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Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett's mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET

Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.

Oesophageal intraluminal impedance is currently used for assessment of reflux in gastro-oesophageal reflux disease (GORD). Oesophageal mucosa integrity may have a key role in heartburn perception in non-erosive reflux disease (NERD). Severe erosive oesophagitis is associated with low impedance baseline. We hypothesised that impedance baseline measurements could be used to evaluate changes in oesophageal mucosa integrity in man.We measured oesophageal impedance baseline before, during and after acid perfusion in rabbits and healthy subjects. Transepithelial resistance (TER) was determined and dilated intercellular spaces (DIS) were assessed in isolated rabbit oesophageal mucosa. Impedance baseline was measured retrospectively at different levels of the oesophagus in impedance-pH recordings from asymptomatic volunteers and patients with GORD.In healthy subjects and rabbits, impedance baseline dropped dramatically during perfusion of control solution (pH 7.2) but after perfusion, impedance recovered. In rabbits, after perfusion with saline pH 1.5 and 1.0 impedance values remained a 39.1 ± 7.0% and 63.9 ± 6.5% (p0.05) lower respectively. There was a positive correlation between in vivo basal impedance and in vitro TER values (r = 0.72, p = 0.0021). Tissue showed no erosions but both acidic solutions induced DIS. In healthy subjects, after perfusion with saline pH 2.0 and 1.0 the impedance baseline remained lower a 21.9 ± 6.5% and 52.7 ± 5.0%, (p0.0001) respectively. Patients with GORD have a lower impedance baseline than healthy volunteers at the distal oesophagus.Impedance baseline measurements might be used to evaluate the status of the oesophageal mucosa and to study the role of the impaired mucosal integrity in acid-induced heartburn in healthy volunteers and in patients with GORD.

BackgroundOesophageal mucosa dilated intercellular spaces (DIS) may be important for symptom perception in non-erosive reflux disease (NERD). Patients with NERD might have DIS even in the proximal oesophagus. We aimed to assess the effect of oesophageal perfusions with acid and weakly acidic solutions on ‘exposed’ and ‘non-exposed’ oesophageal mucosa and its relationship to symptoms in healthy subjects.Methods14 healthy volunteers underwent upper gastrointestinal endoscopy with biopsies at 3 and 13 cm proximal to the oesophagogastric junction (OGJ). In following sessions, subjects received 30 min perfusions with neutral, weakly acidic, acidic and acidic-bile acid solutions at 5 cm above the EGJ (separated 4 weeks). Biopsies were taken 20 min after perfusions. Electron microscopy was used to measure DIS. Subjects scored heartburn during perfusions using a visual analogue scale.Results(1) Oesophageal perfusion with acid solutions, with or without bile acids, provoked DIS in the ‘exposed’ oesophageal mucosa; (2) oesophageal perfusion with weakly acidic solutions provoked identical changes to those observed after perfusion with acid solutions; (3) distal oesophageal perfusions not only provoked changes in the ‘exposed’ but also in the more proximal ‘non-exposed’ mucosa; and (4) in spite of the presence of perfusion-induced DIS, most healthy subjects did not perceive heartburn during the experiments.ConclusionsThe human oesophageal mucosa is very sensitive to continuous exposure with acidic and weakly acidic solutions. In spite of the presence of intraluminal acid and DIS, healthy subjects did not experience heartburn, suggesting that NERD patients should have other critical factors underlying their symptoms.

Gastro-oesophageal reflux (GOR) is increased in cystic fibrosis (CF), but its prevalence, characteristics, association with gastric aspiration and respiratory impact are not well characterised. We investigated acid and weakly acidic reflux, aspiration and respiratory symptoms/function in adult CF patients.Thirty-three CF patients [19 men; 29 (18-55) years, [10 post-lung transplant (LTx)] underwent impedance-pH monitoring for detection of acid (pH4) and weakly acid GOR (pH 4-7). In 16 patients cough was objectively recorded with oesophageal manometry, and the symptom association probability (SAP) was calculated. Saliva and bronchoalveolar lavage fluid (BALF) were tested for bile acids.Twenty-eight patients had increased GOR (21 acid, 5 weakly acidic and 2 acid+weakly acidic) and 10 had a positive SAP for reflux cough. GOR parameters were similar in non-LTx and post-LTx CF patients. The sequence reflux cough was significantly more common than cough reflux. Sixteen of 38 patients had bile acids in saliva and 6/10 in BALF and this was almost exclusively observed in patients with genotype DF508/DF508. Only 12/28 with increased GOR and 9/22 with bile acids in saliva/BALF had typical reflux symptoms. There was a positive correlation (r = 0.53, p = 0.03) between oesophageal acid exposure and cough. SAP-positive patients with for reflux cough had a lower lung function than SAP-negative patients.Increased GOR is prevalent in CF and not secondary to cough. Acid GOR is common, but weakly acidic GOR may also occur. CF patients have a high risk of aspiration and reflux seems to be associated with more cough and poorer lung function. Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in CF progression.

The mechanisms underlying symptoms in gastro-oesophageal reflux disease, particularly in non-erosive reflux disease (NERD), remain to be fully elucidated. Weakly acidic reflux and the presence of gas in the refluxate could be relevant in the pathogenesis of symptoms.To assess the relationship between symptoms and weakly acidic, acid and mixed (liquid-gas) reflux, 24 h oesophageal pH-impedance monitoring was performed in 32 NERD and in 20 oesophagitis patients. In 12 NERD patients the study was repeated following 4 weeks treatment with a proton pump inhibitor (PPI). Impedance-pH data were compared with those of 10 asymptomatic controls. Heartburn and acid regurgitation were considered in the analysis of symptoms.15 NERD patients showed a physiological acid exposure time (pH-negative). Weakly acidic reflux was significantly less frequent in patients (25% (2%), mean (SE)) than in controls (54% (4%), p0.01). Gas was present in 45-55% of reflux events in patient groups and controls, and decreased following PPI treatment. In NERD pH-negative patients, weakly acidic reflux accounted for 32% (10%) (vs 22% (6%) in NERD pH-positive and 12% (8%) in oesophagitis patients) and mixed reflux for more than two-thirds of all symptom-related refluxes. Multivariate logistic analysis showed that in NERD pH-negative patients, the risk of reflux perception was significantly higher when gas was present in the refluxate (odds ratio, 3.2; 95% CI, 1.2 to 10; p0.01).The large majority of symptoms, in all patients, are related to acid reflux. In NERD patients, the presence of gas in the refluxate significantly enhances the probability of reflux perception. These patients are also more sensitive to less acidic reflux than oesophagitis patients.

