- Email: [email protected]
Mo1149 Directional Differentiation of Biliary Tract Disease Allele Risks Across Human Populations
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duodenal ulcer (3), and periampullary diverticulm (2). 17 cases didn't have explainable findings. There were no change in CBD (37), increase in CBD diameter without obstructing lesion (4), development of gallstone (6) after follow up and 1 developed stricture in distal bile duct area. Dilated CBD with smooth tapering end, normal transaminase or total bilirubin level, past gastrectomy or choecystectomy were related with no change in diameter. Conclusion: Most cases of asymptomatically dilated CBD without obvious obstructing lesion were benign condition and did not change. So, close observation with CT scan could be optimal strategy. From this preliminary results, a comparison between the group with MRCP or ERCP and with only repeated CT scan would be possible in the future.
Efficacy of Diagnosis for Acute Cholecystitis With Contrast Enhanced Ultrasonography: Evaluation for Blood Flow of the Gall Bladder Wall Hiroki Utsunomiya, Atsushi Hiraoka, Miki Kan, Yusuke Imai, Haruka Tatsukawa, Nayu Tazuya, Hiroka Yamago, Yuko Shimizu, Nobukazu Yorimitsu, Satoshi Hidaka, Tetsuya Tanihira, Aki Hasebe, Yasunao Miyamoto, Tomoyuki Ninomiya, Kojiro Michitaka Aim/background: In early phase of acute cholecystitis (AC), ultrasonography (US) or enhanced computed tomography (CECT) sometimes do not show the typical findings. Therefore, its diagnosis is difficult in many patients. We evaluated the efficacy for diagnosis of AC with contrast enhanced US (CEUS). Methods: Subjects were 21 patients who were suspected for AC and 13 controls. B-mode US, CECT, and CEUS were performed in all of them. The symptoms of 21 patients, who were suspected for AC, were any one of upper abdominal pain and/or an attack of fever with elevation of the levels of white blood cell and/or C-reactive protein. B-mode US and CECT were reviewed for distension of GB, GB wall thickness, existence of debris in GB, pericholecystic fluid, subserosal edema, pericholecystic stranding. For diagnosis of AC by B-mode US, more than two findings of the three typical findings (distension of GB, GB wall thickness, existence of debris in GB) were necessary and distension of GB was an indispensable finding. Definitive diagnosis of AC was done by histopathological examination, the result of culture of bile juice from GB, and/or the typical finding of CECT including pericholecystic stranding. CEUS was performed with Perfulbutane (Sonazoid®). Movie video was recorded during the procedure and analysis was done with Receiver Operating Characteristic (ROC), that was focused on the GB wall in arterial phase of CEUS (20-60 seconds after injection of Sonazoid®). The results of analysis for ROC and clinical results were evaluated. Results: Nineteen of 21 patients, who were suspected for AC, were diagnosed as AC. Time intensity curve (TIC) was higher and acceleration time (ACT) was shorter in patients with AC than those without AC (4.50±2.31 vs. 2.34±1.26, P<0.01, and 8.2±2.4 vs. 15.8±7.1 seconds, P<0.01, respectively). These findings indicated the increase of the blood flow and the acceleration of the flow speed, respectively. Cut off values of TIC and ACT for diagnosis in ROC analysis were settled as >1.34, and as <15.8 respectively. With the cut off values of both TIC and ACT, seventeen patients were diagnosed as AC (17/19, 89.5%). Diagnostic value for AC with CEUS using above cut off values was equal to that of CECT (sensitivity and specificity: 89.5% and 100% vs. 73.7% and 100%, respectively). On the other hand, diagnostic value for AC of B-mode was worse (sensitivity and specificity: 21.1% and 100%). In five cases that could not be diagnosed by CECT, CEUS could diagnose them as AC. Conclusion: TIC was high and ACT was shortened in patients with AC. CEUS enabled the accurate diagnosis of AC in majority of patients whose findings of CECT or B-mode US were not typical with AC. CEUS was useful for the diagnosis of AC by analyzing TIC and ACT.
