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Sa1003 Mechanisms Underlying Deoxycholylglycine (DCG)-Induced Reduction of Vascular Tone in Rat Resistance Mesenteric Arteries
Sa1000
Table 2: Bivariate and Multivariate Regression Results
Medications Affecting the Autonomic Nervous System (ANS) Do Not Explain Abnormal Diastolic Blood Pressure in Patients With Chronic Hepatitis C (ChC) or Non-Alcoholic Fatty Liver Disease (NAFLD) Jillian K. Price, Carey Escheik, Ali A. Weinstein, Patrice M. Winter, Zareen Arsalla, Lynn Gerber, Zobair M. Younossi Background: Previous work has shown that high resting diastolic blood pressure in patients with liver disease is associated with low levels of physical performance. Anti-hypertensive medications and some other commonly prescribed anti-depression medications can influence the ANS and, in part, may be able to explain these findings. Aim: The purpose of this analysis was to determine whether medication influencing ANS activity such as beta-2 adrenergic agonists may be significantly associated with abnormal diastolic blood pressure in patients with CH-C and NAFLD. Methods: 47 subjects (62% male, 45% NAFLD, 55% HCV, age 50.5 ± 9.0, BMI 31.5 ± 5.8, 59% obese; 37% diagnosed hypertension, 35% hyperlipidemia, 24% diabetes mellitus, 22% metabolic syndrome, AST 50.2 ± 36.5, ALT 58.0 ± 39.0) were enrolled. Current medications of CH-C and NAFLD patients were categorized by mechanism of action and indication along with clinico-demographic information. Pearson's correlation and regression of diastolic blood pressure was run. Results: 27.3% of patients had elevated diastolic blood pressure at baseline. Of these patients, 17.6% were not taking antihypertensive medications, 76.5% were not taking any medications to increase ANS activity. As expected, the use of anti-hypertension medications were diffierent between those diagnosed with hypertension and those without hypertension (p=0.0001). On the other hand, the prevalence of beta-2 adrenergic agonists was not significantly different between the two groups(p=.642). Pearson's correlation showed no significant correlations between diastolic blood pressure and any medication indication. No correlation existed between diastolic blood pressure and either beta-2 adrenergic agonists (r=0.083) or medications with known ANS effects (r=0.071). The medication model of diastolic blood pressure (All current medications = GERD/digestion + depression/sleep + antihypertensive + GABA/anxiety + diabetes + allergy/asthma/pulmonary + hyperlipidemia/hypercholesterolemia + beta2 adrenergic agonists + supplements/other) did not show any correlation (r= 0.266, p=0.427). Conclusions: The presence of beta-2 adrenergic agonists and medications with ANS activity does not significantly impact diastolic pressure in patients with chronic liver diseases. In these patients, the majority of diastolic blood pressure variance cannot be explained by medication. This data suggest that diastolic blood pressure abnormality in chronic liver disease is related to other currently unknown reasons.
Sa1002
Background: Esophageal variceal bleeding is a life-threatening complication of cirrhotic liver disease, currently managed by endoscopic band ligation. Among patients who survive primary variceal hemorrhage, re-breeding is common so repeat surveillance endoscopy is recommended until varices obliteration. Little data exists regarding compliance with surveillance endoscopy recommendations. Aim: To characterize compliance rates with surveillance endoscopy following primary band ligation and of its potential impact on re-bleeding rates Method: We conducted a retrospective study of patients with cirrhosis and esophageal varices who underwent esophageal variceal ligation (EVL) at Parkland Hospital between Jan 2008 and March 2012. Eligible patients were identified using ICD9 codes for esophageal varices, with or without bleeding. Patients with incomplete data were excluded from the analysis. Clinical, radiological and laboratory data were reviewed and extracted in a standard database. We recorded dates of primary and follow-up EVL, with timely follow-up EVL being defined as repeat EVL within 30 days. Univariate and multivariate logistic regression was used to identify predictors of timely follow-up EVL and re-bleeding. Results: We identified 234 patients who underwent EVL for bleeding esophageal varices, of whom 44 were excluded for incomplete data. Median age was 49 (IQR 44 - 56) years and 78% were male. The cohort was diverse with respect to race/ethnicity (58% Hispanic, 28% White 28%, and 13% Black). Repeat EVL was performed in only 139 (73%) patients. Of those with follow-up EV, median time to follow-up was 31 days, with timely follow-up EVL being done in 67 (35%) patients. Timely follow-up EVL was less likely among Black patients (OR 0.04, 95%CI 0.10 - 0.87). Re-bleeding occurred in 65 (34%) patients, occurring a with median of 89 (IQR 21 - 236) days after primary EVL. Re-bleeding was significantly associated wtih active alcohol abuse (OR 0.42, 95%CI 0.21 - 0.83), year of presentation (0.52, 95%CI 0.36 - 0.75), and having timely follow-up EVL (OR 0.41, 95%CI 0.20 - 0.84). Patients with timely follow-up EVL had re-bleeding in 43.0 % of cases, compared to 29 % in those with delayed follow-up EVL. Conclusion: Less than 1 of 4 patients who present with variceal bleeding undergoes timely repeat EVL, leading to higher rates of re-bleeding and worse outcomes. Interventions are needed to improve rates and timing of repeat variceal banding.
