- Email: [email protected]
Su1720 Differentiation of Alcoholic Liver Disease From Nonalcoholic Fatty Liver Disease Using a Logistic Regression Model Based on Clinical Parameters
months. Six months data will be available in April 2013. In our study, treatment was well tolerated even in severe cirrhosis. These results should be validated by a large multicentric study. Su1720
AASLD Abstracts
Differentiation of Alcoholic Liver Disease From Nonalcoholic Fatty Liver Disease Using a Logistic Regression Model Based on Clinical Parameters Nobuyuki Toshikuni, Nobuhiko Hayashi, Atsushi Fukumura, Yasuhiro Matsue, Takahiro Minato, Tomoe Nomura, Takashi Saito, Kazuaki Ozaki, Hisakazu Shiroeda, Mutsumi Tsuchishima, Tomiyasu Arisawa, Mikihiro Tsutsumi [Background] A simple method for discriminating alcoholic liver disease (ALD) from nonalcoholic fatty liver disease (NAFLD) could be helpful in the management of fatty liver disease. Although ALD/NAFLD index is known to be useful in Caucasian subjects (Dunn et al. Gastroenterology 2006;131:1057-1063), no corresponding indices for Asian subjects have been reported yet. In this study, we aimed to develop a discrimination index for Japanese subjects using readily available clinical parameters. [Materials and Methods] Between 2009 and 2010, we conducted a nationwide survey for Japanese subjects to evaluate the status of fatty liver disease and collected data from 695 subjects with biopsy-proven ALD (n = 147) or NAFLD (n = 548). The index was developed on the basis of clinical parameters that were significant on multiple logistic regression analysis. [Results] This multivariate analysis identified the following significant parameters: gender, body mass index (BMI), aspartate aminotransferase level/alanine aminotransferase level, γ-glutamyl transpeptidase level, and mean corpuscular erythrocyte volume. Discrimination index greater than 0 was suggestive of ALD and that less than 0 was suggestive of NAFLD. The index had an area under the receiver operating characteristic (ROC) curve of 0.936 (95% confidence interval, 0.910-0.962). For diagnosing ALD, following were the suggested values for assessment: sensitivity, 66.7%; specificity, 96.7%; positive predictive value, 84.5%; and negative predictive value, 91.5%. On the other hand, for diagnosing NAFLD, following were the suggested values for assessment: sensitivity, 96.7%; specificity, 66.7%; positive predictive value, 91.5%; and negative predictive value, 84.5%. The index was validated for use in subgroups classified according to histological findings or BMI. In the simple steatosis group, the sensitivity and specificity for diagnosing ALD were 42.3% and 93.5%, respectively; in the fibrosis group, the sensitivity and specificity for diagnosing ALD were 80.0% and 97.5%, respectively. In the group with BMI ,25 kg/m2, the sensitivity and specificity for diagnosing ALD were 77.2% and 92.2%, respectively; in the group with BMI ≥25 kg/m2, the sensitivity and specificity for diagnosing ALD were 43.5% and 98.7%, respectively. [Conclusions] This index is excellent for differentiating ALD from NAFLD: it is particularly helpful for ruling in ALD and ruling out NAFLD. Thus, we believe that this index should be validated in other Asian populations. Su1721 Liver Related and Overall Mortality of Patients With Alcohol Related Liver Disease Li Zheng, Gregory Trimble, Alita Mishra, Maria Stepanova, James Cooper, Zobair M. Younossi Background and Aim: Although excessive alcohol consumption has been associated with development of chronic liver disease, its impact on patients' mortality is not very clear. The aim of this study was to assess the mortality outcomes of patients with alcohol-related liver disease using population-based data. Methods: Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES III)-mortality linked files. Alcohol consumption was estimated as grams per day. Excessive alcohol use was defined as average daily alcohol consumption of ≥20 grams. Alcohol related liver disease was presumed in participants who reported excessive alcohol use in the past 12 months and had elevated liver enzyme at the time of survey examination in the absence of other chronic liver diseases (negative HCV RNA, negative HBs-Antigen, normal ferritin, and no drug-related liver disease). Multivariate Cox proportional hazards model was utilized to assess the effects of alcohol related liver disease on follow-up time to mortality from all causes, cardiovascular disease, and liver disease. Results: A total of 8,306 participants from NHANES were included. Of these, 1.37% (N=148) fulfilled the criteria for alcohol related liver disease, with an average alcohol consumption of 43.9±3.5 grams per day. Participants with alcohol related liver disease were more likely than their controls to be male (78% vs. 43%), of age 55-64 (21% vs. 12%), Mexican American (12% vs. 5%), smokers (76% vs. 52%), obese (46% vs. 32%), with diabetes or insulin resistance (34% vs. 17%) and hypertension (41% vs. 17%). Mortality follow up data was available after a median time of 178.27 months. Participants with alcohol related liver disease had significantly increased risk for liver-related mortality [adjusted hazard ratio (aHR) 7.06 (95% confidence interval, 2.09-23.79)] but not an increased risk for overall mortality [aHR 1.14 (0.70-1.85)] and cardiovascular mortality [aHR 0.61 (0.113.25)]. Conclusions: Alcohol related liver disease is associated with increased risk of liverrelated mortality but not cardiovascular or overall mortality.
