487 ATP-Binding Cassette Transporter Gene Polymorphisms and Insulin Resistance as Risk Factors for...
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lithogenic diet feeding IL10 -/- mice still maintain a low prevalence of cholesterol gallstone formation (25%). No significant alterations in cholesterol, bile salts or phospholipids were noted demonstrating that this protective effect occurs independently of gallbladder bile lipid concentration. Conclusion: These data demonstrate that IL10 deficiency appreciably and chronically reduces the prevalence of cholesterol gallstones. This protection, at least at the time-point analyzed, appears to be independent of lipid concentration. Because IL10 -/- mice displayed significantly reduced gallbladder volumes and mucin gel accumulation, a potential mechanism for this protection is repression of mucin glycoprotein production as well as maintenance of gallbladder wall contractility. These data contrast starkly with other models of chronic gastrointestinal inflammation (i.e., colitis) in which IL10 deficiency promotes disease. 486 Lack of Endogenous Cholecystokinin (CCK) Promotes Cholelithogenesis in Mice: A Model Relevant to Celiac Disease Helen H. Wang, Piero Portincasa, Min Liu, Linda C. Samuelson, Patrick Tso, David Q. Wang Celiac disease is becoming an increasingly recognized autoimmune enteropathy caused by a permanent intolerance to gluten. Consequently, CCK release from the small intestine and gallbladder emptying in response to a fatty meal are greatly decreased before starting the gluten-free diet, and this puts the patients at risk of increased gallstone incidence rates. Aims: To better provide a pathophysiologically relevant basis in celiac disease, we investigated the effect of the absence of endogenous CCK on gallstone formation in mice. Methods: After cholecystectomy, fresh gallbladder bile was examined for the presence or absence of mucin, solid and liquid crystals, and gallstones by polarizing light microscopy in male CCK (-/-) and (+/+) mice (n=4 per group) before and at frequent intervals following a lithogenic diet from day 1 to 28. Gallbladder size and emptying function were measured by gravity after an overnight fast or a high-fat meal, respectively. Biliary lipid secretion was determined. Intestinal cholesterol absorption was measured by fecal dual-isotope ratio methods. Results: Fasting gallbladder volumes (50-65 μL) were significantly (P<0.05) larger in (-/-) mice compared with (+/+) mice (20-30 μL). The response of gallbladder emptying to the high- fat diet was impaired in (-/-) mice. During 28 days of feeding the lithogenic diet, there was earlier onset and severity of cholesterol gallstone formation in (-/-) mice compared with (+/ +) mice. Due to the absence of CCK, small intestinal transit time was prolonged so that intestinal cholesterol absorption was significantly increased (31% vs. 39%). These observa- tions could explain, in part, why hepatic secretion of biliary cholesterol was higher in (-/- ) mice than (+/+) mice. The combination of increased bile cholesterol levels and gallbladder stasis due to the absence of CCK-induced contraction, enhanced crystallization and growth of classic plate-like cholesterol monohydrate crystals, and promoted gallstone formation in (-/-) mice. In contrast, daily CCK intraperitoneal administration (0.1 μg/kg, twice per day) could reduce gallstone formation in (-/-) mice challenged to the lithogenic diet. Conclusions: The lack of CCK impairs gallbladder motility function, inducing enlarged gallbladder size and prolonged the residence time of excess cholesterol in the gallbladder lumen to promote cholesterol crystallization, as well as retards small intestinal transit times, resulting in increased intestinal cholesterol absorption and biliary cholesterol secretion rates. All these changes enhance cholelithogenesis. These results could partly explain why gallstone forma- tion is increased in patients with celiac disease. 