- Email: [email protected]
Mo1995 Predictors of Histological Features in Nonalcholic Fatty Liver Disease in Non-Diabetic Subjects
(losartan, clarithromycin, phenobarbital, diclofenac, gemfibrozil, fenofibrate, simvastatin, metformin, trimethoprim/sulfa, carvedilol, trinessa, trazodone) but hepatotoxicity was not reported among adverse effects in these clinical trials. Conclusions: A large number of widely prescribed medicines carry hepatotoxicity labeling in their official package inserts with substantial discrepancy in hepatotoxicity labeling between US and European agencies. There is little published evidence to suggest that DILI in individuals with underlying liver disease has worse outcome.
Sitagliptin Inhibits the Development of Hepatic Steatosis by Down-Regulated Expressions of Hepatic Acetyl-CoA Carboxyrase (ACC) and Fatty Acid Synthase (Fas) Tetsuya Sujishi, Shinya Fukunishi, Keisuke Yokohama, Hideko Ohama, Yusuke Tsuchimoto, Akira Asai, Yasuhiro Tsuda, Kazuhide Higuchi Aims; Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and a key factor of obesity-related metabolic dysfunctions featuring dyslipidemia, insulin resistance, and loss of glycemic control. Although sitagliptin (dipeptidyl peptidase-4 inhibitior) is a treatment drug used for type 2 diabetic mellitus (T2DM) patients, the role of sitagliptin in the development NAFLD has not yet been well known. It has yet to be completely understood how much dysregulated de novo lipogenesis contributes to the pathogenic development of hepatic steatosis. We investigated whether the treatment of sitagliptin is metabolically connected to hepatic steatosis. Methods: Five-week-old male ob/ob mice, which develop T2DM and NAFLD by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks (Control group; n=6) as controls, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks (Sitagliptin group; n=6). Results: Histological comparison between the liver of Control group and that of Sitagliptin group showed significantly more inhibition of hepatic steatosis than in Sitagliptin group. It was suggested that sitagliptin inhibited the development of hepatic steatosis in the mice induced by histologically. The enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) regulate the synthesis of fatty acids. Sitagliptin reduced the hepatic expressions of ACC and FAS, markedly inhibited hepatic de novo lipogenesis, and protected against hepatic steatosis in ob/ob mice. Conclusion: These findings suggested that sitagliptin has effects of downregulated hepatic ACC and FAS in lipid metabolism. Therefore, sitagliptin may serve as a potential target to treat NAFLD and T2DM.
Mo1994 Prevalence and Significance of Ultrasound Diagnosed Hepatic Steatosis in an Irish Cohort Orla F. Craig, Esther Jack, Ciara McGrath, Ihedinachi I. Ndukwe, Numan Khan, Brian Christopher, John Keohane, Subhasish Sengupta Background : Hepatic steatosis may be associated with both alcohol liver disease and non alcoholic fatty liver disease. It is a frequent finding on ultrasound, characterised on by a bright hepatic echo pattern compared to the right kidney, increased attenuation of the echo beam and the presence of focal fatty sparing. While our understanding of the implications of histologically defined non-alcoholic steatosis and steatohepatitis continues to evolve, the majority of patients with fatty infiltration of the liver reported on ultrasound will not have a liver biopsy. Aim : To determine the prevalence of increased echogenicity suggestive of hepatic steatosis on abdominal ultrasound and to elucidate its significance in terms of the presence of abnormal liver bloods, the presence of hyperglycemia, hypercholesteralemia and progression to cirrhosis over a 10 year period. Methods : We examined