P346 TAUROURSODESOXICOLATE (TUDC) PREVENTS ACTIVATION OF THE PRO-CHOLESTATIC SIGNALLING PATHWAYS,...
1
POSTERS (NGAL) is one of the most up-regulated genes. NGAL gene expression was assessed in patients with AH and other types liver diseases. NGAL expression was also studied in animal models of acute and chronic liver injury (CCl4), acute-on-chronic liver injury (CCl4 plus LPS) and alcoholic liver disease (CCl4 plus ethanol) is a cytokine typically released by activated neutrophils. Finally, the effects of recombinant human NGAL was assed in hepatic stellate cells (HSC). Results: NGAL gene expression was markedly up-regulated in patients with AH compared to other liver disease such as HCV, compensated alcoholic cirrhosis and NASH. Serum levels were also found elevated in patients with AH. Importantly, the baseline hepatic mRNA expression of NGAL correlated with disease severity and 90-day survival. Hepatic NGAL expression was induced by an acute and acute-on-chronic liver injury and in mice with alcoholic liver disease. Finally recombinan NGAL induced procollagen I and MCP-1 expression in human HSC. Conclusions: NGAL is markedly overexpressed in AH and in animal models of acute-on-chronic liver injury and it exerts inflammatory effects in hepatic cells. These results suggest that NGAL is a potential target for therapy in AH. 12. AUTOIMMUNE AND CHRONIC CHOLESTATIC LIVER DISEASE P345 PRIMARY PREVENTION OF GALLBLADDER STONES DURING WEIGHT LOSS: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS C.S. Stokes 1 , L.L. Gluud 2 , M. Casper 1 , F. Lammert 1 . 1 Department of Medicine II, Saarland University Medical Center, Homburg, Germany; 2 Department of Internal Medicine, University of Copenhagen, Hellerup, Denmark E-mail: [email protected] Background and Aims: The incidence of gallstones is rising partly due to the obesity epidemic. Cholecystectomy for (symptomatic) gallbladder stones poses a major burden on healthcare resources. We systematically evaluated the efficacy of non-surgical interventions for the primary prevention of gallbladder stones in obese adults undergoing weight loss, which is a known risk factor for stone formation. Methods: A Cochrane review of randomised controlled trials comparing ursodeoxycholic acid (UDCA) or a high-fat weight loss diet versus control interventions was conducted. Electronic and manual searches identified a total of 13 trials comprising 1,837 obese participants undergoing weight loss through dieting or after bariatric surgery. Random-effects meta-analyses were performed to assess the efficacy of these interventions with regards gallstone prevention. Inter-trial heterogeneity and bias were evaluated with subgroup, sensitivity, regression, and sequential analyses. Results: UDCA reduced the risk of ultrasonically verified gallstones compared with control interventions (RR 0.33, 95% CI 0.18 to 0.60, I 2 =65%, NNT=9). UDCA was more beneficial in participants undergoing weight loss through diet alone (RR 0.17, 95%CI 0.11 to 0.25, I 2 =0%) than after bariatric surgery (RR 0.42, 95% CI 0.21 to 0.83, I 2 =64%). A high versus a low dietary fat content also reduced gallstones (RR 0.09, 95%CI 0.01 to 0.61, I 2 =0%). No major adverse events were reported, and regression analysis showed no evidence of small study effects. Conclusions: The results of this meta-analysis indicate that during weight loss, UDCA and a high-fat weight loss diet prevent formation of gallstones and show potential as cost-effective alternatives to cholecystectomy. P346 TAUROURSODESOXICOLATE (TUDC) PREVENTS ACTIVATION OF THE PRO-CHOLESTATIC