Sa1001 Blood Transfusion Is Associated With Increased Mortality in Upper Gastrointestinal Hemorrhage Due to Varices: A Nationwide Study Gaurav Arora, Samir Gupta, Don C. Rockey Background & Objective: Upper gastrointestinal hemorrhage (UGIH) remains a common problem associated with substantial morbidity and mortality. The current standard of care is to support patients with volume, typically with the use of blood products, and to treat bleeding lesions endoscopically. However, in certain clinical settings, including operative and trauma, blood transfusion has been associated with excess mortality. While the use of blood products is a logical step in the care of GIH patients, we have noticed transfusion overuse. Further, in the case of UGIH secondary to varices, some have suggested that overtransfusion might lead to increased portal pressure and an increased risk of bleeding and adverse outcomes. Therefore, we hypothesized that blood transfusion might be associated with increased risk for mortality in the setting of UGIH. Methods: We used the Nationwide Inpatient Sample database which is a 20% stratified sample of all inpatient hospitalizations in the United States and represents the total population. Using ICD-9 codes specific to UGIH, we extracted all records from the year 2006 for variceal and non-variceal GIH (analyzed separately); presence of shock and comorbid conditions was similarly identified. The primary outcome measure was in-hospital mortality. The primary independent variable was transfusion of blood or blood products (transfusion). Other analytic variables included age, gender, Charlson comorbidity index and shock. All reported frequencies are weighted. Bivariate and multivariate logistic regression incorporating strata, clusters and weights to account for the complex nature of the database were used. Results: We identified 447,906 patients with UGIH: 37,759 variceal and 410,147 non-variceal (Table 1). Patients with nonvariceal bleeding were more likely to be older, but less likely to be male compared to those with variceal bleeding. Shock was the strongest predictor of mortality regardless of the type of UGIH, and was more prevalent in patients receiving transfusion (Table 2). On multivariate analyses adjusted for age, gender, presence of shock, and Charlson comorbidity index score, mortality was higher among patients receiving transfusion in variceal, but not in non-variceal bleeding cohort (Table 2). Conclusion: In a large cohort of patients with UGIH, we identified previous well known predictors of mortality such as age, gender, comorbidity burden, and the presence of shock. Further, we found that blood transfusion was an independent predictor of mortality among patients with variceal, but not non-variceal hemorrhage. These data point out an opportunity to improve the quality of care of patients with UGIH. Table 1: Baseline Characteristics of the Variceal and Non-variceal Hemorrhage Cohorts
Sa1003 Mechanisms Underlying Deoxycholylglycine (DCG)-Induced Reduction of Vascular Tone in Rat Resistance Mesenteric Arteries Ravirajsinh Jadeja, Jean-Pierre Raufman, Thomas Pallone, Sandeep Khurana The mechanisms underlying systemic vasodilation, a major contributor to morbidity in cirrhosis, are poorly understood. In cirrhosis, the bile acid (BA) pool shifts to the systemic circulation; previously we showed that DCG, the glycine conjugate of deoxycholic acid, causes reversible, endothelium-independent, Ca2+-dependent reduction in vascular tone (PLoS ONE 7(2):e32006, 2012 ). To investigate further the mechanisms underlying DCGmediated reduction of vascular tone, we assessed the effects of DCG on U46619 (thromboxane analogue)- and phorbol myristate acetate (PMA, a PKC activator)-induced vasoconstriction in pressurized rat resistance mesenteric arteries (luminal diameter: 170-275 microns) using videomicroscopy. To assess myogenic response, we incubated arteries with drugs ± DCG and subjected them to intraluminal pressure steps from 20 to 100 mmHg for 5 min/pressure step. The pressure-response was repeated in Ca2+-free physiological salt solution (PSS) with 3 mM EGTA and 0.1 mM sodium nitroprusside; myogenic tone was calculated as percent difference in diameter for Ca2+-containing vs. Ca2+-free PSS at each pressure. At 70 mmHg, arterial preparations developed spontaneous constriction, ∼25% of passive diameter (PD, P,0.001 ). U46619 (10 μM) induced marked vasoconstriction ( ∼72% of PD, P,0.001) that was reduced by DCG (0.3-100 μM) in a