Su1798 A High FIB-4 Score Predicts the Likelihood of Liver Related Outcomes in the General Population Tuyet A. Nguyen, Jonathan P. DeShazo, Arun J. Sanyal BACKGROUND: Chronic liver disease (CLD) affects up to 10% of the world's population. It is often asymptomatic until late in its course and only 10-20% of patients with CLD in the US have been identified. A major barrier to identification of asymptomatic but advanced liver disease (bridging fibrosis/cirrhosis) is a lack of a test that identifies such asymptomatic patients at risk of liver-related outcomes in a general outpatient setting. The FIB-4 Index is a simple non-invasive test (based on age, AST, ALT and platelets) that correlates with advanced fibrosis in several types of CLD. HYPOTHESIS: We hypothesized that the FIB-4 Index would identify those who were at increased risk for liver-related outcomes and death in a relatively unselected population within an ambulatory care setting. METHODS: A retrospective cohort analysis of adults in an ambulatory outpatient setting was performed using the Cerner Health Facts® database which is composed of de-identified patient information from the electronic medical record of multiple facilities. Subjects ages 18 years and older, who had a calculable FIB-4 Index, and who had a follow up encounter were included. Those who had a liver transplant or who had already developed liver-related outcomes at the index visit were excluded. The ability of FIB-4 to predict mortality and liver-related outcomes (ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, variceal hemorrhage and hepatocellular cancer) was measured. RESULTS: A total of 2.08 million subjects during 1994-2011 were studied with approximately 1.46 million person-years duration of follow up; 22,115 were known to have CLD at the index visit. The risk of liver outcomes was an exponential function of the FIB-4 Index both in those known to have CLD and those not known to have CLD. In 2.05 million subjects who were not known to have CLD, a FIB4 score ≥ 3.25 was associated with a significantly higher allcause inpatient mortality (RR: 5.36, CL 5.05-5.72, p , 0.0001) and all liver-related outcomes (RR: 12.37, CL 11.55-13.24, p, 0.0001) at one year and at five years (mortality RR: 4.90, CL 4.64-5.18, p ,0.0001; liver related outcomes RR 11.90, CL 11.19-12.67, p ,0.0001). The risk of each individual liver-related outcome was also significantly increased in those with a FIB4 ≥ 3.25 at both 1 and 5 years. The ability of FIB4 to predict outcomes was unaffected by age (up to 90 years), gender, race, or common co-morbidities. The total accuracy of the FIB-4 Index for identification of liver-related outcomes was 96%. CONCLUSIONS: A FIB-4 Index of 3.25 identifies asymptomatic individuals at risk of death and liver-related outcomes with a total accuracy of 96%. Su1799 Transient Elastography and Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) for the Diagnosis of Fibrosis and Cirrhosis in HIV-HCV Co-Infected Patients: A Systematic Review and Meta-Analysis Basile Njei, Ivo C. Ditah, Pardha Devaki, Joseph K. Lim Background: Liver biopsy remains the gold standard to assess the degree of liver fibrosis. However, the utility of liver biopsy is limited by adverse events, sampling error and interobserver variability. Transient elastography (TE) and Aspartate aminotransferase-to-platelet ratio index (APRI) are noninvasive alternatives for detecting fibrosis. Fibrosis assessment is particularly important in HIV-HCV co-infected patients because of a faster rate of fibrosis progression when compared to HCV-mono-infected patients. This study aimed to estimate the diagnostic accuracy of TE and APRI for diagnosing fibrosis and cirrhosis in this susceptible group of patients. Methods: Two