Aim: A subset of functional dyspepsia patients respond to acid suppressive therapy, but the prevalence of non-erosive reflux disease in functional dyspepsia and its relevance to symptoms have never been established. The aim of the present study was to study 24 hour pH monitoring in consecutive functional dyspepsia patients. Methods: A total of 247 patients with dyspeptic symptoms (166 women, mean age 44 (SEM 1) year), with a negative upper gastrointestinal endoscopy and without dominant symptoms of heartburn participated in the study. In all patients, the severity of dyspeptic symptoms and the presence of heartburn was assessed by a questionnaire and a 24 hour oesophageal pH monitoring study was performed. All patients underwent a gastric emptying breath test and in 113 a gastric barostat study was performed. Results: Abnormal pH monitoring (acid exposure >5% of time) was found in 58 patients (23%). Of 21 patients with a positive heartburn questionnaire, 76% had pathological pH monitoring, while this was the case in only 18.5% of patients with a negative heartburn questionnaire. Demographic characteristics and the prevalence of other pathophysiological mechanisms did not differ between heartburn negative patients with normal or abnormal acid exposure. Pathological acid exposure in heartburn negative patients was associated with the presence of epigastric pain (65 v 84%, p v 69%, p = 0.005). Conclusion: Pathological oesophageal acid exposure is only present in a subset of heartburn negative functional dyspepsia patients, which are characterised by a higher prevalence of epigastric pain.

In patients with gastro-oesophageal reflux disease (GORD), oesophageal and extraoesophageal symptoms are traditionally attributed to increased contact time between the mucosa and refluxates. However, the volume of reflux may be important by increasing the total amount of highly concentrated damaging substances, either by prolonging distal mucosal exposure or by expanding to more proximal areas. To date, it has not been possible to accurately measure the volume of gastro-oesophageal reflux. Determination of the volume of reflux will help to better understand the pathophysiology of GORD and to evaluate the efficacy of antireflux treatments.

Background: Patients with aerophagia are believed to have excessive belches due to air swallowing. Intraluminal impedance monitoring has made it possible to investigate the validity of this concept.Methods: The authors measured oesophageal pH and electrical impedance before and after a meal in 14 patients with excessive belching and 14 healthy controls and identified patterns of air transport through the oesophagus. The size of the gastric air bubble was measured radiographically. In four patients prolonged oesophageal manometry was performed simultaneously.Results: In all subjects, impedance tracings showed that a significant amount of air is propulsed in front of about a third of the swallow induced peristaltic waves. Two types of retrograde gas flow through the oesophagus ( belch) were observed. In the first type air flowed from the stomach through the oesophagus in oral direction ("gastric belch''). In the second type air entered the oesophagus rapidly from proximal and was expulsed almost immediately in oral direction ("supragastric belch''). The incidence of air-containing swallows and gastric belches was similar in patients and controls but supragastric belches occurred exclusively in patients. There was no evidence of lower oesophageal sphincter relaxation during supragastric belches. Gastric air bubble size was not different between the two groups.Conclusions: In patients with excessive belching the incidence of gaseous reflux from stomach to oesophagus is similar to that in healthy subjects. Their excess belching activity follows a distinct pattern, characterised by rapid antegrade and retrograde flow of air in the oesophagus that does not reach the stomach.

Oesophageal clearance of acid and bile: a combined radionuclide, pH, and Bilitec study.Koek GH, Vos R, Flamen P, Sifrim D, Lammert F, Vanbilloen B, Janssens J, Tack J.Centre for Gastroenterological Research, University Hospital Gasthuisberg, KU Leuven, Belgium.BACKGROUND: Studies combining pH and Bilitec monitoring found a high prevalence of both acid and duodeno-gastro-oesophageal reflux in severe reflux disease. Clearance of refluxed material is a major defence mechanism against reflux. Several studies have been devoted to oesophageal acid clearance but oesophageal clearance of refluxed duodenal contents (DC) has rarely been addressed. Aim: To compare oesophageal acid and DC clearance. METHODS: Ten healthy volunteers (five women, mean age 23 (1) years) were studied. Firstly, a balloon tip catheter, positioned in the duodenum under fluoroscopy, was used to aspirate DC after stimulation by a high caloric liquid meal (200 ml, 300 kcal). During the second session, pH and Bilitec probes were positioned 5 cm above the lower oesophageal sphincter and a small infusion catheter was introduced into the proximal oesophagus. The subject was placed supine under a gamma camera. One of two different solutions (DC mixed with 0.2 mCi Tc99m pertechnetate or citric acid (pH 2) mixed with 0.2 mCi Tc99m pertechnetate) was infused into the proximal oesophagus and the subject was instructed to swallow at 20 second intervals. Clearance was assessed using scintigraphy (dynamic acquisition, one frame per second in the anterior view; calculation of time to clear peak counts to background level), pH (time to pH0.14) monitoring, with or without continuous saliva aspiration. Each condition was studied twice in a randomised design; measurement time was four minutes, interrupted by water flushing, with a two minute rest period. Results are given as mean (SEM) and were compared by Student's t test and Pearson correlation. RESULTS: Scintigraphic evaluation showed a volume clearance time of 29 (3) seconds for acid and 28 (9) seconds for DC (NS). Saliva aspiration had no significant influence on volume clearance of acid or DC (28 (4) and 30 (13) seconds, respectively; NS). pH monitoring showed an acid clearance time of 217 (15) seconds, which was significantly prolonged to 324 (30) seconds during saliva aspiration (p

