- Email: [email protected]
873 PROGRESSION OF NAFLD IN HUMANS IS ASSOCIATED WITH THE ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM
POSTERS of adipocytes. Aim was to assess the relationship between FFAs, adiponectin, and NAFLD, and to evaluate whether PNPLA3 genotype influences fasting levels of FFAs and adiponectin. Patients and Methods: We considered 144 consecutive Italian patients with NAFLD (115 with biopsy performed for persistently altered liver enzymes) and 68 healthy controls. The rs738409 PNPLA3 genotype (encoding for I148M) was evaluated by a Taqman assay, adiponectin by ELISA (Assaypro), and FFAs by an enzymatic assay. Results: The presence of NAFLD was significantly associated with FFAs (OR 1.013, 95% CI 1.01–1.02; p < 0.0001), and adiponectin (OR 0.870, 95% CI 0.79–0.95; p = 0.003), independently of age, sex, BMI, glucose, and insulin. In biopsied patients, adiponectin, but not FFAs, levels were significantly associated with a reduced risk of moderate/severe steatosis (OR 0.83, 95% CI 0.72–0.96; p = 0.012), with NASH (OR 0.86, 0.75–0.98, p = 0.025), and with the presence of fibrosis (OR 0.84, 0.74–0.95; p = 0.006) independently of age, sex, BMI, ALT, insulin, glucose levels, and FFAs. As expected, the 148M PNPLA3 variant was associated with NAFLD and NASH (p < 0.0001). At ordinal logistic regression analysis, the PNPLA3 148M variant was associated with low adiponectin levels (<6 mcg/ml), independently of gender, presence of diabetes, ALT levels, and dyslipidemia (tryglicerides/HDL ratio) both in patients (OR 0.10, 95% CI 0.01– 0.19, p = 0.03), and in the whole series of patients and controls (OR 0.11, 95% CI 0.04–0.19, p = 0.03), but not with fasting FFAs or insulin levels. Conclusions: Modulation of the release of adiponectin, a molecule with insulin sensitizing, anti-inflammatory, and anti-fibrotic activity, which is associated with the risk of NAFLD, NASH and progressive liver damage, may be involved in mediating the susceptibility to steatosis and NASH in carriers of the 148M PNPLA3 variant. 873 PROGRESSION OF NAFLD IN HUMANS IS ASSOCIATED WITH THE ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM J. Vergniol1 , V. Barbu2 , M. Lemoine3 , D. Wendum2 , C. Chatzantoniou4 , L. Serfaty3 , C. Housset3 , V. Ratziu5 . 1 Service d’h´epato-gastroent´erologie, Hˆ opital Haut-Leveque, Pessac, 2 INSERM, UMR_S 938, CdR Saint-Antoine, Universit´e Pierre et Marie Curie, 3 INSERM, UMR_S 938, CdR Saint-Antoine, 4 INSERM, UMR_S 702, CdR Tenon, Universite Pierre et Marie Curie, 5 Hˆ opital Piti´e Salpˆetri`ere, Universit´e Pierre et Marie Curie, Paris, France E-mail: [email protected] Background and Aim: The renin-angiotensin system (RAS) displays various regulatory functions and is involved in many human diseases such as hypertension, cardiac insufficiency or renal fibrosis. Its role in the physiopathology of liver fibrosis has already been established. Animal data suggest it may be involved in the progression of non-alcoholic fatty liver disease (NAFLD) but no human data are available. We studied the hepatic expression of different RAS components at various stages of human NAFLD. Methods: Liver biopsies of 34 patients with NAFLD, (9 with steatosis, 13 with steatohepatitis (NASH) and no or mild fibrosis, 12 with NASH and advanced fibrosis) and of 13 controls with increased aminotransferases and normal liver biopsy, all matched for age, gender and hypertension were analyzed by real time RT-PCR for the expression of angiotensinogen (ATG), renin, angiotensinconverting enzyme (ACE), type 1 angiotensin II receptor (AT1), angiotensin-converting enzyme 2 (ACE2), mas receptor. 12 monthold transgenic mice overexpressing renin and fed regular chow were analysed for liver lesions of NAFLD. Results: Contrary to previous reports (Wei, J Hepatol 2008; 49: 417–428) overexpression of renin in transgenic mice did not result in steatosis or steatohepatitis which was corroborated by human data showing no difference between control, steatosis and NASH patients. There was a strong induction of the hepatic expression S348
of ATG (2.7-fold, p < 0.01) and AT1 (2.1-fold, p = 0.014) in NASH patients vs. controls with a step wise increase between controls, steatosis and steatohepatitis. The alternative pathway was also induced with a 2.8-fold increase of ACE2 (p < 0.002) in NASH patients and a strong reduction in mas expression (6.7-fold vs. controls, p = 0.001 and 3.4-fold vs. steatosis, p < 0.02). These results were not confounded by the fibrosis stage. Conclusion: In human NAFLD, there is a step-wise increase in the expression of some genes of the RAS from both the direct and alternative pathways suggesting that this biological system may be involved in the transition of steatosis to NASH. 874 AMINOTRANSFERASE LEVELS ACCURATELY PREDICT NAFLD ACTIVITY SCORE AFTER 24 WEEKS OF INTERVENTION. RESULTS BASED ON MULTIPLE LINEAR REGRESSION MODEL E. Vilar Gomez1 , E. Arus Soler2 , A. Yasells Garcia3 , M.D.R. Abreu Vazquez1 . 