SIGNALLING PATHWAYS, cPKC AND PI3K/Akt, IN ESTRADIOL 17b-D-GLUCURONIDE (E 2 17G)-INDUCED CHOLESTASIS A.C. Boaglio, G.S. Miszczuk, I.R. Barroso, F.D. Toledo, F.A. Crocenzi, M.G. Roma. National University of Rosario, Institute of Experimental Physiology (IFISE) – CONICET, Rosario, Argentina E-mail: [email protected] Background and Aims: E 2 17G induces cholestasis by triggering endocytosis and further intracellular retention of Bsep and Mrp2, in a cPKC- and PI3K-dependent manner, respectively. Pregnancy induced cholestasis, associated with high E 2 17G levels, is routinely treated with ursodeoxycholic acid (UDCA). Since protective UDCA action mechanisms in E 2 17G-induced cholestasis have not been elucidated, we ascertained here whether TUDC, the main, active UDCA metabolite, prevents activation of cPKC and PI3K/Akt. Methods: Activation of cPKC and PI3K/Akt was evaluated in isolated rat hepatocytes by immunoblotting (assessment of membrane- bound and phosphorylated form, respectively). Bsep/Mrp2 function was quantified in isolated rat hepatocyte couplets (IRHCs) by assessing canalicular vacuolar accumulation (CVA) of their fluorescent substrates, CGamF and GS-MF, respectively. We also studied the preventive mechanisms of TUDC in E 2 17G-induced cholestasis in isolated, perfused rat liver (IPRL), and Bsep/Mrp2 localization by immunofluorescence. Results: E 2 17G (200 mM) activated both cPKC and PI3K/Akt. Pretreatment with TUDC (100 mM) prevented activation of cPKC (−34±4%) and PI3K/Akt (−37±2%); p < 0.05 vs.E 2 17G alone. The E 2 17G-mediated decrease in CVA of cGamF (−59±2%) and GS- MF (−55±3%) was partially prevented by TUDC (+72±6%) and (+78±3%); p < 0.05 vs.E 2 17G alone. In IPRL, E 2 17G (2 mmol/liver) induced an acute decrease in bile flow (−59±14%; p < 0.001), which was completely prevented by TUDC (p < 0.001). A similar behaviour was observed for the biliary excretion of the Bsep and Mrp2 substrates, TC and DNP-SG, respectively. Immunofluorescence revealed that TUDC prevented E 2 17G-induced Bsep/Mrp2 endocytosis. Conclusions: TUDC restores function and localization of Bsep/Mrp2 as impaired by E 2 17G, by preventing both cPKC and PI3K/Akt activation. P347 INCIDENCE AND RISK FACTORS FOR EXTRA-HEPATIC MALIGNANCIES (EM) IN PRIMARY BILIARY CIRRHOSIS: A COMPARATIVE STUDY FROM TWO EUROPEAN REFERRAL CENTERS N. Cazzagon 1 , A. Par` es 2 , A. Spinazz ` e 1 , L. Caballeria 2 , A. Reig 2 , I. Franceschet 1 , V. Baldo 3 , A. Buja 3 , P. Furlan 3 , A. Floreani 1 . 1 Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; 2 Liver Unit, Digestive Diseases Institute, Centro de Investigaci´ on Biom´ edica en Red de Enfermedades Hep´ aticas y Digestivas, Hospital Cl´ ınic, IDIBAPS, Barcelona, Spain; 3 Department of Molecular Medicine, Public Health Section, University of Padua, Padua, Italy E-mail: [email protected] Background and Aims: There is limited information on the prevalence/incidence, survival, and risk factors for developing EM in PBC. Aim: To analyze the incidence/prevalence, risk factors and survival for EM in patients with PBC in two European centers. Methods: The study was carried out in two series of PBC patients (361 of Padova, Italy and 397 of Barcelona, Spain) followed-up for a mean period of 7.7±7 and 12.2±7 years respectively. The incidence of EM was compared to the estimated incidence data from IARC. Demographic features and factors associated with tumor S182 Journal of Hepatology 2014 vol. 60 | S67–S214
Transcript of P346 TAUROURSODESOXICOLATE (TUDC) PREVENTS ACTIVATION OF THE PRO-CHOLESTATIC SIGNALLING PATHWAYS,...