the reports of all abdominal ultrasounds conducted in our institution in 2002 and selected those with ultrasound features suggestive of hepatitis steatosis. We performed a retrospective review of electronic and paper records of those identified to establish the presence of alcohol abuse, baseline liver function test abnormalities, hyperglycemia and hypercholesterolemia and the subsequent development of these abnormalities between 2002 and 2012. All subsequent imaging was examined to look for regression or progression of the ultrasound findings and the development of cirrhosis. Results : Findings suggestive of hepatic steatosis were identified in 150/2725 patients (88 male, median age 56) undergoing abdominal ultrasound in our institution in 2002. 12/150 had a liver biopsy. 29 were described as having ultrasound changes suggestive of mild fatty infiltration. LFTs were available in 124 patients. 77/124 had abnormal LFTs at baseline (62 elevated γGT, 55 elevated transaminases, 22 elevated alkaline phosphatase, 19 elevated bilirubin). 14/25 of those described as having mild fatty change had abnormal LFTS. 23/41 had an elevated total cholesterol level. 9/44 had elevated blood glucose. 7/9 of those with high blood glucose had normal LFTs. 34 had a follow up ultrasound over the subsequent 10 years. 6 progressed to cirrhosis. 8 had normal liver parenchyma on subsequent imaging. Conclusion : Abnormal LFTs are present in 62% of those with hepatic steatosis on ultrasound but a minority undergo liver biopsy. An elevated blood glucose does not increase the likelihood of having abnormal LFTs in association with hepatic steatosis. Those with ultrasound changes suggestive of mild fatty infiltration are not less likely to have abnormal LFTs. 4% in our cohort progressed to cirrhosis over a 10 year period.
Mo1992 An Analysis of Hypofunctioning Gallbladder in Patients With NAFLD Undergoing Cholecystectomy Harini Rathinamanickam, Gorman J. Reynolds, Srinivasan Ganesan PURPOSE: Gallstones have been associated with Non Alcoholic Fatty Liver Disease (NAFLD). However recent studies have shown an association between NAFLD and cholecystectomy independent of gallstones. The cause for cholecystectomy in these patients was not analyzed. This raises the question of what could be the predominant cause of cholecystectomy in patients with NAFLD. The aim of this study is to determine the predominant cause of cholecystectomy in patients with NAFLD. METHODS: A retrospective chart review was performed on patients with diagnosis code of fatty liver disease and cholecystectomy in our hospital database from 1996 to 2013.We recorded patient age, gender and indications for cholecystectomy. We reviewed the imaging and histopathology to confirm the diagnosis of NAFLD and the indications for cholecystectomy. RESULTS: We identified 251 patients with fatty liver disease who underwent cholecystectomy. The number of patients who underwent cholecystectomy due to Hypo functioning gallbladder was 90 (36%) as compared to 120 (48%) (p=0.00008) who had gallstones or sludge. Among the patients undergoing cholecystectomy due to hypofunctioning gallbladder 29% were men and 71% were women.The mean gallbladder ejection fraction for patients with NAFLD undergoing cholecystectomy was 15.41% CONCLUSION: Gallstones are the predominant cause of cholecystectomy in patients with NAFLD. However, rate of cholecystectomy due to Hypofunctioning gallbladder in patients with NAFLD is 36% in our study. Of note, this rate is much higher than the reported rate of 5 to 22% in the general population undergoing cholecystectomy due to hypofunctioning gallbladder. Further studies are required to analyze this association and investigate gallbladder dyskinesia in patients with NAFLD.
