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Background/Aims Single swallow integrated relaxation pressure (IRP) on high-resolution manometry (HRM) does not always accurately predict esophagogastric outflow obstruction on timed barium esophagogram (TBE). Furthermore, neither single swallow IRP or TBE is reliable in predicting symptoms, particularly after treatment with dilatation or myotomy. A 200 mL rapid drink challenge (RDC) has been proposed as an adjunctive test during HRM. This serves as a "stress-test" to the esophagogastric junction, and may yield clinically useful parameters. We aim to assess HRM parameters during RDC, and their ability to predict outflow obstruction on TBE in patients with dysphagia, and to correlate with symptoms in patients' achalasia. Methods Thirty patients with dysphagia were recruited. All underwent standard single swallow HRM analysis, 200 mL RDC, then TBE. RDC parameters, including esophagogastric pressure gradient, IRP, and RDC duration were evaluated. Multiple regression analysis was performed to assess the best predictive parameter for obstruction on TBE. A further 21 patients with achalasia were evaluated with Eckhardt score, single swallow HRM, RDC, and TBE. Parameter correlation with Eckhardt score was evaluated. Results Mean IRP during RDC was the best HRM parameter at predicting outflow obstruction on TBE. This performed much better in untreated patients (sensitivity 100% and specificity 85.5%) than in previously treated patients (sensitivity 50% and specificity 66%). In patients with achalasia, mean IRP during RDC was the only parameter that correlated with symptom score. Conclusion Mean IRP during RDC appears to be a clinically useful "stress test" to the esophagogastric junction during HRM.

Background/Aims Supragastric belching (SGB) is a phenomenon during which air is sucked into the esophagus and then rapidly expelled through the mouth. Patients often complain of severely impaired quality of life. Our objective was to establish the prevalence of excessive SGB within a high-volume gastrointestinal physiology unit, and evaluate its association with symptoms, esophageal motility and gastresophageal reflux disease. Methods We established normal values for SGB by analyzing 24-hour pH-impedance in 40 healthy asymptomatic volunteers. We searched 2950 consecutive patient reports from our upper GI Physiology Unit (from 2010-2013) for SGB. Symptoms were recorded by a standardized questionnaire evaluating for reflux, dysphagia, and dyspepsia symptoms. We reviewed the predom inant symptoms, 24-hour pH-impedance and high-resolution esophageal manometry results. Results Excessive SGB was defined as ＞ 13 per 24 hours. We identified 100 patients with excessive SGB. Ninety-five percent of these patients suffered from typical reflux symptoms, 86% reported excessive belching, and 65% reported dysphagia. Forty-one percent of patients with excessive SGB had pathological acid reflux. Compared to the patients with normal acid exposure these patients trended towards a higher number of SGB episodes. Forty-four percent of patients had esophageal hypomotility. Patients with hypomotility had a significantly higher frequency of SGB compared to those with normal motility (118.3 ± 106.1 vs 80.6 ± 75.7, P = 0.020). Conclusions Increased belching is rarely a symptom in isolation. Pathological acid exposure and hypomotility are associated with more SGB frequency. Whether SGB is a disordered response to other esophageal symptoms or their cause is unclear.

Patients with nonerosive reflux disease exhibit impaired esophageal mucosal integrity, which may underlie enhanced reflux perception. In vitro topical application of an alginate solution can protect mucosal biopsies against acid-induced changes in transepithelial electrical resistance (TER). We aimed to confirm this finding in a second model using 3D cell cultures and to assess prolonged protection in a biopsy model. We assessed the protective effect of a topically applied alginate solution 1 h after application. 3D cell cultures were grown by using an air-liquid interface and were studied in Ussing chambers. The apical surface was “protected” with 200 μl of either alginate or viscous control or was unprotected. The tissue was exposed to pH 3 + bile acid solution for 30 min and TER change was calculated. Distal esophageal mucosal biopsies were taken from 12 patients and studied in Ussing chambers. The biopsies were coated with either alginate or viscous control solution. The biopsies were then bathed in pH 7.4 solution for 1 h. The luminal chamber solution was replaced with pH 2 solution for 30 min. Percentage changes in TER were recorded. In five biopsies fluorescein-labeled alginate solution was used to allow immunohistological localization of the alginate after 1 h. In the cell culture model, alginate solution protected tissue against acid-induced change in TER. In biopsies, 60 min after protection with alginate solution, the acidic exposure caused a −8.3 ± 2.2% change in TER compared with −25.1 ± 4.5% change after protection with the viscous control ( P < 0.05). Labeled alginate could be seen coating the luminal surface in all cases. In vitro, alginate solutions can adhere to the esophageal mucosa for up to 1 h and exert a topical protectant effect. Durable topical protectants can be further explored as first-line/add-on therapies for gastroesophageal reflux disease.

Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus 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 fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03], however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus ( P < 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus, but proximal mucosal afferent nerves are in a more superficial location. The enhanced sensitivity to reflux-evoked symptoms of the proximal esophagus most likely has an anatomical basis.

Background/Aims The diagnosis of functional heartburn is important for management, however it stands on fragile pH monitoring variables, ie, acid exposure time varies from day to day and symptoms are often few or absent. Aim of this study was to investigate consistency of the diagnosis of functional heartburn in subsequent days using prolonged wireless pH monitoring and its impact on patients’ outcome. Methods Fifty proton pump inhibitotor refractory patients (11 male, 48 years [range, 38–57 years]) with a diagnosis of functional heart-burn according to Rome III in the first 24 hours of wireless pH monitoring were reviewed. pH variables were analysed in the following 24-hour periods to determine if tracings were indicative of diagnosis of non-erosive reflux disease (either acid exposure time > 5% or normal acid exposure time and symptom index ≥ 50%). Outcome was assessed by review of hospital files and/or telephone interview. Results Fifteen out of 50 patients had a pathological acid exposure time after the first day of monitoring (10 in the second day and 5 in subsequent days), which changed their diagnosis from functional heartburn to non-erosive reflux disease. Fifty-four percent of non-erosive reflux disease vs 11% of functional heartburn patients (P < 0.003) increased the dose of proton pump inhibitors or underwent fundoplication after the pH test. Outcome was positive in 77% of non-erosive reflux disease vs 43% of functional heartburn patients (P < 0.05). Conclusions One-third of patients classified as functional heartburn at 24-hour pH-monitoring can be re-classified as non-erosive reflux disease after a more prolonged pH recording period. This observation has a positive impact on patients’ management.

Background Microscopic inflammation and impairment of the esophageal epithelial barrier are considered relevant for perception of symptoms in patients with nonerosive reflux disease (NERD). In these patients, the receptor transient receptor potential vanilloid 1 (TRPV1) is overexpressed in the esophageal mucosa, but its role is not yet fully understood. We evaluated the role of TRPV1 in esophageal inflammation and mucosal barrier impairment in a murine model of NERD. Methods Nonerosive reflux disease was surgically induced in Swiss mice by pyloric substenosis and ligature of the gastric fundus, and the mice were killed 7 days post surgery. The experimental groups were: I, sham surgery (negative control); II, NERD untreated; III and IV, NERD + SB366791 or capsazepine (TRPV1 antagonists); and V, NERD + resiniferatoxin (for long-term desensitization of TRPV1). The esophagus was collected for western blotting and histopathology and for evaluation of wet weight, myeloperoxidase (MPO), keratinocyte-derived chemokine (KC), transepithelial electrical resistance (TEER), and basal permeability to fluorescein. Key results Compared to sham, NERD mice had increased esophageal wet weight and MPO and KC levels. The mucosa had no ulcers but exhibited inflammation. NERD mice showed mucosal TRPV1 overexpression, a more pronounced decrease in TEER at pH 0.5 (containing pepsin and taurodeoxycholic acid), and increased basal permeability. Pharmacological modulation of TRPV1 prevented esophageal inflammation development, TEER changes by acidic exposure, and increase in esophageal permeability. Conclusions & inferences The TRPV1 receptor has a critical role in esophageal inflammation and mucosal barrier impairment in NERD mice, suggesting that TRPV1 might be a pharmacological target in patients with NERD.

Gastroesophageal reflux is considered to be a significant contributing factor to chronic unexplained cough. Patients are often presumed to have reflux-induced cough and are exposed to high-dose and long-term empirical therapy with proton pump inhibitors (PPIs) despite the limited treatment efficacy in this population. We aimed to assess the diagnostic value of 24-hour ambulatory pH-impedance-pressure monitoring for the diagnosis of reflux-induced chronic cough. In this multicenter study, we evaluated 192 patients with chronic cough using 24-hour pH-impedance-pressure monitoring off PPIs. Manometry was used to detect all cough bursts while pH-impedance allowed for the evaluation of all reflux episodes, including weakly acidic reflux. The symptom association probability was used to determine a temporal relationship between reflux and cough. A diagnosis of reflux-induced cough was made in 25.5% of the patients. If only acid reflux episodes were used, 22.4% of those patients would not have been diagnosed. Significantly more patients with reflux-induced cough had typical reflux symptoms (P = 0.031) and a pathological distal acid exposure time (P = 0.025) in comparison to patients without the diagnosis. A diagnosis of cough-induced reflux was made in 24.0% of the patients. Only 59% of all cough bursts were registered by the patients. Overall, only approximately one quarter of patients with chronic unexplained cough have reflux-induced cough, explaining the observation that the vast majority of patients with chronic cough do not benefit from antireflux therapy. pH-impedance-pressure monitoring helps to identify patients who are likely to have reflux as a cause of their chronic cough.