authors independently conducted a comprehensive search of PUBMED, MEDLINE, and the Cochrane Library from January 1980 to November 2012. Studies were included if they allowed construction of 2 x 2 contingency tables of TE or APRI compared with biopsy. Our primary outcome measure was the overall diagnostic accuracy for prediction of fibrosis. In addition, subgroup analysis by stage of fibrosis [significant fibrosis (≥F2), advanced fibrosis (≥F3) and cirrhosis (F4)], CD4 count and presence of steatosis, was also performed. Random-effect models were used to estimate the pooled sensitivity, specificity, positive Likelihood Ratio (LR), negative LR and diagnostic odds ratio (DOR). Summary receiver operating characteristic (SROC) curves were constructed by the
Su1722 Kupffer Cell-Specific Calcium Signaling Drives Inflammation in Alcoholic Liver Disease (ALD) in Mice Terence N. Bukong, Tracie C. Lo, Keisaku Sato, Christopher D. Tournade, Angela Dolganiuc Background: Alcohol abuse leads to alcoholic liver disease (ALD). Inflammation is key to ALD progression. Liver macrophages (Mf) Kupffer cells (KC) express TLR4 and are key to inflammation in ALD. Multiple cellular receptors, including TLR4, employ calcium-dependent signaling to deliver pro-inflammatory signals and propel inflammation. The Aim of our study was to evaluate the role of calcium-dependent signaling in ALD. Methods: We fed alcohol (Lieber-deCarli) or control diet to control, macrophage-depleted (by exposure
AASLD Abstracts
to clodronate liposomes) or cyclosporine-treated C57Bl6 mice. Kupffer cells (KC) and hepatocytes (Hpt) were isolated by enzymatic digestion and gradient centrifugation. Livers were analyzed by histology, RNA by PCR, protein by western blot, NFAT activity by EMSA, cytokines by ELISA and Multiplex. Results: Feeding of control diet revealed no differences between control, clodronate- or cyclosporine-treated C57Bl6 mice. Alcohol diet led to significant increase in serum ALT, suggestive of liver injury and serum cytokines (TNFa, IL1, IL6, KC), suggestive of inflammation, in control C57Bl6 mice. Depletion of KCs with clodronate was protective against alcohol diet-induced liver injury and inflammation, suggesting Mf drive the alcohol abuse-induced inflammation in the liver. Similar to KC-depleted mice, animals treated with cyclosporine were protected against alcohol diet-induced liver injury and inflammation, however the protection was only partial. Livers of alcohol-fed C57Bl6 mice showed significant elevation of TLR4, MyD88, Calcineurin, PLC, PKC, and MAPKp38 compared to control diet-fed counterpart. Calcineurin and NFAT activity, which are suggestive of active calcium-dependent signaling, was significantly higher in livers of alcohol-fed compared to control diet-fed animals. Both clodronate and cyclosporin treatments lead to significant inhibition of liver DNA-binding NFAT activity in alcohol diet-fed mice. NFAT was detected in both KCs and Hpt; there were no differences in the NFAT total protein levels between control diet- and alcohol diet-fed animals in Hpt. In contrast alcohol feeding lead to significant upregulation of NFAT in KCs. In vitro, using RAW264.7 as KC model, chronic alcohol did not affect NFAT protein expression but led to significantly higher LPS/TLR4-triggered NFAT DNA-binding activity compared to controls; pre-treatment with cyclosporine inhibited this effect. These data suggested that functional involvement rather than cellular-specific, Mf vs Hpt, distribution of calcium-dependent signaling is protective in ALD. In conclusion, we report novel finding that calcium signaling is, in part, responsible for development of the inflammatory component of ALD in mice. These results suggest potential therapeutic targets in ALD.
