease in terms of association with pruritus. Methods: 1) Morphological study: CB1 and CB2 receptors were characterized in biopsy specimens of 2 normal human liver and 9 PBC (IV stage) by immunohistochemistry. CB1 and CB2 mRNA expression was also assayed through RT-PCR in liver samples. 2) Genetic study: the following groups of subjects have been enrolled: 68 consecutive PBC Italian pts, 84 PBC pts residents in USA; 70 controls, matched for sex, age, and geographical area with the Italian PBC pts. Genomic DNA was extracted from peripheral venous blood leucocytes with standard method. PCR was used to amplify the coding regions of the CB1 and CB2 genes with specific primers. Results: in PBC, CB1 was markedly expressed in hepatocytes, biliary epithelial cells and in Kupffer cells; conversely, in control livers was virtually absent. CB2 was markedly expressed in hepatocytes and in biliary epithelial cells, in CBP. The variability of mRNA expression of CB1 and CB2 receptors, that are expressed in liver samples both CBP, both in normal liver, makes it impossible to prove a transcriptional iper-regulation of CB1 and CB2 receptors during cholestatic disease (CBP). CB1 polymorphism (1359 G/A) was present in 26.5% of Italian PBC pts, in 22.9% of healthy controls, and in 27.4% of an US PBC series (p=n.s.). CB2 polymorphism (188-189 AA/GG) was present in 24.4% vs 30.4% of Italian and US PBC respectively, and in 28% of Italian controls (p=n.s.) Stratifying the PBC patients according to pruritus there was no difference in either Italian and US series in the distribution of CB1 and CB2 mutation in patients with or without pruritus. CB1 SNP (1359 G/A) was correlated with CBP histologic evolution (p=0,05) and with response to treatment with UDCA (p=0,028). Conclusions: EC system is up-regulated in PBC and CB1 SNP (1359 G/A) seems to correlate with the evolution of the disease, in terms of reduced effectiveness of UDCA therapy in slowing the rate of progression of the disease, but this system probably exert a role regulating metabolic homeostasis.