Mo1147 Inhibition of Sphingolipid Pathway Affects Cholesterol Gallstone Formation in Mice by the Modulation of IL-6/STAT3 Pathway Eun-Hye Lim, Jae Seon Kim, Beom Jae Lee, Yoon A Jeong, Jong-Jae Park, Joon Young Lee, Wonho Jung, Sang-ah Lim, Sehe Dong Lee, Young-Tae Bak Background: Previous our study has shown that sphingolipid pathway was associated with cholesterol gallstone formation in mice. Sphingolipid pathways are driven by inflammatory cytokines including IL-6. IL-6-driven Stat3 activation is associated with inflammation and cell proliferation. The aim of out study was whether the modulation of sphingolipid pathway has an impact on IL-6/Stat3 signaling in the inhibition of cholesterol gallstone formation Method: We used the cholesterol gallstone formation model (CB57BL/6J with lithogenic diet for 8 weeks, n=20 each group). Myriocin (serine palmitoyltransferase inhibitor, 0.3 mg/ kg/d, IP) was treated in experimental group and PBS was treated in control group. At the time of euthanization, GB and serum were extracted for the analysis. Gallstone formation was examined by naked eye. Extracted GB was cultured for 24hrs in RPMI medium for the assay for IL-6 by ELISA. Gene expressions of IL-6, SphK1 and S1PR1(S1P receptor 1) were determined using real-time RT-PCR and Western blot for Stat3 was performed. Results: Cholesterol gallstone formation was significantly decreased in myriocin treatment group (11% vs 85%, p<0.05). IL-6 concentrations of both serum and GB were decreased by myriocin (p<0.05). Phosphorylation of Stat3 in GB with gallstone significantly increased. Myriocin downregulated IL-6, SphK1 and S1PR1 gene expressions in GB and inhibited Stat3 activation. Conclusion: SphK/S1PR1 gene expression in GB was associated with cholesterol gallstone formation in mice. Inhibition of sphingolipid pathway affected the formation of cholesterol gallstone by the modulation of IL-6/Stat3 pathway in mice model. Mo1148 Liver Biochemical Tests are Often Normal in Patients With Common Bile Duct Stones Mel Wilcox, Milind A. Phadnis, Jessica Trevino, Shyam Varadarajulu
Mo1145 Regulation of CYP7A1: by Bile Acid or FGF15/19? Quan Shang, Gerald Salen, Guorong Xu
Background Abnormal liver chemistry tests (LFT's) are the hallmark of common bile duct (CBD) stones. However, there has been little study of the frequency and risk factors for normal liver tests in patients with CBD stones. Methods Using a prospective database, over a 10 year, 10 month period, all patients undergoing ERCP were prospectively identified. Patients undergoing ERCP for suspected or radiographically identified CBD stones had LFT's recorded at the time of initial clinical presentation and/or at the time of ERCP. CBD stones were confirmed by endoscopic sphincterotomy and extraction in all patients. Results Over the study period, 4782 patients underwent ERCP in whom 584 patients (67% white, 62% female, mean age 56 years +/- 21.6 years) had the procedure for suspected or radiographically identified CBD stones in whom laboratory results at the time of clinical presentation were available. Ultrasound or computed tomography was abnormal in 43% and 47% of patients, respectively. At the time of clinical presentation, LFT's were abnormal in 532 (51.1%) patients (95% CI - 48% - 54.1%). The most current LFT's prior to ERCP were normal in an additional 47 patients while 379 had abnormal LFTs. For those with abnormal LFT's, the median values were: total bilirubin of 2.7 (0.1 - 38); alkaline phosphatase 200 (range 37 - 1057); AST/ALT 105/139.5 range (3.5/9 - 1114/1152); GGT 249.5 range (4 - 1194). Patients with normal LFT's were more likely older (OR = 1.016; p=0.046) and had a longer duration since cholecystectomy (OR=1.004; p=0.044) as compared to patients with abnormal LFTs. Presence or absence of a solitary or multiple CBD stones, or abnormal ultrasound and computed tomography were not found to significantly associated. Conclusion Normal LFT's in patients presenting with a clinical picture compatible with common bile duct stones is more common than previously recognized. For those with abnormal LFT's, elevation of serum transaminases was the most common abnormal laboratory value.
Aim: It is proposed that CYP7A1 expression is regulated through a gut-liver signaling pathway FGF15/19-FGFR4 which is initiated by activation of FXR in the intestine rather than in the liver. This study evaluates whether the role of intestinal FGF15/19 in the regulation of CYP7A1 has been overstated. Method: New Zealand White rabbits were used (n=6/each group). Study 1 consisted of rabbits fed 0.5% or 2% cholesterol (Ch) and controls. Study 2: controls and rabbits with bile fistula alone (BF) or bile fistula plus 6 hrs of glycodeoxycholic acid perfusion (GDCA) directly into the portal vein to bypass the ileum. Results: In Study 1, portal bile acid concentrations, used to represent the bile acid flux returning to the liver, were increased 76% (p<0.01) in the rabbits fed 2% Ch but unchanged in those fed 0.5% Ch. Ileal FGF19 mRNA increased 100-fold (p<0.001) in rabbits fed either 0.5% or 2% Ch while hepatic CYP7A1 mRNA levels were suppressed only in the 2% Ch (77%, p<0.001) but not the 0.5% Ch group. For the first time, we measured FGF19 protein, the “signal”, in the portal blood which was 4.1±2.8 (control), 4.5±1.8 (0.5%Ch), and 4.7±2.7 pg/ml (2% Ch) respectively with no significant difference. In Study 2, portal bile acid concentrations in the GDCA group increased 3-fold due to the perfusion that bypassed the ileum. Ileal FGF19 mRNA was decreased (p<0.05) in both GDCA and BF groups while hepatic CYP7A1 expression was suppressed 80% (p<0.01) in the GDCA group and unchanged in the BF group. However, portal FGF19 protein concentrations were similar in the control (9.4±3.5pg/ ml), BF (9.4±3.7pg/ml) and GDCA (9.7±3.1pg/ml) groups. Conclusion: In rabbits, the expression of FGF19 in the ileum does not always determine the expression of CYP7A1 in the liver. The signal FGF19 concentration in the portal blood did not reflect the changes in FGF19 expression in the ileum nor correlated with the expression of CYP7A1 in the liver. Our results suggest that in rabbits, portal bile acid flux represents a more consistent signal than FGF19 on the regulation of CYP7A1 expression.