S-1006
AASLD Abstracts
Differentiation of Alcoholic Liver Disease From Nonalcoholic Fatty Liver Disease Using a Logistic Regression Model Based on Clinical Parameters Nobuyuki Toshikuni, Nobuhiko Hayashi, Atsushi Fukumura, Yasuhiro Matsue, Takahiro Minato, Tomoe Nomura, Takashi Saito, Kazuaki Ozaki, Hisakazu Shiroeda, Mutsumi Tsuchishima, Tomiyasu Arisawa, Mikihiro Tsutsumi [Background] A simple method for discriminating alcoholic liver disease (ALD) from nonalcoholic fatty liver disease (NAFLD) could be helpful in the management of fatty liver disease. Although ALD/NAFLD index is known to be useful in Caucasian subjects (Dunn et al. Gastroenterology 2006;131:1057-1063), no corresponding indices for Asian subjects have been reported yet. In this study, we aimed to develop a discrimination index for Japanese subjects using readily available clinical parameters. [Materials and Methods] Between 2009 and 2010, we conducted a nationwide survey for Japanese subjects to evaluate the status of fatty liver disease and collected data from 695 subjects with biopsy-proven ALD (n = 147) or NAFLD (n = 548). The index was developed on the basis of clinical parameters that were significant on multiple logistic regression analysis. [Results] This multivariate analysis identified the following significant parameters: gender, body mass index (BMI), aspartate aminotransferase level/alanine aminotransferase level, γ-glutamyl transpeptidase level, and mean corpuscular erythrocyte volume. Discrimination index greater than 0 was suggestive of ALD and that less than 0 was suggestive of NAFLD. The index had an area under the receiver operating characteristic (ROC) curve of 0.936 (95% confidence interval, 0.910-0.962). For diagnosing ALD, following were the suggested values for assessment: sensitivity, 66.7%; specificity, 96.7%; positive predictive value, 84.5%; and negative predictive value, 91.5%. On the other hand, for diagnosing NAFLD, following were the suggested values for assessment: sensitivity, 96.7%; specificity, 66.7%; positive predictive value, 91.5%; and negative predictive value, 84.5%. The index was validated for use in subgroups classified according to histological findings or BMI. In the simple steatosis group, the sensitivity and specificity for diagnosing ALD were 42.3% and 93.5%, respectively; in the fibrosis group, the sensitivity and specificity for diagnosing ALD were 80.0% and 97.5%, respectively. In the group with BMI ,25 kg/m2, the sensitivity and specificity for diagnosing ALD were 77.2% and 92.2%, respectively; in the group with BMI ≥25 kg/m2, the sensitivity and specificity for diagnosing ALD were 43.5% and 98.7%, respectively. [Conclusions] This index is excellent for differentiating ALD from NAFLD: it is particularly helpful for ruling in ALD and ruling out NAFLD. Thus, we believe that this index should be validated in other Asian populations. Su1721 Liver Related and Overall Mortality of Patients With Alcohol Related Liver Disease Li Zheng, Gregory Trimble, Alita Mishra, Maria Stepanova, James Cooper, Zobair M. Younossi Background and Aim: Although excessive alcohol consumption has been associated with development of chronic liver disease, its impact on patients' mortality is not very clear. The aim of this study was to assess the mortality outcomes of patients with alcohol-related liver disease using population-based data. Methods: Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES III)-mortality linked files. Alcohol consumption was estimated as grams per day. Excessive alcohol use was defined as average daily alcohol consumption of ≥20 grams. Alcohol related liver disease was presumed in participants who reported excessive alcohol use in the past 12 months and had elevated liver enzyme at the time of survey examination in the absence of other chronic liver diseases (negative HCV RNA, negative HBs-Antigen, normal ferritin, and no drug-related liver disease). Multivariate Cox proportional hazards model was utilized to assess the effects of alcohol related liver disease on follow-up time to mortality from all causes, cardiovascular disease, and liver disease. Results: A total of 8,306 participants from NHANES were included. Of these, 1.37% (N=148) fulfilled the criteria for alcohol related liver disease, with an average alcohol consumption of 43.9±3.5 grams per day. Participants with alcohol related liver disease were more likely than their controls to be male (78% vs. 43%), of age 55-64 (21% vs. 12%), Mexican American (12% vs. 5%), smokers (76% vs. 52%), obese (46% vs. 32%), with diabetes or insulin resistance (34% vs. 17%) and hypertension (41% vs. 17%). Mortality follow up data was available after a median time of 178.27 months. Participants with alcohol related liver disease had significantly increased risk for liver-related mortality [adjusted hazard ratio (aHR) 7.06 (95% confidence interval, 2.09-23.79)] but not an increased risk for overall mortality [aHR 1.14 (0.70-1.85)] and cardiovascular mortality [aHR 0.61 (0.113.25)]. Conclusions: Alcohol related liver disease is associated with increased risk of liverrelated mortality but not cardiovascular or overall mortality.