Introduction Dysphagia is commonly reported by patients with NERD. 1 In the absence of mechanical obstruction or erosions, the mechanism underlying dysphagia in NERD is unclear. Impaired oesophageal motility with delayed bolus clearance, increased resistance at the OGJ or impairment of mucosal integrity could potentially underlie this symptom. The aim of this study was to evaluate these potential causes of dysphagia in NERD patients. Methods All adult patients, presenting to the Upper GI Physiology unit between January 2014 and October 2015, with typical GERD symptoms, normal OGD, acid exposure time > 4.2%, no major manometric abnormalities and no structural, systemic or neurologic abnormalities were included. A composite dysphagia score was prospectively recorded (0–45). Motility was evaluated using HRM and Chicago classification 2015. Bolus clearance was assessed on 24 h pH-MII using bolus exposure time and post-reflux peristaltic wave (PSPW) score. Mucosal integrity was evaluated using Mean Nocturnal Baseline Impedance (MNBI). Results Out of the 76 eligible patients, 17 patients (8 M:9 F) with typical NERD and dysphagia symptoms (Group A) and 26 patients (15 M:11 F) with NERD only symptoms (Group B) fulfilled the inclusion criteria. Mean age for both groups was 49 years. Acid exposure time and number of reflux episodes between groups were similar (NS). The median composite dysphagia score for Group A was 19.5 (range 3.5–45). Minor oesophageal motility abnormalities were identified in 10/17 patients from Group A and 12/26 patients from Group B (P > 0.05). The median IRP was 6 mmHg in group A and 7 mmHg in group B (NS). There was no statistically significant difference in the bolus exposure time and PSPW index. Mucosal integrity evaluated with baseline impedance (MNBI) was slightly low in the distal oesophagus, without difference between groups. MNBI in the proximal oesophagus was normal and not different between groups (Table). Conclusion 40% of NERD patients reported dysphagia; majority reporting moderately severe symptoms. Impairment of oesophageal motility, bolus clearance and mucosal integrity do not seem to explain the pathophysiology of dysphagia in these patients. Esophageal hypersensitivity to mechanical stimulation and/or hypervigilance remained as potential causes of dysphagia in patients with NERD. Reference 1 Locke 3rd GR, et al. Prevalence and clinical spectrum of gastroesophageal reflux: A population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112 (5):1448–1456. Disclosure of Interest None Declared

We present a case of a patient with sarcoidosis and who subsequently developed dysphagia for solids, and some difficulty in swallowing liquids. High-resolution manometry of the oesophagus showed absent peristalsis in the oesophageal body and incomplete relaxation of the lower oesophageal sphincter. The diagnosis of sarcoidosis with oesophageal involvement was made and treatment with prednisolone 30 mg OD initiated. The patient improved symptomatically and high-resolution manometry was repeated showing complete recovery of oesophageal peristalsis and a deeper relaxation of the lower oesophageal sphincter. This is thus the first description of high-resolution manometry in sarcoidosis-induced changes of the oesophagus and of the effect treatment has on these motility changes. Oesophageal involvement of sarcoidosis is extremely rare and only a few cases have been reported. The symptoms and manometric pattern of this disorder mimics that of achalasia. However, we show that treatment with prednisolone results in a completely disappearance of the symptoms of dysphagia and subsequently lead to a large improvement of oesophageal motility.

Introduction Many patients present to gastroenterology services with multiple upper GI symptoms. Complaints of postprandial retrosternal/epigastric discomfort with regurgitation are common and can suggest gastro-oesophageal reflux disease, gastroparesis, or both. Disentangling the differentials can be difficult on clinical history alone. The need for several tests to exclude each diagnosis has cost and time implications for clinicians and patients. It is known that intragastric pH rises from a baseline of ~1 to a median of 4.5 during a meal, and gradually returns to fasting-state as the buffer (i.e. ingested food) leaves the stomach (Gardner et al, 2002). We aimed to establish if reflux monitoring, where intragastric pH is recorded routinely, could also detect longer periods of high pH postprandially in subjects with confirmed gastroparesis compared to those with normal gastric emptying. Methods From our database of patients seen in our tertiary referral GI physiology unit, we identified patients with confirmed delayed gastric emptying on 13C-octanoic acid breath test from 2009–2015 who had also undergone 24 hour reflux monitoring off PPI (pH-only or combined pH-impedance). Another group of symptomatic patients with normal gastric emptying times on breath test, who also had reflux monitoring, were identified as controls. We interrogated reflux monitoring traces for baseline fasted pH, then measured the time taken for intragastric pH to return to baseline from the end of self-reported mealtimes. Median times for return of postprandial intragastric pH to baseline were compared between groups. Results 80 eligible patients with gastroparesis (54 female; age range 13 to 84 years, median 42 years) were identified and compared with 20 subjects with normal gastric emptying times (12 female; age range 14 to 70 years, median 42 years). Median baseline fasting intragastric pH in both groups was 1.3. The median duration for postprandial intragastric pH to return to baseline for the gastroparesis group was 118 minutes (95% CI: 109–153 min) compared to 42.5 min for the control group (95% CI: 36–68 min). The difference between the two groups was extremely significant (two-tailed p Conclusion Intragastric pH is elevated for longer periods postprandially in patients with gastroparesis. The intragastric pH data readily captured on reflux monitoring shows promise as an alternative modality for identifying gastroparesis. To evaluate this hypothesis, a prospective study where 13 C-octanoic acid breath testing using standardised meals is performed with concurrent reflux monitoring is currently underway at our unit. Disclosure of Interest J. Ooi: None Declared, G. Amarasinghe: None Declared, K. Nikaki: None Declared, S. Gabieta-Sonmez: None Declared, E. Yazaki: None Declared, D. Sifrim Grant/research support from: Reckitt Benckiser, Hull, UK; Sandhill Scientific, Colorado, USA, P. Woodland Grant/research support from: Reckitt Benckiser, Hull, UK

