M1829 Chronic Inflammation of the Cardia in Gastroesophageal Reflux Disease (GERD) Is Not Regulated By FOXP3 Expressing Regulatory T Cells

M1829 Chronic Inflammation of the Cardia in Gastroesophageal Reflux Disease (GERD) Is Not Regulated By FOXP3 Expressing Regulatory T Cells

M1825 the esophagus. TLESR events with onset during sleep stages were considered sleep-related. RESULTS: A total of 105 TLESR-related GER events in h...

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the esophagus. TLESR events with onset during sleep stages were considered sleep-related. RESULTS: A total of 105 TLESR-related GER events in healthy subjects and 43 events in GERD patients during awake state, and 17 events in healthy subjects and 18 events in GERD patients during sleep were analyzable. The proportion of UES response to GER events in healthy subjects in awake state was similar to that in sleep state. However, GERD patients had significantly more UES relaxation responses to reflux events in the awake state (χ2, P<0.01). This UES relaxation response was less frequent in GERD patients during sleep (χ2, P=0.03). CONCLUSIONS: In healthy controls and GERD patients the predominant UES response to TLESR-related GER events in the recumbent position is contraction. However, GERD patients are significantly more likely to have UES relaxation response, which could predispose them to esophago-pharyngeal reflux. This inappropriate UES response is inhibited during sleep. Supported in part by research grant 5R01DK025731-28

AGA Abstracts

Esophageal Acid Perception Is Not Influenced By Acute Psychological Stress Gerrit J. Hemmink, Albert J. Bredenoord, Bas L. Weusten, Robin Timmer, André Smout Background & Aim: GERD patients often report an exaggeration of their reflux symptoms during stressful situations. The aim of our study was to assess the influence of acute psychological stress on esophageal acid perception in both healthy volunteers and patients with GERD. Methods: An acid perfusion test was performed in 15 healthy volunteers and 10 patients with GERD, once with and once without the presence of an acute psychological stressor. The time from onset of the acid infusion to first acid perception, discomfort and pain was noted. A modified Raven Progressive Matrices IQ test was used to induce stress and watching a video documentary served as a control task. The order of the measurements was randomized. Blood pressures were observed in order to assess the effect of the stress task. The state and trait anxiety questionnaire (STAI) was used to compare the baseline stress of the subjects on both days of the measurements. Results: In healthy subjects, the time to first perception (video: 234 (57-988)s vs. stress task: 291 (92-558)s), discomfort (video: 512 (375-969)s vs. stress task: 577 (419-882)s), or pain (video: 1073 (714-1324)s vs. stress task: 1289 (734-1456)s) did not differ significantly between both measurements, although a significant rise in systolic blood pressure during the stress task was observed (control task: -0.6±1.1 mmHg, stress task: 5.9±1.1 mmHg; p<0.001). In patients with GERD, no significant differences between both measurements were found either in time to first perception (video: 25 (16-99)s vs. stress task: 26 (17-54)s), discomfort (video: 73 (58-336)s vs. stress task: 243 (54-394)s) or pain (video: 503 (223-712)s vs. stress task: 577 (357830)s). Systolic blood pressure rose significantly during the stress task (8.7±2.0 mmHg) video: -3±1.9 mmHg). Baseline stress levels before the measurements did not differ between the two days in both healthy volunteers and GERD patients. Conclusion: Both in healthy volunteers and GERD patients, acute psychological stress did not influence esophageal acid perception. The observed increase in systolic blood pressure shows that the experimental stressors were effective. These findings indicate that an acute psychological stressor does not affect esophageal hypersensitivity.