Little is known about the causes of heartburn in patients with gastro-esophageal reflux disease. Visible epithelial damage is seldom associated with symptom severity, evidenced by the significant symptom burden in patients with nonerosive reflux disease (NERD) compared with patients with erosive reflux disease (ERD) or Barrett's esophagus (BE). We studied the distribution of mucosal nerve fibers in patients with NERD, ERD, and BE, and compared the results with those of healthy subjects.We performed a prospective study of 13 patients with NERD, 11 patients with ERD, and 16 patients with BE undergoing endoscopic evaluation in the United Kingdom or Greece. Biopsies were obtained from the proximal and distal esophageal mucosa of patients with NERD, from the distal esophageal mucosa of patients with ERD, and the distal-most squamous epithelium of patients with BE. These were examined for the presence and location of nerve fibers that reacted with a labeled antibody against calcitonin gene-related peptide (CGRP), a marker of nociceptive sensory nerves. The results were compared with those from 10 healthy volunteers (controls).The distribution of CGRP-positive nerves did not differ significantly between the distal esophageal mucosa of controls (median, 25.5 cell layers to surface; interquartile range [IQR], 21.4-28.8) vs patients with ERD (median, 23 cell layers to surface; IQR, 16-27.5), or patients with BE (median, 21.5 cell layers to surface; IQR, 16.1-27.5). However, CGRP-positive nerves were significantly more superficial in mucosa from patients with NERD-both distal (median, 9.5 cell layers to surface; IQR, 1.5-13.3; P.0001 vs ERD, BE, and controls) and proximal (median, 5.0 cell layers to surface; IQR, 2.5-9.3 vs median 10.4 cell layers to surface; IQR, 8.0-16.9; P = .0098 vs controls).Proximal and distal esophageal mucosa of patients with NERD have more superficial afferent nerves compared with controls or patients with ERD or BE. Acid hypersensitivity in patients with NERD might be partially explained by the increased proximity of their afferent nerves to the esophageal lumen, and therefore greater exposure to noxious substances in refluxate.

ObjectiveGastro-oesophageal reflux is considered to be an important contributing factor in chronic unexplained cough. It remains unclear why some reflux episodes in the same patient causes cough while others do not. To understand more about the mechanism by which reflux induces cough, we aimed to identify factors which are important in triggering cough.DesignIn this multicentre study, 49 patients with reflux-associated chronic cough were analysed using 24-hour pH-impedance-pressure monitoring. The characteristics of reflux episodes that were followed by cough were compared with reflux episodes not associated with cough.ResultsThe majority (72.4%) of the reflux episodes were acidic (pHConclusionsThe presence of a larger volume of refluxate and oesophageal exposure to reflux for a longer period of time seems to play an important role in inducing cough, while the acidity of the refluxate seems to be less relevant. This helps explain the observation that most patients with chronic cough tend not to benefit from acid inhibitory treatment.

Esophageal function testing should be used for differential diagnosis of dysphagia. Dysphagia can be the consequence of hypermotility or hypomotility of the muscles of the esophagus. Decreased esophageal or esophagogastric junction distensibility can provoke dysphagia. The most well established esophageal dysmotility is achalasia. Other motility disorders can also cause dysphagia. High-resolution manometry (HRM) is the gold standard investigation for esophageal motility disorders. Simultaneous measurement of HRM and intraluminal impedance can be useful to assess motility and bolus transit. Impedance planimetry measures distensibility of the esophageal body and gastroesophageal junction in patients with achalasia and eosinophilic esophagitis.

Background Motilin agonists promote human gastric motility and cholinergic activity, but excitatory and inhibitory actions are reported in the esophagus. The effect of 5-HT4 agonists in esophagus is also unclear. Perhaps the use of drugs with additional actions explains the variation. The aim, therefore, was to examine how motilin and prucalopride, selective motilin and 5-HT4 receptor agonists, modulate neuromuscular functions in human esophagus and gastric fundus. Methods Electrical field stimulation (EFS) evoked nerve-mediated contractions of circular and longitudinal muscle from human esophageal body and circular muscle from gastric fundus. Key Results In esophageal circular muscle EFS evoked brief contraction, followed by another contraction on termination of EFS, each prevented by atropine. Nitric oxide synthase inhibition facilitated contraction during EFS and the overall contraction became monophasic. In esophagus longitudinal muscle and gastric fundus, EFS evoked cholinergically mediated, monophasic contractions, attenuated by simultaneous nitrergic activation. Motilin (100–300 nM) reduced esophagus circular muscle contractions during EFS, unaffected by L-NAME or apamin. Motilin 300 nM also reduced EFS-evoked contractions of longitudinal muscle. Similar concentrations of motilin facilitated cholinergic activity in the fundus and increased baseline muscle tension. Prucalopride facilitated EFS-evoked contractions in esophagus (tested at 30 μM) and fundus (0.1–30 μM). Conclusions & Inferences Selective motilin and 5-HT4 agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT4) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT4 agonists may reduce gastro-esophageal reflux in different ways.

