Sa1337 Treatment With Milk Thistle, Ursodeoxycholic Acid or Their Combination Attenuates Liver Injury in Bile Duct-Ligated Rats

cholangitis increased by 327.8 % from $151,274,411± 15,512,171 in 1997 to $495,826,085 ± 33,670,119 in 2012 (p<0.001). The percentage of national bill for cholangitis discharges (national bill for cholangitis/total national bill) has markedly increased over the last 16 years (0.04 % in 1997 versus 0.08 % in 2012). DISCUSSION: The number of inpatient admissions for cholangitis has relatively stayed the same over the last 16 years. However, the cost associated with these admissions has increased significantly. Fortunately, the in-patient mortality rate, however, has decreased. Inpatient costs associated with cholangitis contribute significantly to the total healthcare bill. Further research on cost-effective evaluation and management of cholangitis is required.

repression of CYP7A1 in E2-treated mice. As a result, a significant increase in the ratio of Ch to BA leads to the imbalance of biliary lipids for keeping Ch solubilized in bile, contributing to the formation of Ch-supersaturated bile.

Treatment With Milk Thistle, Ursodeoxycholic Acid or Their Combination Attenuates Liver Injury in Bile Duct-Ligated Rats Nuray Alaca, Dilek Ozbeyli, Serap Uslu, Hasan H. Sahin, Hizir Kurtel, Berrak C. Yegen Cholestasis, which may lead to death and fibrosis of liver cells, cirrhosis, and eventually liver failure, is associated with oxidative stress and inflammation. For the treatment of primary biliary cirrhosis, intrahepatic cholestasis, and other cholestatic conditions, ursodeoxycholic acid (UDCA) is the only approved treatment. On the other hand, the leaf and flower extracts of milk thistle (MT) have been used for hepatic disorders as an herbal remedy. The aim of this study was to evaluate the effects of MT and UDCA on cholestatic liver injury and to elucidate whether combination of MT and UDCA therapy is superior to only UDCA treatment. Under anesthesia, bile ducts of Sprague Dawley rats were either ligated (BDL rats; n=30) or an abdominal incision was made without a ligation (control rats; n=6). Starting at the 24th hour of surgery, BDL rats were administered saline, UDCA (15mg/kg/day), MT (600mg/kg/day) or UDCA+MT by gavage for 10 days, while the control rats received saline. On the 10th day of the experiment, rats were decapitated and blood and liver samples were obtained. Serum alanine aminotransferase (ALT) and hepatic malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity were measured as indicators of hepatic function, lipid peroxidation and neutrophil infiltration, respectively. Serial liver sections (5 µm) were stained with hematoxylin eosin and van Gieson stains to evaluate the degree of inflammation and fibrosis, using the Knodell and Ishak scoring system. Expressions of c-kit and c-myc were evaluated immunohistochemically in hepatic oval stem cells and inducible pluripotent stem cells. Histological scores, serum ALT and hepatic MDA levels were higher in the salinetreated BDL group as compared to the control rats (p<0.001), while UDCA, MT or UDCA+MT treatments significantly reduced the histological scores, ALT and MDA levels (p<0.05). The reduction in ALT was significantly greater in UCDA+MT-treated group (p<0.05) than only UDCA- or only MT-treated groups. UDCA, MT and their combination demonstrated similar anti-inflammatory and anti-proliferative effects on cholestatic liver injury augmenting the regenerative response of the cholestatic rat liver, while addition of MT to UDCA had a greater protective impact on the preservation of liver function, suggesting that MT+UDCA combination may have a therapeutic potential in the treatment of cholestatic liver injury.

