- Email: [email protected]
O072 : Statin use significantly decreases decompensation and death in veterans with hepatitis C-related compensated cirrhosis
ORAL PRESENTATIONS O071 TELOMERASE REVERSE TRANSCRIPTASE MUTATIONS ARE ASSOCIATED WITH HEPATOCELLULAR CARCINOMA IN NASH B. Donati1 , E. Vanni2 , P. Dongiovanni3 , M. Iavarone4 , R. Rametta1 , C. Rosso2 , A. Carnelutti5 , S. Petta6 , A.L. Fracanzani1 , H.L. Reeves7 , J.F. Dofour8 , L. Miele9 , Q. Anstee10 , E. Bugianesi11 , G. Soardo5 , S. Fargion1 , L. Valenti1 . 1 Pathophysiology and Transplantation, Universit` a degli Studi di Milano, Milano, 2 Medical Sciences, University of Turin, Turin, 3 Internal Medicine, 4 Gastroenterology, Fondazione IRCCS Ca’ Granda, Milano, 5 Internal Medicine, University of Udine, Udine, 6 Gastroenterology, University of Palermo, Palermo, Italy; 7 Medicine, Freeman Hospital, Newcastle Upon Tyne, United Kingdom; 8 Clinical Research, University of Bern, Bern, Switzerland; 9 Internal Medicine, Catholic University, Rome, Italy; 10 Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom; 11 Gastroenterology, University of Turin, Turin, Italy E-mail: [email protected] Background and Aims: In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in nonalcoholic steatohepatitis (NASH). Mutations in telomerase reverse-transcriptase (hTERT), the main regulator of telomere length, have been associated with a spectrum of progressive familial liver disease characterized by steatosis, and telomere attrition characterizes cirrhosis and cancer development. Aim was to determine whether shortened telomeres and functional hTERT mutations predispose to HCC in NASH. Methods: In 40 consecutive Italian unrelated patients with HCC occurring in NASH-related liver disease (78% with cirrhosis), 40 patients with NASH-related cirrhosis, and 60 healthy subjects with normal liver enzymes, telomere length was evaluated by qRT-PCR and hTERT coding regions and intron-exon boundaries were analyzed by Sanger sequencing on DNA from peripheral blood leukocytes. Prediction of functional consequences of genetic variants was estimated in silico by consulting Telomere Database (http://telomerase.asu.edu) and bioinformatic algorithms. Results: Telomere length was reduced in HCC patients (median: 1.01 IQR: 0.76–1.42; calculated as ratio of telomere repeat copy number to 36B4 single gene copy number) vs. cirrhosis (median: 1.12 IQR: 0.83–1.70;p = 0.1) and vs. healthy subjects (median: 1.40 IQR: 1.00–1.72;p = 0.002). We detected novel rare coding variants of hTERT in NASH HCC patients, while no mutations were found in those with cirrhosis and healthy controls (prevalence 10%; p = 0.040 vs. cirrhosis, p = 0.012 vs. healthy subjects; p = 0.001 vs. controls overall). Three HCC patients were carriers of missense mutations: Ala67Val in homozygosity and Pro193Leu in heterozygosity located in the N-terminal (template binding domain, possibly damaging), while one was heterozygous for the Glu668Asp (catalytic domain, likely damaging). One patient presented a heterozygous frameshift mutation (Glu113Arg_fs*79, likely damaging). All patients positive for hTERT mutations had cirrhosis and were carriers of the I148M PNPLA3 variant predisposing to HCC in NASH; mortality at 24 months was 100% (vs. 65% in negative patients). Conclusions: These data suggest that multiple rare hTERT mutations may frequently contribute to the pathogenesis of HCC in NASH by favouring telomere attrition, with possible clinical implications for relatives of the probands. We are currently validating these findings in an independent European cohort.