Introduction Non-cardiac chest pain can present a clinical challenge to the gastroenterologist. Many causes remain undiagnosed and untreated. Oesophageal spasm is frequently considered a cause of non-cardiac chest pain, but current diagnostic tools are often poor at making this diagnosis. High resolution oesophageal manometry is now the gold standard oesophageal motility test, and is a swallow-based assessment. Unfortunately most episodes of chest pain in this context are not swallow-related, and are usually sporadic and unpredictable. Thus most manometry assessments occur in the absence of a symptom event. We propose that prolonged, ambulatory high resolution may be a tool that can detect these sporadic chest pain events and allow correlation to symptom episodes. We aimed to test the diagnostic yield of a novel, ambulatory high resolution oesophageal manometry device in the diagnosis of non-cardiac chest pain. Methods We studied 17 patients (7 male, 10 female, age range 14 to 66) with chest pain. All had cardiac pain excluded by cardiology review, and all had been studied with normal upper GI endoscopy. All had also had major oesophageal motor disorder (including spasm) excluded by swallow-based high resolution manometry (with liquid and solid swallows). An ultra-thin high resolution solid-state catheter was inserted transnasally into the oesophagus. This was connected to a small laptop and battery pack carried in a backpack. Patients were sent home and encouraged to mobilise. Patients were asked to keep the catheter in place at least until a symptomatic pain event was perceived. Symptom events were self-marked on a recorder device that was subsequently synchronised with the manometry output. Manometry tracings were read manually, and motor events at the time of symptoms were examined in detail. Results The median duration of recording with the system was 12 hours, 13 minutes (range 5 hours, 30 minutes to 26 hours, 40 minutes). 12 of the 17 patients perceived typical chest pain symptom during recording. Of the 12 with typical symptoms, 3 (25%) had clinically important findings that changed management. They had significant oesophageal spasm, pressurisation and shortening associated with pain events. These have been treated successfully with oesophageal body Botox injections (2 patients) and with long laparoscopic myotomy (1 patient). The remaining 9 patients either had no abnormalities, or minor abnormalities that did not correspond to symptoms. Conclusion Ambulatory high-resolution manometry is a novel tool for investigation of non-cardiac chest pain. In our series, we identified management-altering abnormalities in 3 of 17 patients who had previously been investigated with normal cardiac, endoscopic and stationary manometric evaluation. Disclosure of Interest J. Ooi: None Declared, E. Yazaki: None Declared, K. Nikaki: None Declared, D. Sifrim Grant/research support from: Research grant from Sandhill Scientific, P. Woodland: None Declared

Introduction Achalasia is a relatively rare primary oesophageal motor disorder characterised by absent peristalsis and failure of relaxation of the lower oesophageal sphincter (LOS). The standards of treatment for achalasia are pneumatic balloon dilatation and surgical myotomy. Although 85–95% success at 2 years is reported with these procedures, in the longer term, dysphagia may return in over 50%, prompting consideration of re-treatment. The definition of recurrence is often based on symptom evaluation, particularly dysphagia. Treatment of dysphagia in achalasia is targeted at the LOS, but in some patients dysphagia may be multifactorial and may not be improved by attempting to further lower LOS pressure. We aimed to evaluate the GI physiological findings of patients undergoing studies in our tertiary referral unit to investigate recurrence of dysphagia post-treatment. Method We interrogated our database for patients undergoing high resolution oesophageal manometry +/- 24-hour pH studies due to dysphagia post-treatment for achalasia between 2010–2014. We recorded achalasia subtype, LOS relaxation pressure (known as integrated relaxation pressure, or IRP), and reflux study results if performed. Results 80 eligible patients (38 female; age range 11–83 years, median 46 years) were identified with recurrent dysphagia. All had high resolution oesophageal manometry performed, and 18 patients had 24-hour pH studies due to concomitant heartburn and/or regurgitation. 52 patients had undergone at least one previous pneumatic dilatation, 23 had undergone surgical myotomy, and 5 had no response to Botox injection. 40 patients were found to have type 1 achalasia, 25 had type 2 achalasia, and 6 had type 3 achalasia. 9 patients had normal peristalsis unlikely to be consistent with a diagnosis of achalasia. 22 of the 80 patients had an IRP >15 mmHg (upper range of normal). 10 patients had a very low ( Conclusion We investigated a large cohort of patients with recurrent dysphagia post-treatment of achalasia. The most frequent achalasia subtype was type 1. Although 28% patients had high residual LOS pressures, a significant proportion of patients had findings not consistent with a need to re-treat with dilatation or myotomy (due to very low LOS pressure, gastro-oesophageal reflux disease, or possible incorrect diagnosis). These results highlight the need to carefully re-evaluate patients presenting with recurrent dysphagia after achalasia treatment before deciding on repeat therapy. Disclosure of interest None Declared.