Nausea is the subjective unpleasant sensation that immediately precedes vomiting. Studies using barostats suggest that gastric fundus and lower esophageal sphincter (LES) relaxation precede vomiting. Unlike barostat, high-resolution manometry allows less invasive, detailed measurements of fundus pressure (FP) and axial movement of the gastroesophageal junction (GEJ). Nausea was induced in 12 healthy volunteers by a motion video and rated on a visual analog scale. FP was measured as the mean value of the five pressure channels that were clearly positioned below the LES. After intubation, a baseline (BL) recording of 15 min was obtained. This was followed by presentation of the motion video (at least 10 min, maximum 20 min) followed by 30 min recovery recording. Throughout the experiment we recorded autonomic nervous system (ANS) parameters [blood pressure, heart rate (HR), and cardiac vagal tone (CVT), which reflects efferent vagal activity]. Ten out of 12 subjects showed a drop in FP during peak nausea compared with BL (−4.0 ± 0.8 mmHg; P = 0.005), and 8/10 subjects showed a drop in LES pressure (−8.8 ± 2.5 mmHg; P = 0.04). Peak nausea preceded peak fundus and LES pressure drop. Nausea was associated with configuration changes at the GEJ such as LES shortening and esophageal lengthening. During nausea we observed a significantly increased HR and decreased CVT. In conclusion, nausea is associated with a drop in fundus and LES pressure, configuration changes at the GEJ as well as changes in the ANS activity such as an increased sympathetic tone (increased HR) and decreased parasympathetic tone (decreased CVT).

Gastroesophageal reflux disease, especially when refractory to standard therapy, remains a significant clinical problem. Although symptom pathogenesis in erosive reflux disease is relatively easy to understand, it is less clear how exposure of the macroscopically normal mucosa in nonerosive reflux disease (NERD) is able to cause heartburn. Over recent years it has become apparent that there may be microscopic and functional defects in the esophageal epithelial barrier in NERD, a so-called impairment of esophageal mucosal integrity. This can be expressed in morphologic or in functional terms. Morphologically the epithelium in NERD displays dilated intercellular spaces, which may represent a failed epithelial barrier, probably due to disruption of cell apical junctional complexes. Functionally, the mucosa in NERD displays more permeability to ions and small molecules than that of control subjects. Both morphologic and functional changes can be induced by exposure to refluxate-like solutions in vitro and in vivo. This article summarizes the evidence for impairment of esophageal mucosal integrity, and discusses its possible role in disease pathogenesis.

Background/Aims Symptom reflux association analysis is especially helpful for evaluation and management of proton pump inhibitor (PPI) refractory patients. An accurate calculation requires manual editing of 24-hour multichannel intraluminal impedance-pH (MII-pH) tracings after automatic analysis. Intra- and inter-observer agreement as well as reliability of rapid editing confined to the time around symptomatic episodes are unknown. Aim of this study was to explore these topics in a prospective multicenter study. Methods Forty consecutive patients who were off PPI therapy underwent MII-pH recordings. After automatic analysis, their tracings were anonymized and randomized. Three experienced observers, each one trained in a different European center, independently performed manual editing of 24-hour tracings on 2 separate occasions. Values of symptom index and symptom association probability for acid and non acid reflux were transformed into binary response (i.e., positive or negative). Results Intra-observer agreement on symptom reflux association was 92.5% to 100.0% for acid and 85.0% to 97.5% for non-acid reflux. Inter-observer agreement was 100.0% for acid and 82.5% to 95.0% for non-acid reflux. Values for symptom index and symptom association probability were similar. Concordance between 24-hour and rapid (2 minutes-window before each symptomatic episode) editings for symptom reflux association occured in 39 to 40 patients (acid) and in 37 to 40 (non-acid), depending on the observer. Conclusions Intra- and inter-observer agreement in classifying patients with or without symptom reflux association at manual editing of 24-hour tracings was high, especially for acid reflux. Classifying patients according to a rapid editing showed excellent concordance with the 24-hour one and can be adopted in clinical practice.

