The effects of simulated gastroesophageal reflux on infant pig oropharyngeal feeding physiology.

The neural connectivity among the oral cavity, pharynx, and esophagus is a critical component of infant feeding physiology. Central integration of oral and pharyngeal afferents alters motor outputs to structures that power swallowing, but the potential effects of esophageal afferents on preesophageal feeding physiology are unclear. These effects may explain the prevalence of oropharyngeal dysphagia in infants suffering from gastroesophageal reflux (GER), though the mechanism underlying this relationship remains unknown. Here we use the validated infant pig model to assess the impacts of simulated GER on preesophageal feeding parameters. We used high-speed videofluoroscopy and electromyography to record bottle-feeding before and following the infusion of a capsaicin-containing solution into the lower esophagus. Sucking parameters were minimally affected by capsaicin exposure, such that genioglossus activity was unchanged and tongue kinematics were largely unaffected. Aspects of the pharyngeal swallow were altered with simulated GER, including increased thyrohyoid muscle activity, increased excursions of the hyoid and thyroid per swallow, decreased swallow frequency, and increased bolus sizes. These results suggest that esophageal afferents can elicit changes in pharyngeal swallowing. In addition, decreased swallowing frequency may be the mechanism by which esophageal pathologies induce oropharyngeal dysphagia. Although recent work indicates that oral or pharyngeal capsaicin may improve dysphagia symptoms, the decreased performance following esophageal capsaicin exposure highlights the importance of designing sensory interventions based upon neurophysiology and the mechanisms underlying disordered feeding. This mechanistic approach requires comprehensive data collection across the entirety of the feeding process, which can be achieved using models such as the infant pig.NEW & NOTEWORTHY Simulated gastroesophageal reflux (GER) in an infant pig model resulted in significant changes in pharyngeal swallowing, which suggests that esophageal afferents are centrally integrated to alter motor outputs to the pharynx. In addition, decreased swallow frequency and increased bolus sizes may be underlying mechanisms by which esophageal pathologies induce oropharyngeal dysphagia. The infant pig model used here allows for a mechanistic approach, which can facilitate the design of intervention strategies based on neurophysiology.

Update on extraesophageal manifestations of gastroesophageal reflux.

PURPOSE OF REVIEW: Symptoms/complications related to extraesophageal reflux (EER) are increasingly prevalent presentations and pose significant challenges for clinicians. We summarize and discuss clinical advances and developments in pathophysiology, testing and treatment algorithms of upper/lower airway manifestations of EER. RECENT FINDINGS: Growing evidence supports likely multifactorial causes of laryngeal symptoms, including EER, oropharyngeal pathologies, allergic conditions, and cognitive-affective processes (brain-larynx interaction). Diagnostic paradigm for laryngopharyngeal reflux (LPR) is shifting towards a personalized approach with noninvasive strategies/prediction tools to risk-stratify patients for upfront reflux testing over empiric acid suppression trials. Management should be multipronged to include antireflux therapies and treatments targeting other causes. Lower airway complications of EER may result in lung dysfunction and poor transplant outcomes. Esophageal symptoms are often absent and routine esophageal/reflux testing to guide timely antireflux therapies may lead to improved outcomes. Modalities that leverage impedance technology may be important, given the potential role of nonacidic reflux. Novel impedance-based metrics such as mean nocturnal baseline impedance and postreflux swallow-induced peristaltic wave index may provide adjunctive diagnostic values. SUMMARY: Standardized approach to diagnosis/management of EER should include multidisciplinary care teams and consider different phenotypes, nonreflux contributors, and the complex gut-airway relationships. Prompt antireflux therapies after careful candidate selection may improve outcomes of these airway complications.

Recent advances in the knowledge of the mechanism of reflux hypersensitivity.

Reflux hypersensitivity (RH) is a subtype of gastroesophageal reflux disease. The Rome IV criteria separated RH from the original nonerosive reflux disease subgroup and classified it as a new functional oesophageal disease. Recently, the pathogenesis of RH has become the focus of research. According to the latest research reports, upregulation of acid-sensitive receptors, distribution of calcitonin gene-related peptide-positive nerve fibres, and psychiatric comorbidity have key roles in the pathogenesis of RH. This work reviews the latest findings regarding RH mechanisms.