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Cirrhosis and complications 1 O072 STATIN USE SIGNIFICANTLY DECREASES DECOMPENSATION AND DEATH IN VETERANS WITH HEPATITIS C-RELATED COMPENSATED CIRRHOSIS A. Mohanty1,2 , J.P. Tate3,4 , G. Garcia-Tsao1,2 . 1 Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, 2 Section of Digestive Diseases, Yale School of Medicine, New Haven, 3 Department of Internal Medicine, VA Connecticut Healthcare System, West Haven, 4 Department of Internal Medicine, Yale School of Medicine, New Haven, United States E-mail: [email protected] Background and Aims: Statin use has been shown to decrease portal pressure in patients with cirrhosis, and improve survival in patients who have bled from varices. However, the long-term effect of statin use on cirrhosis decompensation and mortality in patients with compensated cirrhosis is unknown. Aim: To study the effect of statin use on decompensation and mortality in hepatitis C virus (HCV)-infected patients with compensated cirrhosis. Methods: Using the Veteran Affairs clinical case registry from 01/1996 to 12/2009 (n = 342,157), we identified a cohort of HCV mono-infected patients with compensated cirrhosis and no statin use at baseline. New statin users (median time of use was 2.8 years) were propensity matched to up to 5 non-users. The propensity score was created using variables associated with statin prescription: demographics, calendar year of index visit, site of statin prescription, site prescribing pattern, number and type of lipid tests, laboratory data including liver tests, and
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ORAL PRESENTATIONS comorbid conditions. As previously validated, decompensation was defined by the presence of one inpatient or two outpatient ICD-9 codes for esophageal varices with bleeding, ascites and/or spontaneous bacterial peritonitis. The association between statin use and decompensation and death was estimated using cox proportional hazards model with adjustment for age + Child score and age + MELD score. Results: Among 40,512 patients with HCV compensated cirrhosis (98% male, median age 56 years), 2,802 statin users were identified. From this group 685 statin users were propensity score matched with 2,062 non-users. Discrimination of propensity score model was excellent (c = 0.92). The figure shows plots of time to decompensation (A) or death (B) by statin use in the matched cohort. Statin use was associated with lower risk of decompensation [HR 0.55 (95% CI 0.39, 0.77)] or death [HR 0.56 (95% CI 0.46, 0.69)] compared to non-users. These findings persisted after adjustment for age + Child score [decompensation HR 0.53 (95% CI 0.37, 0.74); death HR 0.54 (95% CI 0.44, 0.66)] or age + MELD score [decompensation HR 0.53 (95% CI 0.38, 0.75); death HR 0.54 (95% CI 0.44, 0.66)]. Conclusions: Statin use in U.S. Veterans with HCV compensated cirrhosis is associated with over 40% lower risk of hepatic decompensation and death.
by a daily NSBB dose ≥80 mg or <80 mg, a MELD score ≥18 or <18, a mean arterial pressure ≥82 mmHg or <82 mmHg, or with or without a history of spontaneous bacterial peritonitis: NSBB use did not increase mortality in any of these subgroups. Conclusions: NSBB use did not affect mortality in these cirrhosis patients with ascites.
O074 A METABOLOMIC STUDY OF SERUM FROM PATIENTS WITH CIRRHOSIS IDENTIFIES 2 METABOLITES THAT ACCURATELY PREDICT THE ACUTE HVPG RESPONSE TO b-BLOCKER THERAPY
O073 NON-SELECTIVE BETA-BLOCKERS AND MORTALITY IN CIRRHOSIS PATIENTS WITH OR WITHOUT REFRACTORY ASCITES: POST HOC ANALYSIS OF THREE LARGE RCT’S WITH 1198 PATIENTS L. Bossen1,2 , A. Krag3 , H. Vilstrup1 , H. Watson4 , P. Jepsen1,2 . 1 Department of Hepatology and Gastroenterology, 2 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3 Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; 4 Sanofi Aventis R&D, Sanofi, Paris, France E-mail: [email protected]