Introduction Up to 40% of patients with gastro-oesophageal reflux disease remain symptomatic despite PPI therapy. In addition to acid the refluxate contains pepsin and bile acids, which may be important in symptom perception. A topical therapy could protect against all components of the refluxate. A reliable model for testing could be used to screen compounds for clinical evaluation. We aimed to evaluate and compare the topical protective effect of an alginate solution in a cell culture and human biopsy model. Method Primary human oesophageal epithelial cells were established into multilayer stratified squamous epithelia using an air-liquid interface technique. After placing in Ussing chambers the apical surface was “protected” with 200 µl of either alginate, viscous control, or was unprotected. After 15 min washing in neutral solution the tissue was exposed to pH 3 + bile acid solution for 30 min and TER change was calculated. Distal human oesophageal biopsies were taken, placed in Ussing chambers and “protected” as above. After 15 min or 60 min washing in neutral solution, change in TER on 30 min exposure to pH 1 + bile acid + pepsin solution was measured. Thickness of a fluorescent-labelled alginate coating on the biopsy luminal surface was measured after 15 min (5 biopsies) and 60 min (5 biopsies) washing in pH 7.4 solution. Results Acid-induced change in TER was significantly less in alginate-protected epithelium than in epithelium protected with viscous control or unprotected tissue. This was seen in both the cell culture (–1.2 ± 5.1%, n = 5 vs. –38.4 ± 6.2%, n = 4 vs. –41.9 ± 8.1%, n = 3) and human biopsy models (−2.7 ± 1.8% vs. −15.26 ± 3.7% vs. −21.1 ± 4.4%, all n = 12) after 15 min washing. Statistically significant protection was still seen after 60 min washing (–8.3 ± 2.2% vs. –25.1 ± 4.5% vs. –26.4 ± 5.3%, n = 12). After 15 min washing the mean alginate layer thickness was 5.7 ± 0.3 µm, and was 4.3 ± 0.3 µm after 60 min washing. Conclusion Alginate topical protection of human oesophageal epithelium against acid-injury is demonstrated in both cell culture and human biopsy models. Epithelial adherence persists for up to 60 min. Topical alginate mucosal protection may be promising as an add-on/alternative therapy for gastro-oesophageal reflux disease. Since the cell culture model was able to reproduce ex vivobiopsy results, it could be an effective tool to screen candidate products prior to clinical evaluation. Disclosure of interest F. Batista-Lima: None Declared, C. Lee: None Declared, D. Sifrim Grant/ Research Support from: Research grant from Reckitt-Benckiser, P. Woodland: None Declared.

Introduction In patients with GORD, including refractory disease, reflux events reaching the proximal oesophagus are more likely to be perceived than those only reaching the distal oesophagus. There is also experimental data suggesting an increased sensitivity of the proximal oesophagus relative to the distal. As such, the proximal oesophagus is likely to be highly significant in the pathogenesis of GORD symptoms. Reasons for this proximal oesophageal sensitivity are not clear, but may include reflux volume, impairment in mucosal integrity or changes in sensory innervation. It has recently been shown that distal mucosal integrity (its ability to perform a protective barrier function) is more vulnerable to acid exposure in GORD than in controls. The integrity of the proximal oesophagus has not been tested. To our knowledge, there are no studies evaluating mucosal afferent innervation of the distal and proximal oesophagus. We aimed to compare mucosal integrity and afferent nerve distribution in the proximal and distal oesophagus in patients with heartburn without oesophagitis. Methods In 23 patients with heartburn and 10 healthy volunteers baseline proximal and distal oesophageal impedance was measured in vivo . Oesophageal mucosal biopsies from the distal and proximal oesophagus were taken and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP) immunoreactive nerve fibres. Results Baseline impedance was higher in the proximal than in the distal oesophagus in healthy volunteers (2935 ± 204 Ω vs. 2234 ± 290 Ω, p Conclusion The baseline mucosal integrity of the proximal oesophagus is not more impaired than that of the distal, nor is it more impaired in patients with heartburn symptoms versus healthy controls. Increased sensitivity of the proximal oesophagus in GORD may instead be associated with a more superficial location of mucosal afferent nerves. Topical protection of the proximal oesophageal mucosa is a potential treatment strategy to reduce this sensitivity. Disclosure of Interest None Declared.

Introduction Patients with non-erosive reflux disease (NERD) exhibit impaired oesophageal mucosal barrier integrity in the form of dilated intercellular spaces and low transepithelial electrical resistance (TER). Such refluxate-induced changes to the mucosal integrity may underlie increased sensitivity to perception of reflux events, even on PPI, and could potentially be modified by application of topical solutions. Sodium alginate solutions are used in treatment of GORD, with proposed mechanisms of action including acid buffering, displacement of the gastric acid pocket, and reduction of reflux events. We have recently described that in vitro topical application of a sodium alginate solution is able to protect mucosal biopsies against impairment of oesophageal mucosal integrity when exposed to acidic solutions shortly after application. The durability of this protection is unclear. We aimed to assess the protective effect and physical location of a topically applied sodium alginate solution 1 h after application. Methods 3 mucosal biopsies were taken from the distal oesophagus (3 cm above the z-line) in 10 patients attending the Royal London Hospital for gastroscopy. Biopsies were transferred immediately to Krebs buffer pH 7.4. The luminal surfaces of 2 biopsies were coated with 200 µl of either a sodium alginate solution (Gaviscon Advance, Reckitt Benckiser, Hull, UK) or a viscous control solution (of same viscosity, but without alginate). The biopsies were mechanically washed with 5 ml Krebs, then each placed in an Using chambers and bathed in pH 7.4 solution for 1 h. The luminal aspect of the biopsy was then exposed for 30 min to an acidic solution pH 2 + 1 mg/ml pepsin + 1 mM taurodeoxycholate. Percentage changes in TER from baseline at the end of exposure were recorded. For the 3 rd biopsy sodium alginate solution containing fluorescein-labelled alginate was used, and after 1 h bathing in pH 7.4 solution the biopsy was fixed for immunohistological detection of the alginate. Results Our previous experiments have demonstrated that exposure of unprotected biopsies to the acidic solution results in a –14.4 ± 2.9% change in TER from baseline. 1 h after protection with alginate solution the same exposure caused a –8.2 ± 4.2% change in TER compared to –15.9 ± 3.0% change after protection with the viscous control (p Labelled alginate could be seen coating the luminal surface after 1 h in all cases. Conclusion In vitro , alginate solutions can adhere to the oesophageal mucosa for up to 1 h and exert a topical protectant effect against refluxate-like solutions. This suggests that durable topical protectants can be further explored and developed as first-line/add-on therapies for GORD. Disclosure of Interest P. Woodland: None Declared, C. Lee: None Declared, P. Dettmar Employee of: Technostics Limited, S. Preston: None Declared, D. Sifrim Grant/research support from: Reckitt-Benckiser, Sandhill Scientific, Consultant for: Sandhill Scientific.