487 ATP-Binding Cassette Transporter Gene Polymorphisms and Insulin Resistance as Risk Factors for Advanced Fibrosis Following Liver Transplantation for HCV Infection Speranta Iacob, Vito Cicinnati, Alexander Dechene, Christian G. Klein, Irinel Popescu, Andreas Paul, Guido Gerken, Susanne Beckebaum Background: Hepatitis C Virus (HCV) reinfection after liver transplantation (LT) has a critical influence on graft and patient survival. Hepatic insulin resistance increases expression of the ATP-binding cassette (ABC) transporter G8 implicated in the regulation of cholesterol metabolism as well as the severity of HCV infection. Expression of multidrug resistance (MDR)1 gene expression has been shown to be increased in activated hepatic stellate cells in chronic liver diseases. Aim: To assess predictive factors of severe HCV recurrence after LT. Methods: We genotyped ABCG8 (C1199A and C1895T) and MDR1 (C3435T) in 165 LT recipients (46 with recurrent hepatitis C after LT, 119 controls transplanted for other liver diseases) by PCR-restriction fragment length polymorphism assay. Uni- and multivariate logistic regression analyses were used to identify predictors of severe HCV recurrence follow- ing LT. Results: Analyses of single nucleotide polymorphisms (SNPs) revealed the following results: ABCG8 exon 8 C1199A (CC 69.1%, CA 29.7%, AA 1.2%), ABCG8 exon 13 C1895T (CC 46.1%, CT 44.2%, TT 9.7%), and MDR1 exon 26 C3435T (CC 22.4%, CT 40%, TT 37.6%). In the univariate analysis ABCG8 C1199C (p=0.006), MDR1 T3435T (p=0.03), presence of type 2 diabetes mellitus (p=0.01), acute rejection episodes (p=0.002), cytomegalo- virus infection (p=0.005), lower cholinesterase (p=0.0003), higher direct bilirubin (p=0.03) and aspartate aminotransferase (p=0.01) were identified as predictors of severe HCV recur- rence. Independent predictors of severe HCV recurrence included ABCG8 C1199C (p= 0.01), MDR1 T3435T (p=0.03), presence of type 2 diabetes mellitus (p=0.03). Conclusions: HCV LT recipients with ABCG8 and MDR1 polymorphisms have a significantly higher prevalence of advanced fibrosis. Active screening of these mutations may help to predict and to manage severe HCV recurrence in LT recipients. S-69 AGA Abstracts 488 Early Institution of Tinidazole May Prevent Pouchitis Following Ileal-Pouch Anal Anastomosis (IPAA) Surgery in Ulcerative Colitis (UC) Patients Christina Y. Ha, Joel J. Bauer, Mark Lazarev, Arun Swaminath, Miles Sparrow, Seamus J. Murphy, Steven J. Brown, Daniel H. Present Objective: Pouchitis is a frequent post-operative complication experienced by UC patients following IPAA. Although nitroimidazole antibiotics are effective for acute pouchitis treat- ment, there are no data relating to their potential role as a primary prophylaxis for pouchitis. We performed a randomized double-blind placebo-controlled clinical trial to determine if tinidazole reduces or prevents the incidence of pouchitis in UC patients at 12 months after IPAA. Methods: 38 UC patients were randomized in a 2:1 ratio to receive either tinidazole (Tindamax, Mission Pharmacal Inc., Boerne, TX) 500mg by mouth daily or placebo daily within one month of their final stage of IPAA surgery for a total duration of 12 months. Clinical information regarding UC disease history and basic demographic information were assessed at baseline. Patients were withdrawn from the study if they developed pouchitis during the study period or experienced significant adverse events. Clinical data including the abbreviated Pouch Disease Activity Index (PDAI) were assessed throughout the study. Statistical analysis was performed per protocol and with intention-to-treat. Results: Approx- imately half of the patients finished 12 months of treatment without developing pouchitis. Per protocol, 8.0% of the tinidazole group developed pouchitis compared with 38.5% of patients taking placebo (P=0.03). Following intention-to-treat analysis, an additional 3 patients in the tinidazole group developed pouchitis 4-10 months after discontinuation of study drug (P=0.26). There were no differences in the number of adverse events between placebo and tinidazole (P=0.64). Patients treated with tinidazole had lower median PDAI scores (P=0.04) compared to placebo. Conclusions: Early institution of tinidazole may be an effective strategy to prevent pouchitis following IPAA surgery, however, additional larger scale studies are needed. 