1 Researches, 2 Director, 3 Gastroenterology, National Institute of Gastroenterology, Havana, Cuba E-mail: [email protected] Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a significant health problem for which there is no universally accepted pharmacological treatment. Weight loss, thiazolidinediones, and antioxidants are the most extensively used. The NAFLD activity score (NAS) provides the rational for therapeutic trials; however, predictive factors of NAS improvement are unknown. Our study evaluated capability of a mathematical model based on ALT levels to predict NAS after 24 weeks of treatment. Methods: Forty-two patients with paired liver biopsies were selected from a randomized and controlled study with an antioxidant (viusid) and weight loss through lifestyle modification, published at (Aliment Pharmacol Ther 2009; 30: 999–1009). Pearson’s bivariate correlations were implemented to identify linear correlation between NAS after 24 weeks of treatment and age, percentage of weight loss, and ALT, uric acid, triglycerides, cholesterol, HOMA-IR levels after 24 weeks of intervention. Stepwise multiple linear regression was performed to identify independent variables that best predict the NAS. Multiple regression coefficients (R), determination coefficients (R2 ), adjusted R2 and standard error (SE) were analyzed to select the best predictived model. The Durbin–Watson estimate was computed to check indepence. The area under the receiver operating characteristic (ROC) curve was computed to select a threshold for ALT levels to predict NAS ≤ 2 (no NASH) after 24 weeks of treatment. Results: Stepwise linear regression analysis included those variables linearly correlated to NAS (ALT, r = 0.726 [P < 0.0001]; uric acid, r = 0.334 [P = 0.03]; percentage of weight loss, r = −0.471 [P = 0.001]) resulting from Pearson’s bivariate correlations. Of the candidate variables, only ALT (Beta, 0.781 [P < 0.0001]) was independently predictive of NAS in the multiple linear regression analysis. The R, R2 , adjusted R2 and SE were 0.781, 0.610, 0.600 and 0.861 respectively for a predictive model that included ALT only. The Durbin–Watson value (1.768) shows that independence assumption is satisfied. The area under the ROC curve for ALT levels was 0.947 (95% CI, 0.83 to 0.99; SE, 0.03; P < 0.0001). A threshold of ALT ≤ 30 U/L showed an 88% of sensitivity and 86% of specificity. Conclusions: Our data suggest that ALT levels accurately predict NAS after 24 weeks of treatment.
Journal of Hepatology 2011 vol. 54 | S209–S361
of ATG (2.7-fold, p < 0.01) and AT1 (2.1-fold, p = 0.014) in NASH patients vs. controls with a step wise increase between controls, steatosis and steatohepatitis. The alternative pathway was also induced with a 2.8-fold increase of ACE2 (p < 0.002) in NASH patients and a strong reduction in mas expression (6.7-fold vs. controls, p = 0.001 and 3.4-fold vs. steatosis, p < 0.02). These results were not confounded by the fibrosis stage. Conclusion: In human NAFLD, there is a step-wise increase in the expression of some genes of the RAS from both the direct and alternative pathways suggesting that this biological system may be involved in the transition of steatosis to NASH. 874 AMINOTRANSFERASE LEVELS ACCURATELY PREDICT NAFLD ACTIVITY SCORE AFTER 24 WEEKS OF INTERVENTION. RESULTS BASED ON MULTIPLE LINEAR REGRESSION MODEL E. Vilar Gomez1 , E. Arus Soler2 , A. Yasells Garcia3 , M.D.R. Abreu Vazquez1 . 1 Researches, 2 Director, 3 Gastroenterology, National Institute of Gastroenterology, Havana, Cuba E-mail: [email protected] Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a significant health problem for which there is no universally accepted pharmacological treatment. Weight loss, thiazolidinediones, and antioxidants are the most extensively used. The NAFLD activity score (NAS) provides the rational for therapeutic trials; however, predictive factors of NAS improvement are unknown. Our study evaluated capability of a mathematical model based on ALT levels to predict NAS after 24 weeks of treatment. Methods: Forty-two patients with paired liver biopsies were selected from a randomized and controlled study with an antioxidant (viusid) and weight loss through lifestyle modification, published at (Aliment Pharmacol Ther 2009; 30: 999–1009). Pearson’s bivariate correlations were implemented to identify linear correlation between NAS after 24 weeks of treatment and age, percentage of weight loss, and ALT, uric acid, triglycerides, cholesterol, HOMA-IR levels after 24 weeks of intervention. Stepwise multiple linear regression was performed to identify independent variables that best predict the NAS. Multiple regression coefficients (R), determination coefficients (R2 ), adjusted R2 and standard error (SE) were analyzed to select the best predictived model. The Durbin–Watson estimate was computed to check indepence. The area under the receiver operating characteristic (ROC) curve was computed to select a threshold for ALT levels to predict NAS ≤ 2 (no NASH) after 24 weeks of treatment. Results: Stepwise linear regression analysis included those variables linearly correlated to NAS (ALT, r = 0.726 [P < 0.0001]; uric acid, r = 0.334 [P = 0.03]; percentage of weight loss, r = −0.471 [P = 0.001]) resulting from Pearson’s bivariate correlations. Of the candidate variables, only ALT (Beta, 0.781 [P < 0.0001]) was independently predictive of NAS in the multiple linear regression analysis. The R, R2 , adjusted R2 and SE were 0.781, 0.610, 0.600 and 0.861 respectively for a predictive model that included ALT only. The Durbin–Watson value (1.768) shows that independence assumption is satisfied. The area under the ROC curve for ALT levels was 0.947 (95% CI, 0.83 to 0.99; SE, 0.03; P < 0.0001). A threshold of ALT ≤ 30 U/L showed an 88% of sensitivity and 86% of specificity. Conclusions: Our data suggest that ALT levels accurately predict NAS after 24 weeks of treatment.
Journal of Hepatology 2011 vol. 54 | S209–S361