dose-dependent manner (maximal dilatation ∼50%, P,0.001). To identify the contribution of voltage-gated Ca2+ channels (VGCC) and Rho kinase in vasoconstriction, we measured effects of U46619 in the presence of 30 μM diltiazem (VGCC blocker), 10 μM Y27632 (a Rho kinase inhibitor) alone and in combination; Diltiazem, Y27632 and their combination reduced vasoconstriction to ∼34%, 47% and 16% (all P,0.01) of PD respectively, indicating that in rat mesenteric resistance arteries U46619-induced vasoconstriction is predominantly mediated by VGCC and Rho kinase activation. To elucidate their role in DCG-mediated vasodilation we assessed the effect of DCG on U46619-induced vasoconstriction in the presence of diltiazem and Y27632. Despite the presence of diltiazem or Y27632 alone, DCG induced vasodilation in a dose-dependent (0.3-100 μM) manner (∼90%, P,0.001 and ∼80%, P=0.004, respectively). However in arteries incubated with both diltiazem plus Y27632, DCG (0.3-100 μM)-induced vasodilation was only ∼10% (P,0.05). These data indicate that in rat mesenteric resistance arteries, DCG reduces vascular tone predominantly by inhibiting VGCC and Rho kinase activation. PMA (0.05 μM)-induced
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AASLD Abstracts
AASLD Abstracts
Delayed Repeat Esophageal Variceal Banding Is Associated With Higher Rates of Re-Bleeding Mahendra S. Nehra, Don C. Rockey, Amit G. Singal
vasoconstriction was ∼60% of PD (P,0.001), however DCG did not alter PMA-induced vasoconstriction or myogenic response. These data provide novel mechanistic insight into BA-mediated regulation of vascular tone and suggest potential therapeutic targets to reduce systemic vasodilation in cirrhosis. Sa1004
AASLD Abstracts
Celecoxib Ameliorated Fibrosis and Portal Pressure Through Antiangiogenesis in Cirrhotic Rats Jinhang Gao, Shilei Wen, Wenjuan Yang, Yaoyao Lu, Chengwei Tang Background: Liver cirrhosis is inevitable outcome triggered by consistent chronic inflammation. Recent studies have implied that liver cirrhosis accompanied with angiogenesis. Our previous studies demonstrated that celecoxib could reduce angiogenesis in hepatocellular carcinoma and gastric adenocarcinoma. However, the effect of celecoxib on the antiangiogenesis of cirrhotic liver is still controversial. Objective: To investigate the effect of celecoxib on angiogenesis of cirrhotic liver. Methods: Peritoneal injection of thiacetamide (TAA) was employed to induce liver cirrhosis (200 mg/kg every three days × 16 weeks). 36 male Sprague-Dawley rats were assigned to three groups: group 1 (TAA + celecoxib, n = 12) received TAA plus celecoxib (20 mg/kg/day) by gavage from the initiation of TAA administration on, group 2 (TAA, n = 12) received TAA plus placebo and group 3 (Control, n = 12) received injections of 0.9% saline (1mL i.p., every three days). Serum biochemistry for liver and kidney function parameters and serum prostaglandin E2 (PGE2) were determined. Portal pressure and mean artery pressure were also measured. Histopathological study and vascular casting by scanning electron microscope (SEM) of liver vascular were performed. Additionally, immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blot for CD31, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and Cyclooxygenase-2 (COX-2) were determined. Results: Compared with TAA group, the fibrotic areas of liver tissues in TAA+celecoxib group were significantly decreased by one fold (20.8 ± 1.5% vs. 10.6 ± 0.9%, p , 0.001). Histological sections, vascular casts of hepatic portal vein by SEM, IHC and qRT-PCR for CD31 showed that hepatic fibrosis was accompanied with significant neoangiogenesis in TAA group when compared with Control group (0.1502 ± 0.0143 vs. 0.0325 ± 0.0086 mm2, p , 0.001). Impressively, the increased vascular areas were greatly reduced after celecoxib treatment (0.0485 ± 0.0097 vs. 0.1502 ± 0.0143 mm2, p , 0.001). The up-regulation of VEGF and VEGFR-2, COX-2 and PGE2 induced by TAA administration were significantly inhibited after celecoxib treatment. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8% (14.88 ± 0.84 vs. 12.23 ± 1.09 mmHg, p , 0.001). No significant differences in arterial pressure, heart rate and liver and kidney function parameters were observed among three groups (p . 0.05). Conclusions: Anti-angiogenesis therapy with celecoxib ameliorated hepatic angiogenesis, portal pressure as well as fibrosis. This result suggested that celecoxib would be beneficial for the treatment of liver cirrhosis.
