925 GLUCOCORTICOSTEROIDS FOR ALCOHOLIC HEPATITIS

08. ALCOHOLIC LIVER DISEASE, NAFLD AND DRUG-INDUCED LIVER DISEASE Conclusion: Angiotensin receptor blockers seem to be efficient in hypertension-associated NASH. Telmisartan shows a higher efficacy regarding insulin resistance and histology, perhaps because its specific PPAR-gamma ligand effect. 925 GLUCOCORTICOSTEROIDS FOR ALCOHOLIC HEPATITIS A. Rambaldi1 , H.H. Saconato2 , E. Christensen3 , K. Thorlund1 , J. Wetterslev1 , C. Gluud1 . 1 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark; 2 Universidade Federal Do Rio Grande Do Norte, Natal, Brazil; 3 Clinic of Internal Medicine I, Copenhagen, Denmark E-mail: [email protected] Background and Aims: To evaluate the benefits and harms of glucocorticosteroids in patients with alcoholic hepatitis. Methods: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and full text searches were conducted. Manufacturers and researchers in the field were contacted. Randomised clinical trials of glucocorticosteroids for patients with alcoholic hepatitis. Data were assessed and extracted by at least two authors independently. The bias risk of the randomised clinical trials was evaluated by methodological components. RevMan Analyses was used for analyses of dichotomous outcomes with relative risks (RR) with 95% confidence intervals (CI). We analysed the data with trial sequential analyses and applied weighted logistic regression analyses using the summarised descriptive data of the treatment and control groups of trials that gave this information. Results: Fifteen trials were included randomising 721 patients. A total of 39.5% died. More than 80% of the trials had high risks of bias and there was evidence of funnel plot asymmetry. Glucocorticosteroids had no statistically significant effect on mortality compared with placebo or no intervention (RR 0.83, 95% CI 0.63 to 1.11). Glucocorticosteroids significantly reduced mortality in the subgroup of trials with low-bias risk (RR 0.33, 95% CI 0.11 to 0.97) and with patients with Maddrey’s score of at least 32 or hepatic encephalopathy (RR 0.37, 95% CI 0.16 to 0.86). In all analyses heterogeneity was significant (P < 0.1) and substantial (I2 above 50%). Trial sequential analyses using heterogeneity-corrected information size demonstrated no significant effects of glucocorticosteroids on mortality and that additional large trials are needed. Weighted logistic regression analysis taking prognostic factors at randomisation into consideration found no significant effect on mortality (adjusted RR 0.91, 95% CI 0.60 to 1.36). Glucocorticosteroids significantly increased adverse events (RR 3.63, 95% CI 1.95 to 6.76). Conclusions: Glucocorticosteroids for patients with alcoholic hepatitis can neither be supported nor refuted. Large randomised trials with low risk of bias should be conducted and more beneficial than harmful effects of glucocorticosteroids should be demonstrated before glucocorticosteroids are used in patients with alcoholic hepatitis. 926 RETINOL BINDING PROTEIN-4 EXPRESSION IS UP REGULATED IN RATS WITH FATTY LIVER DURING QUIESCENT AND REGENERATIVE STATE AND IMPROVES WITH INSULIN SENSITIZING AGENTS M. Grozovski1 , T. Shatil1 , Z. Beniashvili2 , S. Korem1 , N. Assy2,3 . 1 Department of Biotechnology, Ort Braude College, Carmiel, Israel; 2 Liver Unit, Sieff Hospital, Safed, Israel; 3 Technion Institute, Faculty of Medicine, Haifa, Israel E-mail: [email protected] Background: Serum RBP-4 levels are increased very early in insulin resistance states. The good relationship between NAFLD and insulin

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resistance suggests that RBP-4 play a role in the pathogenesis of NAFLD. AIM: 1) Determine whether there is a relationship between NAFLD and RBP-4 levels in quiescent and in regenerating rat fatty liver 2) determine the effect of insulin sensitizing agents (ISA) on RBP4 expression and on other metabolic parameters. Methods: Forty-eight SD rats were treated with fructose enriched diet (FED), or FED with Metformin (2 mg/Kg/d), FED with Rosiglitazone (3 mg/Kg/d), or the combination of both drugs for a total of 5 wks. 30% PHX was performed at WK 5. RBP-4 expression (ELISA & RT-PCR), lipids, antioxidants, and hepatic fat content were measured before and 24, 48 hours after PHX. Results: Hepatic and serum RBP-4 were significantly higher in rats with fatty liver than control rats (83.2±8.8 mg/ml Vs 68.3±13.0, +22%, p < 0.001 and 7.48±0.27 Vs 3.6±0.02, +52%, p < 0.01) respectively. RBP-4 was independent factor associated with NAFLD (r = 0.4, P < 0.001) and the extent of hepatic RBP-4 expression increases significantly 24 and 48 hours after PHX. (+90%, p < 0.001, +47%, p < 0.001) respectively. The combination of metformin and rosiglitazone decreased hepatic and serum RBP-4 expression at 48 hours after PHX by −55% and −45% respectively. Serum RBP-4 correlate positively with MDA levels (r = 0.4, P < 0.01), TG levels (r = 0.23, p < 0.01), and markers of liver regeneration. Conclusion: Hepatic and serum RBP-4 levels are highly associated with fatty liver, are up regulated during liver regeneration and improve after treatment with insulin sensitizing agents. These finding suggests that the liver is the principle source of circulating RBP-4 and RBP-4 might be related to the pathogenesis of NAFLD

927 PROPOFOL ENHANCES ANTIOXIDANT CAPACITY IN A RAT MODEL OF ACUTE LIVER INJURY INDUCED BY PARACETAMOL INTOXICATION A.D. Grypioti1,2,3 , M.G. Mykoniatis1 , C.A. Demopoulos2 , Z. Daifoti1 , G. Kostopanagiotou1,3 . 1 Department of Experimental Pharmacology, 2 Department of Chemistry, 3 Second Department of Anesthesiology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece E-mail: [email protected] Background and Aims: Hepatic outcome after paracetamol intoxication is compromised by tissue injury and may result from oxidant-mediated cellular damage. Recent interest has been focused on the use of antioxidants to prevent such injury. Propofol, a highly lipid soluble general anaesthetic, possesses antioxidant activity in vitro and in vivo. This property makes it suitable to test for efficacy in clinical and experimental settings of paracetamol-induced injury. The purpose of the current study was to investigate whether propofol protects liver against an oxidant attack induced by paracetamol overdose. Methods: Male Wistar rats were divided into two groups: the control group received a toxic dose of paracetamol (3.5g/Kg BW) under ether anaesthesia and the propofol-treated group received a single dose of propofol (60 mg/Kg BW) intraperitoneally and the same dose of paracetamol. The animals were sacrificed at time points of 8, 16, 24, 32 and 40h after treatment. The hepatic injury was evaluated at the different times interval after intoxication by determination of serum enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and by the degree of inflammation and apoptosis. Hepatic levels of malondialdehyde (MDA), serum cholesterol/HDL cholesterol fraction and glutathione S-transferase (GST-p) activity were also measured as indicators of tissue damage and as parameters of oxidantantioxidant balance. Liver regeneration was evaluated by assessing the rate of [3H]thymidine incorporation into hepatic DNA, the enzymatic activity of liver thymidine kinase and the mitotic index. Results: All indicators of liver oxidative stress showed significant decrease after propofol pretreatment. In contrast, all biochemical and histopathological parameters examined for the estimation of liver injury did not show