Mo1149 Directional Differentiation of Biliary Tract Disease Allele Risks Across Human Populations Saowanee Ngamruengphong, Tushar Patel
Mo1146 Clinical Course of Asymptomatically Dilated Common Bile Duct Anna Kim, Sung Hee Jung, Hyeon Woong Yang, Yun Jung Lee, Sae Hee Kim, Hyun Cheol Koo, JiWoong Jang, Chan Woong Park, Ho Sup Song, Sang Ok Lee
Background: Primary sclerosing cholangitis (PSC) and Primary biliary cirrhosis (PBC) are the most common chronic cholestatic liver diseases in adults. The geographic prevalence of these conditions varies considerably. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) associated with susceptibility to these conditions. Differences in SNP allele frequency between populations can provide evidence that a locus has been subject to selection, with differing selection pressures between the populations. Thus, our aims were to characterize evolutionary trends in the genetic profile of PSC and PBC. Methods: We analyzed the impact of human migration on the genetic risk of these chronic cholestatic disorders, and compared with genetic risk for alcoholic liver disease, or ulcerative colitis (UC). Disease associated SNPs were identified from the NHGRI GWAS database. The frequency of disease associated risk alleles across 53 indigenous populations spanning all continents and obtained from the human genome diversity project was analyzed. A population risk score was derived for these diverse populations based on the relative risk of each SNP and allelic frequency within a population. The data were superimposed on human migration patterns to derive temporal and spatial determinants of the impact of
Introduction: To evaluate dilated common bile duct (CBD), EUS, ERCP, or MRCP are needed. These modalities are expensive and some are invasive. When dilated CBD are found incidentally and abdominal CT scan shows no evidence of obstructing lesion, it is unclear if evaluation is needed or which modality should be chosen. We retrospectively collected cases with asymptomatically dilated CBD and evaluated the clinical course. Method: We retrospectively reviewed CT findings with CBD dilation from 2008 January to 2011 October in our institution. Total of 153 cases with dilated CBD were investigated. 54 cases with obvious obstructing lesions on CT findings or symptoms consistent with cholangitis, and 61 cases followed less than 6 months were excluded. Finally 48 cases were included. Results: Median observation period was 19 months (6-138 months). Mean age of the patients was 66.7 ± 11.7 years. 43/48 cases (89.6%) had normal ALT. All had normal serum bilirubin level. Associated conditions were gastrectomy (11), cholecystectomy (11), gallstone (4),
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human migration on genetic risk using Geneworld. Results: Several disease-associated SNPs were used for the analysis: PBC (18), PSC (3), alcoholic liver disease (1) and ulcerative colitis (32). PSC associated risk alleles were highest in populations from Africa and decreased with subsequent human migrations across Asia, Oceania and into the Americas. In marked contrast the allelic frequency of SNPs associated with PBC increased with human migrations. SNPs associated with alcoholic liver disease showed changes with migration similar to those for PBC. The pattern of change in risk score for PSC was remarkably similar to that for UC with a trend towards a decrease with migration from Africa through to Eastern Asia but with an increase in Europe. Conclusions: There are substantial differences in risk allele frequencies for PSC and PBC between indigenous human populations which may partly account for geographic differences in disease prevalence. Human migration is associated with a decreased frequency of PSC risk alleles, whereas the risk of PBC increased with migration. These divergent patterns of change in genetic risk suggest that chronic cholestasis alone does not provide an adequate selection pressure. The similarity of molecular evolution of risk alleles for PSC and UC across human migration indicates a common selection pressure on genetic susceptibility factors for these diseases. Table 1. Sensitivity, specificity and accuracy of USS in detection of gallstone, compared with histology finding as gold standard Accuracy of identifying number of stone on USS (compared with Histology report)
Mo1150 RAG1 Deficiency Inhibits Hepatic CYP7A1 Expression and Promotes Cholesterol Gallstone Formation in C57BL/6 Background Mice Kirk J. Maurer Introduction: We previously demonstrated that Rag2 deficiency protects against cholesterol gallstone formation in BALB/c inbred mice (Maurer KJ et al. Gastroenterology 133(4) 2007). This protection occurred primarily through the decreased expression of mucin genes and decreased mucin gel production in knockout mice and was mediated by T lymphocytes. The study described herein details a markedly contrasting finding in Rag1 knockout mice of C57BL/6 inbred origin. Methods: Male Rag1 knockout (n=8) or wild-type C57BL/6 mice (n=5) were fed a lithogenic diet containing 1.0% cholesterol, 0.5% cholic acid and 15% dairy triglyceride for 4 weeks. At the conclusion of the study, gallbladders were removed and weighed intact, and gallbladder bile was removed and analyzed by polarized and light microscopy. Gallbladders and livers were flash frozen for gene expression analysis. Results: After 4 weeks of diet feeding, 75% of knockout mice developed cholesterol gallstones whereas significantly fewer (0%) of the wild-type C57BL/6 mice developed stones at this time-point (P<0.05). Additionally, gallbladders from Rag1 knockout mice were significantly larger when compared to their wild-type counterparts (53 +/-9 mg vs. 24 +/-3 mg; P<0.05) consistent with hypomotility associated with gallstones. Mucin gene expression from the gallbladders of both strains displayed no significant differences for Muc1, Muc3, Muc4, Muc5Ac or Muc5b genes. In contrast, Rag1 mice displayed marked and significant differences in gene expression levels of lipid metabolism genes which were consistent with the altered gallstone phenotype noted. Specifically, Rag1 knockout mice displayed a > 100 fold inhibition of Cyp7a1 expression when compared to their wild-type counterparts (P<0.005). Conclusions: Rag1 deficiency promotes gallstones in C57BL/6 mice and suppresses expression of hepatic Cyp7a1. Since deficiencies in Cyp7a1 are known to promote gallstones it seems likely that this pronounced expression difference is responsible, at least in part, for the phenotypic differences noted in these strains. It is unclear, at this point, what factors alter Cyp7a1 gene expression; however, it seems likely that differences in hepatic inflammation in the two isogenic strains contribute to Cyp7a1 suppression.