M1828 Intercellular Space Distance Is Increased in Refractory Heartburn Patients with Positive Symptom Index Regardless of Whether Symptoms Are Caused By Acid or Nonacid Reflux: A Study Using Impedance-pH and Electron Microscopy Marcelo F. Vela, Brandon M. Craft, Neeraj Sharma, Janice Freeman, Debra Hazen-Martin

M1826 The Role of Body Mass Index and Waist Circumference in Determining Reflux Pattern and Proximal Extent of Reflux Events Emidio Scarpellini, Kathleen Blondeau, Rita Vos, Jan F. Tack

INTRODUCTION: Refractory heartburn despite acid suppression may be due to: (a) ongoing acid reflux (AR), (b) ongoing nonacid reflux (NAR), (c) mixed acid+nonacid reflux, (d) not related to reflux (i.e. functional heartburn if non-reflux causes excluded). Multichannel Intraluminal Impedance and pH (MII-pH) detects both AR and NAR. NAR can cause symptoms that are indistinguishable from those elicited by AR. Increased intercellular space distance (ISD) in esophageal epithelium measured by electron microscopy (EM) is a marker of epithelial damage present in both erosive and non-erosive GERD. The relationship between ISD and symptomatic AR vs NAR is unknown. AIM: Compare ISD in healthy controls and two groups of refractory heartburn patients: positive symptom index (SI) due solely to NAR and positive SI due solely to AR. METHODS: Patients with persistent heartburn despite BID PPI underwent MII-pH on therapy and endoscopy with biopsies for ISD measurement by Electron Microscopy (EM). Patients with positive SI on MII-pH (>50% heartburn events associated with a reflux episode) categorized as: (a) SI-NAR (heartburn due solely to NAR), (b) SI-AR (heartburn due solely to AR), (c) SI-Mixed (heartburn due to mixed NAR+AR). Controls (asymptomatic, normal 24-h pH study) underwent endoscopy with esophageal biopsies for ISD measurement. ISD determined in all subjects by transmission EM of esophageal biopsies at 5,000x magnification using computer-assisted morphometry (Image J software). 10 measurements of ISD taken in each of 10 micrographs; mean ISD was the average of these 100 measurements. RESULTS: 10 healthy controls, 7 SI-NAR, 2 SI-AR patients studied so far (1 SI-Mixed patient excluded). Results shown in the table. Mean ISD was significantly higher in both SI-NAR and SI-AR patients compared to controls (p = 0.04 and p = 0.03, respectively). Mean ISD was not different for SI-NAR compared to SI-AR. CONCLUSION: Patients with refractory heartburn and positive SI have increased ISD compared to controls regardless of whether heartburn is due to NAR or AR. In the presence of increased ISD, NAR may theoretically cause heartburn by stimulating chemoreceptors because of hyperrosmolarity rather than acidity of refluxate; NAR may also stimulate mechanoreceptors irrespective of chemical properties of refluxate or underlying ISD.

Background: Epidemiological studies established that symptoms and lesions of gastroesophageal reflux disease (GERD) are associated to increasing body weight, and especially increased waist circumference (IWC). Proximal extent of the refluxate has been implicated in the occurrence of symptoms during reflux events. It is unclear whether IWC, through higher intra-abdominal pressure, is associated with a higher proximal extent of reflux events. Aims: To evaluate the impact of body mass index (BMI) and waist circumference on the characteristics of reflux events. Methods: Nineteen GERD patients underwent measurement of body mass index (BMI), waist circumference and ambulatory 24h Multichannel intraluminal impedance-pH (MII-pH) monitoring. Composition (liquid, air, acid or weakly acidic) and proximal extent of reflux events were determined from MII-pH. Data (mean±SEM) were compared by student's t-test. Results: Six patients were studied on and 13 off PPI. Overweight patients (BMI>25, n=12) had a higher number of reflux events (76±14 vs. 37±5, p<0.05), especially liquid (43.6±15.3 vs. 6.1±1.5, p<0.05) and upright (69.9±13.8 vs 34.3±4.2, p<0.05) reflux events, compared to those without overweight. Acid exposure did not differ significantly between both groups (4.9±2.1 vs. 2.1±1.1%, NS). The number of reflux events with extent to 15 cm above the lower esophageal sphincter (LES) did not differ significantly (25.9±4.7 vs. 13.9±4.9, NS). Patients with IWC (>85cm, n=14) had a higher number of reflux events (72.1±12.4 vs. 33.0±5.9, p=0.01), especially liquid events (38.6±13.4 vs. 5.2±1.7, p=0.03), non-acid events (47±11.4 vs. 20.6±5.8, p=0.05), compared to those without IWC. The increase was found for upright (65.9±12.0 vs. 31.4±5.3, p=0.02) as well as supine (6.3±1.6 vs. 1.6±0.7, p=0.02) reflux events. Acid exposure did not differ significantly between both groups (4.5±1.8 vs. 2.0±1.4%, NS). The number of reflux events with extent to 15 cm above LES was significantly higher in those with IWC (26.3±4.1 vs. 8±4.3, p= 0.01). Patients with IWC had a higher number of weakly-acidic reflux-related cough events (1.4±0.7 vs. 0±0, p<0.05). The mean symptom index for weakly acidic reflux-related symptoms was significantly higher in those with IWC (27±10 vs. 0±0, p<0.05). Most of these differences were preserved when the patients on PPI were excluded from the analysis. Conclusions: A higher BMI is associated with a higher number of upright liquid reflux events. An IWC is associated with a higher number of liquid and non-acid reflux events. In subjects with IWC, proximal extent of the refluxate is higher and associated with symptoms related to weakly acidic reflux, like cough.