Su1798 A High FIB-4 Score Predicts the Likelihood of Liver Related Outcomes in the General Population Tuyet A. Nguyen, Jonathan P. DeShazo, Arun J. Sanyal BACKGROUND: Chronic liver disease (CLD) affects up to 10% of the world's population. It is often asymptomatic until late in its course and only 10-20% of patients with CLD in the US have been identified. A major barrier to identification of asymptomatic but advanced liver disease (bridging fibrosis/cirrhosis) is a lack of a test that identifies such asymptomatic patients at risk of liver-related outcomes in a general outpatient setting. The FIB-4 Index is a simple non-invasive test (based on age, AST, ALT and platelets) that correlates with advanced fibrosis in several types of CLD. HYPOTHESIS: We hypothesized that the FIB-4 Index would identify those who were at increased risk for liver-related outcomes and death in a relatively unselected population within an ambulatory care setting. METHODS: A retrospective cohort analysis of adults in an ambulatory outpatient setting was performed using the Cerner Health Facts® database which is composed of de-identified patient information from the electronic medical record of multiple facilities. Subjects ages 18 years and older, who had a calculable FIB-4 Index, and who had a follow up encounter were included. Those who had a liver transplant or who had already developed liver-related outcomes at the index visit were excluded. The ability of FIB-4 to predict mortality and liver-related outcomes (ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, variceal hemorrhage and hepatocellular cancer) was measured. RESULTS: A total of 2.08 million subjects during 1994-2011 were studied with approximately 1.46 million person-years duration of follow up; 22,115 were known to have CLD at the index visit. The risk of liver outcomes was an exponential function of the FIB-4 Index both in those known to have CLD and those not known to have CLD. In 2.05 million subjects who were not known to have CLD, a FIB4 score ≥ 3.25 was associated with a significantly higher allcause inpatient mortality (RR: 5.36, CL 5.05-5.72, p , 0.0001) and all liver-related outcomes (RR: 12.37, CL 11.55-13.24, p, 0.0001) at one year and at five years (mortality RR: 4.90, CL 4.64-5.18, p ,0.0001; liver related outcomes RR 11.90, CL 11.19-12.67, p ,0.0001). The risk of each individual liver-related outcome was also significantly increased in those with a FIB4 ≥ 3.25 at both 1 and 5 years. The ability of FIB4 to predict outcomes was unaffected by age (up to 90 years), gender, race, or common co-morbidities. The total accuracy of the FIB-4 Index for identification of liver-related outcomes was 96%. CONCLUSIONS: A FIB-4 Index of 3.25 identifies asymptomatic individuals at risk of death and liver-related outcomes with a total accuracy of 96%. Su1799 Transient Elastography and Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) for the Diagnosis of Fibrosis and Cirrhosis in HIV-HCV Co-Infected Patients: A Systematic Review and Meta-Analysis Basile Njei, Ivo C. Ditah, Pardha Devaki, Joseph K. Lim Background: Liver biopsy remains the gold standard to assess the degree of liver fibrosis. However, the utility of liver biopsy is limited by adverse events, sampling error and interobserver variability. Transient elastography (TE) and Aspartate aminotransferase-to-platelet ratio index (APRI) are noninvasive alternatives for detecting fibrosis. Fibrosis assessment is particularly important in HIV-HCV co-infected patients because of a faster rate of fibrosis progression when compared to HCV-mono-infected patients. This study aimed to estimate the diagnostic accuracy of TE and APRI for diagnosing fibrosis and cirrhosis in this susceptible group of patients. Methods: Two