This study aimed to investigate a standardized biopolymer, cashew gum (CG), in human oesophageal mucosa and mice with experimentally-induced non-erosive reflux disease (NERD). Human oesophageal biopsies from NERD patients were collected to evaluate the mucosal protection of CG through transepithelial electrical resistance (TER), mucosal permeability, and mucoadhesiveness tests. A surgical model of NERD in mice was induced, and barrier functions followed by suggestive oesophageal inflammatory hallmarks were evaluated. Pre-coating of CG was effective in human oesophageal mucosa by attenuating drop of TER and mucosal permeability. Labelled-CG adheres to human oesophageal mucosa for up to 1 h. In animal studies, CG improved parameters of barrier function (TER and mucosal permeability) in distal oesophagus mucosa. CG also promoted sequential support by reducing inflammatory hallmarks of oesophageal damage. CG confers topical oesophageal mucosal protection due to its mucoadhesiveness and anti-inflammatory profile. Long-duration mucoprotective products can be further explored as first-line/adjuvant NERD therapy.

This paper reports on the neurophysiology of the esophagus, including on the uneven distribution of innervation in the esophagus, reflected by the increased sensitivity and perception of gastroesophageal reflux disease (GERD) events in the proximal rather than distal esophagus; the role of the enteric nervous system (ENS) in swallowing; the role of the physiological stress-responsive systems, including the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis in mediating esophageal pain; the advances in understanding pain mechanisms and brain structure provided by technological imaging advances; investigations into the efficacy of the descending-pain control system, including diffuse noxious inhibitory control (DNIC); the role of abnormal nervous signaling in afferent pathways in the pathogenesis of Barrett's esophagus (BE); and the contribution of the esophageal mucosa to reflux symptoms.

The nadir esophageal pH of reflux observed during pH monitoring in the postprandial period is often more acidic than the concomitant intragastric pH. This paradox prompted the discovery of the “acid pocket”, an area of unbuffered gastric acid that accumulates in the proximal stomach after meals and serves as the reservoir for acid reflux in healthy individuals and gastroesophageal reflux disease (GERD) patients. However, there are differentiating features between these populations in the size and position of the acid pocket, with GERD patients predisposed to upward migration of the proximal margin onto the esophageal mucosa, particularly when supine. This upward migration of acid, sometimes referred to as an “acid film”, likely contributes to mucosal pathology in the region of the squamocolumnar junction. Furthermore, movement of the acid pocket itself to a supradiaphragmatic location with hiatus hernia increases the propensity for acid reflux by all conventional mechanisms. Consequently, the acid pocket is an attractive target for GERD therapy. It may be targeted in a global way with proton pump inhibitors that attenuate acid pocket development, or with alginate/antacid combinations that colocalize with the acid pocket and displace it distally, thereby demonstrating the potential for selective targeting of the acid pocket in GERD.

Approximately 30–40% of patients taking proton pump inhibitors (PPIs) for presumed gastro-oesophageal reflux (GOR) symptoms do not achieve adequate symptom control, especially when no oesophageal mucosal breaks are present at endoscopy and when extra-oesophageal symptoms are concerned. After failure of optimization of medical therapy, a careful work up is mandatory that aims at determining whether symptoms are related to GOR or not. Most patients with refractory symptoms do not have GOR-related symptoms. Some may have symptoms related to weakly acidic reflux and/or oesophageal hypersensitivity. Baclofen is currently the only antireflux compound available as add-on therapy to PPIs, but its poor tolerability limits its use in clinical practice. There is room for pain modulators in patients with hypersensitive oesophagus and functional heartburn. Antireflux surgery is a suitable option in patients responding to medical therapy who want to avoid taking medication or if persisting symptoms can be clearly attributed to poorly controlled GOR.

Many patients with gastroesophageal reflux disease (GERD) have persistent reflux despite treatment with proton pump inhibitors (PPIs). Mixed gas-liquid reflux events are more likely to be perceived as symptomatic. We used esophageal impedance monitoring to investigate whether esophageal gas is processed differently among patients with GERD who do and do not respond to PPI therapy. We performed a prospective study of 44 patients with typical reflux symptoms with high levels of esophageal acid exposure during a 24-hour period; 18 patients were fully responsive, and 26 did not respond to PPI therapy. Twenty-four-hour pH impedance recordings were analyzed for fasting and prandial air swallows and reflux characteristics, including the presence of gas in the refluxate. PPI-refractory patients had a higher number (83.1 ± 12.7 vs 47.8 ± 7.3, P

The Chicago classification (CC) is most valued for its systematic approach to esophageal disorders and great impact in unifying practice for esophageal manometric studies. In view of the ever-growing wealth of knowledge and experience gained by the expanding use of high-resolution manometry (HRM) in various clinical scenarios, the CC is regularly updated. Its clinical impact and ability to predict clinical outcome, both in adults and pediatrics, will be further promoted by recognizing its current limitations, incorporating new metrics in its diagnostic algorithms and adjusting the HRM protocols based on the clinical question posed. Herein, we discuss the current limitations of the CC and highlight some areas of improvement for the future.