Table 2. Accuracy of USS in identifying number of gallstone. Mo1152 Outcome of Severe Cholangitis is Affected by the Teaching Status of the Hospital: A Nationwide Analysis Nilay Kumar, Shahryar Ahmad, Muhammad Ali, Gagan Kumar, Young Oh Introduction - Severe cholangitis is life threatening illness with a very high risk of mortality and morbidity. Associated multi-organ dysfunction also further increases the risk. Variables that affect the outcomes of severe cholangitis are not well understood. Our aim was to look at these variables in a national inpatient sample. Methods - We utilized the National Inpatient Sample (NIS) Database for this study. Primary diagnosis of acute cholangitis was identified using the appropriate International Classification of Diseases (ICD-9CM) codes. The severity markers like need for central venous catheterization, endotracheal intubation, mechanical ventilation etc. were also identified by the appropriate ICD-9CM codes. Primary outcome evaluated was the mortality. Statistical analysis was done using the Stata software using the Chi Square and multiple logistic regression analysis. A Wilcoxon rank-sum test was also performed. Results - There were total of 12,020 estimated patients with severe cholangitis. Out of these 5168 (43%) patients were admitted to non-teaching hospital and 6852 (57%) were admitted to teaching hospitals. The overall mortality was 17%. The mortality was 765 (15%) in non-teaching hospitals vs. 1301 (19%) in teaching hospitals (p-.01). After logistic regression and adjusting for confounders the overall Odds Ratio (OR) for mortality in teaching hospitals for severe cholangitis was 1.35 (Confidence Interval CI - 1.07-170). Also noted was increasing mortality with age and Charlson's index. The mean length of stay (LOS) was 11.5 days vs. 14.6 days in non-teaching and teaching hospitals respectively (p0.000). Conclusion - Teaching hospitals have an overall higher mortality for patients with severe cholangitis and also have an increased LOS. This difference persisted even after adjusting for severity and Charlson's index. This observed discrepancy needs further investigation to look for the variables that could be responsible for such differences and warrants further studies.
Mo1151 Comparison of Gallstones Findings Between Ultrasonographical and Histological Investigations Ho Yan Leung, Zaher Toumi, Kishore G Pursnani Introduction: Ultrasound Scan (USS) is a routine investigation for patient with suspected gallstone disease, and is important to determine further management. Previous studies have concluded that it was a sensitive and specific investigation to detect gallstone and acute cholecystitis. The present study aimed at evaluating the reliability of USS in detection of gallstones in our department. Method: Patients were identified retrospectively by retrieving cholecystectomy operative notes between May 2005 and November 2011. Patients with preoperative USS performed by radiologists and sonographers were included. Number and size of gallstones were reviewed on USS and histology reports. The accuracy, sensitivity and specificity of USS were evaluated by comparing with histology reports as gold standard. The accuracy of identifying the number of gallstone was also evaluated. Size of stones reported on USS and histology were also compared. Result: There were 515 cholecystectomy performed in this period, with 457 patients having pre-operative USS. There were 58 patients with no pre-operative USS, and 13 histology reports did not indicate the absence or presence of gallstones. This left 444 patients in the study. The sensitivity, specificity and accuracy of USS were 97.2%, 25.0% and 89.4% respectively when compared with histology finding. The sensitivity, specificity and accuracy of radiologist performed USS was 97.0%, 40.2% and 89.7% respectively; while sonographer was 97.3%, 18.2% and 89.3% respectively. The sensitivity and positive predictive value of USS in detecting polyp in gallbladder were 50% and 20% respectively. The overall accuracy for identifying the number of stone on USS was 76.6%. The accuracy of detecting zero, one and multiple stones were 52.5%, 48.9% and 86.0% respectively. The accuracy of radiologist and sonographer were 76.7% and 76.5% respectively. There were 17 patients with size of the largest gallstone indicated on both USS and histology reports. The average size of stones measured on USS and histology were 15.9mm (95% confidence interval (CI) 12.6 - 19.2mm) and 19.7mm (95% CI 15.3 24.1mm) respectively. On average the USS underestimated the size of stone by 3.8mm (95% CI 1.6 -6.1mm, p=0.004), which was significant. Conclusion: The result indicated that the sensitivity and accuracy of the USS performed in our department was comparable top previous reports. However, specificity was lower than expected. There was no major difference in sensitivity and accuracy between radiologist and sonographer. However, radiologists have a higher specificity. USS is moderately accurate in terms of identifying the number of stones present. A positive polyp finding on USS was not reliable. There was a significant difference between the size of stones measured on USS and histology. USS Finding compared with Histology Finding
Mo1153 The Clinical Significance of Incidentally Detected Bile Duct Dilatation Joon Seong Ahn, Song Yi Song, Jong Kyun Lee, Kyu Taek Lee, Kwang Hyuck Lee, Mun Hee Bae We encounter without specific biliary symptoms and have ultrasonographic findings of mild dilatation of the bile duct, and have normal or trivially abnormal laboratory findings. Old age, post-cholecystectomy state, gastrectomy state, choledocholithiasis is commonly known cause of bile duct dilatation, rarely benign biliary stricture or pancreatobiliary tumor can also be the cause. But the studies examined the natural course of patients with bile duct dilatation and the final diagnosis were enrolled low number of patient and long term followup data were lacking. This study aimed to evaluate the causes and clinical significance of incidentally detected bile duct dilatation patients. Between January 2005 and April 2008, we evaluated individuals who were detected bile duct dilatation on ultrasonography from health promotion center of Samsung-Medical Center. Extrahepatic duct more than a 7mm, Intrahepatic duct, if extended over accompanied portal vein was defined as an bile duct dilatation. We analyzed age, operation history, location of bile duct dilatation, laboratory findings, and final diagnoses of this patients. In 435 patients who met the inclusion criteria (median age 60), 172 had undergone cholecystectomy or gastrectomy. Average follow-up period was 37 months. By analyzing the causes of bile dilatation were classified into group A (unnecessary treatment) and group B (needs treatment or close follow up). In statistical analysis, patient age was higher in group B than in group A. The extrahepatic duct diameter of the group B was significantly greater than group A. The dilatation of both intrahepatic and extrahepatic bile duct was more common in group B than in group A. The elevation of serum alkaline phosphatase was more common in group B than in group A. When
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duodenal ulcer (3), and periampullary diverticulm (2). 17 cases didn't have explainable findings. There were no change in CBD (37), increase in CBD diameter without obstructing lesion (4), development of gallstone (6) after follow up and 1 developed stricture in distal bile duct area. Dilated CBD with smooth tapering end, normal transaminase or total bilirubin level, past gastrectomy or choecystectomy were related with no change in diameter. Conclusion: Most cases of asymptomatically dilated CBD without obvious obstructing lesion were benign condition and did not change. So, close observation with CT scan could be optimal strategy. From this preliminary results, a comparison between the group with MRCP or ERCP and with only repeated CT scan would be possible in the future.
