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sT1976

Increased Risk of Gastroesophageal Reflux Disease Associated with GenePolymorphisms in NOD1 Signaling Pathway in Helicobacter pylori InfectedPatientsTomoyuki Oikawa, Akira Imatani, Sho Asonuma, Naoki Asano, Yasuhiko Abe, TomoyukiKoike, Katsunori Iijima, Shuichi Ohara, Tooru Shimosegawa

Background & Aim: NOD1 is an intracellular recognition molecule of innate immune systemthat leads to the secretion of IL-8, which induces gastric mucosal damage in Helicobacterpylori(Hp) infection. This damage induces mucosal atrophy and reduction of acid secretion,which are generally protective against gastroesophageal reflux disease (GERD). However,some Hp-infected patients develop GERD, suggesting that the host genetic factors mayinfluence the susceptibility to GERD. We have previously reported that ND1+32656(ND1)[T/GG] is associated with the risk of GERD in DDW 2007. In this study, we investigatedthe effect of both ND1 [T/GG] and IL-8-251(IL8) [A/T] polymorphisms on susceptibility toGERD, gastric mucosal atrophy and acid secretion in Japanese population. Subjects &Methods: Genomic DNA was prepared from 202 Hp infected healthy subjects and from211 GERD patients with reflux esophagitis and/or Barrett's esophagus. In these GERDpatients, 110 were Hp-positive and 101 were Hp-negative. ND1 [T/GG] and IL8 [A/T]polymophisms were genotyped by direct sequence analysis. In addition, gastritis scores wereassessed with biopsy specimens according to the updated Sydney system. We also measuredserum pepsinogen (PG) and gastric acid secretion. Results: The Hp-infected patients carryingND1 GG allele showed an increased risk of GERD with odds ratio (OR) 1.9[95% confidenceinterval (CI), 1.2-3.0], and those carrying IL8 T/T showed the risk with OR 1.7[95% CI,1.1-2.8] compared with Hp-infected control subjects, respectively. Combination of bothND1 GG allele and IL8 T/T, in the Hp-infected carriers synergistically increased the risk ofGERD with odds ratio (OR) 3.1[95% CI, 1.6-6.2] compared with those of ND1 T/T andIL8 A allele. In histological assessments, inflammation score was significantly lower in theND1 GG allele group than the ND1 T/T group. Atrophy score showed a tendency to belower in the IL8 T/T group than the IL8 A allele group. In addition, PG I/II ratio, whichindicates the severity of atrophy, showed a tendency to be higher (meaning less atrophy)in the ND1 GG allele group than the ND1 T/T group. Similarly, PG I/II ratio tended to behigher in the IL8 T/T group compared with the IL8 A allele group. Gastric acid secretionwas significantly lower in the IL8 A allele group than the IL8 T/T group. Conclusions: ND1GG allele and IL8 T/T may be associated with the diminished host immune response to Hpinfection, and may inhibit the progression to gastric atrophy and acid secretion. Therefore,these polymorphisms may increase the risk of GERD even in Hp infected patients.

T1977

Pressure Dynamics in the Lower Esophagus in Subjects with Hiatal HerniaUsing High-Resolution ManometryAnnapurna Korimilli, Anil K. Vegesna, Larry S. Miller, Henry P. Parkman, Robert S.Fisher

Purpose - To evaluate the pressure dynamics of the lower esophageal sphincter (LES), cruraldiaphragm (CD), pressure within the hiatal hernia sac (HH) and intra-gastric pressure at restand during increased intra-abdominal pressure. Methods: Sierra high resolution manometrysystem was used to simultaneously evaluate the pressures in the distal esophagus at theLES, CD, HH and stomach in 7 patients with HH and heartburn and 4 patients with HHbut without heartburn. Pressures were measured at rest and during increased intra-abdominalpressure with leg lifts. The HPZ pressures in the distal esophagus were measured prior toand during leg lifts. The pressures were measured using the smart mouse feature on theManoView analysis software. Results - The mean pressure (mm Hg) in patients with hiatalhernia and with or without heartburn was measured before and after leg lifts at the LES,CD, HH and stomach and shown in the table below. There was an increase in all thepressures at the LES, CD, HH and stomach after leg lifts. In patients with hiatal hernia andheartburn, the pressure in the hiatal hernia sac, at rest was significantly higher than thegastric pressure at rest (p=0.005) as opposed to subjects with hiatal hernia and withoutheartburn (p=0.193). Conclusion: A new technique for simultaneous evaluation of dynamicpressure profiles in hiatal hernia patients was developed. Mean pressure in the hiatal herniasac at rest in patients with heartburn was significantly higher than the pressure within thestomach, while it was not higher in patients without heartburn. Mean pressures within thehiatal hernia sac in patients with and without heart burn are not significantly different.Table: All pressures (mm Hg) expressed as Mean +/- SD, *= Statistical significance.