Introduction Current diagnostic tests for GORD have moderate sensitivity/specificity and can be invasive and expensive. Pepsin detection in saliva has been proposed as an “office-based” method for GORD diagnosis. The aims of this study were to establish normal values of salivary pepsin in a large cohort of healthy asymptomatic subjects and to determine its value to discriminate patients with reflux-related symptoms (GORD, hypersensitive oesophagus) from functional heartburn. Methods 100 asymptomatic controls and 111 patients with heartburn underwent MII-pH monitoring and simultaneous salivary pepsin determination on waking, after lunch and dinner. Cut off value for pepsin positivity was 16 ng/ml. Patients were divided into GORD (increased acid exposure time (AET) n = 58); Hypersensitive Oesophagus (HO) (normal AET and + SAP), n = 26) and Functional Heartburn (FH) (normal AET and – SAP, n = 27). Multiple group comparisons were performed using one-way ANOVA followed by with Tukey’s Test for Gaussian distributed data and the Kruskall-Wallis Test with Dunns comparison for non-Gaussian data. Receiver Operator Characteristic curves were constructed to determine and compare the sensitivity and specificity of different pepsin cut-off concentrations. Results 1/3 of asymptomatic subjects had pepsin in saliva at low concentration (0(0–59) ng/ml). Patients with reflux-related symptoms (GORD and HO) had higher prevalence (77–89%) and pepsin concentration than controls (HO, 237(52–311) ng/ml and GORD, 121(29–252) ng/ml) (p 210 ng/ml pepsin suggested the presence of GORD/HO with 95% probability. Conclusion In patients with symptoms suggestive of GORD, salivary pepsin can be used to confirm or reject the diagnosis before empirical PPI treatment. This may lessen the use of unnecessary anti-reflux therapy and the need for further invasive and expensive diagnostic methods. Disclosure of Interest J. Hayat: None Declared, S. Gabieta-Somnez: None Declared, E. Yazaki: None Declared, J.-Y. Kang: None Declared, A. Woodcock Employee of: RD Biomed Ltd, P. Dettmar Employee of: RD Biomed Ltd, J. Mabary Employee of: Sandhill Sci., C. Knowles: None Declared, D. Sifrim Grant/research support from: Sandhill Sci.

Introduction Sleeve gastrectomy is increasingly used as both a definitive and staggered weight loss procedure. The effect of sleeve gastrectomy on gastro-oesophageal reflux (GOR) remains uncertain. We studied the effect of sleeve gastrectomy on GOR, pressure parameters at the Lower Oesophageal Sphincter (LOS), oesophageal and gastric motility. Methods Sixteen patients (median age 46 (range 25–71)) with morbid obesity underwent high resolution oesophageal manometry and 24hr ambulatory pH-impedance monitoring, at least 2 weeks pre-op and 3 months post sleeve gastrectomy (median no. of days post-op 129 (range 84–202)). All patients documented reflux and dysphagia symptoms at the time of testing. Nine patients also underwent concurrent gastric emptying with 13C labelled octanoate breath test. Parametric data was analysed using the paired t-test and non-parametric data with Wilcoxon matched pairs test. Results Mean Body Mass Index (BMI) fell from 49 (41.3–58.3) to 38.5(35–46.3). 5/16 patients reported new or worsening reflux symptoms (31%). Basal LOS pressure fell from 14.4mmHg (9.7–28.5) pre-op to 8.9mmHg (0.7–40.5) post-op (p Conclusion Both acid and non-acid gastro-oesophageal reflux is increased after sleeve gastrectomy with 31% of patients developing de novo acid reflux post-op. This is despite a reduction in BMI and accelerated gastric emptying. A reduction in LOS pressure and increased G-O pressure gradient are likely to be contributing factors. Future studies should determine whether decreased gastric compliance stimulates increased numbers of transient lower oesophageal sphincter relaxations. Disclosure of Interest None Declared

Introduction The presence of pepsin in the oesophagus or more proximally (pharynx or airways) suggests gastro-oesophageal reflux (GOR). However, appropriate normal values and correlation with acid and non acid reflux are still limited. The aim of this study was to measure pepsin in expectorated saliva together with objective assessment of GOR by pH-impedance in a large cohort of healthy asymptomatic subjects. Methods 100 healthy subjects, age 30.7 (range 19–55), BMI 23.7 (17.7–32.8) with no typical or atypical reflux symptoms underwent MII-pH monitoring “off” PPI. Oesophageal pH was measured 5 cm above the LOS and impedance sensors were positioned at 3.7.9.12 and 15 cm above LOS. Subjects collected expectorated saliva on waking, one hour after lunch and one hour after dinner. Saliva was collected into tubes containing 0.5 ml of 0.01 M citric acid and analysed for the presence of pepsin using a lateral flow test comprising two unique human monoclonal antibodies to pepsin (Peptest™, RDBiomed Ltd). The cut off value to determine pepsin positivity was 25 ng/ml. Results Of 300 saliva samples tested, 19% were +ve for pepsin. 64% of subjects had all three saliva samples negative; 20% had 1 sample positive, 12% had 2 samples positive and 4% had 3 samples positive. A similar percentage of samples were positive after lunch (24%) and dinner (22%), but lower on waking (10%). Median acid exposure time was 0.3% (IQR – 0.1–0.8%, 95 th centile 3.5%). Median no. of reflux events was 32 (15–42, 77) being acid 11 (5–22.47) and non-acid 15 (8–25, 46). Saliva samples positive for pepsin were preceded by significantly more reflux events during the 60 min interval before sampling compared to negative samples both after lunch and dinner (+ve pepsin 6 reflux (4–9) vs. -ve pepsin 3 reflux (1–5) p Conclusion Pepsin was found in the expectorated saliva of a proportion of healthy individuals who did not experience reflux symptoms, particularly post-prandially. However, only 4% of healthy subjects had 3 positive samples. An increased number of reflux episodes were found prior to giving saliva samples with detectable levels of pepsin. Our results suggest that the presence of pepsin in saliva can be a potential screening tool for GERD when at least 3 samples throughout a day are positive or samples contain more than 250 ng/ml pepsin. Disclosure of Interest None Declared