The role of high-resolution impedance manometry to identify rumination syndrome in children with unexplained foregut symptoms.

OBJECTIVES: Diagnosis of rumination syndrome (RS) relies on Rome IV criteria. Oesophageal high-resolution impedance manometry (HRIM) can objectively demonstrate the episodes of rumination, but its role in the diagnostic pathway is not yet established. We aimed to demonstrate the clinical contribution of this tool for the timely diagnosis of RS and diagnostic work-up of children with unexplained foregut symptoms deemed to be due to other conditions. METHODS: HRIMs performed between 2012 and 2021 were searched to retrieve all diagnoses of RS. Medical records were reviewed for clinical data. RESULTS: Out of 461 HRIMs performed, 76 children had manometric diagnosis of RS (35 male, median age: 13 years). Of them, 47% were not clinically suspected as the symptoms did not fulfil clinical criteria for RS. The indications for HRIM in these cases were investigation of unexplained foregut symptoms (37%), suspected refractory gastroesophageal reflux disease (8%) and dysphagia (2%). Among all HRIMs performed for investigations of unexplained foregut symptoms (n = 80), 35% demonstrated rumination episodes. CONCLUSION: Identification of characteristic patterns of rumination on HRIM in children with unexplained foregut symptoms enables the immediate diagnosis of RS. Thus, in situations of diagnostic uncertainty, the use of HRIM at early stages of the diagnostic pathway would reduce unnecessary investigations and treatments.

Differences Between Patients with Heartburn Refractory to Vonoprazan and Those Refractory to Proton Pump Inhibitors.

BACKGROUND: Vonoprazan, a potassium-competitive acid blocker, demonstrates more potent acid inhibition than proton pump inhibitors (PPIs). This study aimed to evaluate the effect of vonoprazan in patients with unproven gastroesophageal reflux disease (GERD) by comparing patients with vonoprazan-refractory heartburn with those with PPI-refractory heartburn. METHODS: This study included 104 consecutive patients with vonoprazan- or PPI-refractory heartburn (52 patients each), no erosive esophagitis on endoscopy and who underwent combined multichannel intraluminal impedance-pH (MII-pH) testing with vonoprazan/PPI discontinuation. Patients' backgrounds, symptom scores from four questionnaires, MII-pH results and high-resolution manometry results were compared between the two groups. RESULTS: The vonoprazan group demonstrated significantly higher GERD symptoms and scores of abdominal pain and diarrhea on the Gastrointestinal Symptom Rating Scale questionnaire. MII-pH results revealed that the vonoprazan group demonstrated 40.4%, 17.3%, and 42.3% and the PPIs group exhibited 26.9%, 17.3%, and 55.8% of abnormal acid reflux [true non-erosive reflux disease (NERD)], reflux hypersensitivity and functional heartburn, respectively. The vonoprazan group demonstrated higher true NERD rates but with no significant difference (p = 0.307). Among the vonoprazan group, eight patients with true NERD underwent another MII-pH test on vonoprazan, and all cases demonstrated normal acid exposure times (0.0% [0.0-0.3]). CONCLUSION: Patients with unproven GERD with vonoprazan-refractory heartburn demonstrated more symptoms, including not only GERD symptoms but also functional dyspepsia and irritable bowel syndrome symptoms, than those with PPI-refractory heartburn.

Saliva Production and Esophageal Motility Influence Esophageal Acid Clearance Related to Post-reflux Swallow-Induced Peristaltic Wave.