Detailed investigations and objective measurements in patients with symptoms of gastro-oesophageal reflux should be performed with the intent of making the correct diagnosis, thus enabling choice of appropriate therapy. Establishing the most effective therapy is particularly important in adults who do not respond to standard treatment and in children. The use of PPIs for suspected GERD has increased substantially over the past decade, providing great relief in patients with acid-related symptoms, but also leading to adverse effects and a considerable economic burden. Adults with functional heartburn do not benefit from PPIs, while prolonged PPI use in patients with extraoesophageal symptoms remains a controversial area. Moreover, PPIs are not indicated in infants with GERD unless symptoms are proven to be acid-related. With regard to antireflux surgery, patients must be carefully selected to avoid the need for ongoing PPI treatment postoperatively. Correct diagnosis and phenotyping of patients with symptoms attributed to gastro-oesophageal reflux through detailed investigations is therefore imperative, leading to improved patient outcomes and rationalized use of available treatment options. In this Review, we outline currently available diagnostic tests and discuss approaches to limit any unnecessary medical or surgical interventions.

BACKGROUND: Criteria for transient lower esophageal sphincter relaxations (TLESRs) are well-defined for Dentsleeve manometry. As high-resolution manometry (HRM) is now the gold standard to assess esophageal motility, our aim was to propose a consensus definition of TLESRs using HRM. METHODS: Postprandial esophageal HRM combined with impedance was performed in 10 patients with gastroesophageal reflux disease. Transient lower esophageal sphincter relaxations identification was performed by 17 experts using a Delphi process. Four investigators then characterized TLESR candidates that achieved 100% agreement (TLESR events) and those that achieved less than 25% agreement (non-events) after the third round. Logistic regression and decision tree analysis were used to define optimal diagnostic criteria. KEY RESULTS: All diagnostic criteria were more frequently encountered in the 57 TLESR events than in the 52 non-events. Crural diaphragm (CD) inhibition and LES relaxation duration >10 seconds had the highest predictive value to identify TLESR. Based on decision tree analysis, reflux on impedance, esophageal shortening, common cavity, upper esophageal sphincter relaxation without swallow and secondary peristalsis were alternate diagnostic criteria. CONCLUSION & INFERENCES: Using HRM, TLESR might be defined as LES relaxation occurring in absence of swallowing, lasting more than 10 seconds and associated with CD inhibition.

The fundamental gastrointestinal functions include motility, sensation, absorption, secretion, digestion and intestinal barrier function. Digestion of food and absorption of nutrients normally occurs without conscious perception. Symptoms of functional gastrointestinal disorders are often triggered by meal intake suggesting abnormalities in the physiological processes are involved in the generation of symptoms. In this manuscript, normal physiology and pathophysiology of gastrointestinal function, and the processes underlying symptom generation are critically reviewed. The functions of each anatomical region of the digestive tract are summarized. The pathophysiology of perception, motility, mucosal barrier, and secretion in functional gastrointestinal disorders as well as effects of food, meal intake and microbiota on gastrointestinal motility and sensation are discussed. Genetic mechanisms associated with visceral pain and motor functions in health and functional gastrointestinal disorders are reviewed. Understanding the basis for digestive tract functions is essential to understand dysfunctions in the functional gastrointestinal disorders.

The development of the high-resolution esophageal manometry (HRM) and the Chicago classification have improved the diagnosis and management of esophageal motility disorders. However, some conditions have yet to be addressed by this classification. This review describes findings in HRM which are not included in the current Chicago classification based on the experience in our center. This includes the analysis of the upper esophageal sphincter, proximal esophagus, longitudinal muscle contraction, disorders related to gastroesophageal reflux disease and respiratory symptoms. The utility of provocative tests and the use of HRM in the evaluation of rumination syndrome and post-surgical patients will also be discussed. We believe that characterization of the manometric findings in these areas will eventually lead to incorporation of new criteria into the existing classification.

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.