E. Reverter1,2 , J.J. Lozano2 , C. Alonso3 , A. Berzigotti1,2 , S. Seijo1,2 , F. Turon1,2 , M.L. Mart´ınez-Chantar4 , J. Mar´ıa Mato4 , V. Hernandez´ Gea1,2 , J. Bosch1,2 , J.C. Garc´ıa-Pagan ´ 1,2 . 1 Hepatic Hemodynamic Laboratory, Liver Unit, IDIBAPS. Hospital Cl´ınic, 2 Centro de Invetigaciones en Red de Enfermedades Hep´ aticas y Digestivas (CIBERehd), Barcelona, 3 OWL Genomics, 4 CIC bioGUNE, Bizkaia, Spain E-mail: [email protected]
Background and Aims: Non-selective b-blockers (NSBB) are the standard treatment to prevent bleeding from esophageal varices, but their safety in patients with refractory ascites has been questioned. We used data from randomised trials to examine the effect of NSBB on mortality in cirrhosis patients with or without refractory ascites. Methods: In 2006–2008, 1198 patients were enrolled in three multicentre randomised trials to determine the efficacy of satavaptan in treating ascites. Two of the trials were stopped early, but even so all participants’ vital status was assessed after the planned 52 weeks of treatment. We used these data to compare the mortality of NSBB users vs. non-users. With Cox regression we adjusted for confounding by age, gender, MELD score, Child– Pugh score, serum sodium, history of variceal bleeding, cirrhosis aetiology and refractory ascites. Results: NSBB users (n = 562) were more likely than non-users (n = 636) to have a history of variceal bleeding (30% vs. 13%), but they were less likely to have Child–Pugh class C cirrhosis (class A/B/C = 8%/68%/24% vs. 8%/64%/28%) or refractory ascites (46.4% vs. 52.5% among non-users of NSBB). MELD scores (median 12 [IQR 8–15] vs. 11 [IQR 8–15]) and serum sodium (median 137 [IQR 134–140] vs. 136 [IQR 133–139]) were similar in the two groups. During the follow-up (median follow-up for survival = 52.5 weeks) 129 NSBB users and 163 non-users died, and the cumulative mortality was 24.2% vs. 27.1%. Confounder adjustment did not change this overall impression that NSBB use did not affect mortality (adjusted HR = 0.92, 95% CI 0.72 to 1.18). When we examined patients with refractory ascites separately, NSBB use still had no effect on mortality (n = 595, adjusted HR = 1.02, 95% CI 0.74 to 1.39). Nor did it affect mortality among patients with diureticresponsive ascites (n = 603, adjusted HR = 0.78, 95% CI 0.53 to 1.16) (Figure). We also examined the effect of NSBB in subgroups defined
Background and Aims: Complications of cirrhosis (ascites, encephalopathy, variceal bleeding) are related to the presence of portal hypertension (PHT). A decrease in hepatic venous pressure gradient (HVPG) greater than 10% (HVPG responders) after the acute i.v. administration of propranolol is associated with a lower risk for these complications to appear and with a better survival. However, only about a half of patients are HVPG responders to propranolol and, up to now, there are not non-invasive markers to identify them. Thus, an invasive study of HVPG is needed. The present study aims at identifying a metabolomic serum profile in patients with cirrhosis and PHT that allows predicting a good HVPG response to acute i.v. propranolol. Methods: 40 patients with cirrhosis (Child–Pugh A/B/C=21/12/7) and HVPG≥10 mmHg, in whom HVPG response to i.v. propranolol was assessed, were prospectively included. HVPG was measured at baseline and 20 minutes after i.v. propranolol (0.15 mg/kg). A targeted metabolomic analysis of serum samples using UPLC-MS (ultra-performance liquid chromatography coupled to mass spectrometry; 562 metabolites) was performed. The best combination of metabolites to identify HVPG responders (HVPG reduction >10%) was obtained using stepwise logistic regression (LR) from the subset of metabolites with a p value <0.1. Baseline clinical variables associated to a good response to propranolol were also studied. Results: 25 of 40 patients (63%) were HVPG responders. The metabolomic study identified 65 metabolites that were significantly different among HVPG responders and non-responders. LR analysis identified 2 lipidic metabolites that showed a good prediction of the response to propranolol (AUC=0.872, CI=0.754–0.989), being a robust model at internal cross-validation (mean AUC 0.841). This model had a specificity of 80%, sensibility of 84%, Positive PV of 88% and Negative PV of 75% to identify HVPG responders, with a