Sa1006 Effectiveness of Oral Antiviral Therapy for Treatment-Naive Chronic Hepatitis B (CHB) in Routine Clinical Practice Mindie H. Nguyen, Huy N. Trinh, Kevin T. Chaung, Vincent G. Nguyen, Hong Tang, Timothy Juday Purpose: Lamivudine (LAM), adefovir (ADV), entecavir (ETV) and tenofovir (TDF) are 4 commonly used agents for CHB though more recently, given their higher potency and lack of significant viral resistance of long-term therapy, ETV and TDF have become the recommended first-line therapy over the older agents such as LAM and ADV. However, it is not clear whether the effectiveness of ETV and TDF in routine clinical setting is similar to the efficacy reported from pivotal registration trials since study patients are generally more motivated and are followed much more closely with strict protocol and requirement of adherence. The goals of this study were to examine the treatment outcomes of antiviral therapy for CHB in a routine clinical setting. Methods: Using ICD-9 query, 845 consecutive treatment-naive patients undergoing therapy in 3 U.S. liver clinics from 1/2001-1/2011 were identified: LAM=93, ADV=198, ETV=447, TDF=107. Primary study endpoint was complete viral suppression rate (undetectable HBV DNA of , 40-60 IU/mL) at end of month 12 and was analyzed using Kaplan-Meier method and log-rank test. Results: The majority of patients were Asians (99%), male (64%) and hepatitis B e antigen negative (63%) with mean age of 47±13 years. Baseline HBV DNA were similar between the groups (6.1-6.27 log IU/mL±1.561.64 log IU/mL) except for lower level in the ADV group (5.68±1.32 log IU/mL). Complete viral suppression rates at 12 months were significantly different among the treatment groups: 39% for LAM, 54% for ADV, 75% for ETV, and 81% for TDF (Figure 1); however, complete viral suppression rates between ETV and TDF groups were not statistically different (p= 0.416). ETV or TDF patients had similar median ALT (59 [6-1237] vs. 51 [6-1405] U/L) and mean HBV DNA (6.10±1.59 vs. 6.14±1.56 log10 IU/mL). Cumulative rates of virologic breakthrough were 2.5% for ETV and 8.6% for TDF at 12 months, and all were due to either confirmed or presumed nonadherence. Conclusion: Treatment outcomes were clearly favorable with newer agents (ETV and TDF) compared to old agents (LAM and ADV). In this study cohort, complete viral suppression rates were similar for TDF and ETV in the first 12 months and were approximately 80%. Antiviral therapy with either ETV or TDF is highly effective in suppressing HBV viral replication, and nonadherence is the primary cause of treatment failure, not viral resistance, up to 8-9% after only 12 months. Further patient education and close clinical monitoring by care providers are needed to improve patient adherence to anti-HBV therapy, which is long-term or even life-long in the majority of cases.
Sa1005 Antiviral Treatment Eligibility and Treatment Rates in Patients With Chronic Hepatitis B (CHB) At Primary Care, Community and University Referral Clinics: A Comparative Study Lily H. Kim, Vincent G. Nguyen, Huy N. Trinh, Jiayi Li, Jian Q. Zhang, Mindie H. Nguyen Introduction: Professional guidelines recommend antiviral therapy for CHB patients who meet treatment criteria; however, data on how such guidelines are being applied in different real-life clinical settings is limited. Our goals were to evaluate the proportion of treatmenteligible patients by 6-month follow-up and of those who actually initiated therapy by 12month follow-up in such settings. Methods: This is a retrospective cohort study of 1976 consecutive treatment-naïve CHB patients evaluated between March 2007 - March 2011 at 2 single-specialty and 2 multi-specialty medical centers in the U.S.: 329 at community primary care clinics (Group 1), 1,268 at community gastroenterology clinics (Group 2), and 379 at university liver clinics (Group 3). Treatment eligibility was based on the US panel 2008 and the AASLD 2009 guidelines. Results: Group 1, 2, and 3 had similar mean age (44-45), similar gender distribution (50-55% male), and were mostly Asian (99% vs. 97% vs. 88%, p,0.001, respectively). More patients had cirrhosis in Group 3 (8%) than in Groups 2 (3%) and 1 (2%) (p ,0.001). While Group 2 had the highest median baseline HBV DNA levels (4.5 vs. 4.1 vs. 4.0 log IU/mL, p=0.0053) and HBeAg+ rate (26% vs. 17% vs. 14%, p=0.0021) compared to Group 3 and Group 1, Group 3 had significantly higher median ALT level compared to Group 2 and Group 1: 42 (10-2809) vs. 33 (2-1582) vs. 29 (7-307) U/L, p=0.0012.Group 2 and Group 3 had similar rates of treatment-eligibility by both US Panel (53-54%) and AASLD guidelines (24-25%) (Figure). Treatment rates were also similar between these 2 groups by AASLD guideline (68% vs. 73%, p=0.35) but was significantly higher in Group 3 by US Panel guideline (59% vs. 45%, p=0.001). Both treatment-eligibility and treatment rates were significantly lower in Group 1 compared to either Group 2 or 3. Only 25% of US Panel and 50% of AASLD treatment-eligible patients in Group 1 received therapy. The main reasons for non-treatment in all 3 groups were patients' request and/or physicians' recommendation for further observation and ALT perceived to be within normal range. Conclusions: Only a quarter to half of treatment-eligible patients evaluated in primary care clinics receive antiviral therapy by 12-month follow-up. Treatment rates in tertiary care liver clinics were higher than in community gastroenterology clinics whose rate was in turn higher than that of primary care clinic. However, treatment rates were still only 60-70% even in tertiary care clinics. Additional studies are needed to better understand such treatment disparity and to improve the management of CHB patients in all clinical settings.