489 Preoperative pANCA Expression Influences the Outcome of Ileal Pouch- Anastomosis in Inflammatory Bowel Disease-Unclassified (IBDU) Diana Cheng-Robles, Gil Y. Melmed, Eric A. Vasiliauskas, Marla Dubinsky, Dermot P. McGovern, Andrew Ippoliti, David Q. Shih, Stephan R. Targan, Phillip Fleshner PURPOSE: The long-term outcome of ileal pouch-anal anastomosis (IPAA) in patients with inflammatory bowel disease-unclassified (IBDU) is controversial. Although clinical factors alone cannot predict outcome in IBDU patients (Murrell et al., Dis Colon Rectum 2009;52:872), the role of subclinical markers such as IBD seromarker expression has yet to be examined. The aim of this study was to investigate whether preoperative serologic profiles can be used to predict outcome of IPAA in IBDU patients. METHODS: Prospectively generated serologic profiles on consecutive IBDU patients undergoing IPAA with close postoperative follow-up by one surgeon were reviewed. Patients were classified as having IBDU when they had preoperative clinical, endoscopic, or pathologic criteria of UC with some features suggestive but not diagnostic of Crohn's disease (CD), including discontinuous inflammation possibly related to medical therapy, history of an anal fistula or ulcer which was inactive at the time of surgery, noncaseating granulomas thought to be related to crypt rupture, or small bowel inflammation 3 cm proximal to the ileocecal valve. IBD seromarkers (pANCA, ASCA-IgG, ASCA-IgA, anti-OmpC, anti-CBir1, anti-I2) were measured before surgery using ELISA and immunofluorescence. pANCA+ patients were substratified into high-level (>100 EU/ml) and low-level (<100 EU/ml) groups Long-term outcomes included acute pouchitis (antibiotic responsive), chronic pouchitis (antibiotic dependent or refractory), or denovo CD (small bowel inflammation above the pouch inlet or pouch fistula). RESULTS: The study cohort of 96 patients had a median age of 39 years (range, 8-73 years) and included 59 (59%) males. pANCA, ASCA-IgG, ASCA-IgA, anti-OmpC, anti-CBir1 and anti- I2 were detected in 72%, 6%, 16%, 27%, 24% and 28%, respectively. After a median follow- up of 39 months (range, 3 to 150 months), 16 patients (17%) developed acute pouchitis, 13 patients (14%) developed chronic pouchitis and 16 patients (17%) developed denovo CD. Although acute pouchitis was not influenced by pANCA level, chronic pouchitis developed in 36% of high-level pANCA+ patients vs. 11% of low-level pANCA+ patients (p=0.03). Denovo CD developed in 43% of high-level pANCA+ patients compared to 12% of low-level pANCA+ patients (p=0.01). No other significant associations were noted between seromarker expres- sion and clinical outcome. CONCLUSIONS: IBDU patients who express high-level pANCA (> 100 EU/ml) have a higher incidence of developing either chronic pouchitis or denovo CD after IPAA. Assessing pANCA before IPAA appears to have prognostic significance in IBDU patients. AGA Abstracts
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Transcript of 487 ATP-Binding Cassette Transporter Gene Polymorphisms and Insulin Resistance as Risk Factors for...
lithogenic diet feeding IL10-/- mice still maintain a low prevalence of cholesterol gallstoneformation (25%). No significant alterations in cholesterol, bile salts or phospholipids werenoted demonstrating that this protective effect occurs independently of gallbladder bile lipidconcentration. Conclusion: These data demonstrate that IL10 deficiency appreciably andchronically reduces the prevalence of cholesterol gallstones. This protection, at least at thetime-point analyzed, appears to be independent of lipid concentration. Because IL10 -/- micedisplayed significantly reduced gallbladder volumes and mucin gel accumulation, a potentialmechanism for this protection is repression of mucin glycoprotein production as well asmaintenance of gallbladder wall contractility. These data contrast starkly with other models ofchronic gastrointestinal inflammation (i.e., colitis) in which IL10 deficiency promotes disease.
486
Lack of Endogenous Cholecystokinin (CCK) Promotes Cholelithogenesis inMice: A Model Relevant to Celiac DiseaseHelen H. Wang, Piero Portincasa, Min Liu, Linda C. Samuelson, Patrick Tso, David Q.Wang