Mo1995 Predictors of Histological Features in Nonalcholic Fatty Liver Disease in NonDiabetic Subjects Kavish R. Patidar, Mohammad S. Siddiqui, Ankit Patel, Michael O. Idowu, Nitai D. Mukhopadhyay, Velimir A. Luketic, Richard K. Sterling, R. Todd Stravitz, Puneet Puri, Scott C. Matherly, Sherry Boyett, Carol C. Sargeant, Arun J. Sanyal BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated serum aminotransferase (ALT and AST). NAFLD spans a histological spectrum from simple steatosis to hepatic steatosis with necroinflammatory activity (steatohepatitis or NASH) to advanced fibrosis. Although NAFLD is closely associated with diabetes mellitus (DM), not all patients with NAFLD have DM. Therefore it is currently unknown if the clinical parameters associated with histological features in non-diabetic subjects is similar to those without DM. AIM: To better define clinical and biochemical parameters associated with histological features in non-diabetic subjects with NAFLD. METHODS: This was a singlecenter retrospective analysis of all patients who underwent a liver biopsy for NAFLD between 2009-2012. All biopsies were graded according to NASH-CRN criteria. Presence of DM was defined according to American Diabetes Association. Regression analysis was used to show association between histological features and clinical parameters. RESULTS: The non-diabetic patients (N=105) were similar to diabetic patients (N=58) in regards to age, BMI, gender, serum ALT and AST levels. Non-diabetic patients were less likely to have NASH compared to diabetics (56.9% vs. 84.2%, p<0.001). Similarly, non-diabetic patients were less likely to have advanced fibrosis (stage 3-4) (19.1% vs. 46.9%, p<0.001). While not observed in those with DM, steatosis in non-diabetics was associated with serum ALT (R = 0.379, p<0.001), AST (R=0.303, p=<0.01), and inversely with serum homocysteine levels (R= -0.24, p=0.03) and fibrinogen (R= -0.19, p=0.007). In non-diabetic patients, serum insulin (R= 0.22, p=0.04) and AST (R=0.202, p=0.041) correlated directly with the extent of cytologic ballooning. Degree of lobular inflammation in non-diabetic subjects was directly related to ratio of small-dense LDL-C:LDL-C (R=0.28, p=0.008) and inversely with serum levels of lipoprotein(a) (R= -0.38, p=0.05), fibrinogen (R= -0.261, p=0.01) and serum free fatty acid levels (R= -0.22, p=0.04). Finally, the degree of fibrosis in non-diabetic patients was directly associated with age (R=0.217, p=0.027), serum insulin levels (R=0.217, p=0.019) and inversely with platelets (R= -0.27, p=0.005). Compared to diabetic patients, non-diabetic patients with NASH had lower BMI (33.5±5.3 vs 36±5.6, p=0.02), hip circumference (114±10 vs 121±17cm, p=0.04) and CRP levels (3.4±3.2 vs. 6.4±5.7, p=0.003). CONCLUSION: Clinical parameters associated with histological features in non-diabetic patients with NAFLD are different than in those with diabetes.
Mo1993 Little Evidence for Serious Outcome in Patients With Chronic Liver Disease Receiving Potentially Hepatotoxic Drugs Einar Bjornsson, Rannveig Einarsdottir, Elin Jacobsen, Naga P. Chalasani Background: According to the Physician Desk Reference (PDR), numerous medications carry a label that they should be used with caution and/or are contraindicated in patients with underlying liver disease. It is unclear whether underlying liver disease increases the risk of drug-induced liver injury (DILI) of potentially hepatotoxic drugs and if DILI occurring in individuals with underlying liver disease leads to poor outcome Aim: To conduct literature search to find documentation for hepatotoxicity labeling in the PDR and European package inserts and search for evidence for poor outcome if these drugs had been used in liver disease. Methods: Pharmacy database (www. drugtopics.com) was used to extract the top 200 generic drugs by prescription volume in the US (2011). Acetaminophen, topical and inhalation agents were excluded. The medications were reviewed in www.pdr.net, www.fass.se and www.medicines.org.uk to identify those which carried a hepatotoxicity label. Utilizing the livertox.nlm.nih.gov and www.pubmed.gov, we examined if there was evidence in the published literature supporting that some of these medications had been described to manifest with DILI in patients with underlying liver disease and if they had been reported to be used safely in liver disease. Results: After excluding 36 compounds, there were 164 medications marketed in the US (US med.) and 145 medicines marketed in Europe (Europe med.) to analyze. 85/164 (52%) US med. and 76/145 (52%) in Europe med. carried caution against use in patients with underlying liver disease. Greater number of the same med. were labeled as contraindicated for use in those with underlying liver disease by European regulators than by the FDA (30% vs. 12%, p<0.001). Discrepancy between US and European labeling for the same drug either in terms of caution or contraindication for use in patients with liver disease was found in 52/144 (36%). We found 15 published case reports and/or case series in patients with underlying liver disease who developed concomitant DILI. All patients survived except one cirrhotic patient who died of liver failure after suspected amoxicillin-clavulanate DILI. A total of 13 published clinical trials in patients with underlying liver disease with drugs contraindicated in US or Europe were identified (n=1378 patients)