AASLD Abstracts
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Table 2: Bivariate and Multivariate Regression Results
Medications Affecting the Autonomic Nervous System (ANS) Do Not Explain Abnormal Diastolic Blood Pressure in Patients With Chronic Hepatitis C (ChC) or Non-Alcoholic Fatty Liver Disease (NAFLD) Jillian K. Price, Carey Escheik, Ali A. Weinstein, Patrice M. Winter, Zareen Arsalla, Lynn Gerber, Zobair M. Younossi Background: Previous work has shown that high resting diastolic blood pressure in patients with liver disease is associated with low levels of physical performance. Anti-hypertensive medications and some other commonly prescribed anti-depression medications can influence the ANS and, in part, may be able to explain these findings. Aim: The purpose of this analysis was to determine whether medication influencing ANS activity such as beta-2 adrenergic agonists may be significantly associated with abnormal diastolic blood pressure in patients with CH-C and NAFLD. Methods: 47 subjects (62% male, 45% NAFLD, 55% HCV, age 50.5 ± 9.0, BMI 31.5 ± 5.8, 59% obese; 37% diagnosed hypertension, 35% hyperlipidemia, 24% diabetes mellitus, 22% metabolic syndrome, AST 50.2 ± 36.5, ALT 58.0 ± 39.0) were enrolled. Current medications of CH-C and NAFLD patients were categorized by mechanism of action and indication along with clinico-demographic information. Pearson's correlation and regression of diastolic blood pressure was run. Results: 27.3% of patients had elevated diastolic blood pressure at baseline. Of these patients, 17.6% were not taking antihypertensive medications, 76.5% were not taking any medications to increase ANS activity. As expected, the use of anti-hypertension medications were diffierent between those diagnosed with hypertension and those without hypertension (p=0.0001). On the other hand, the prevalence of beta-2 adrenergic agonists was not significantly different between the two groups(p=.642). Pearson's correlation showed no significant correlations between diastolic blood pressure and any medication indication. No correlation existed between diastolic blood pressure and either beta-2 adrenergic agonists (r=0.083) or medications with known ANS effects (r=0.071). The medication model of diastolic blood pressure (All current medications = GERD/digestion + depression/sleep + antihypertensive + GABA/anxiety + diabetes + allergy/asthma/pulmonary + hyperlipidemia/hypercholesterolemia + beta2 adrenergic agonists + supplements/other) did not show any correlation (r= 0.266, p=0.427). Conclusions: The presence of beta-2 adrenergic agonists and medications with ANS activity does not significantly impact diastolic pressure in patients with chronic liver diseases. In these patients, the majority of diastolic blood pressure variance cannot be explained by medication. This data suggest that diastolic blood pressure abnormality in chronic liver disease is related to other currently unknown reasons.
Sa1002
Background: Esophageal variceal bleeding is a life-threatening complication of cirrhotic liver disease, currently managed by endoscopic band ligation. Among patients who survive primary variceal hemorrhage, re-breeding is common so repeat surveillance endoscopy is recommended until varices obliteration. Little data exists regarding compliance with surveillance endoscopy recommendations. Aim: To characterize compliance rates with surveillance endoscopy following primary band ligation and of its potential impact on re-bleeding rates Method: We conducted a retrospective study of patients with cirrhosis and esophageal varices who underwent esophageal variceal ligation (EVL) at Parkland Hospital between Jan 2008 and March 2012. Eligible patients were identified using ICD9 codes for esophageal varices, with or without bleeding. Patients with incomplete data were excluded from the analysis. Clinical, radiological and laboratory data were reviewed and extracted in a standard database. We recorded dates of primary and follow-up EVL, with timely follow-up EVL being defined as repeat EVL within 30 days. Univariate and multivariate logistic regression was used to identify predictors of timely follow-up EVL and re-bleeding. Results: We identified 234 patients who underwent EVL for bleeding esophageal varices, of whom 44 were excluded for incomplete data. Median age was 49 (IQR 44 - 56) years and 78% were male. The cohort was diverse with respect to race/ethnicity (58% Hispanic, 28% White 28%, and 13% Black). Repeat EVL was performed in only 139 (73%) patients. Of those with follow-up EV, median time to follow-up was 31 days, with timely follow-up EVL being done in 67 (35%) patients. Timely follow-up EVL was less likely among Black patients (OR 0.04, 95%CI 0.10 - 0.87). Re-bleeding occurred in 65 (34%) patients, occurring a with median of 89 (IQR 21 - 236) days after primary EVL. Re-bleeding was significantly associated wtih active alcohol abuse (OR 0.42, 95%CI 0.21 - 0.83), year of presentation (0.52, 95%CI 0.36 - 0.75), and having timely follow-up EVL (OR 0.41, 95%CI 0.20 - 0.84). Patients with timely follow-up EVL had re-bleeding in 43.0 % of cases, compared to 29 % in those with delayed follow-up EVL. Conclusion: Less than 1 of 4 patients who present with variceal bleeding undergoes timely repeat EVL, leading to higher rates of re-bleeding and worse outcomes. Interventions are needed to improve rates and timing of repeat variceal banding.