SI-NAR =heartburn due solely to nonacid reflux SI-AR =heartburn due solely to acid reflux ISD =intercellular space distance

M1827 UES Response to TLESR-Associated Reflux Events During Sleep in Healthy Subjects and GERD Patients Shiko Kuribayashi, Benson T. Massey, Sri Naveen Surapaneni, Jonathan Huang, Muhammad Hafeezullah, Lilani P. Perera, Linda Tatro, Syed Q. Hussaini, Reza Shaker

M1829 Chronic Inflammation of the Cardia in Gastroesophageal Reflux Disease (GERD) Is Not Regulated By FOXP3 Expressing Regulatory T Cells Arne Kandulski, Thomas Wex, Doerthe Kuester, Klaus Mönkemüller, Lucia C. Fry, Peter Malfertheiner

INTRODUCTION: Earlier studies in recumbent position have documantated upper esophageal sphincter (UES) contractile responses to reflux events (Torrico S, Am J Gastrointest Liver Physiol, 2000). However, the effect of sleep on UES response to transient lower esophageal sphincter relaxation (TLESR)-related reflux events has not been systematically evaluated. AIM: To determine the pattern of UES responses to TLESR-related reflux events (contraction, relaxation and no change) in sleep compared to awake state. METHODS: We studied 15 healthy subjects (7M, age 18-56) and 9 gastroesophageal reflux disease (GERD) patients (5M, 18-39) using concurrent high-resolution 36 channel esophageal manometry and 6 channel impedance/2 channel pH catheters. Subjects were studied in the recumbent position for 2 hours during the daytime and for 6 hours during the nighttime with polysmnographic recordings after a 1000 kcal meal. TLESR events were identified by standard criteria. Gastroesophageal reflux (GER) events were detected by retrograde impedance changes in

AGA Abstracts

Background: Gastroesophageal reflux disease (GERD) is associated with chronic inflammation at the gastric cardia. Regulatory T cells (FOXP3+ Tregs) are involved in the pathogenesis of chronic inflammatory diseases independent of their etiology. Their pathogenetic role has not been studied in GERD. Aim: To characterize FOXP3+ Tregs in GERD associated chronic inflammation at the cardia. Methods: 22 patients with typical GERD-related symptoms where included and underwent upper GI endoscopy with mucosal biopsies taken from the cardia. Patients with no GERD symptoms (controls n=17) were included as well as patients with dyspeptic symptoms and H. pylori infection (n=31). Gene expression analysis of FOXP3, a marker of various regulatory T cell populations, was performed by quantitative RT-PCR and