BACKGROUND: The post-reflux swallow-induced peristaltic wave (PSPW) brings salivary bicarbonate to neutralize residual distal esophageal mucosal acidification. AIMS: To determine if reduced saliva production and esophageal body hypomotility would compromise PSPW-induced pH recovery in the distal esophagus. METHODS: In this multicenter retrospective cross-sectional study, patients with confirmed Sjogren's syndrome and scleroderma/mixed connective tissue disease (MCTD) who underwent high resolution manometry (HRM) and ambulatory pH-impedance monitoring off antisecretory therapy were retrospectively identified. Patients without these disorders undergoing HRM and pH-impedance monitoring for GERD symptoms were identified from the same time-period. Acid exposure time, numbers of reflux episodes and PSPW, pH recovery with PSPW, and HRM metrics were extracted. Univariate comparisons and multivariable analysis were performed to determine predictors of pH recovery with PSPW. RESULTS: Among Sjogren's syndrome (n = 34), scleroderma/MCTD (n = 14), and comparison patients with reflux symptoms (n = 96), the scleroderma/MCTD group had significantly higher AET, higher prevalence of hypomotility, lower detected reflux episodes, and very low numbers of PSPW (p ≤ 0.004 compared to other groups). There was no difference in pH-impedance metrics between Sjogren's syndrome, and comparison patients (p ≥ 0.481). Proportions with complete pH recovery with PSPW was lower in Sjogren's patients compared to comparison reflux patients (p = 0.009), predominantly in subsets with hypomotility (p < 0.001). On multivariable analysis, diagnosis of Sjogren's syndrome, scleroderma/MCTD or neither (p = 0.014) and esophageal hypomotility (p = 0.024) independently predicted lack of complete pH recovery with PSPW, while higher total reflux episodes trended (p = 0.051). CONCLUSIONS: Saliva production and motor function are both important in PSPW related pH recovery.

How to diagnose GERC more effectively: reflections on post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance.

INTRODUCTION: Post-reflux swallow-induced peristaltic wave index (PSPWI) and mean nocturnal baseline impedance (MNBI) are novel parameters reflect esophageal clearance capacity and mucosal integrity. They hold potential in aiding the recognition of gastroesophageal reflux-induced chronic cough (GERC). Our study aims to investigate their diagnostic value in GERC. METHODS: This study included patients suspected GERC. General information and relevant laboratory examinations were collected, and final diagnosis were determined following guidelines for chronic cough. The parameters of multichannel intraluminal impedance-pH monitoring (MII-pH) in patients were analyzed and compared to explore their diagnostic value in GERC. RESULTS: A total of 186 patients were enrolled in this study. The diagnostic value of PSPWI for GERC was significant, with the area under the working curve (AUC) of 0.757 and a cutoff value of 39.4%, which was not statistically different from that of acid exposure time (AET) (p > 0.05). The combined diagnostic value of AET > 4.4% and PSPWI < 39.4% was superior to using AET > 4.4% alone (p < 0.05). Additionally, MNBI and distal MNBI also contributed to the diagnosis of GERC, with AUC values of 0.639 and 0.624, respectively. AET > 4.4% or PSPWI < 39.4% is associated with a 44% reduction in missed diagnoses of non-acid GERC compared to AET > 6.0% or symptom association probability (SAP) ≥ 95%, and may be more favorable for identifying GERC. CONCLUSION: The diagnostic value of PSPWI for GERC is comparable to that of AET. Combining PSPWI < 39.4% or AET > 4.4% can improve the diagnostic efficiency by reducing the risk of missed diagnoses in cases where non-acid reflux is predominant. Distal MNBI and MNBI can serve as secondary reference indices in the diagnosis of GERC.

[Use of flexible transnasal esophagogastroscopy in patients with unclear globus sensation]. / Einsatz der flexiblen transnasalen Ösophagogastroskopie bei Patienten mit unklarem Globus pharyngeus.

BACKGROUND: Globus pharyngeus is a common symptom with considerable suffering. Globus sensation can be caused by reflux. In many places, endoscopy of the esophagus is recommended for clarification, especially when there is a question about the presence of a hiatal hernia as the cause of reflux. Transnasal esophagogastroscopy (TNE) represents an alternative to conventional gastroesophagoscopy. It enables a quick low-complication examination of the upper aerodigestive tract in the sitting, non-sedated patient. OBJECTIVE: The aim of this work was to assess the feasibility of outpatient TNE in patients with globus sensation. Furthermore, the results of dual-probe pH monitoring were compared with the results of TNE in order to assess the value of TNE in the clarification of globus sensation and reflux. MATERIALS AND METHODS: In 30 patients with globus symptoms, 24-hour dual-probe pH monitoring and TNE were performed. In pH monitoring, reflux number, fraction time, reflux surface area index, and DeMeester score were evaluated as indicators of laryngopharyngeal reflux (LPR) and gastroesophageal reflux (GERD). Abnormalities of the esophageal mucosa and the gastroesophageal junction were recorded in TNE. The results were compared. RESULTS: The TNE could be performed without any complications. Mean examination time was 5.34 ± 0.12 min. Reflux was measured in 80% of the patients (24/30) with pH monitoring. In almost half of these patients (46%), abnormalities were detected in TNE as indirect evidence of reflux. In addition to an axial hiatal hernia, these included mucosal changes such as erosive esophagitis and Barrett's metaplasia. Patients with a hiatal hernia also suffered significantly more often from LPR than patients without a hernia (9:1). CONCLUSION: TNE is a quick and safe examination method for diagnosing patients with an unclear globus sensation. Detection of a hiatal hernia can be seen as an indication of reflux disease. Lack of evidence of a hernia does not rule out reflux. Thus, TNE is a useful addition to pH monitoring in patients with globus sensation, because reflux-related changes in the mucosa can be recognized early and adequately treated.