Up to 80% of patients with cystic fibrosis (CF) may have increased gastroesophageal reflux and aspiration of duodenogastric contents into the lungs. We aimed to assess aspiration in patients with CF by measuring duodenogastric components in induced sputum and to investigate whether the presence of bile acids (BAs) in sputum was correlated with disease severity and markers of inflammation.In 41 patients with CF, 15 healthy volunteers, 29 patients with asthma, and 28 patients with chronic cough, sputum was obtained after inhalation of hypertonic saline. Sputum supernatant was tested for BA and neutrophil elastase. Spirometry and BMI were assessed on the day of sputum collection.Two of 15 healthy patients (13%), eight of 29 patients (28%) with asthma, four of 28 patients (14%) with chronic cough, and 23 of 41 patients (56%) with CF had BA in sputum. BA concentrations were similar in patients who are positive for BA with genotype F508del homozygote, F508del heterozygote, and other CF mutations and were not related with BMI and age. Patients with CF with BA in sputum had a higher concentration of neutrophil elastase compared with patients without BA in sputum (31.25 [20.33-54.78] μg/mL vs 14.45 [7.11-27.88] μg/mL, P.05). There was a significant correlation between BA concentrations and dynamic lung volumes (FEV(1) % predicted [r = -0.53, P.01], FVC% [r = -0.59, P.01]) as well as with number of days of antibiotic IV treatment (r = 0.58, P.01).BAs are present in the sputum of more than one-half of patients with CF, suggesting aspiration of duodenogastric contents. Aspiration of BA was associated with increased airway inflammation. In patients with BA aspiration, the levels of BA were clearly associated with the degree of lung function impairment as well as the need for IV antibiotic treatment.

Background High-resolution manometry and esophageal pressure topography have enhanced our ability to analyze esophageal motor disturbances by improving the detail and accuracy of measurements of peristaltic activity.This has been extremely helpful in the evaluation of disorders of rapid propagation as the technique is able to define important time points and physiologic landmarks that are crucial in defining peristaltic velocity and latency intervals. Purpose The goal of the current review will be to assess how esophageal pressure topography has impacted our ability to define important phenotypes of rapid propagation. Additionally, this review will also be utilized to complement the description of the Chicago Classification of Esophageal Motor Disorders, which is presented in this supplement issue.

Swallowing induces an inhibitory wave that is followed by a contractile wave along the esophageal body. Deglutitive inhibition in the skeletal muscle of the esophagus is controlled in the brain stem whilst in the smooth muscle, an intrinsic peripheral control mechanism is critical. The latency between swallow and contractions is determined by the pattern of activation of the inhibitory and excitatory vagal pathways, the regional gradients of inhibitory and excitatory myenteric nerves, and the intrinsic properties of the smooth muscle. A wave of inhibition precedes a swallow-induced peristaltic contraction in the smooth muscle part of the human oesophagus involving both circular and longitudinal muscles in a peristaltic fashion. Deglutitive inhibition is necessary for drinking liquids which requires multiple rapid swallows (MRS). During MRS the esophageal body remains inhibited until the last of the series of swallows and then a peristaltic contraction wave follows. A normal response to MRS requires indemnity of both inhibitory and excitatory mechanisms and esophageal muscle. MRS has recently been used to assess deglutitive inhibition in patients with esophageal motor disorders. Examples with impairment of deglutitive inhibition are achalasia of the LES and diffuse esophageal spasm.

Introduction Supragastric belching (SGB) is considered a behavioural disorder. SGB can manifest as a large number of belch episodes during daytime, or can be associated with reflux symptoms or rumination. Supragastric belches can be immediately followed by acid reflux and in some GORD patients, SGB-associated reflux can contribute to up to 1/3 of the total acid exposure (AET) (Koukias, 2015). Current treatments for SGB are cognitive behavioural therapy (CBT) and Baclofen. We hypothesised that reducing SGB might improve QOL and reduce acid GOR. The aim of our study was to assess the effectiveness of CBT on subjective and objective outcomes in patients with pathological SGB. Method Patients were recruited from the upper GI Physiology Unit after performance of pH-impedance (Sandill Sci, USA). Visual analysis of tracing was performed to identify SGB and patients with more than 13 SGB/day were invited to participate. Patients attended a total of 5 CBT sessions. The CBT protocol was adapted from Katzka et al (2013) and consisted of teaching 1. diaphragmatic breathing, 2. mouth opening/tongue position and 3. recognition of a warning signal/feeling pre-belching. Patients exercised these manoeuvres daily and tried to apply them to prevent belching. Before and after CBT, subjective evaluation included a 4-item visual analogue scale (VAS) regarding severity of belching. Objective evaluation included pH-impedance at baseline and after CBT. Parameters were number of SGB, the acid exposure time, and proportion of AET associated with SGB. Results 45 patients were recruited since March 2016. So far, 21 patients completed the protocol (age: 44, (21-72), 10 females) of which 17 had a second pH-impedance study. Subjective evaluation: VAS scores decreased after CBT in 20/21 patients [before: 250 (210-310) mm vs. after: 130(80-200) mm, p 50%. Objective evaluation: Number of SGB decreased significantly after CBT in 15/17 patients [before: 90 (51-228) vs. after 45 (24-149), p=0.0041]. 8/17 patients had reduction of SGB by more than 50%. Ten patients had increased AET pre-treatment, [AET: 8.6 (SEM 0.93). In these patients SGB contributed to 32% of the AET. Overall, AET after CBT was: 6.08 (SEM 0.82), p=0.06). In 5/10 patients with baseline increased AET, we observed after CBT a reduction of number of reflux episodes driven by SGB and AET (by 31.5%). Conclusion Cognitive behavioural therapy ameliorates supragastric belching. It reduces the number of belches and improves social and daily activities in 50% of patients. Careful analysis of pH-impedance allows identification of a subgroup of GORD patients with acid reflux predominantly driven by SGB. In these patients, CBT can reduce daytime esophageal acid exposure. Disclosure of Interest E. Glasinovic: None Declared, E. Wynter: None Declared, J. Arguero: None Declared, J. Ooi: None Declared, P. Hajek: None Declared, D. Sifrim Conflict with: Reckitt Benckiser (Hull, UK); Sandhill Scientific (CO, USA)