Introduction Although macroscopically normal, the oesophageal mucosa in patients with non-erosive reflux disease (NERD) displays epithelial dilated intercellular spaces (DIS). Such loss of barrier integrity is thought to be important in disease pathogenesis. Patients with NERD have DIS in both the distal and proximal oesophagus. Patients with functional heartburn (FH) do not have DIS. In healthy volunteers acid perfusion of the distal ooesophagus induces DIS not only in the exposed distal, but also the unexposed proximal oesophagus. It is unknown what impact distal acid perfusion has in the proximal oesophageal mucosa in symptomatic patients. Oesophageal impedance measurements can be an “in vivo” surrogate marker of functional mucosal integrity. We aimed to assess with impedance the proximal oesophageal mucosal integrity during distal acid perfusion in symptomatic patients with NERD (+ve DIS) and FH (-ve DIS). Methods We studied 22 patients (mean age 48, range 20–75) with typical reflux symptoms and negative endoscopy. 24-hour MII-pH monitoring identified 11 patients with NERD and 11 with FH. A pH-impedance catheter was inserted transnasally such that the proximal impedance segment was 15cm above the LOS. A 10 minute perfusion (10ml/min) of a neutral (pH7), then acidic (pH1) solution was performed in the distal oesophagus (10 cm from LOS) whilst simultaneously measuring proximal impedance. The absence of proximal fluid contamination was suggested by a lack of impedance drop during the neutral perfusion. Baseline impedance, and percentage change from baseline during the perfusion was calculated. Results Distal perfusion of neutral solution caused no fall in proximal impedance (mean impedance 107 ± 2.8% of baseline). Distal perfusion of acidic solution caused a significant reduction in proximal impedance (mean impedance 80.3 ± 5.3% of baseline, p Conclusion In keeping with morphological studies of healthy volunteers, distal oesophageal acidification modifies mucosal functional integrity of the proximal, unexposed oesophagus. This appears to occur regardless of the presence of pre-existing proximal DIS, suggesting that mechanisms of functional mucosal integrity as measured by impedance are beyond DIS formation. Disclosure of Interest None Declared.

Introduction It is suggested that hoarseness along with typical signs on laryngoscopy can be caused by oesophago-pharyngeal reflux, often referred to as LPR. New methods are proposed to assess pharyngeal exposure to gastric contents. They are suggested to measure (1) liquid or mixed gas-liquid acid and non-acid reflux (HMII-pH), (2) aerosolized acid reflux (Dx-pH measuring system, Restech), and (3) presence of pepsin in saliva. We aimed to quantify pharyngeal exposure to gastric contents in patients with hoarseness and healthy controls using the above techniques. Methods 21 patients with hoarseness and a positive laryngoscopy (mean age: 51 range: 23–75) and 10 asymptomatic controls (mean age: 26, range: 21–34) underwent simultaneous HMII-pH monitoring, oropharyngeal pH monitoring and saliva pepsin sampling. The HMII-pH catheter was located with impedance sensors in the oesophageal body, 3–5 cm distal and 0–2 cm proximal to the UOS. The Dx-pH catheter was located posterior to the uvula and pepsin in saliva was measured using an in vitro device utilising two pepsin monoclonal antibodies (PepTest) at five different times during the 24-h period. Patients were studied “off” PPI. Results Healthy controls had (1) no liquid or mixed gas/liquid reflux in the pharynx, (2) two controls had +ve Dx-pH and (3) two controls had more than one saliva sample +ve for pepsin with the other tests negative. Patients were classified into four groups: (a) all tests +ve (n=2); (b) two tests +ve (MII-pH + pepsin (n=5) or MII-pH + Dx-pH (n=3); (c) all tests negative (n=5) and (d) patients with +ve Dx-pH or pepsin without evidence of HMII detected reflux. These patients were considered negative (n=6). Dx-pH drops were poorly associated with HMII-pH reflux. 11% of Dx-pH drops to pH Conclusion We identified a subgroup of patients with hoarseness with objective detection of oesophago-pharyngeal reflux (10/21). (b) the majority of oropharyngeal pH drops detected by Dx-pH do not correlate with retrograde flow (liquid or gas) in the oesophageal body. (c) Detection of pepsin in saliva suggests the likelihood of reflux episodes in the previous 60 min. Competing interests None declared.

Reducing transient LOS relaxations in patients with gastro-oesophageal reflux disease Gastro-oesophageal reflux disease (GORD), defined as the presence of symptoms or lesions that can be attributed to the reflux of gastric contents into the oesophagus, is one of the most common disorders affecting the gastrointestinal tract. Gastric acid is essential in the development of GORD and the duration of oesophageal acid exposure is a major determinant of the severity of reflux oesophagitis.1 This is the reason why proton pump inhibitors, with their strong acid suppressing action, have brought relief to the majority of these patients, although most GORD patients do not have increased gastric acid secretion.2 The pathophysiology of GORD is multifactorial, including alterations in the volume, composition, or distribution of gastric contents, anatomical and/or motor dysfunction of the antireflux barrier at the gastro-oesophageal junction, impaired clearance mechanisms, and defective resistance to injury at the mucosal level. Acid suppressive therapy addresses one of the pathophysiological mechanisms—that is, gastric acid volume—without affecting others such as the non-acid component of the gastric contents or the function of the antireflux barrier. In spite of the efficacy of acid suppressive therapy, there have been many attempts to target other aspects of GORD pathophysiology, such as basal lower oesophageal sphincter (LOS) pressure, oesophageal body motility, or gastric emptying. Unfortunately, most of these approaches have been clinically disappointing. The prerequisite …