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immunohistochemical staining of FOXP3 and CD45. Furthermore, mucosal transcript levels of TGF-beta1 and IL-10 were studied and all data were correlated with histopathological values according to the updated Sydney classification. Results: GERD was associated with a chronic inflammation (P=0.065) and reduced FOXP3-mRNA in the cardiac mucosa (84%) as compared to controls, whereas H. pylori-positive patients revealed a 25.1-fold (P= 0.03) increase of FOXP3 gene expression. These results were confirmed by immunohistochemical analysis of intramucosal FOXP3+ Tregs. The absolute number [0.78+/-0.15 versus 2.65+/-0.44, P<0.001] as well as their proportion among all infiltrating immune cells [2.65+/0.61% versus 8.14+/-1.38%, P<0.001] were significantly reduced in patients with GERD than those infected with H. pylori. Conclusion: The GERD-associated chronic inflammation at the cardia is not associated with an infiltration of FOXP3+ Tregs. The regulation of chronic inflammation in GERD is distinct from the common involvement of FOXP3+ Tregs in other chronic inflammatory diseases of the GI tract as presented for H. pylori infection.

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Background & Aim: An occupation-related susceptibility of several categories of orchestral musicians, as the wind instruments players, to experience gastro-esophageal reflux was hypothesized. We investigated a series of professional orchestral musicians, comparing reflux symptoms referred from wind instruments players with those from players of other instruments (control). Methods: A structured questionnaire was distrubuted to 1083 musicians (414 wind instruments players and 669 players of other instruments) of 21 orchestras of 15 Italian towns in order to obtain information on reflux symptoms in the year preceding the survey together with selected individual characteristics and life style habits. Prevalence rate ratios, adjusted for the type of instrument played, gender, age, body mass index, smoking status, alcohol consumption and other confounding factors, were computed. Results: Wind instrument players reported a statistically significant higher prevalence of heartburn and regurgitation than the other instrument players, with adjusted prevalent rate ratios of 1.23 (CI 95% 1.04-1.46) and 1.23 (CI=0.97-1.55). Conclusions: Wind instrument players among orchestral musicians reported a higher prevalence of reflux symptoms than other instruments players. Future studies will be needed to clarify whether reflux symptoms in professional opera choristers are stress-induced and therefore may be considered as a work-related discomfort.

M1830 Modulation of Salivation and Heartburn in Response to the Site of Acid Infusion in Human Esophagus Sudhir K. Dutta, Kireet Agrawal, Mitchell Mah'moud Introduction: Gastroesophageal reflux disease (GERD) is associated with a variety of clinical manifestations ranging from heartburn (HB) to chest pain (Gastroenterol. Clin. North Am. 2008; 37:845). Salient factors in the pathogenesis of this disorder include amount of acid reflux (frequency, duration and extent of mucosal exposure), salivation, and esophageal peristalsis. Several clinical observations suggest that there may be a differential expression of the disease depending on its magnitude of mucosal exposure to the acid reflux. Aim/ Objective: We postulated that salivation and heartburn in response to intraluminal acid exposure may vary according to site of acid infusion in human esophagus. Materials/Methods: To test this hypothesis, twelve healthy subjects were enrolled in this study after obtaining informed consent. Each study subject received infusions of Hydrochloric acid (HCl) (100mmol/L) in the upper {20cm above lower esophageal sphincter (LES)} and the lower esophagus (10cm above LES). HCl was infused for 20 minutes and parotid saliva was collected periodically. HB severity score was tabulated using a standardized and validated scale. Standard statistical methods were used to determine the significance of difference between the various groups. Results: Intraluminal perfusion of HCl in the upper esophagus was associated with greater mean Parotid saliva flow rate (PSFR) (0.75±0.03ml/min) as compared to the lower half (10cm above LES) (0.54±0.05 ml/min) (p<0.05). The heartburn score per unit of time was also significantly elevated in the upper esophagus (8±1) as compared to the lower esophagus (5.5±1) with acid infusion (p<0.05). There was no heartburn at all upon acid infusion in the stomach. Summary: Our data suggest that intraluminal HCl infusion in the upper esophagus is associated with greater parotid salivary secretion and higher HB score (p<0.05). These observations may be related greater number of Hydrogen ion receptor exposure in the esophageal mucosa and/or increased density of sensory innervations by the vagus nerve in the upper esophagus. Keywords: Acid infusion, Heartburn, salivation.