Sa1001 Blood Transfusion Is Associated With Increased Mortality in Upper Gastrointestinal Hemorrhage Due to Varices: A Nationwide Study Gaurav Arora, Samir Gupta, Don C. Rockey Background & Objective: Upper gastrointestinal hemorrhage (UGIH) remains a common problem associated with substantial morbidity and mortality. The current standard of care is to support patients with volume, typically with the use of blood products, and to treat bleeding lesions endoscopically. However, in certain clinical settings, including operative and trauma, blood transfusion has been associated with excess mortality. While the use of blood products is a logical step in the care of GIH patients, we have noticed transfusion overuse. Further, in the case of UGIH secondary to varices, some have suggested that overtransfusion might lead to increased portal pressure and an increased risk of bleeding and adverse outcomes. Therefore, we hypothesized that blood transfusion might be associated with increased risk for mortality in the setting of UGIH. Methods: We used the Nationwide Inpatient Sample database which is a 20% stratified sample of all inpatient hospitalizations in the United States and represents the total population. Using ICD-9 codes specific to UGIH, we extracted all records from the year 2006 for variceal and non-variceal GIH (analyzed separately); presence of shock and comorbid conditions was similarly identified. The primary outcome measure was in-hospital mortality. The primary independent variable was transfusion of blood or blood products (transfusion). Other analytic variables included age, gender, Charlson comorbidity index and shock. All reported frequencies are weighted. Bivariate and multivariate logistic regression incorporating strata, clusters and weights to account for the complex nature of the database were used. Results: We identified 447,906 patients with UGIH: 37,759 variceal and 410,147 non-variceal (Table 1). Patients with nonvariceal bleeding were more likely to be older, but less likely to be male compared to those with variceal bleeding. Shock was the strongest predictor of mortality regardless of the type of UGIH, and was more prevalent in patients receiving transfusion (Table 2). On multivariate analyses adjusted for age, gender, presence of shock, and Charlson comorbidity index score, mortality was higher among patients receiving transfusion in variceal, but not in non-variceal bleeding cohort (Table 2). Conclusion: In a large cohort of patients with UGIH, we identified previous well known predictors of mortality such as age, gender, comorbidity burden, and the presence of shock. Further, we found that blood transfusion was an independent predictor of mortality among patients with variceal, but not non-variceal hemorrhage. These data point out an opportunity to improve the quality of care of patients with UGIH. Table 1: Baseline Characteristics of the Variceal and Non-variceal Hemorrhage Cohorts
Sa1003 Mechanisms Underlying Deoxycholylglycine (DCG)-Induced Reduction of Vascular Tone in Rat Resistance Mesenteric Arteries Ravirajsinh Jadeja, Jean-Pierre Raufman, Thomas Pallone, Sandeep Khurana The mechanisms underlying systemic vasodilation, a major contributor to morbidity in cirrhosis, are poorly understood. In cirrhosis, the bile acid (BA) pool shifts to the systemic circulation; previously we showed that DCG, the glycine conjugate of deoxycholic acid, causes reversible, endothelium-independent, Ca2+-dependent reduction in vascular tone (PLoS ONE 7(2):e32006, 2012 ). To investigate further the mechanisms underlying DCGmediated reduction of vascular tone, we assessed the effects of DCG on U46619 (thromboxane analogue)- and phorbol myristate acetate (PMA, a PKC activator)-induced vasoconstriction in pressurized rat resistance mesenteric arteries (luminal diameter: 170-275 microns) using videomicroscopy. To assess myogenic response, we incubated arteries with drugs ± DCG and subjected them to intraluminal pressure steps from 20 to 100 mmHg for 5 min/pressure step. The pressure-response was repeated in Ca2+-free physiological salt solution (PSS) with 3 mM EGTA and 0.1 mM sodium nitroprusside; myogenic tone was calculated as percent difference in diameter for Ca2+-containing vs. Ca2+-free PSS at each pressure. At 70 mmHg, arterial preparations developed spontaneous constriction, ∼25% of passive diameter (PD, P,0.001 ). U46619 (10 μM) induced marked vasoconstriction ( ∼72% of PD, P,0.001) that was reduced by DCG (0.3-100 μM) in a