Journal of Hepatology 2015 vol. 62 | S213–S234
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Cirrhosis and complications 1 O072 STATIN USE SIGNIFICANTLY DECREASES DECOMPENSATION AND DEATH IN VETERANS WITH HEPATITIS C-RELATED COMPENSATED CIRRHOSIS A. Mohanty1,2 , J.P. Tate3,4 , G. Garcia-Tsao1,2 . 1 Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, 2 Section of Digestive Diseases, Yale School of Medicine, New Haven, 3 Department of Internal Medicine, VA Connecticut Healthcare System, West Haven, 4 Department of Internal Medicine, Yale School of Medicine, New Haven, United States E-mail: [email protected] Background and Aims: Statin use has been shown to decrease portal pressure in patients with cirrhosis, and improve survival in patients who have bled from varices. However, the long-term effect of statin use on cirrhosis decompensation and mortality in patients with compensated cirrhosis is unknown. Aim: To study the effect of statin use on decompensation and mortality in hepatitis C virus (HCV)-infected patients with compensated cirrhosis. Methods: Using the Veteran Affairs clinical case registry from 01/1996 to 12/2009 (n = 342,157), we identified a cohort of HCV mono-infected patients with compensated cirrhosis and no statin use at baseline. New statin users (median time of use was 2.8 years) were propensity matched to up to 5 non-users. The propensity score was created using variables associated with statin prescription: demographics, calendar year of index visit, site of statin prescription, site prescribing pattern, number and type of lipid tests, laboratory data including liver tests, and
Journal of Hepatology 2015 vol. 62 | S213–S234
ORAL PRESENTATIONS comorbid conditions. As previously validated, decompensation was defined by the presence of one inpatient or two outpatient ICD-9 codes for esophageal varices with bleeding, ascites and/or spontaneous bacterial peritonitis. The association between statin use and decompensation and death was estimated using cox proportional hazards model with adjustment for age + Child score and age + MELD score. Results: Among 40,512 patients with HCV compensated cirrhosis (98% male, median age 56 years), 2,802 statin users were identified. From this group 685 statin users were propensity score matched with 2,062 non-users. Discrimination of propensity score model was excellent (c = 0.92). The figure shows plots of time to decompensation (A) or death (B) by statin use in the matched cohort. Statin use was associated with lower risk of decompensation [HR 0.55 (95% CI 0.39, 0.77)] or death [HR 0.56 (95% CI 0.46, 0.69)] compared to non-users. These findings persisted after adjustment for age + Child score [decompensation HR 0.53 (95% CI 0.37, 0.74); death HR 0.54 (95% CI 0.44, 0.66)] or age + MELD score [decompensation HR 0.53 (95% CI 0.38, 0.75); death HR 0.54 (95% CI 0.44, 0.66)]. Conclusions: Statin use in U.S. Veterans with HCV compensated cirrhosis is associated with over 40% lower risk of hepatic decompensation and death.
by a daily NSBB dose ≥80 mg or <80 mg, a MELD score ≥18 or <18, a mean arterial pressure ≥82 mmHg or <82 mmHg, or with or without a history of spontaneous bacterial peritonitis: NSBB use did not increase mortality in any of these subgroups. Conclusions: NSBB use did not affect mortality in these cirrhosis patients with ascites.