S-711
AGA Abstracts
AGA Abstracts
Mo1991
Sitagliptin Inhibits the Development of Hepatic Steatosis by Down-Regulated Expressions of Hepatic Acetyl-CoA Carboxyrase (ACC) and Fatty Acid Synthase (Fas) Tetsuya Sujishi, Shinya Fukunishi, Keisuke Yokohama, Hideko Ohama, Yusuke Tsuchimoto, Akira Asai, Yasuhiro Tsuda, Kazuhide Higuchi Aims; Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and a key factor of obesity-related metabolic dysfunctions featuring dyslipidemia, insulin resistance, and loss of glycemic control. Although sitagliptin (dipeptidyl peptidase-4 inhibitior) is a treatment drug used for type 2 diabetic mellitus (T2DM) patients, the role of sitagliptin in the development NAFLD has not yet been well known. It has yet to be completely understood how much dysregulated de novo lipogenesis contributes to the pathogenic development of hepatic steatosis. We investigated whether the treatment of sitagliptin is metabolically connected to hepatic steatosis. Methods: Five-week-old male ob/ob mice, which develop T2DM and NAFLD by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks (Control group; n=6) as controls, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks (Sitagliptin group; n=6). Results: Histological comparison between the liver of Control group and that of Sitagliptin group showed significantly more inhibition of hepatic steatosis than in Sitagliptin group. It was suggested that sitagliptin inhibited the development of hepatic steatosis in the mice induced by histologically. The enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) regulate the synthesis of fatty acids. Sitagliptin reduced the hepatic expressions of ACC and FAS, markedly inhibited hepatic de novo lipogenesis, and protected against hepatic steatosis in ob/ob mice. Conclusion: These findings suggested that sitagliptin has effects of downregulated hepatic ACC and FAS in lipid metabolism. Therefore, sitagliptin may serve as a potential target to treat NAFLD and T2DM.
Mo1994 Prevalence and Significance of Ultrasound Diagnosed Hepatic Steatosis in an Irish Cohort Orla F. Craig, Esther Jack, Ciara McGrath, Ihedinachi I. Ndukwe, Numan Khan, Brian Christopher, John Keohane, Subhasish Sengupta Background : Hepatic steatosis may be associated with both alcohol liver disease and non alcoholic fatty liver disease. It is a frequent finding on ultrasound, characterised on by a bright hepatic echo pattern compared to the right kidney, increased attenuation of the echo beam and the presence of focal fatty sparing. While our understanding of the implications of histologically defined non-alcoholic steatosis and steatohepatitis continues to evolve, the majority of patients with fatty infiltration of the liver reported on ultrasound will not have a liver biopsy. Aim : To determine the prevalence of increased echogenicity suggestive of hepatic steatosis on abdominal ultrasound and to elucidate its significance in terms of the presence of abnormal liver bloods, the presence of hyperglycemia, hypercholesteralemia and progression to cirrhosis over a 10 year period. Methods : We examined the reports of all abdominal ultrasounds conducted in our institution in 2002 and selected those with ultrasound features suggestive of hepatitis steatosis. We performed a retrospective review of electronic and paper records of those identified to establish the presence of alcohol abuse, baseline liver function test abnormalities, hyperglycemia and hypercholesterolemia and the subsequent development of these abnormalities between 2002 and 2012. All subsequent imaging was examined to look for regression or progression of the ultrasound findings and the development of cirrhosis. Results : Findings suggestive of hepatic steatosis were identified in 150/2725 patients (88 male, median age 56) undergoing abdominal ultrasound in our institution in 2002. 12/150 had a liver biopsy. 29 were described as having ultrasound changes suggestive of mild fatty infiltration. LFTs were available in 124 patients. 77/124 had abnormal LFTs at baseline (62 elevated γGT, 55 elevated transaminases, 22 elevated alkaline phosphatase, 19 elevated bilirubin). 14/25 of those described as having mild fatty change had abnormal LFTS. 23/41 had an elevated total cholesterol level. 9/44 had elevated blood glucose. 7/9 of those with high blood glucose had normal LFTs. 34 had a follow up ultrasound over the subsequent 10 years. 6 progressed to cirrhosis. 8 had normal liver parenchyma on subsequent imaging. Conclusion : Abnormal LFTs are present in 62% of those with hepatic steatosis on ultrasound but a minority undergo liver biopsy. An elevated blood glucose does not increase the likelihood of having abnormal LFTs in association with hepatic steatosis. Those with ultrasound changes suggestive of mild fatty infiltration are not less likely to have abnormal LFTs. 4% in our cohort progressed to cirrhosis over a 10 year period.