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Sa1338 Concordance of Presenting Symptoms With 3D High Definition Anorectal Manometry: A Retrospective Study C. Prakash Gyawali, Ghadah Al Ismail, Laura R. Haroian, Beverly J. Connor, Kimberly Butz Introduction: Pelvic floor disorders affect 10-15% of the US population. Objective tests complement symptom assessment and physical exam in evaluating these disorders. In recent years, 3D high definition anorectal manometry (HDARM) has enhanced identification of pelvic floor disorders. We characterized patients referred for evaluation of pelvic floor symptoms using HDARM to assess correlation between presenting symptoms and diagnoses based on HDARM. Methods: All adult patients undergoing HDARM (Covidien, Duluth, GA) between Jan and Nov 2014, with dominant presenting symptoms characterized into either constipation or fecal incontinence were eligible for inclusion. Exclusion criteria included prior pelvic floor surgery, neoplasia or radiation, incomplete studies, studies with artifacts, or studies performed with techniques other than 3D HDARM. Electronic medical reports and procedure reports were scrutinized to extract demographics, presenting symptoms, HDARM findings and clinical impression. Correlation between presenting symptoms and final clinical impressions after HDARM analysis was determined, and rates of concordance and discordance of final diagnosis with presenting symptom were assessed. Results: Over the 10 mo study period, 200 unique HDARM studies (age 59 ±1 yr, 82.5 % Female) were performed; 178 fulfilled study inclusion criteria and were included in this analysis. Of these, 102 (57.3%) presented with constipation and 76 (42.7%) with fecal incontinence. 20 (11.2%) HDARM studies were interpreted as normal, without a mechanism for symptoms (constipation=9, fecal incontinence=11). There was evidence for dyssynergia in 102 (56.7%) studies, while a weak sphincter was diagnosed in 47 (26.4%). When analyzed by final diagnosis, proportions with constipation as a dominant symptom was higher in patients with dyssynergia (69.8% vs. 21.3%), while incontinence was more frequent with a weak sphincter (27.4% vs. 72.3%, p<0.0001). A sector defect in the sphincter was identified on 3D pressure topography in 29 of 47 patients (61.7%) with a weak sphincter; this was not observed with dyssynergia. When analyzed by dominant symptom, 74 (71.6%) of constipation patients had dyssynergia, but only 37 (48.7%) with fecal incontinence had weak sphincter (p=0.002). Symptoms were concordant with final diagnosis in 120 patients (68.0%,); constipation with dyssynergia in 61.7%, and incontinence with weak sphincter in 30.8%. Discordance (58 patients, 32.0%) was related to weak sphincter with constipation in 17.2% and dyssynergia with incontinence in 48.3%, and normal HDARM with either symptom in 34.5%. Conclusion: While most HDARM studies are concordant with presenting symptoms, a substantial number of studies demonstrate findings discordant with presenting symptoms that may impact management decisions. This adds to the value of HRARM in evaluating pelvic floor symptoms.

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Sa1336 Molecular Mechanisms Underlying the Critical Role of the G Protein-Coupled Receptor 30 (GPR30), a Novel Estrogen Receptor, in the Formation of Lithogenic Bile Through a Non-Transcriptional Regulatory Mode in 17bEstradiol (E2)-Treated Mice Ornella de Bari, Helen H. Wang, Piero Portincasa, Min Liu, David Q. Wang Background: A failure of hepatic cholesterol (Ch) homoeostasis, in which the physicalchemical balance of Ch solubility in bile is disrupted, induces the formation of lithogenic bile. However, few studies were performed to address the metabolic abnormalities underlying the source of excess Ch that causes bile supersaturation induced by E2 through GPR30. Of note is that ~50% of Ch is converted to bile acids (BA) in the liver each day in humans and mice. Because GPR30 is expressed in the endoplasmic reticulum and not in the nucleus of hepatocytes, we hypothesized that the epidermal growth factor receptor (EGFR) is required for GPR30 to produce a non-transcriptional regulatory role in suppressing hepatic expression of Ch 7 a-hydroxylase (CYP7A1) and the classical pathway of BA synthesis, leading to the availability of excess amounts of Ch for hepatic hypersecretion and the formation of supersaturated bile. Methods: The effect of GPR30 on the formation of lithogenic bile and Ch crystallization were studied in ovariectomized (OVX) GPR30(-/-)/ER a(-/-) and GPR30(+/+)/ERa(-/-) mice implanted subcutaneously with pellets releasing E2 at 6 µg/day and fed a lithogenic diet for 8 weeks. To study whether the metabolic abnormalities underlying the major source of the excess Ch molecules lead to Ch-supersaturated bile as induced by GPR30, we examined the role of GPR30 in regulating CYP7A1 and the classical pathway of BA synthesis through EGFR. Results: E2 induced rapid Ch crystallization mainly through the liquid crystalline pathway and promoted gallstone formation in OVX GPR30(+/+)/ER a(-/) mice fed the lithogenic diet. By contrast, the prevalence of gallstones was drastically reduced in OVX GPR30(-/-)/ERa(-/-) mice. Hepatic secretion of biliary BA was significantly reduced in mice expressing GPR30, leading to an increased ratio of Ch to BA. After E2 treatment, there was a significant increase in mRNA and protein levels of EGFR and a significant decrease in expression levels of liver receptor homolog-1 (LRH-1), coupled with reduced CYP7A1 mRNA and protein levels in OVX GPR30(+/+)/ER a(-/-), but not GPR30(-/-)/ERa(-/) mice. In vitro studies using cultured primary hepatocytes isolated from GPR30(+/+)/ER a(-/) mice showed that when EGFR was inhibited by AG1478, a highly potent EGFR kinase inhibitor, the mRNA and protein levels of CYP7A1 were unchanged even though GPR30 was activated by E2. Conclusions: These results indicate that GPR30 regulates Cyp7a1 expression through the EGFR cascade. In the lithogenic state, reduced hepatic synthesis of BA from the classical pathway significantly inhibits the conversion of Ch to BA due to GPR30

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Sa1337