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T1978

Gastric Pressure Increases Above Lower Esophageal Sphincter (LES) Pressurein Subjects with Hiatal Hernia and GERD During Increases in Intra-Abdominal PressureAnnapurna Korimilli, Anil K. Vegesna, Larry S. Miller, Henry P. Parkman, Frank K.Friedenberg, Robert S. Fisher

Background: The driving force (DF) behind GERD is the pressure differential between theLES and the stomach. As the gastric pressure increases with increasing intra-abdominalpressure, the LES pressure needs to compensate or reflux will occur. Purpose: To simultan-eously measure the change in LES and gastric pressure during increased intra-abdominalpressure in subjects with and without GERD. Methods: Sierra high resolution manometrysystem was used to evaluate the LES and gastric pressure simultaneously during increasesin intra-abdominal pressure with leg lifts in 11 subjects with hiatal hernia (7 with heartburn,4 without heart burn) and 24 subjects without hiatal hernia (12 with heartburn, 12 withoutheartburn). Delta LES pressure = the LES pressure during leg lifts (LL) minus the LESpressure before LL. Delta gastric pressure = the gastric pressure during LL minus the gastricpressure before LL. Driving Force (DF) = Delta LES/Delta gastric. Results: In subjects withhiatal hernia and heart burn the mean DF = 0.56 +/- 0.17. In subjects with hiatal herniabut without heart burn the mean DF = 1.21+/- 0.33 (p<0.002). There was no difference indriving force between GERD and non GERD subjects without hiatal hernia 1.44 +/- 0.45and 1.78 +/- 0.60 respectively (p<0.12) Conclusions: Increased intra-abdominal pressuredoes not cause the gastric pressure to rise above the LES pressure in non hiatal herniapatients with or without heartburn. However, in subjects with hiatal hernia and heartburn,increased intra-abdominal pressure causes the gastric pressure to rise above the LES pressurewhile in subjects with hiatal hernia and without heartburn increased intra-abdominal pressuredoes not cause the gastric pressure to rise above the LES pressure (sensitivity and specifi-city = 100%).

T1979

Enhanced Esophageal NADPH Oxidase Expression in Response to AcidEisuke Iwasaki, Hidekazu Suzuki, Tatsuhiro Masaoka, Toshihiro Nishizawa, TetsufumiTakahashi, Yoshimasa Saito, Hitoshi Tsugawa, Toshifumi Hibi

Background. Reactive oxygen species (ROS) play a critical role in the inflammation ofesophageal mucosa of patients with reflux esophagitis. Although it has been reported thatlow levels of ROS seen in nonphagocytic cells is by-product of aerobic metabolism, recentlysuperoxide generating homologues of phagocytic NADPH oxidase (Nox) have been foundin several cell types (Nature. 1999, 401:79-82). The role of Nox family members in acid-induced esophageal injury, however, has not been fully investigated. The present study isdesigned to examine the expression of Nox homologues in the esophageal mucosa afteracidic liquid loading by using originally developed experimental In Vivo and ex vivo ratmodel. Materials and Methods. (Experiment 1) 7-week-old male Sprague-Dawley (SD) ratswere used. After 24 hours' food deprivation, operation was performed under the generalanesthesia. A 2-cm midline incision was made in the lower neck to expose the esophagus.The esophagus was ligated with attention to avoid injuring the vagus and carotid artery.The rats were laparotomized and insert catheter to esophagus through the forestomach toinject reagents. Immediately esophago-gastric junction was ligated. Rats were divided intofour groups by contents of loading reagent, as follows; Group A (control group with noreagent), Group B (saline), Group C (0.001N HCl), Group D (1N HCl). Four hours later,esophagus was removed and expression of Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 andDuox2 mRNA was evaluated by quantitative RT-PCR. (Experiment 2) Esophagus of 7-week-old male SD rat was removed after deep ether anesthesia. Extracted esophageal tubes withtied at both end were filled with Krebs buffer (n=8) or 0.001N HCl (n=8). These tubes werekept in Krebs buffer for 30min or 120min, and then tubes were collected and analyzed toexamine mRNA expression of Nox family. Results. (Experiment 1) In group C and D,significant increase in the Nox3 (C: 4.91-fold; D: 2.47-fold, p<0.01) and Duox1 (C: 3.19-fold; D: 2.38-fold, p<0.01) mRNA were found. In addition, Nox3 (1.82-fold, p<0.05) wasalso increased in group B. (Experiment 2) Expression of Duox1 (1.91-fold, p<0.01) andDoux2 (1.79-fold, p<0.05) mRNA at 30 min and Nox3 (1.87-fold) mRNA at 120 min afteracid exposure were significantly enhanced as compared with the control. Conclusion. Thisis the first to report the esophageal NADPH oxidase expression in response to the acid.Enhanced levels of Nox3, Duox1 and 2 mRNA expressions were found in esophagus, not onlyacidic liquid loading, but also with neutral liquid loading, suggesting the acid independentmechanism of non-erosive reflux disease.

T1980

How Does GERD Evolve During a 5-Year Follow-Up Period? the Progerd StudyPeter Malfertheiner, Marc Nocon, Michael R. Höcker, Daniel Jaspersen, Joachim Labenz,Hans R. Koelz, Tore Lind, Manfred Stolte, Michael Vieth, Stefan Willich

Aim: The evolution of gastroesophageal reflux disease (GERD) under current managementoptions (including continuous, intermittent and on-demand gastric acid suppressant therap-ies) is uncertain. The ProGERD study is a prospective assessment of the evolution of GERDduring a 5-year follow-up period under routine medical care in Germany. Methods: Ptswith the primary symptom of heartburn were included at baseline, and stratified into non-erosive (NERD) and erosive reflux disease (ERD), LA grades A-D (Los Angeles classification).The presence of columnar lined epithelium in the esophagus (endoscopic Barrett's) incombination with the histological finding of specialized intestinal metaplasia led to a diagnosisof 'confirmed' Barrett's esophagus (BE). After a 2-8 week course with esomeprazole therapyto achieve endoscopic healing in ERD and symptom relief in NERD, pts were treated routinelyat the discretion of their physician. We report esophagitis status and presence of endoscopicand confirmed BE after 5 years. Results: 6215 pts were enrolled in the original study, ofwhom 2721 pts completed the 5-year follow up, including upper GI endoscopy. At baseline,240 pts were classified as having either endoscopic (n=115) or confirmed BE (n=125).Progression, regression or stability of GERD categories observed from baseline to 5 years