Mo1992 An Analysis of Hypofunctioning Gallbladder in Patients With NAFLD Undergoing Cholecystectomy Harini Rathinamanickam, Gorman J. Reynolds, Srinivasan Ganesan PURPOSE: Gallstones have been associated with Non Alcoholic Fatty Liver Disease (NAFLD). However recent studies have shown an association between NAFLD and cholecystectomy independent of gallstones. The cause for cholecystectomy in these patients was not analyzed. This raises the question of what could be the predominant cause of cholecystectomy in patients with NAFLD. The aim of this study is to determine the predominant cause of cholecystectomy in patients with NAFLD. METHODS: A retrospective chart review was performed on patients with diagnosis code of fatty liver disease and cholecystectomy in our hospital database from 1996 to 2013.We recorded patient age, gender and indications for cholecystectomy. We reviewed the imaging and histopathology to confirm the diagnosis of NAFLD and the indications for cholecystectomy. RESULTS: We identified 251 patients with fatty liver disease who underwent cholecystectomy. The number of patients who underwent cholecystectomy due to Hypo functioning gallbladder was 90 (36%) as compared to 120 (48%) (p=0.00008) who had gallstones or sludge. Among the patients undergoing cholecystectomy due to hypofunctioning gallbladder 29% were men and 71% were women.The mean gallbladder ejection fraction for patients with NAFLD undergoing cholecystectomy was 15.41% CONCLUSION: Gallstones are the predominant cause of cholecystectomy in patients with NAFLD. However, rate of cholecystectomy due to Hypofunctioning gallbladder in patients with NAFLD is 36% in our study. Of note, this rate is much higher than the reported rate of 5 to 22% in the general population undergoing cholecystectomy due to hypofunctioning gallbladder. Further studies are required to analyze this association and investigate gallbladder dyskinesia in patients with NAFLD.
Mo1995 Predictors of Histological Features in Nonalcholic Fatty Liver Disease in NonDiabetic Subjects Kavish R. Patidar, Mohammad S. Siddiqui, Ankit Patel, Michael O. Idowu, Nitai D. Mukhopadhyay, Velimir A. Luketic, Richard K. Sterling, R. Todd Stravitz, Puneet Puri, Scott C. Matherly, Sherry Boyett, Carol C. Sargeant, Arun J. Sanyal BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated serum aminotransferase (ALT and AST). NAFLD spans a histological spectrum from simple steatosis to hepatic steatosis with necroinflammatory activity (steatohepatitis or NASH) to advanced fibrosis. Although NAFLD is closely associated with diabetes mellitus (DM), not all patients with NAFLD have DM. Therefore it is currently unknown if the clinical parameters associated with histological features in non-diabetic subjects is similar to those without DM. AIM: To better define clinical and biochemical parameters associated with histological features in non-diabetic subjects with NAFLD. METHODS: This was a singlecenter retrospective analysis of all patients who underwent a liver biopsy for NAFLD between 2009-2012. All biopsies were graded according to NASH-CRN criteria. Presence of DM was defined according to American Diabetes Association. Regression analysis was used to show association between histological features and clinical parameters. RESULTS: The non-diabetic patients (N=105) were similar to diabetic patients (N=58) in regards to age, BMI, gender, serum ALT and AST levels. Non-diabetic patients were less likely to have NASH compared to diabetics (56.9% vs. 84.2%, p<0.001). Similarly, non-diabetic patients were less likely to have advanced fibrosis (stage 3-4) (19.1% vs. 46.9%, p<0.001). While not observed in those with DM, steatosis in non-diabetics