S44 Saturday, April 25 Conclusions: 1. AST-120 is as effective as lactulose for treatment of low-grade HE and better tolerated; 2. differentiation of lower grades of encephalopathy (Grades 0 and 1) remains a challenge. The results suggest a role for AST-120 for treatment of cognitive impair- ments associated with lower grades of HE. 106 IDENTIFICATION OF AN EXTREMELY BENIGN ASYMPTOMATIC PRESENTATION IN A LARGE COHORT OF PATIENTS WITH PRIMARY BILIARY CIRRHOSIS A. Par´ es. Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, Barcelona, Spain E-mail: pares@ub.edu Background and Aims: Asymptomatic primary biliary cirrhosis (PBC) is becoming more prevalent in recent series, but the natural history, prognosis and outcome of this presentation is not completely defined. Therefore, in the current study we analysed a cohort of patients diagnosed with PBC in 17 hospitals from Spain regarding the presentation, natural history and outcome. Patients and Methods: 1058 patients (92% female; mean age: 53.1±0.4 years) diagnosed with PBC between 1971 and 2006 (mean follow-up 8.1±0.2 years). The clinical features and histological stage at presentation, incident characteristics of disease progression, and the outcome, including death or liver transplantation, were recorded as well as if patients were symptomatic or asymptomatic at presentation or remained symptom-free during the follow-up. Results: 651 patients (62%) were asymptomatic at presentation. There were no differences between symptomatic and asymptomatic patients regarding gender, presence of antimitochondrial and antinuclear antibod- ies, but age was higher and the disease severity and survival free of transplantation was significantly better in asymptomatic patients. Most patients were treated with UDCA. The asymptomatic patients have a different course since 71% remained symptom-free while 191 patients developed symptoms. The 20-year survival free of transplantation was extremely good in patients who remained symptom free (87%) while it decreased in patients developing symptoms, who experienced a survival closely comparable but better to that observed in symptomatic patients (56% and 46%). Asymptomatic patients who remained symptom free were older and had milder disease characterized by earlier histological stages, lower bilirubin, alkaline phosphatase, alanine aminotransferase and higher albumin and hemoglobin levels and platelet count than patients who developed symptoms(p < 0.01). Moreover, the multivariate analysis identi- fied baseline alkaline phosphatase >560 u/L, albumin >40 g/L, hemoglobin >13 g/L and age >53 years as indicators of lack of symptom progression in asymptomatic patients. Conclusions: The asymptomatic PBC have a different course, since most patients remain symptom free during the follow-up and have a very good life span. These patients are older and have milder disease at presentation, thus identifying an extremely benign form and course of the disease in patients under UDCA treatment. On behalf of Spanish Group of Chronic Cholestasis, AEEH, Spain Parallel Session 13: LIVER REGENERATION AND CARCINOGENESIS 107 ACCELERATED ENTRY INTO S PHASE AND INCREASED HEPATOCYTE PROLIFERATION IN C-JUN CONDITIONAL KNOCKOUT MICE FOLLOWING ADMINISTRATION OF THE CAR AGONIST TCPOBOP V.P. Leoni 1 , M. Simbula 1 , M. Pibiri 1 , M.A. Kowalik 1 , P. Sulas 1 , M. Ravo 2 , O. Grober 2 , A. Weisz 2 , G.M. Ledda-Columbano 1 , A. Columbano 1 . 1 Toxicology, University of Cagliari, Cagliari, 2 Department of Pathology, II University of Naples, Naples, Italy E-mail: vera.leoni@tiscali.it Background and Aims: The AP-1 transcription factor component c-Jun is a key regulator of hepatocyte proliferation. Mice lacking c-jun in the liver display impaired liver regeneration after partial hepatectomy (PH), and this phenotype correlates with increased protein levels of the cdk- inhibitor p21 [1,2]; hepatocyte proliferation, however, can also occur with- out previous cell loss/death, and in the absence of many changes essential for liver regeneration (i.e. increased expression of immediate early genes and growth factors, activation of NF-kB, AP-1 and STAT3, increased generation of cytokines etc.). Ligands of certain nuclear receptors (i.e. TRs, PPARs, CAR, PXR) belonging to the superfamily of steroid/thyroid hormone receptors share the ability to stimulate liver growth. Methods: C-jun conditional knockout and wt mice were administered a single dose of TCPOBOP, a ligand of CAR. Hepatocyte proliferation was determined immunohistochemically by BrdU incorporation and by Western blot analysis. Results: Here we show that when liver growth is induced by TCPOBOP, hepatocytes from c-Jun conditional knockout mice exhibit an accelerated entry into S phase and an overall much higher proliferative response. The anticipated entry into S phase, measured as BrdU incorporation was associated with an increased protein content of cell cycle associated proteins (cyclin D1, Cyclin A, PCNA). Entry into S phase was followed by an increased mitotic activity; no cell death was observed at any time point examined. Expression profiling analysis was carried out to identify differences in early genes between the two groups (from 1 to 6 hours after treatment). Preliminary results indicate that no significant changes occurred in the expression of immediate early genes classically associated to hepatocyte “priming”, suggesting that the accelerated entry into S phase observed in c-jun knockout mice is associated to changes occurring at later time points. Conclusions: The results obtained show that c-jun, i. is not an absolute requirement for the entry of hepatocytes into the cell cycle, and, ii. most important, it may, under certain conditions, negatively regulate liver cell proliferation. Supported by funds from AIRC (Milan, Italy). References [1] Eferl R. et al Cell 112, 181, 2003. [2] Stepniak E. et al. Genes Dev 20, 2306, 2006. 108 CANNABINOID CB2 RECEPTORS STIMULATE LIVER REGENERATION M.-P. Belot 1 , F. Teixeira-Clerc 1 , S. Manin 1 , V. Deveaux 1 , J. tran Van Nhieu 1 , A. Zimmer 2 , A. Mallat 1,3 , S. Lotersztajn 1,3 . 1 INSERM U955, Creteil Cedex, France; 2 Dept of Molecular Psychiatry, University of Bonn, Bonn, Germany; 3 Dept of Hepatology, AP-HP, Hˆ opital Henri Mondor, Creteil, France E-mail: marie-pierre.belot@inserm.fr The liver has a remarkable ability to regenerate in response to partial hepatectomy or liver injury. The regenerative process is triggered by