M1833 Strong Correlation Between Squamocolumnar Junction Position and Age in Healthy Volunteers John P. Seenan, Angela A. Wirz, Alan T. Clarke, Andrew W. Kelman, Kenneth E. McColl INTRODUCTION: The gastric cardia is an important site of pathology with a high incidence of inflammation, metaplasia and neoplasia. However this complex area is poorly understood and it has been proposed that cardia mucosa itself may be pathological, arising from columnar metaplasia of the distal esophageal squamous mucosa. Previous autopsy studies show a near absence of cardia epithelium in neonates and an increase in length with age. AIMS & METHODS: Aim: To determine if the position of the squamocolumnar junction (SCJ) within the lower esophageal high pressure zone (HPZ) changes with age in healthy subjects. Methods:15 Helicobacter pylori negative subjects (9 males) were studied. Each underwent upper GI endoscopy with clipping of a radio-opaque endoclip at the squamocolumnar junction. On a separate study day, synchronized 36 sensor high resolution manometry and videofluoroscopy was performed with subjects fasted and in a semi-recumbent position. A 10 second analysis period of stable sphincter tone (out with sphincter relaxations) was selected. The proximal high pressure zone was identified from manometry data as a stepdown in pressure to the intrathoracic pressure. The location of the SCJ was determined using image analysis software with the measured distance of a pH sensor (known to be 1cm) used as a scale. The distance between the position of the SCJ and the proximal HPZ was calculated for each individual. RESULTS: The median age of the subjects was 25 years (Range 20-59). The median distance between SCJ position and proximal HPZ position for the group was 3.59cm (Range 0.31-4.46) . There was a strong negative correlation between age and distance between SCJ and proximal HPZ ,(r = -0.831, p<0.001) with the squamocolumnar junction closer to the proximal HPZ with increasing age. The correlation was even stronger in males alone (r = -0.961, p<0.001). In multiple regression analysis the combination of both increasing age and body mass index was significantly associated with movement of the SCJ closer to the proximal HPZ (R2=73.6%, P<0.001) with a strong trend towards significance for both individual variables (p=0.053 and p=0.088 respectively). CONCLUSION: The position of the squamocolumnar junction relative to the proximal high pressure zone is strongly correlated to age in healthy subjects. This is consistent with proximal migration of the squamocolumnar junction due to columnar metaplasia of the distal esophageal squamous mucosa.