Manometric esophagogastric junction barrier metrics as predictors of gastroesophageal reflux.

BACKGROUND: High-resolution manometry (HRM) tools, like esophagogastric junction contractile integral (EGJ-CI), assess EGJ barrier function. GOALS: This study aimed to evaluate the relationships between manometric EGJ metrics with esophageal acid exposure. STUDY: We conducted a retrospective review of 284 patients who underwent HRM and ambulatory reflux testing between 11/2017-1/2020. EGJ-CI and total-EGJ-CI were manually calculated. Pathologic acid exposure was defined as pH < 4 with esophageal acid exposure time (EAET) exceeding 6.0%. Pearson's correlation, univariable and multivariable regression models were utilized to assess the relationships between pathologic acid exposure and EGJ parameters. Sensitivity and specificity thresholds for EGJ-CI and total EGJ-CI were optimized with ROC analyses. RESULTS: On univariable analysis, patients with pathologic acid exposure had increased odds of having lower mean basal LES pressures, EGJ-CI, and total EGJ-CI than patients without pathologic acid exposure. On multivariable analysis, age, EGJ-CI and mean DCI were significant predictors of pathologic acid exposure. There were significant, though weak, correlations between EAET and EGJ-CI and total EGJ-CI (r = - 0.18, - 0.19, p < 0.01, respectively). An EGJ-CI cutoff of 44.16 as a predictor for pathologic acid exposure had a sensitivity of 46% and specificity of 42% (AUC 0.60). Total EGJ-CI cutoff of 11,461.3 for pathologic acid exposure had a sensitivity of 44% and a specificity of 43% (AUC 0.62). CONCLUSION: EGJ-CI can independently predict pathologic acid exposure. However, the poor correlation between EGJ-CI and acid exposure, as well as the low sensitivity and specificity of calculated thresholds, indicate that mechanisms other than EGJ barrier function may impact acid exposure.

Value of pH Impedance Monitoring While on Twice-Daily Proton Pump Inhibitor Therapy to Identify Need for Escalation of Reflux Management.

BACKGROUND AND AIMS: Acid exposure time (AET) and reflux episode thresholds from the Lyon Consensus may not apply for pH impedance studies performed while on proton pump inhibitor (PPI) therapy. We aimed to determine metrics from "on PPI" pH impedance studies predicting need for escalation of therapy. METHODS: De-identified pH impedance studies performed while on twice-daily PPI (Diversatek, Boulder, CO) in healthy volunteers (n = 66, median age 37.5 years, 43.9% female), and patients with proven gastroesophageal reflux disease (GERD) (European heartburn-predominant cohort: n = 43, median age 57.0 years, 55.8% female; North American regurgitation-predominant cohort: n = 42, median age 41.6 years, 42.9% female) were analyzed. Median values and interquartile ranges for pH impedance metrics in healthy volunteers were compared with proven GERD patients with and without 50% symptom improvement on validated measures. Receiver operating characteristic (ROC) analyses identified optimal thresholds predicting symptom response. RESULTS: Both conventional and novel reflux metrics were similar between PPI responders and nonresponders (P ≥ .1 for each) despite differences from healthy volunteers. Combinations of metrics associated with conclusively abnormal reflux burden (AET >4%, >80 reflux episodes) were seen in 32.6% and 40.5% of heartburn and regurgitation-predominant patients, respectively, 57.1% and 82.4% of whom reported nonresponse; and 85% with these metrics improved with invasive GERD management. On ROC analysis, AET threshold of 0.5% modestly predicted nonresponse (sensitivity, 0.62; specificity, 0.51; P = .22), and 40 reflux episodes had better performance characteristics (sensitivity, 0.80; specificity, 0.51; P = .002); 79% with these metrics improved with invasive GERD management. CONCLUSION: Combinations of abnormal "on PPI" pH impedance metrics are associated with PPI nonresponse in proven GERD patients, and can be targeted for treatment escalation, including surgery, particularly in regurgitation-predominant GERD.