dose-dependent manner (maximal dilatation ∼50%, P,0.001). To identify the contribution of voltage-gated Ca2+ channels (VGCC) and Rho kinase in vasoconstriction, we measured effects of U46619 in the presence of 30 μM diltiazem (VGCC blocker), 10 μM Y27632 (a Rho kinase inhibitor) alone and in combination; Diltiazem, Y27632 and their combination reduced vasoconstriction to ∼34%, 47% and 16% (all P,0.01) of PD respectively, indicating that in rat mesenteric resistance arteries U46619-induced vasoconstriction is predominantly mediated by VGCC and Rho kinase activation. To elucidate their role in DCG-mediated vasodilation we assessed the effect of DCG on U46619-induced vasoconstriction in the presence of diltiazem and Y27632. Despite the presence of diltiazem or Y27632 alone, DCG induced vasodilation in a dose-dependent (0.3-100 μM) manner (∼90%, P,0.001 and ∼80%, P=0.004, respectively). However in arteries incubated with both diltiazem plus Y27632, DCG (0.3-100 μM)-induced vasodilation was only ∼10% (P,0.05). These data indicate that in rat mesenteric resistance arteries, DCG reduces vascular tone predominantly by inhibiting VGCC and Rho kinase activation. PMA (0.05 μM)-induced
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AASLD Abstracts
AASLD Abstracts
Delayed Repeat Esophageal Variceal Banding Is Associated With Higher Rates of Re-Bleeding Mahendra S. Nehra, Don C. Rockey, Amit G. Singal
vasoconstriction was ∼60% of PD (P,0.001), however DCG did not alter PMA-induced vasoconstriction or myogenic response. These data provide novel mechanistic insight into BA-mediated regulation of vascular tone and suggest potential therapeutic targets to reduce systemic vasodilation in cirrhosis. Sa1004
AASLD Abstracts
Celecoxib Ameliorated Fibrosis and Portal Pressure Through Antiangiogenesis in Cirrhotic Rats Jinhang Gao, Shilei Wen, Wenjuan Yang, Yaoyao Lu, Chengwei Tang Background: Liver cirrhosis is inevitable outcome triggered by consistent chronic inflammation. Recent studies have implied that liver cirrhosis accompanied with angiogenesis. Our previous studies demonstrated that celecoxib could reduce angiogenesis in hepatocellular carcinoma and gastric adenocarcinoma. However, the effect of celecoxib on the antiangiogenesis of cirrhotic liver is still controversial. Objective: To investigate the effect of celecoxib on angiogenesis of cirrhotic liver. Methods: Peritoneal injection of thiacetamide (TAA) was employed to induce liver cirrhosis (200 mg/kg every three days × 16 weeks). 36 male Sprague-Dawley rats were assigned to three groups: group 1 (TAA + celecoxib, n = 12) received TAA plus celecoxib (20 mg/kg/day) by gavage from the initiation of TAA administration on, group 2 (TAA, n = 12) received TAA plus placebo and group 3 (Control, n = 12) received injections of 0.9% saline (1mL i.p., every three days). Serum biochemistry for liver and kidney function parameters and serum prostaglandin E2 (PGE2) were determined. Portal pressure and mean artery pressure were also measured. Histopathological study and vascular casting by scanning electron microscope (SEM) of liver vascular were performed. Additionally, immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blot for CD31, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and Cyclooxygenase-2 (COX-2) were determined. Results: Compared with TAA group, the fibrotic areas of liver tissues in TAA+celecoxib group were significantly decreased by one fold (20.8 ± 1.5% vs. 10.6 ± 0.9%, p , 0.001). Histological sections, vascular casts of hepatic portal vein by SEM, IHC and qRT-PCR for CD31 showed that hepatic fibrosis was accompanied with significant neoangiogenesis in TAA group when compared with Control group (0.1502 ± 0.0143 vs. 0.0325 ± 0.0086 mm2, p , 0.001). Impressively, the increased vascular areas were greatly reduced after celecoxib treatment (0.0485 ± 0.0097 vs. 0.1502 ± 0.0143 mm2, p , 0.001). The up-regulation of VEGF and VEGFR-2, COX-2 and PGE2 induced by TAA administration were significantly inhibited after celecoxib treatment. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8% (14.88 ± 0.84 vs. 12.23 ± 1.09 mmHg, p , 0.001). No significant differences in arterial pressure, heart rate and liver and kidney function parameters were observed among three groups (p . 0.05). Conclusions: Anti-angiogenesis therapy with celecoxib ameliorated hepatic angiogenesis, portal pressure as well as fibrosis. This result suggested that celecoxib would be beneficial for the treatment of liver cirrhosis.