Celiac disease is becoming an increasingly recognized autoimmune enteropathy caused bya permanent intolerance to gluten. Consequently, CCK release from the small intestine andgallbladder emptying in response to a fatty meal are greatly decreased before starting thegluten-free diet, and this puts the patients at risk of increased gallstone incidence rates.Aims: To better provide a pathophysiologically relevant basis in celiac disease, we investigatedthe effect of the absence of endogenous CCK on gallstone formation in mice. Methods: Aftercholecystectomy, fresh gallbladder bile was examined for the presence or absence of mucin,solid and liquid crystals, and gallstones by polarizing light microscopy in male CCK (-/-)and (+/+) mice (n=4 per group) before and at frequent intervals following a lithogenic dietfrom day 1 to 28. Gallbladder size and emptying function were measured by gravity afteran overnight fast or a high-fat meal, respectively. Biliary lipid secretion was determined.Intestinal cholesterol absorption was measured by fecal dual-isotope ratio methods. Results:Fasting gallbladder volumes (50-65 μL) were significantly (P<0.05) larger in (-/-) micecompared with (+/+) mice (20-30 μL). The response of gallbladder emptying to the high-fat diet was impaired in (-/-) mice. During 28 days of feeding the lithogenic diet, there wasearlier onset and severity of cholesterol gallstone formation in (-/-) mice compared with (+/+) mice. Due to the absence of CCK, small intestinal transit time was prolonged so thatintestinal cholesterol absorption was significantly increased (31% vs. 39%). These observa-tions could explain, in part, why hepatic secretion of biliary cholesterol was higher in (-/-) mice than (+/+) mice. The combination of increased bile cholesterol levels and gallbladderstasis due to the absence of CCK-induced contraction, enhanced crystallization and growthof classic plate-like cholesterol monohydrate crystals, and promoted gallstone formation in(-/-) mice. In contrast, daily CCK intraperitoneal administration (0.1 μg/kg, twice per day)could reduce gallstone formation in (-/-) mice challenged to the lithogenic diet. Conclusions:The lack of CCK impairs gallbladder motility function, inducing enlarged gallbladder sizeand prolonged the residence time of excess cholesterol in the gallbladder lumen to promotecholesterol crystallization, as well as retards small intestinal transit times, resulting inincreased intestinal cholesterol absorption and biliary cholesterol secretion rates. All thesechanges enhance cholelithogenesis. These results could partly explain why gallstone forma-tion is increased in patients with celiac disease.
487
ATP-Binding Cassette Transporter Gene Polymorphisms and InsulinResistance as Risk Factors for Advanced Fibrosis Following LiverTransplantation for HCV InfectionSperanta Iacob, Vito Cicinnati, Alexander Dechene, Christian G. Klein, Irinel Popescu,Andreas Paul, Guido Gerken, Susanne Beckebaum
Background: Hepatitis C Virus (HCV) reinfection after liver transplantation (LT) has a criticalinfluence on graft and patient survival. Hepatic insulin resistance increases expression ofthe ATP-binding cassette (ABC) transporter G8 implicated in the regulation of cholesterolmetabolism as well as the severity of HCV infection. Expression of multidrug resistance(MDR)1 gene expression has been shown to be increased in activated hepatic stellate cellsin chronic liver diseases. Aim: To assess predictive factors of severe HCV recurrence afterLT. Methods: We genotyped ABCG8 (C1199A and C1895T) and MDR1 (C3435T) in 165LT recipients (46 with recurrent hepatitis C after LT, 119 controls transplanted for otherliver diseases) by PCR-restriction fragment length polymorphism assay. Uni- and multivariatelogistic regression analyses were used to identify predictors of severe HCV recurrence follow-ing LT. Results: Analyses of single nucleotide polymorphisms (SNPs) revealed the followingresults: ABCG8 exon 8 C1199A (CC 69.1%, CA 29.7%, AA 1.2%), ABCG8 exon 13 C1895T(CC 46.1%, CT 44.2%, TT 9.7%), and MDR1 exon 26 C3435T (CC 22.4%, CT 40%, TT37.6%). In the univariate analysis ABCG8 C1199C (p=0.006), MDR1 T3435T (p=0.03),presence of type 2 diabetes mellitus (p=0.01), acute rejection episodes (p=0.002), cytomegalo-virus infection (p=0.005), lower cholinesterase (p=0.0003), higher direct bilirubin (p=0.03)and aspartate aminotransferase (p=0.01) were identified as predictors of severe HCV recur-rence. Independent predictors of severe HCV recurrence included ABCG8 C1199C (p=0.01), MDR1 T3435T (p=0.03), presence of type 2 diabetes mellitus (p=0.03). Conclusions:HCV LT recipients with ABCG8 and MDR1 polymorphisms have a significantly higherprevalence of advanced fibrosis. Active screening of these mutations may help to predictand to manage severe HCV recurrence in LT recipients.