Efficacy of Diagnosis for Acute Cholecystitis With Contrast Enhanced Ultrasonography: Evaluation for Blood Flow of the Gall Bladder Wall Hiroki Utsunomiya, Atsushi Hiraoka, Miki Kan, Yusuke Imai, Haruka Tatsukawa, Nayu Tazuya, Hiroka Yamago, Yuko Shimizu, Nobukazu Yorimitsu, Satoshi Hidaka, Tetsuya Tanihira, Aki Hasebe, Yasunao Miyamoto, Tomoyuki Ninomiya, Kojiro Michitaka Aim/background: In early phase of acute cholecystitis (AC), ultrasonography (US) or enhanced computed tomography (CECT) sometimes do not show the typical findings. Therefore, its diagnosis is difficult in many patients. We evaluated the efficacy for diagnosis of AC with contrast enhanced US (CEUS). Methods: Subjects were 21 patients who were suspected for AC and 13 controls. B-mode US, CECT, and CEUS were performed in all of them. The symptoms of 21 patients, who were suspected for AC, were any one of upper abdominal pain and/or an attack of fever with elevation of the levels of white blood cell and/or C-reactive protein. B-mode US and CECT were reviewed for distension of GB, GB wall thickness, existence of debris in GB, pericholecystic fluid, subserosal edema, pericholecystic stranding. For diagnosis of AC by B-mode US, more than two findings of the three typical findings (distension of GB, GB wall thickness, existence of debris in GB) were necessary and distension of GB was an indispensable finding. Definitive diagnosis of AC was done by histopathological examination, the result of culture of bile juice from GB, and/or the typical finding of CECT including pericholecystic stranding. CEUS was performed with Perfulbutane (Sonazoid®). Movie video was recorded during the procedure and analysis was done with Receiver Operating Characteristic (ROC), that was focused on the GB wall in arterial phase of CEUS (20-60 seconds after injection of Sonazoid®). The results of analysis for ROC and clinical results were evaluated. Results: Nineteen of 21 patients, who were suspected for AC, were diagnosed as AC. Time intensity curve (TIC) was higher and acceleration time (ACT) was shorter in patients with AC than those without AC (4.50±2.31 vs. 2.34±1.26, P<0.01, and 8.2±2.4 vs. 15.8±7.1 seconds, P<0.01, respectively). These findings indicated the increase of the blood flow and the acceleration of the flow speed, respectively. Cut off values of TIC and ACT for diagnosis in ROC analysis were settled as >1.34, and as <15.8 respectively. With the cut off values of both TIC and ACT, seventeen patients were diagnosed as AC (17/19, 89.5%). Diagnostic value for AC with CEUS using above cut off values was equal to that of CECT (sensitivity and specificity: 89.5% and 100% vs. 73.7% and 100%, respectively). On the other hand, diagnostic value for AC of B-mode was worse (sensitivity and specificity: 21.1% and 100%). In five cases that could not be diagnosed by CECT, CEUS could diagnose them as AC. Conclusion: TIC was high and ACT was shortened in patients with AC. CEUS enabled the accurate diagnosis of AC in majority of patients whose findings of CECT or B-mode US were not typical with AC. CEUS was useful for the diagnosis of AC by analyzing TIC and ACT.
Mo1147 Inhibition of Sphingolipid Pathway Affects Cholesterol Gallstone Formation in Mice by the Modulation of IL-6/STAT3 Pathway Eun-Hye Lim, Jae Seon Kim, Beom Jae Lee, Yoon A Jeong, Jong-Jae Park, Joon Young Lee, Wonho Jung, Sang-ah Lim, Sehe Dong Lee, Young-Tae Bak Background: Previous our study has shown that sphingolipid pathway was associated with cholesterol gallstone formation in mice. Sphingolipid pathways are driven by inflammatory cytokines including IL-6. IL-6-driven Stat3 activation is associated with inflammation and cell proliferation. The aim of out study was whether the modulation of sphingolipid pathway has an impact on IL-6/Stat3 signaling in the inhibition of cholesterol gallstone formation Method: We used the cholesterol gallstone formation model (CB57BL/6J with lithogenic diet for 8 weeks, n=20 each group). Myriocin (serine palmitoyltransferase inhibitor, 0.3 mg/ kg/d, IP) was treated in experimental group and PBS was treated in control group. At the time of euthanization, GB and serum were extracted for the analysis. Gallstone formation was examined by naked eye. Extracted GB was cultured for 24hrs in RPMI medium for the assay for IL-6 by ELISA. Gene expressions of IL-6, SphK1 and S1PR1(S1P receptor 1) were determined using real-time RT-PCR and Western blot for Stat3 was performed. Results: Cholesterol gallstone formation was significantly decreased in myriocin treatment group (11% vs 85%, p<0.05). IL-6 concentrations of both serum and GB were decreased by myriocin (p<0.05). Phosphorylation of Stat3 in GB with gallstone significantly increased. Myriocin downregulated IL-6, SphK1 and S1PR1 gene expressions in GB and inhibited Stat3 activation. Conclusion: SphK/S1PR1 gene expression in GB was associated with cholesterol gallstone formation in mice. Inhibition of sphingolipid pathway affected the formation of cholesterol gallstone by the modulation of IL-6/Stat3 pathway in mice model. Mo1148 Liver Biochemical Tests are Often Normal in Patients With Common Bile Duct Stones Mel Wilcox, Milind A. Phadnis, Jessica Trevino, Shyam Varadarajulu