was associated with serum ALT (R = 0.379, p<0.001), AST (R=0.303, p=<0.01), and inversely with serum homocysteine levels (R= -0.24, p=0.03) and fibrinogen (R= -0.19, p=0.007). In non-diabetic patients, serum insulin (R= 0.22, p=0.04) and AST (R=0.202, p=0.041) correlated directly with the extent of cytologic ballooning. Degree of lobular inflammation in non-diabetic subjects was directly related to ratio of small-dense LDL-C:LDL-C (R=0.28, p=0.008) and inversely with serum levels of lipoprotein(a) (R= -0.38, p=0.05), fibrinogen (R= -0.261, p=0.01) and serum free fatty acid levels (R= -0.22, p=0.04). Finally, the degree of fibrosis in non-diabetic patients was directly associated with age (R=0.217, p=0.027), serum insulin levels (R=0.217, p=0.019) and inversely with platelets (R= -0.27, p=0.005). Compared to diabetic patients, non-diabetic patients with NASH had lower BMI (33.5±5.3 vs 36±5.6, p=0.02), hip circumference (114±10 vs 121±17cm, p=0.04) and CRP levels (3.4±3.2 vs. 6.4±5.7, p=0.003). CONCLUSION: Clinical parameters associated with histological features in non-diabetic patients with NAFLD are different than in those with diabetes.
Mo1993 Little Evidence for Serious Outcome in Patients With Chronic Liver Disease Receiving Potentially Hepatotoxic Drugs Einar Bjornsson, Rannveig Einarsdottir, Elin Jacobsen, Naga P. Chalasani Background: According to the Physician Desk Reference (PDR), numerous medications carry a label that they should be used with caution and/or are contraindicated in patients with underlying liver disease. It is unclear whether underlying liver disease increases the risk of drug-induced liver injury (DILI) of potentially hepatotoxic drugs and if DILI occurring in individuals with underlying liver disease leads to poor outcome Aim: To conduct literature search to find documentation for hepatotoxicity labeling in the PDR and European package inserts and search for evidence for poor outcome if these drugs had been used in liver disease. Methods: Pharmacy database (www. drugtopics.com) was used to extract the top 200 generic drugs by prescription volume in the US (2011). Acetaminophen, topical and inhalation agents were excluded. The medications were reviewed in www.pdr.net, www.fass.se and www.medicines.org.uk to identify those which carried a hepatotoxicity label. Utilizing the livertox.nlm.nih.gov and www.pubmed.gov, we examined if there was evidence in the published literature supporting that some of these medications had been described to manifest with DILI in patients with underlying liver disease and if they had been reported to be used safely in liver disease. Results: After excluding 36 compounds, there were 164 medications marketed in the US (US med.) and 145 medicines marketed in Europe (Europe med.) to analyze. 85/164 (52%) US med. and 76/145 (52%) in Europe med. carried caution against use in patients with underlying liver disease. Greater number of the same med. were labeled as contraindicated for use in those with underlying liver disease by European regulators than by the FDA (30% vs. 12%, p<0.001). Discrepancy between US and European labeling for the same drug either in terms of caution or contraindication for use in patients with liver disease was found in 52/144 (36%). We found 15 published case reports and/or case series in patients with underlying liver disease who developed concomitant DILI. All patients survived except one cirrhotic patient who died of liver failure after suspected amoxicillin-clavulanate DILI. A total of 13 published clinical trials in patients with underlying liver disease with drugs contraindicated in US or Europe were identified (n=1378 patients)
S-711
AGA Abstracts
AGA Abstracts
Mo1991