POSTERS
(NGAL) is one of the most up-regulated genes. NGAL gene
expression was assessed in patients with AH and other types liver
diseases. NGAL expression was also studied in animal models of
acute and chronic liver injury (CCl4), acute-on-chronic liver injury
(CCl4 plus LPS) and alcoholic liver disease (CCl4 plus ethanol) is
a cytokine typically released by activated neutrophils. Finally, the
effects of recombinant human NGAL was assed in hepatic stellate
cells (HSC).
Results: NGAL gene expression was markedly up-regulated in
patients with AH compared to other liver disease such as HCV,
compensated alcoholic cirrhosis and NASH. Serum levels were
also found elevated in patients with AH. Importantly, the baseline
hepatic mRNA expression of NGAL correlated with disease severity
and 90-day survival. Hepatic NGAL expression was induced by an
acute and acute-on-chronic liver injury and in mice with alcoholic
liver disease. Finally recombinan NGAL induced procollagen I and
MCP-1 expression in human HSC.
Conclusions: NGAL is markedly overexpressed in AH and in animal
models of acute-on-chronic liver injury and it exerts inflammatory
effects in hepatic cells. These results suggest that NGAL is a potential
target for therapy in AH.
12. AUTOIMMUNE AND CHRONICCHOLESTATIC LIVER DISEASE
P345
PRIMARY PREVENTION OF GALLBLADDER STONES DURING
WEIGHT LOSS: SYSTEMATIC REVIEW AND META-ANALYSIS OF
RANDOMISED CONTROLLED TRIALS
C.S. Stokes1, L.L. Gluud2, M. Casper1, F. Lammert1. 1Department of
Medicine II, Saarland University Medical Center, Homburg, Germany;2Department of Internal Medicine, University of Copenhagen, Hellerup,
Denmark
E-mail: [email protected]
Background and Aims: The incidence of gallstones is rising
partly due to the obesity epidemic. Cholecystectomy for
(symptomatic) gallbladder stones poses a major burden on
healthcare resources. We systematically evaluated the efficacy of
non-surgical interventions for the primary prevention of gallbladder
stones in obese adults undergoing weight loss, which is a known
risk factor for stone formation.
Methods: A Cochrane review of randomised controlled trials
comparing ursodeoxycholic acid (UDCA) or a high-fat weight loss
diet versus control interventions was conducted. Electronic and
manual searches identified a total of 13 trials comprising 1,837
obese participants undergoing weight loss through dieting or after
bariatric surgery. Random-effects meta-analyses were performed
to assess the efficacy of these interventions with regards gallstone
prevention. Inter-trial heterogeneity and bias were evaluated with
subgroup, sensitivity, regression, and sequential analyses.
Results: UDCA reduced the risk of ultrasonically verified gallstones
compared with control interventions (RR 0.33, 95%CI 0.18 to
0.60, I2=65%, NNT=9). UDCA was more beneficial in participants
undergoing weight loss through diet alone (RR 0.17, 95%CI 0.11 to
0.25, I2=0%) than after bariatric surgery (RR 0.42, 95%CI 0.21 to
0.83, I2=64%). A high versus a low dietary fat content also reduced
gallstones (RR 0.09, 95%CI 0.01 to 0.61, I2=0%). No major adverse
events were reported, and regression analysis showed no evidence
of small study effects.
Conclusions: The results of this meta-analysis indicate that during
weight loss, UDCA and a high-fat weight loss diet prevent formation
of gallstones and show potential as cost-effective alternatives to
cholecystectomy.