Reflux Monitoring in Lung Disease: Is There a Better Metric than Esophageal Acid Exposure Time?

ABSTRACT: Ambulatory reflux monitoring can be performed with either a telemetry capsule to monitor for esophageal acid exposure alone for a period of 48-96 hours, and a 24 hour catheter based impedance/pH study which is most valuable for evaluating patients with objective evidence of GERD who are incompletely relieved with proton pump inhibitors. Some would consider catheter-based impedance/pH as the "best" test to evaluate patients with extraesophageal symptoms including suspected pulmonary complications of GERD. This editorial provides comment on the use of novel advanced metrics, mean nocturnal baseline impedance and post-reflux induced-swallow peristaltic wave index in analysis of these studies.

Associations Between Sleep Position and Nocturnal Gastroesophageal Reflux: A Study Using Concurrent Monitoring of Sleep Position and Esophageal pH and Impedance.

INTRODUCTION: The aim of this study was to investigate the effect of spontaneous sleep positions on the occurrence of nocturnal gastroesophageal reflux. METHODS: In patients referred for ambulatory pH-impedance reflux monitoring, the concurrent sleep position was measured using a sleep position measurement device (measuring left, right, supine, and prone positions). RESULTS: Fifty-seven patients were included. We observed a significantly shorter acid exposure time in the left (median 0.0%, P25-P75, 0.0%-3.0%), compared with the right lateral position (median 1.2%, 0.0%-7.5%, P = 0.022) and the supine position (median 0.6%, 0.00%-8.3%, P = 0.022). The esophageal acid clearance time was significantly shorter in the left lateral decubitus position (median 35 seconds, 16-115 seconds), compared with the supine (median 76 seconds, 22-257 seconds, P = 0.030) and right lateral positions (median 90 seconds, 26-250 seconds, P = 0.002). DISCUSSION: The left lateral decubitus position is associated with significantly shorter nocturnal esophageal acid exposure time and faster esophageal acid clearance compared with the supine and right lateral decubitus positions (see visual abstract).

Estimation of mechanical work done to open the esophagogastric junction using functional lumen imaging probe panometry.

In this study, we quantify the work done by the esophagus to open the esophagogastric junction (EGJ) and create a passage for bolus flow into the stomach. Work done on the EGJ was computed using functional lumen imaging probe (FLIP) panometry. Eighty-five individuals underwent FLIP panometry with a 16-cm catheter during sedated endoscopy including asymptomatic controls (n = 14), 45 patients with achalasia (n = 15 each, three subtypes), those with gastroesophageal reflux disease (GERD; n = 13), those with eosinophilic esophagitis (EoE; n = 8), and those with systemic sclerosis (SSc; n = 5). Luminal cross-sectional area (CSA) and pressure were measured by the FLIP catheter positioned across the EGJ. Work done on the EGJ (EGJW) was computed (millijoules, mJ) at 40-mL distension. Additionally, a separate method was developed to estimate the "work required" to fully open the EGJ (EGJROW) when it did not open during the procedure. EGJW for controls had a median [interquartile range (IQR)] value of 75 (56-141) mJ. All achalasia subtypes showed low EGJW compared with controls (P < 0.001). Subjects with GERD and EoE had EGJW 54.1 (6.9-96.3) and 65.9 (10.8-102.3) mJ, similar to controls (P < 0.08 and P < 0.4, respectively). The scleroderma group showed low values of EGJW, 12 mJ (P < 0.001). For patients with achalasia, EGJROW was the greatest and had a value of 210.4 (115.2-375.4) mJ. Disease groups with minimal or absent EGJ opening showed low values of EGJW. For patients with achalasia, EGJROW significantly exceeded EGJW values of all other groups, highlighting its unique pathophysiology. Balancing the relationship between EGJW and EGJROW is potentially useful for calibrating achalasia treatments and evaluating treatment response.NEW & NOTEWORTHY Changes in pressure and diameter occur at the EGJ during esophageal emptying. Similar changes can be observed during FLIP panometry. Data from healthy and diseased individuals were used to estimate the mechanical work done on the EGJ during distension-induced relaxation or, in instances of failed opening, work required to open the EGJ. Quantifying these parameters is potentially valuable to calibrate treatments and gauge treatment efficacy for subjects with disorders of EGJ function, especially achalasia.