Mo1145 Regulation of CYP7A1: by Bile Acid or FGF15/19? Quan Shang, Gerald Salen, Guorong Xu
Background Abnormal liver chemistry tests (LFT's) are the hallmark of common bile duct (CBD) stones. However, there has been little study of the frequency and risk factors for normal liver tests in patients with CBD stones. Methods Using a prospective database, over a 10 year, 10 month period, all patients undergoing ERCP were prospectively identified. Patients undergoing ERCP for suspected or radiographically identified CBD stones had LFT's recorded at the time of initial clinical presentation and/or at the time of ERCP. CBD stones were confirmed by endoscopic sphincterotomy and extraction in all patients. Results Over the study period, 4782 patients underwent ERCP in whom 584 patients (67% white, 62% female, mean age 56 years +/- 21.6 years) had the procedure for suspected or radiographically identified CBD stones in whom laboratory results at the time of clinical presentation were available. Ultrasound or computed tomography was abnormal in 43% and 47% of patients, respectively. At the time of clinical presentation, LFT's were abnormal in 532 (51.1%) patients (95% CI - 48% - 54.1%). The most current LFT's prior to ERCP were normal in an additional 47 patients while 379 had abnormal LFTs. For those with abnormal LFT's, the median values were: total bilirubin of 2.7 (0.1 - 38); alkaline phosphatase 200 (range 37 - 1057); AST/ALT 105/139.5 range (3.5/9 - 1114/1152); GGT 249.5 range (4 - 1194). Patients with normal LFT's were more likely older (OR = 1.016; p=0.046) and had a longer duration since cholecystectomy (OR=1.004; p=0.044) as compared to patients with abnormal LFTs. Presence or absence of a solitary or multiple CBD stones, or abnormal ultrasound and computed tomography were not found to significantly associated. Conclusion Normal LFT's in patients presenting with a clinical picture compatible with common bile duct stones is more common than previously recognized. For those with abnormal LFT's, elevation of serum transaminases was the most common abnormal laboratory value.
Aim: It is proposed that CYP7A1 expression is regulated through a gut-liver signaling pathway FGF15/19-FGFR4 which is initiated by activation of FXR in the intestine rather than in the liver. This study evaluates whether the role of intestinal FGF15/19 in the regulation of CYP7A1 has been overstated. Method: New Zealand White rabbits were used (n=6/each group). Study 1 consisted of rabbits fed 0.5% or 2% cholesterol (Ch) and controls. Study 2: controls and rabbits with bile fistula alone (BF) or bile fistula plus 6 hrs of glycodeoxycholic acid perfusion (GDCA) directly into the portal vein to bypass the ileum. Results: In Study 1, portal bile acid concentrations, used to represent the bile acid flux returning to the liver, were increased 76% (p<0.01) in the rabbits fed 2% Ch but unchanged in those fed 0.5% Ch. Ileal FGF19 mRNA increased 100-fold (p<0.001) in rabbits fed either 0.5% or 2% Ch while hepatic CYP7A1 mRNA levels were suppressed only in the 2% Ch (77%, p<0.001) but not the 0.5% Ch group. For the first time, we measured FGF19 protein, the “signal”, in the portal blood which was 4.1±2.8 (control), 4.5±1.8 (0.5%Ch), and 4.7±2.7 pg/ml (2% Ch) respectively with no significant difference. In Study 2, portal bile acid concentrations in the GDCA group increased 3-fold due to the perfusion that bypassed the ileum. Ileal FGF19 mRNA was decreased (p<0.05) in both GDCA and BF groups while hepatic CYP7A1 expression was suppressed 80% (p<0.01) in the GDCA group and unchanged in the BF group. However, portal FGF19 protein concentrations were similar in the control (9.4±3.5pg/ ml), BF (9.4±3.7pg/ml) and GDCA (9.7±3.1pg/ml) groups. Conclusion: In rabbits, the expression of FGF19 in the ileum does not always determine the expression of CYP7A1 in the liver. The signal FGF19 concentration in the portal blood did not reflect the changes in FGF19 expression in the ileum nor correlated with the expression of CYP7A1 in the liver. Our results suggest that in rabbits, portal bile acid flux represents a more consistent signal than FGF19 on the regulation of CYP7A1 expression.