P346
TAUROURSODESOXICOLATE (TUDC) PREVENTS ACTIVATION
OF THE PRO-CHOLESTATIC SIGNALLING PATHWAYS, cPKC AND
PI3K/Akt, IN ESTRADIOL 17b-D-GLUCURONIDE (E217G)-INDUCED
CHOLESTASIS
A.C. Boaglio, G.S. Miszczuk, I.R. Barroso, F.D. Toledo, F.A. Crocenzi,
M.G. Roma. National University of Rosario, Institute of Experimental
Physiology (IFISE) – CONICET, Rosario, Argentina
E-mail: [email protected]
Background and Aims: E217G induces cholestasis by triggering
endocytosis and further intracellular retention of Bsep and Mrp2,
in a cPKC- and PI3K-dependent manner, respectively. Pregnancy
induced cholestasis, associated with high E217G levels, is routinely
treated with ursodeoxycholic acid (UDCA). Since protective UDCA
action mechanisms in E217G-induced cholestasis have not been
elucidated, we ascertained here whether TUDC, the main, active
UDCA metabolite, prevents activation of cPKC and PI3K/Akt.
Methods: Activation of cPKC and PI3K/Akt was evaluated in isolated
rat hepatocytes by immunoblotting (assessment of membrane-
bound and phosphorylated form, respectively). Bsep/Mrp2 function
was quantified in isolated rat hepatocyte couplets (IRHCs)
by assessing canalicular vacuolar accumulation (CVA) of their
fluorescent substrates, CGamF and GS-MF, respectively. We also
studied the preventive mechanisms of TUDC in E217G-induced
cholestasis in isolated, perfused rat liver (IPRL), and Bsep/Mrp2
localization by immunofluorescence.
Results: E217G (200mM) activated both cPKC and PI3K/Akt.
Pretreatment with TUDC (100mM) prevented activation of cPKC
(−34±4%) and PI3K/Akt (−37±2%); p < 0.05 vs. E217G alone. The
E217G-mediated decrease in CVA of cGamF (−59±2%) and GS-
MF (−55±3%) was partially prevented by TUDC (+72±6%) and
(+78±3%); p < 0.05 vs. E217G alone. In IPRL, E217G (2mmol/liver)
induced an acute decrease in bile flow (−59±14%; p < 0.001),
which was completely prevented by TUDC (p < 0.001). A
similar behaviour was observed for the biliary excretion of
the Bsep and Mrp2 substrates, TC and DNP-SG, respectively.
Immunofluorescence revealed that TUDC prevented E217G-induced
Bsep/Mrp2 endocytosis.
Conclusions: TUDC restores function and localization of Bsep/Mrp2
as impaired by E217G, by preventing both cPKC and PI3K/Akt
activation.
P347
INCIDENCE AND RISK FACTORS FOR EXTRA-HEPATIC
MALIGNANCIES (EM) IN PRIMARY BILIARY CIRRHOSIS:
A COMPARATIVE STUDY FROM TWO EUROPEAN REFERRAL
CENTERS
N. Cazzagon1, A. Pares2, A. Spinazze1, L. Caballeria2, A. Reig2,
I. Franceschet1, V. Baldo3, A. Buja3, P. Furlan3, A. Floreani1.1Department of Surgery, Oncology and Gastroenterology, University of
Padua, Padua, Italy; 2Liver Unit, Digestive Diseases Institute, Centro
de Investigacion Biomedica en Red de Enfermedades Hepaticas y
Digestivas, Hospital Clınic, IDIBAPS, Barcelona, Spain; 3Department
of Molecular Medicine, Public Health Section, University of Padua,
Padua, Italy
E-mail: [email protected]
Background and Aims: There is limited information on the
prevalence/incidence, survival, and risk factors for developing EM
in PBC.
Aim: To analyze the incidence/prevalence, risk factors and survival
for EM in patients with PBC in two European centers.
Methods: The study was carried out in two series of PBC patients
(361 of Padova, Italy and 397 of Barcelona, Spain) followed-up
for a mean period of 7.7±7 and 12.2±7 years respectively. The
incidence of EM was compared to the estimated incidence data
from IARC. Demographic features and factors associated with tumor
S182 Journal of Hepatology 2014 vol. 60 | S67–S214