authors independently conducted a comprehensive search of PUBMED, MEDLINE, and the Cochrane Library from January 1980 to November 2012. Studies were included if they allowed construction of 2 x 2 contingency tables of TE or APRI compared with biopsy. Our primary outcome measure was the overall diagnostic accuracy for prediction of fibrosis. In addition, subgroup analysis by stage of fibrosis [significant fibrosis (≥F2), advanced fibrosis (≥F3) and cirrhosis (F4)], CD4 count and presence of steatosis, was also performed. Random-effect models were used to estimate the pooled sensitivity, specificity, positive Likelihood Ratio (LR), negative LR and diagnostic odds ratio (DOR). Summary receiver operating characteristic (SROC) curves were constructed by the
Su1722 Kupffer Cell-Specific Calcium Signaling Drives Inflammation in Alcoholic Liver Disease (ALD) in Mice Terence N. Bukong, Tracie C. Lo, Keisaku Sato, Christopher D. Tournade, Angela Dolganiuc Background: Alcohol abuse leads to alcoholic liver disease (ALD). Inflammation is key to ALD progression. Liver macrophages (Mf) Kupffer cells (KC) express TLR4 and are key to inflammation in ALD. Multiple cellular receptors, including TLR4, employ calcium-dependent signaling to deliver pro-inflammatory signals and propel inflammation. The Aim of our study was to evaluate the role of calcium-dependent signaling in ALD. Methods: We fed alcohol (Lieber-deCarli) or control diet to control, macrophage-depleted (by exposure
AASLD Abstracts
to clodronate liposomes) or cyclosporine-treated C57Bl6 mice. Kupffer cells (KC) and hepatocytes (Hpt) were isolated by enzymatic digestion and gradient centrifugation. Livers were analyzed by histology, RNA by PCR, protein by western blot, NFAT activity by EMSA, cytokines by ELISA and Multiplex. Results: Feeding of control diet revealed no differences between control, clodronate- or cyclosporine-treated C57Bl6 mice. Alcohol diet led to significant increase in serum ALT, suggestive of liver injury and serum cytokines (TNFa, IL1, IL6, KC), suggestive of inflammation, in control C57Bl6 mice. Depletion of KCs with clodronate was protective against alcohol diet-induced liver injury and inflammation, suggesting Mf drive the alcohol abuse-induced inflammation in the liver. Similar to KC-depleted mice, animals treated with cyclosporine were protected against alcohol diet-induced liver injury and inflammation, however the protection was only partial. Livers of alcohol-fed C57Bl6 mice showed significant elevation of TLR4, MyD88, Calcineurin, PLC, PKC, and MAPKp38 compared to control diet-fed counterpart. Calcineurin and NFAT activity, which are suggestive of active calcium-dependent signaling, was significantly higher in livers of alcohol-fed compared to control diet-fed animals. Both clodronate and cyclosporin treatments lead to significant inhibition of liver DNA-binding NFAT activity in alcohol diet-fed mice. NFAT was detected in both KCs and Hpt; there were no differences in the NFAT total protein levels between control diet- and alcohol diet-fed animals in Hpt. In contrast alcohol feeding lead to significant upregulation of NFAT in KCs. In vitro, using RAW264.7 as KC model, chronic alcohol did not affect NFAT protein expression but led to significantly higher LPS/TLR4-triggered NFAT DNA-binding activity compared to controls; pre-treatment with cyclosporine inhibited this effect. These data suggested that functional involvement rather than cellular-specific, Mf vs Hpt, distribution of calcium-dependent signaling is protective in ALD. In conclusion, we report novel finding that calcium signaling is, in part, responsible for development of the inflammatory component of ALD in mice. These results suggest potential therapeutic targets in ALD.
S-1006