Mo1149 Directional Differentiation of Biliary Tract Disease Allele Risks Across Human Populations Saowanee Ngamruengphong, Tushar Patel
Mo1146 Clinical Course of Asymptomatically Dilated Common Bile Duct Anna Kim, Sung Hee Jung, Hyeon Woong Yang, Yun Jung Lee, Sae Hee Kim, Hyun Cheol Koo, JiWoong Jang, Chan Woong Park, Ho Sup Song, Sang Ok Lee
Background: Primary sclerosing cholangitis (PSC) and Primary biliary cirrhosis (PBC) are the most common chronic cholestatic liver diseases in adults. The geographic prevalence of these conditions varies considerably. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) associated with susceptibility to these conditions. Differences in SNP allele frequency between populations can provide evidence that a locus has been subject to selection, with differing selection pressures between the populations. Thus, our aims were to characterize evolutionary trends in the genetic profile of PSC and PBC. Methods: We analyzed the impact of human migration on the genetic risk of these chronic cholestatic disorders, and compared with genetic risk for alcoholic liver disease, or ulcerative colitis (UC). Disease associated SNPs were identified from the NHGRI GWAS database. The frequency of disease associated risk alleles across 53 indigenous populations spanning all continents and obtained from the human genome diversity project was analyzed. A population risk score was derived for these diverse populations based on the relative risk of each SNP and allelic frequency within a population. The data were superimposed on human migration patterns to derive temporal and spatial determinants of the impact of
Introduction: To evaluate dilated common bile duct (CBD), EUS, ERCP, or MRCP are needed. These modalities are expensive and some are invasive. When dilated CBD are found incidentally and abdominal CT scan shows no evidence of obstructing lesion, it is unclear if evaluation is needed or which modality should be chosen. We retrospectively collected cases with asymptomatically dilated CBD and evaluated the clinical course. Method: We retrospectively reviewed CT findings with CBD dilation from 2008 January to 2011 October in our institution. Total of 153 cases with dilated CBD were investigated. 54 cases with obvious obstructing lesions on CT findings or symptoms consistent with cholangitis, and 61 cases followed less than 6 months were excluded. Finally 48 cases were included. Results: Median observation period was 19 months (6-138 months). Mean age of the patients was 66.7 ± 11.7 years. 43/48 cases (89.6%) had normal ALT. All had normal serum bilirubin level. Associated conditions were gastrectomy (11), cholecystectomy (11), gallstone (4),
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human migration on genetic risk using Geneworld. Results: Several disease-associated SNPs were used for the analysis: PBC (18), PSC (3), alcoholic liver disease (1) and ulcerative colitis (32). PSC associated risk alleles were highest in populations from Africa and decreased with subsequent human migrations across Asia, Oceania and into the Americas. In marked contrast the allelic frequency of SNPs associated with PBC increased with human migrations. SNPs associated with alcoholic liver disease showed changes with migration similar to those for PBC. The pattern of change in risk score for PSC was remarkably similar to that for UC with a trend towards a decrease with migration from Africa through to Eastern Asia but with an increase in Europe. Conclusions: There are substantial differences in risk allele frequencies for PSC and PBC between indigenous human populations which may partly account for geographic differences in disease prevalence. Human migration is associated with a decreased frequency of PSC risk alleles, whereas the risk of PBC increased with migration. These divergent patterns of change in genetic risk suggest that chronic cholestasis alone does not provide an adequate selection pressure. The similarity of molecular evolution of risk alleles for PSC and UC across human migration indicates a common selection pressure on genetic susceptibility factors for these diseases. Table 1. Sensitivity, specificity and accuracy of USS in detection of gallstone, compared with histology finding as gold standard Accuracy of identifying number of stone on USS (compared with Histology report)
Mo1150 RAG1 Deficiency Inhibits Hepatic CYP7A1 Expression and Promotes Cholesterol Gallstone Formation in C57BL/6 Background Mice Kirk J. Maurer Introduction: We previously demonstrated that Rag2 deficiency protects against cholesterol gallstone formation in BALB/c inbred mice (Maurer KJ et al. Gastroenterology 133(4) 2007). This protection occurred primarily through the decreased expression of mucin genes and decreased mucin gel production in knockout mice and was mediated by T lymphocytes. The study described herein details a markedly contrasting finding in Rag1 knockout mice of C57BL/6 inbred origin. Methods: Male Rag1 knockout (n=8) or wild-type C57BL/6 mice (n=5) were fed a lithogenic diet containing 1.0% cholesterol, 0.5% cholic acid and 15% dairy triglyceride for 4 weeks. At the conclusion of the study, gallbladders were removed and weighed intact, and gallbladder bile was removed and analyzed by polarized and light microscopy. Gallbladders and livers were flash frozen for gene expression analysis. Results: After 4 weeks of diet feeding, 75% of knockout mice developed cholesterol gallstones whereas significantly fewer (0%) of the wild-type C57BL/6 mice developed stones at this time-point (P<0.05). Additionally, gallbladders from Rag1 knockout mice were significantly larger when compared to their wild-type counterparts (53 +/-9 mg vs. 24 +/-3 mg; P<0.05) consistent with hypomotility associated with gallstones. Mucin gene expression from the gallbladders of both strains displayed no significant differences for Muc1, Muc3, Muc4, Muc5Ac or Muc5b genes. In contrast, Rag1 mice displayed marked and significant differences in gene expression levels of lipid metabolism genes which were consistent with the altered gallstone phenotype noted. Specifically, Rag1 knockout mice displayed a > 100 fold inhibition of Cyp7a1 expression when compared to their wild-type counterparts (P<0.005). Conclusions: Rag1 deficiency promotes gallstones in C57BL/6 mice and suppresses expression of hepatic Cyp7a1. Since deficiencies in Cyp7a1 are known to promote gallstones it seems likely that this pronounced expression difference is responsible, at least in part, for the phenotypic differences noted in these strains. It is unclear, at this point, what factors alter Cyp7a1 gene expression; however, it seems likely that differences in hepatic inflammation in the two isogenic strains contribute to Cyp7a1 suppression.