Sa1006 Effectiveness of Oral Antiviral Therapy for Treatment-Naive Chronic Hepatitis B (CHB) in Routine Clinical Practice Mindie H. Nguyen, Huy N. Trinh, Kevin T. Chaung, Vincent G. Nguyen, Hong Tang, Timothy Juday Purpose: Lamivudine (LAM), adefovir (ADV), entecavir (ETV) and tenofovir (TDF) are 4 commonly used agents for CHB though more recently, given their higher potency and lack of significant viral resistance of long-term therapy, ETV and TDF have become the recommended first-line therapy over the older agents such as LAM and ADV. However, it is not clear whether the effectiveness of ETV and TDF in routine clinical setting is similar to the efficacy reported from pivotal registration trials since study patients are generally more motivated and are followed much more closely with strict protocol and requirement of adherence. The goals of this study were to examine the treatment outcomes of antiviral therapy for CHB in a routine clinical setting. Methods: Using ICD-9 query, 845 consecutive treatment-naive patients undergoing therapy in 3 U.S. liver clinics from 1/2001-1/2011 were identified: LAM=93, ADV=198, ETV=447, TDF=107. Primary study endpoint was complete viral suppression rate (undetectable HBV DNA of , 40-60 IU/mL) at end of month 12 and was analyzed using Kaplan-Meier method and log-rank test. Results: The majority of patients were Asians (99%), male (64%) and hepatitis B e antigen negative (63%) with mean age of 47±13 years. Baseline HBV DNA were similar between the groups (6.1-6.27 log IU/mL±1.561.64 log IU/mL) except for lower level in the ADV group (5.68±1.32 log IU/mL). Complete viral suppression rates at 12 months were significantly different among the treatment groups: 39% for LAM, 54% for ADV, 75% for ETV, and 81% for TDF (Figure 1); however, complete viral suppression rates between ETV and TDF groups were not statistically different (p= 0.416). ETV or TDF patients had similar median ALT (59 [6-1237] vs. 51 [6-1405] U/L) and mean HBV DNA (6.10±1.59 vs. 6.14±1.56 log10 IU/mL). Cumulative rates of virologic breakthrough were 2.5% for ETV and 8.6% for TDF at 12 months, and all were due to either confirmed or presumed nonadherence. Conclusion: Treatment outcomes were clearly favorable with newer agents (ETV and TDF) compared to old agents (LAM and ADV). In this study cohort, complete viral suppression rates were similar for TDF and ETV in the first 12 months and were approximately 80%. Antiviral therapy with either ETV or TDF is highly effective in suppressing HBV viral replication, and nonadherence is the primary cause of treatment failure, not viral resistance, up to 8-9% after only 12 months. Further patient education and close clinical monitoring by care providers are needed to improve patient adherence to anti-HBV therapy, which is long-term or even life-long in the majority of cases.
Sa1005 Antiviral Treatment Eligibility and Treatment Rates in Patients With Chronic Hepatitis B (CHB) At Primary Care, Community and University Referral Clinics: A Comparative Study Lily H. Kim, Vincent G. Nguyen, Huy N. Trinh, Jiayi Li, Jian Q. Zhang, Mindie H. Nguyen Introduction: Professional guidelines recommend antiviral therapy for CHB patients who meet treatment criteria; however, data on how such guidelines are being applied in different real-life clinical settings is limited. Our goals were to evaluate the proportion of treatmenteligible patients by 6-month follow-up and of those who actually initiated therapy by 12month follow-up in such settings. Methods: This is a retrospective cohort study of 1976 consecutive treatment-naïve CHB patients evaluated between March 2007 - March 2011 at 2 single-specialty and 2 multi-specialty medical centers in the U.S.: 329 at community primary care clinics (Group 1), 1,268 at community gastroenterology clinics (Group 2), and 379 at university liver clinics (Group 3). Treatment eligibility was based on the US panel 2008 and the AASLD 2009 guidelines. Results: Group 1, 2, and 3 had similar mean age (44-45), similar gender distribution (50-55% male), and were mostly Asian (99% vs. 97% vs. 88%, p,0.001, respectively). More patients had cirrhosis in Group 3 (8%) than in Groups 2 (3%) and 1 (2%) (p ,0.001). While Group 2 had the highest median baseline HBV DNA levels (4.5 vs. 4.1 vs. 4.0 log IU/mL, p=0.0053) and HBeAg+ rate (26% vs. 17% vs. 14%, p=0.0021) compared to Group 3 and Group 1, Group 3 had significantly higher median ALT level compared to Group 2 and Group 1: 42 (10-2809) vs. 33 (2-1582) vs. 29 (7-307) U/L, p=0.0012.Group 2 and Group 3 had similar rates of treatment-eligibility by both US Panel (53-54%) and AASLD guidelines (24-25%) (Figure). Treatment rates were also similar between these 2 groups by AASLD guideline (68% vs. 73%, p=0.35) but was significantly higher in Group 3 by US Panel guideline (59% vs. 45%, p=0.001). Both treatment-eligibility and treatment rates were significantly lower in Group 1 compared to either Group 2 or 3. Only 25% of US Panel and 50% of AASLD treatment-eligible patients in Group 1 received therapy. The main reasons for non-treatment in all 3 groups were patients' request and/or physicians' recommendation for further observation and ALT perceived to be within normal range. Conclusions: Only a quarter to half of treatment-eligible patients evaluated in primary care clinics receive antiviral therapy by 12-month follow-up. Treatment rates in tertiary care liver clinics were higher than in community gastroenterology clinics whose rate was in turn higher than that of primary care clinic. However, treatment rates were still only 60-70% even in tertiary care clinics. Additional studies are needed to better understand such treatment disparity and to improve the management of CHB patients in all clinical settings.
AASLD Abstracts
S-970