M1831 Gastroesophageal Reflux Disease Is Inversely Related with Glycemic Control in Morbidly Obese Patients Carlos Augusto S. Madalosso, Richard R. Gurski, Liana O. Ruas, Priscila Santini, Fernando Fornari Background: Recent evidence has linked metabolic syndrome with reflux esophagitis. The aim of this study was to assess the relation between glycemic control (GC) and gastroesophageal reflux disease (GERD) in morbidly obese patients. Methods: Eighty six patients (25 males, aging 38 ± 12 years, BMI 45 ± 8 kg/m2) underwent solid-state esophageal manometry, 24-h esophageal pH-metry, endoscopy and barium swallow X-ray after responding a GERD symptom questionnaire [heartburn ranging 0 (best) to 30 (worst)] and dosing both fasting plasma glucose (FPG in mg/dL) and glycosylated hemoglobin (HbA1c in %). Patients with poor GC (HbA1c 6.1-10 and FPG < 140) and those with very poor GC (HbA1c > 10 or FPG > 140) were compared. Results: Six patients were excluded due to normal HbA1c (< 6.1) with FPG < 140. Out of 80 patients, 63 composed the group poor GC (15 male, aging 38 ± 12 years, BMI 45 ± 7 kg/m2, HbA1c 7.7 ± 0.8) and 17 patients the group very poor GC (8 male, aging 42 ± 11 years, BMI 47 ± 9 kg/m2, HbA1c 10.5 ± 1.3). Patients with very poor GC showed better scores for heartburn [0 (0-4) vs. 8 (0-12); P = 0.003] but similar rates of reflux esophagitis (41% vs. 48%; P = 0.364). Total esophageal acid exposure [median (IQR)] was significantly lower in patients with very poor GC [2.3% (0.8-7.5%) vs. 5.2% (2.5-10.5%); P = 0.041]. Distal esophageal amplitude (134 ± 63 vs. 105 ± 38 mm Hg; P = 0.019) and lower esophageal sphincter pressure (29 ± 11 vs. 23 ± 13 mm Hg; P = 0.025) were both higher in the group of patients with very poor GC. These patients showed significantly less hiatal hernia at X-ray (6% vs. 38%; P = 0.016), as well as lower expiratory gastroesophageal pressure gradient (GEPG: 5.2 ± 3 vs. 7 ± 3.4 mm Hg; P = 0.050) and higher ventilatory gradient (inspiratory - expiratory GEPG: 13.6 ± 4.1 vs. 10.9 ± 3.8 mm Hg; P = 0.012) than patients with poor GC. Conclusions: This study suggests an inverse relation between glycemic control and GERD in morbidly obese patients. This finding seems to be related with lower rates of hiatal hernia in patients with very poor glycemic control. In these patients, increased ventilatory gradient might be a marker of higher abdominal complacence and diaphragm integrity.

M1834 E-Cadherin Cleavage in Gastroesophageal Reflux Disease (GERD) Biljana Jovov, Nicholas J. Shaheen, Zorka Djukic, Roy C. Orlando Background: The presence of dilated intercellular spaces within esophageal squamous epithelium of GERD patients, both erosive and nonerosive forms, suggests the presence of damage to the apical junctional complex (AJC), i.e. zonula occludens and zonula adherens, since the AJC regulates permeability via the intercellular space in this tissue. Methods: For detection of such damage, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunoblots were performed on esophageal biopsies from GERD patients (n=12) and healthy controls (n=4) for zonula occludens-1 (ZO-1), multiple claudins, occludin, and e-cadherin. Immunofluorescence (IF) detection was used to determine localization of proteins of interest, and enzyme-linked immunosorbent assay (ELISA) for quantification of soluble e-cadherin in plasma. Results: qRT-PCR demonstrated prominent down regulation of claudin-4 in GERD patients. Immunoblots, using a C-terminus monoclonal anti e-cadherin antibody, showed cleavage of e-cadherin in GERD patients. Two bands were detected, one of 120 kDa band corresponds to intact e-cadherin, and the other of 38 kDa band corresponds to C-terminus fragment. Interestingly, using an N-terminus antibody, increased levels of a soluble 80 kDa fragment of e-cadherin was detected by ELISA in the plasma of GERD patients (20.5 ± 2.1 μg/ml; n=10), compared to healthy controls 11.74 ± 0.9 μg/ml; n=10. Moreover, since the size of the cleaved e-cadherin fragment suggests possible proteolysis by a disintegrin and metalloprotease10 (ADAM10), Western blot and IF analysis were performed, and those analysis demonstrated increased levels of ADAM10 in GERD patients biopsies. Conclusions: These findings suggest that dysfunction of the AJC in GERD involves both down regulation of claudin-4 and proteolytic cleavage of e-cadherin. Since the product of e-cadherin cleavage is detectable in plasma and at higher levels in GERD patients than controls, consideration should be given to its possible use as a diagnostic or prognostic plasma marker in GERD. (Support: NIH grants DK036013 and DK063669).

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AGA Abstracts

AGA Abstracts

Reflux Symptoms in Orchestral Wind Instrument Players Giovanni Cammarota, Giovanna Masala, Rossella Cianci, Domenico Palli, Benedetta Bendinelli, Gianluca Ianiro, Raffaele Landolfi, Giovanni Gasbarrini, Antonio Gasbarrini