The following on testing for gastroesophageal reflux in the 21st century contains commentaries on wireless pH monitoring; extension of pH recording duration to 48 or 96 h; extraesophageal GERD syndromes, diagnosis paradigms, and related investigating tools; off- or on-PPI reflux monitoring in the preoperative setting; and the potential influence of PPIs on reflux parameters.

Aliment Pharmacol Ther 2011; 34: 799–807 Summary Background Increased gastro-oesophageal reflux (GER) is common in patients with cystic fibrosis (CF). Previous studies showed delayed gastric emptying (GE) and a high prevalence of bile acids in saliva suggesting duodenogastro-oesophageal reflux (DGER). Aim To assess different types of reflux (acid, weakly acidic and bile) and their relationship with rate of GE in adult CF patients. Methods Gastric emptying was assessed in 33 CF patients using breath tests, reflux was monitored in 42 patients using impedance-pH-metry and 14 CF patients underwent combined impedance-pH-Bilitec monitoring. Results Delayed GE was found in 33%, increased GER (predominantly acid) in 67% and pathological DGER in 35% of the CF patients. There was a significant correlation between oesophageal bile and acid exposure (P

Background/Aims Impedance-pH monitoring allows detailed characterization of gastroesophageal reflux and esophageal activity associated with reflux. We assessed the characteristics of nocturnal reflux and esophageal activity preceding and following reflux. Methods Impedance-pH tracings from 11 healthy subjects and 76 patients with gastroesophageal reflux disease off acid-suppressive therapy were analyzed. Characteristics of nocturnal supine reflux, time distribution and esophageal activity seen on impedance at 2 minute intervals preceding and following reflux were described. Results Patients had more nocturnal reflux events than healthy subjects (8 [4-12] vs 2 [1-5], P = 0.002), with lower proportion of weakly acidic reflux (57% [35-78] vs 80% [60-100], P = 0.044). Nocturnal reflux was mainly liquid (80%) and reached the proximal esophagus more often in patients (6% vs 0%, P = 0.047). Acid reflux predominated in the first 2 hours (66%) and weakly acidic reflux in the last 3 hours (70%) of the night. Most nocturnal reflux was preceded by aboral flows and cleared by short lasting volume clearance. In patients, prolonged chemical clearance was associated with less esophageal activity. Conclusions Nocturnal weakly acidic reflux is as common as acid reflux in patients with gastroesophageal reflux disease, and predominates later in the night. Impedance-pH can predict prolonged chemical clearance after nocturnal acid reflux.

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.

The pathogenesis of gastrointestinal reflux disease is multifactoral. Integral to the disease process is the refluxate itself. The characteristics and composition of the refluxate are dependent on several physiological variables. The refluxate may contain varying concentrations of acid, pepsin, gas, or contents of duodenal reflux (such as bile acid and pancreatic enzymes). Characteristics such as volume and proximal extent of the refluxate, and the chemical content of this refluxate can strongly influence the risk of symptom perception. Strong acid (pH4) and duodeno-gastro-oesophageal reflux are also implicated in the development of mucosal damage in the form of oesophagitis, Barrett's metaplasia and oesophageal adenocarcinoma. The manifestation of disease, however, is not entirely reliant on the refluxate, which must be considered in the context of the genetic, environmental and psychological susceptibility of the individual.