O074 A METABOLOMIC STUDY OF SERUM FROM PATIENTS WITH CIRRHOSIS IDENTIFIES 2 METABOLITES THAT ACCURATELY PREDICT THE ACUTE HVPG RESPONSE TO b-BLOCKER THERAPY
O073 NON-SELECTIVE BETA-BLOCKERS AND MORTALITY IN CIRRHOSIS PATIENTS WITH OR WITHOUT REFRACTORY ASCITES: POST HOC ANALYSIS OF THREE LARGE RCT’S WITH 1198 PATIENTS L. Bossen1,2 , A. Krag3 , H. Vilstrup1 , H. Watson4 , P. Jepsen1,2 . 1 Department of Hepatology and Gastroenterology, 2 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3 Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; 4 Sanofi Aventis R&D, Sanofi, Paris, France E-mail: [email protected]
E. Reverter1,2 , J.J. Lozano2 , C. Alonso3 , A. Berzigotti1,2 , S. Seijo1,2 , F. Turon1,2 , M.L. Mart´ınez-Chantar4 , J. Mar´ıa Mato4 , V. Hernandez´ Gea1,2 , J. Bosch1,2 , J.C. Garc´ıa-Pagan ´ 1,2 . 1 Hepatic Hemodynamic Laboratory, Liver Unit, IDIBAPS. Hospital Cl´ınic, 2 Centro de Invetigaciones en Red de Enfermedades Hep´ aticas y Digestivas (CIBERehd), Barcelona, 3 OWL Genomics, 4 CIC bioGUNE, Bizkaia, Spain E-mail: [email protected]
Background and Aims: Non-selective b-blockers (NSBB) are the standard treatment to prevent bleeding from esophageal varices, but their safety in patients with refractory ascites has been questioned. We used data from randomised trials to examine the effect of NSBB on mortality in cirrhosis patients with or without refractory ascites. Methods: In 2006–2008, 1198 patients were enrolled in three multicentre randomised trials to determine the efficacy of satavaptan in treating ascites. Two of the trials were stopped early, but even so all participants’ vital status was assessed after the planned 52 weeks of treatment. We used these data to compare the mortality of NSBB users vs. non-users. With Cox regression we adjusted for confounding by age, gender, MELD score, Child– Pugh score, serum sodium, history of variceal bleeding, cirrhosis aetiology and refractory ascites. Results: NSBB users (n = 562) were more likely than non-users (n = 636) to have a history of variceal bleeding (30% vs. 13%), but they were less likely to have Child–Pugh class C cirrhosis (class A/B/C = 8%/68%/24% vs. 8%/64%/28%) or refractory ascites (46.4% vs. 52.5% among non-users of NSBB). MELD scores (median 12 [IQR 8–15] vs. 11 [IQR 8–15]) and serum sodium (median 137 [IQR 134–140] vs. 136 [IQR 133–139]) were similar in the two groups. During the follow-up (median follow-up for survival = 52.5 weeks) 129 NSBB users and 163 non-users died, and the cumulative mortality was 24.2% vs. 27.1%. Confounder adjustment did not change this overall impression that NSBB use did not affect mortality (adjusted HR = 0.92, 95% CI 0.72 to 1.18). When we examined patients with refractory ascites separately, NSBB use still had no effect on mortality (n = 595, adjusted HR = 1.02, 95% CI 0.74 to 1.39). Nor did it affect mortality among patients with diureticresponsive ascites (n = 603, adjusted HR = 0.78, 95% CI 0.53 to 1.16) (Figure). We also examined the effect of NSBB in subgroups defined
Background and Aims: Complications of cirrhosis (ascites, encephalopathy, variceal bleeding) are related to the presence of portal hypertension (PHT). A decrease in hepatic venous pressure gradient (HVPG) greater than 10% (HVPG responders) after the acute i.v. administration of propranolol is associated with a lower risk for these complications to appear and with a better survival. However, only about a half of patients are HVPG responders to propranolol and, up to now, there are not non-invasive markers to identify them. Thus, an invasive study of HVPG is needed. The present study aims at identifying a metabolomic serum profile in patients with cirrhosis and PHT that allows predicting a good HVPG response to acute i.v. propranolol. Methods: 40 patients with cirrhosis (Child–Pugh A/B/C=21/12/7) and HVPG≥10 mmHg, in whom HVPG response to i.v. propranolol was assessed, were prospectively included. HVPG was measured at baseline and 20 minutes after i.v. propranolol (0.15 mg/kg). A targeted metabolomic analysis of serum samples using UPLC-MS (ultra-performance liquid chromatography coupled to mass spectrometry; 562 metabolites) was performed. The best combination of metabolites to identify HVPG responders (HVPG reduction >10%) was obtained using stepwise logistic regression (LR) from the subset of metabolites with a p value <0.1. Baseline clinical variables associated to a good response to propranolol were also studied. Results: 25 of 40 patients (63%) were HVPG responders. The metabolomic study identified 65 metabolites that were significantly different among HVPG responders and non-responders. LR analysis identified 2 lipidic metabolites that showed a good prediction of the response to propranolol (AUC=0.872, CI=0.754–0.989), being a robust model at internal cross-validation (mean AUC 0.841). This model had a specificity of 80%, sensibility of 84%, Positive PV of 88% and Negative PV of 75% to identify HVPG responders, with a
Journal of Hepatology 2015 vol. 62 | S213–S234
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