Table 2. Accuracy of USS in identifying number of gallstone. Mo1152 Outcome of Severe Cholangitis is Affected by the Teaching Status of the Hospital: A Nationwide Analysis Nilay Kumar, Shahryar Ahmad, Muhammad Ali, Gagan Kumar, Young Oh Introduction - Severe cholangitis is life threatening illness with a very high risk of mortality and morbidity. Associated multi-organ dysfunction also further increases the risk. Variables that affect the outcomes of severe cholangitis are not well understood. Our aim was to look at these variables in a national inpatient sample. Methods - We utilized the National Inpatient Sample (NIS) Database for this study. Primary diagnosis of acute cholangitis was identified using the appropriate International Classification of Diseases (ICD-9CM) codes. The severity markers like need for central venous catheterization, endotracheal intubation, mechanical ventilation etc. were also identified by the appropriate ICD-9CM codes. Primary outcome evaluated was the mortality. Statistical analysis was done using the Stata software using the Chi Square and multiple logistic regression analysis. A Wilcoxon rank-sum test was also performed. Results - There were total of 12,020 estimated patients with severe cholangitis. Out of these 5168 (43%) patients were admitted to non-teaching hospital and 6852 (57%) were admitted to teaching hospitals. The overall mortality was 17%. The mortality was 765 (15%) in non-teaching hospitals vs. 1301 (19%) in teaching hospitals (p-.01). After logistic regression and adjusting for confounders the overall Odds Ratio (OR) for mortality in teaching hospitals for severe cholangitis was 1.35 (Confidence Interval CI - 1.07-170). Also noted was increasing mortality with age and Charlson's index. The mean length of stay (LOS) was 11.5 days vs. 14.6 days in non-teaching and teaching hospitals respectively (p0.000). Conclusion - Teaching hospitals have an overall higher mortality for patients with severe cholangitis and also have an increased LOS. This difference persisted even after adjusting for severity and Charlson's index. This observed discrepancy needs further investigation to look for the variables that could be responsible for such differences and warrants further studies.
Mo1151 Comparison of Gallstones Findings Between Ultrasonographical and Histological Investigations Ho Yan Leung, Zaher Toumi, Kishore G Pursnani Introduction: Ultrasound Scan (USS) is a routine investigation for patient with suspected gallstone disease, and is important to determine further management. Previous studies have concluded that it was a sensitive and specific investigation to detect gallstone and acute cholecystitis. The present study aimed at evaluating the reliability of USS in detection of gallstones in our department. Method: Patients were identified retrospectively by retrieving cholecystectomy operative notes between May 2005 and November 2011. Patients with preoperative USS performed by radiologists and sonographers were included. Number and size of gallstones were reviewed on USS and histology reports. The accuracy, sensitivity and specificity of USS were evaluated by comparing with histology reports as gold standard. The accuracy of identifying the number of gallstone was also evaluated. Size of stones reported on USS and histology were also compared. Result: There were 515 cholecystectomy performed in this period, with 457 patients having pre-operative USS. There were 58 patients with no pre-operative USS, and 13 histology reports did not indicate the absence or presence of gallstones. This left 444 patients in the study. The sensitivity, specificity and accuracy of USS were 97.2%, 25.0% and 89.4% respectively when compared with histology finding. The sensitivity, specificity and accuracy of radiologist performed USS was 97.0%, 40.2% and 89.7% respectively; while sonographer was 97.3%, 18.2% and 89.3% respectively. The sensitivity and positive predictive value of USS in detecting polyp in gallbladder were 50% and 20% respectively. The overall accuracy for identifying the number of stone on USS was 76.6%. The accuracy of detecting zero, one and multiple stones were 52.5%, 48.9% and 86.0% respectively. The accuracy of radiologist and sonographer were 76.7% and 76.5% respectively. There were 17 patients with size of the largest gallstone indicated on both USS and histology reports. The average size of stones measured on USS and histology were 15.9mm (95% confidence interval (CI) 12.6 - 19.2mm) and 19.7mm (95% CI 15.3 24.1mm) respectively. On average the USS underestimated the size of stone by 3.8mm (95% CI 1.6 -6.1mm, p=0.004), which was significant. Conclusion: The result indicated that the sensitivity and accuracy of the USS performed in our department was comparable top previous reports. However, specificity was lower than expected. There was no major difference in sensitivity and accuracy between radiologist and sonographer. However, radiologists have a higher specificity. USS is moderately accurate in terms of identifying the number of stones present. A positive polyp finding on USS was not reliable. There was a significant difference between the size of stones measured on USS and histology. USS Finding compared with Histology Finding
Mo1153 The Clinical Significance of Incidentally Detected Bile Duct Dilatation Joon Seong Ahn, Song Yi Song, Jong Kyun Lee, Kyu Taek Lee, Kwang Hyuck Lee, Mun Hee Bae We encounter without specific biliary symptoms and have ultrasonographic findings of mild dilatation of the bile duct, and have normal or trivially abnormal laboratory findings. Old age, post-cholecystectomy state, gastrectomy state, choledocholithiasis is commonly known cause of bile duct dilatation, rarely benign biliary stricture or pancreatobiliary tumor can also be the cause. But the studies examined the natural course of patients with bile duct dilatation and the final diagnosis were enrolled low number of patient and long term followup data were lacking. This study aimed to evaluate the causes and clinical significance of incidentally detected bile duct dilatation patients. Between January 2005 and April 2008, we evaluated individuals who were detected bile duct dilatation on ultrasonography from health promotion center of Samsung-Medical Center. Extrahepatic duct more than a 7mm, Intrahepatic duct, if extended over accompanied portal vein was defined as an bile duct dilatation. We analyzed age, operation history, location of bile duct dilatation, laboratory findings, and final diagnoses of this patients. In 435 patients who met the inclusion criteria (median age 60), 172 had undergone cholecystectomy or gastrectomy. Average follow-up period was 37 months. By analyzing the causes of bile dilatation were classified into group A (unnecessary treatment) and group B (needs treatment or close follow up). In statistical analysis, patient age was higher in group B than in group A. The extrahepatic duct diameter of the group B was significantly greater than group A. The dilatation of both intrahepatic and extrahepatic bile duct was more common in group B than in group A. The elevation of serum alkaline phosphatase was more common in group B than in group A. When
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