S-69 AGA Abstracts
488
Early Institution of Tinidazole May Prevent Pouchitis Following Ileal-PouchAnal Anastomosis (IPAA) Surgery in Ulcerative Colitis (UC) PatientsChristina Y. Ha, Joel J. Bauer, Mark Lazarev, Arun Swaminath, Miles Sparrow, Seamus J.Murphy, Steven J. Brown, Daniel H. Present
Objective: Pouchitis is a frequent post-operative complication experienced by UC patientsfollowing IPAA. Although nitroimidazole antibiotics are effective for acute pouchitis treat-ment, there are no data relating to their potential role as a primary prophylaxis for pouchitis.We performed a randomized double-blind placebo-controlled clinical trial to determine iftinidazole reduces or prevents the incidence of pouchitis in UC patients at 12 months afterIPAA. Methods: 38 UC patients were randomized in a 2:1 ratio to receive either tinidazole(Tindamax, Mission Pharmacal Inc., Boerne, TX) 500mg by mouth daily or placebo dailywithin one month of their final stage of IPAA surgery for a total duration of 12 months.Clinical information regarding UC disease history and basic demographic information wereassessed at baseline. Patients were withdrawn from the study if they developed pouchitisduring the study period or experienced significant adverse events. Clinical data includingthe abbreviated Pouch Disease Activity Index (PDAI) were assessed throughout the study.Statistical analysis was performed per protocol and with intention-to-treat. Results: Approx-imately half of the patients finished 12 months of treatment without developing pouchitis.Per protocol, 8.0% of the tinidazole group developed pouchitis compared with 38.5% ofpatients taking placebo (P=0.03). Following intention-to-treat analysis, an additional 3patients in the tinidazole group developed pouchitis 4-10 months after discontinuation ofstudy drug (P=0.26). There were no differences in the number of adverse events betweenplacebo and tinidazole (P=0.64). Patients treated with tinidazole had lower median PDAIscores (P=0.04) compared to placebo. Conclusions: Early institution of tinidazole may bean effective strategy to prevent pouchitis following IPAA surgery, however, additional largerscale studies are needed.
489
Preoperative pANCA Expression Influences the Outcome of Ileal Pouch-Anastomosis in Inflammatory Bowel Disease-Unclassified (IBDU)Diana Cheng-Robles, Gil Y. Melmed, Eric A. Vasiliauskas, Marla Dubinsky, Dermot P.McGovern, Andrew Ippoliti, David Q. Shih, Stephan R. Targan, Phillip Fleshner
PURPOSE: The long-term outcome of ileal pouch-anal anastomosis (IPAA) in patients withinflammatory bowel disease-unclassified (IBDU) is controversial. Although clinical factorsalone cannot predict outcome in IBDU patients (Murrell et al., Dis Colon Rectum2009;52:872), the role of subclinical markers such as IBD seromarker expression has yetto be examined. The aim of this study was to investigate whether preoperative serologicprofiles can be used to predict outcome of IPAA in IBDU patients. METHODS: Prospectivelygenerated serologic profiles on consecutive IBDU patients undergoing IPAA with closepostoperative follow-up by one surgeon were reviewed. Patients were classified as havingIBDU when they had preoperative clinical, endoscopic, or pathologic criteria of UC withsome features suggestive but not diagnostic of Crohn's disease (CD), including discontinuousinflammation possibly related to medical therapy, history of an anal fistula or ulcer whichwas inactive at the time of surgery, noncaseating granulomas thought to be related to cryptrupture, or small bowel inflammation 3 cm proximal to the ileocecal valve. IBD seromarkers(pANCA, ASCA-IgG, ASCA-IgA, anti-OmpC, anti-CBir1, anti-I2) were measured beforesurgery using ELISA and immunofluorescence. pANCA+ patients were substratified intohigh-level (>100 EU/ml) and low-level (<100 EU/ml) groups Long-term outcomes includedacute pouchitis (antibiotic responsive), chronic pouchitis (antibiotic dependent or refractory),or denovo CD (small bowel inflammation above the pouch inlet or pouch fistula). RESULTS:The study cohort of 96 patients had a median age of 39 years (range, 8-73 years) andincluded 59 (59%) males. pANCA, ASCA-IgG, ASCA-IgA, anti-OmpC, anti-CBir1 and anti-I2 were detected in 72%, 6%, 16%, 27%, 24% and 28%, respectively. After a median follow-up of 39 months (range, 3 to 150 months), 16 patients (17%) developed acute pouchitis,13 patients (14%) developed chronic pouchitis and 16 patients (17%) developed denovo CD.Although acute pouchitis was not influenced by pANCA level, chronic pouchitis developed in36% of high-level pANCA+ patients vs. 11% of low-level pANCA+ patients (p=0.03). DenovoCD developed in 43% of high-level pANCA+ patients compared to 12% of low-level pANCA+patients (p=0.01). No other significant associations were noted between seromarker expres-sion and clinical outcome. CONCLUSIONS: IBDU patients who express high-level pANCA(> 100 EU/ml) have a higher incidence of developing either chronic pouchitis or denovoCD after IPAA. Assessing pANCA before IPAA appears to have prognostic significance inIBDU patients.
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