Introduction The Joint Hypermobility Syndrome (JHS) is a relatively frequent inherited connective tissue disorder characterised by marked joint hyperextensibility and extra-articular manifestations. Recent work suggests that gastrointestinal (GI) symptom prevalence may be as high as 86%1 in these patients, and that many of them have evidence of GI dysmotility.2 Dysphagia is a symptom which is not uncommon in these patients, but which has never been formally studied. In general terms, dysphagia is either due to a structural abnormality of the oesophagus or a motility problem. Methods A single-centre retrospective observational study was carried out to characterise the cause of non-structural dysphagia in patients with JHS. JHS patients who were referred to the upper GI physiology unit and who complained of dysphagia were identified. Their HRM and 24-h pH-metry traces were analysed to characterise oesophageal motility, presence of a hiatus hernia, lower oesophageal sphincter (LOS) pressure and presence of gastro-oesophageal reflux (GOR). Results 17 patients with JHS and dysphagia were referred by the rheumatologists to our unit in 1 year: 76% female; age range: 12–58. None had evidence of a structural cause for the dysphagia on either gastroscopy or barium studies. 10 (59%) had an oesophageal dysmotility to account for their dysphagia – out of these one had achalasia; the other 9 (53%) had oesophageal hypomotility with 7 having frequent hypotensive peristalsis and 2 having intermittent hypotensive peristalsis. 33% of those with hypomotility had a normal Multiple Rapid Swallow test (MRS). 7 of the 17 patients (41%) had normal oesophageal motility and 6 of these had reflux studies: 50% had GOR, 17% had a hypersensitive oesophagus and the remaining 33% had normal studies. Only 2 patients (12%) had hiatus hernias and both of these had oesophageal hypomotility and no GOR. Conclusion This is the first study of upper GI physiology in patients with JHS and non-structural dysphagia. Oesophageal hypomotility is common in these patients and those patients with normal MRS are likely to show the best response to prokinetics. 50% of those with normal motility had pathological GOR and would benefit from high dose proton pump inhibitor therapy. The remainder had normal studies, suggesting hypersensitivity which may respond to treatment with neuromodulators such as amitriptyline. Only 12% of patients had a hiatus hernia, which is in contrast to previous studies.3 Further prospective studies are required to understand the pathophysiology and management options for dysphagia in JHS.

Introduction Persistent reflux symptoms occur in a subgroup of patients following antireflux surgery. These symptoms can be due failure of the antireflux barrier. GI physiology studies are performed to evaluate the OGJ function and anatomy in these patients. Recent studies with high resolution manometry (HRM) have shown the presence of a dual high pressure zone (HPZ) at the OGJ as an expression of persistent hiatus hernia. However, the relation between dual high pressure zone, oesophageal hypomotility and persistent symptoms is unclear. The aim of this study was to evaluate reflux parameters and oesophageal motility patterns with HRM in a group of symptomatic patients after fundoplication. Methods Ten patients (5 male, 5 female; mean age 55 years) were selected based on the presence of persistent typical reflux symptoms post-Nissen fundoplication. The patients underwent HRM and impedance-pH monitoring ‘off’ PPI. The existence of dual HPZ, oesophageal hypomotility and amplitude of the after-contraction post multiple rapid swallowing (MRS) were evaluated together with acid and non-acid reflux parameters. Increased number of reflux events (post Nissen) was considered if >30/24 h.1 Results Six out of ten patients had a dual HPZ on HRM. Acid exposure time and number of acid reflux events in these patients was significantly higher than those with a single HPZ (12.7% vs 0.5%, p=0.01). The patients with a dual HPZ more commonly exhibited oesophageal hypomotility and poor response to MRS compared to the patients with a single HPZ (4/6 vs 1/4). In addition more of the patients with a dual HPZ showed impaired acid reflux clearance compared to patients with single HPZ (5/5 vs 1/3). Conclusion HRM and impedance-pH measurement allows a precise assessment of patients with symptoms postfundoplication. Our study suggests that the presence of a dual HPZ on oesophageal HRM is associated with impairment of oesophageal motility and impaired oesophageal acid clearance, and hence may be important in the persistence of GORD symptoms postoperatively.

Distension of the proximal stomach is a major stimulus for triggering transient lower oesophageal sphincter (LOS) relaxations. We have shown recently that atropine inhibits triggering of transient LOS relaxations in both normal subjects and patients with gastro-oesophageal reflux disease. Atropine could potentially act centrally by inhibiting the central integrating mechanism in the brain stem, or act peripherally by altering the response of the stomach to distension. The aim of this study was to investigate the effect of atropine on fasting gastric compliance and postprandial gastric tone using an electronic barostat.Fasting and postprandial proximal gastric motor and sensory functions were assessed in 10 normal healthy volunteers. Oesophageal manometry and pH were simultaneously measured. On separate days, atropine (15 microg/kg bolus, 4 microg/kg/h intravenous infusion) or saline was given and maintained for the duration of the recording period.In the fasting period, atropine significantly reduced minimum distending pressure (5.5 (0.4) v 4.4 (0.4) mm Hg; p0.005) and increased proximal gastric compliance (81.3 (5.3) v 102. 1 (8.7) ml/ mm Hg; p0.05). In response to a meal, maximal gastric relaxation was similar on both study days. However, during atropine infusion, there was no recovery of proximal gastric tone in the two hour postprandial observation period. Postprandial fullness scores were higher during atropine infusion and correlated with changes in intrabag volume. Atropine significantly reduced the rate of postprandial transient LOS relaxations: first hour, 7.0 (5.3-10.0) v 3.0 (1.0-4.0) (p0.02); second hour, 5.0 (3.3-5.8) per hour v 1.0 (0-3.0) per hour (p0.05).In humans, fasting and postprandial proximal gastric motor function is under cholinergic control. Atropine induced inhibition of transient LOS relaxations is unlikely to be caused by its effect on the proximal stomach, but rather by a central action on the integrating mechanisms in the brain stem.