Assessment of esophageal body peristaltic work using functional lumen imaging probe panometry.

The goal of this study was to conceptualize and compute measures of "mechanical work" done by the esophagus using data generated during functional lumen imaging probe (FLIP) panometry and compare work done during secondary peristalsis among patients and controls. Eighty-five individuals were evaluated with a 16-cm FLIP during sedated endoscopy, including asymptomatic controls (n = 14) and those with achalasia subtypes I, II, and III (n = 15, each); gastroesophageal reflux disease (GERD; n = 13); eosinophilic esophagitis (EoE; n = 9); and systemic sclerosis (SSc; n = 5). The FLIP catheter was positioned to have its distal segment straddling the esophagogastric junction (EGJ) during stepwise distension. Two metrics of work were assessed: "active work" (during bag volumes ≤ 40 mL where contractility generates substantial changes in lumen area) and "work capacity" (for bag volumes ≥ 60 mL when contractility cannot substantially alter the lumen area). Controls showed median [interquartile range (IQR)] of 7.3 (3.6-9.2) mJ of active work and 268.6 (225.2-332.3) mJ of work capacity. Patients with all achalasia subtypes, GERD, and SSc showed lower active work done than controls (P ≤ 0.003). Patients with achalasia subtypes I and II, GERD, and SSc had lower work capacity compared with controls (P < 0.001, 0.004, 0.04, and 0.001, respectively). Work capacity was similar between controls and patients with achalasia type III and EoE. Mechanical work of the esophagus differs between healthy controls and patient groups with achalasia, EoE, SSc, and GERD. Further studies are needed to fully explore the utility of this approach, but these work metrics would be valuable for device design (artificial esophagus), to measure the efficacy of peristalsis, to gauge the physiological state of the esophagus, and to comment on its pumping effectiveness.NEW & NOTEWORTHY Functional lumen imaging probe (FLIP) panometry assesses esophageal response to distension and provides a simultaneous assessment of pressure and dimension during contractility. This enables an objective assessment of "mechanical work" done by the esophagus. Eighty-five individuals were evaluated, and two work metrics were computed for each subject. Controls showed greater values of work compared with individuals with achalasia, gastroesophageal reflux disease (GERD), and systemic sclerosis (SSc). These values can quantify the mechanical behavior of the distal esophagus and assist in the estimation of muscular integrity.

Measurement of low-grade inflammation of the esophageal mucosa with electrical conductivity shows promise in assessing PPI responsiveness in patients with GERD.

A device that can easily measure electrical impedance might be a helpful tool for investigating the pathophysiology of gastroesophageal reflux disease. The first aim of this study was to validate our newly developed bioelectrical admittance measurement (BAM) through in vitro experimentation. The second aim was to investigate whether evaluation of BAM by this measurement differed between patients with heartburn according to their response to proton pump inhibitor (PPI) therapy. Caco-2 cell monolayers and three-dimensional tissues were examined by BAM using a frequency response analyzer. BAM was also used to measure the impedance through cell layers. Subsequently, BAM was performed during endoscopy in 41 patients experiencing heartburn without esophageal mucosal breaks. After 2-wk administration of 20-mg rabeprazole twice daily, patient responses to PPI were classified as "good" or "poor" according to their clinical course. In each patient, histological alterations and gene expression levels of inflammation mediators and tight junction proteins were evaluated. Impedance profiles indicated that monolayer Caco-2 cells on top of eight-layered normal human dermal fibroblasts had the highest magnitude of impedance over the range of frequencies. In vivo results revealed that patients with good responses to PPI displayed significantly higher admittance. Severity of low-grade inflammation was significantly associated with esophageal wall admittance. Moreover, esophageal wall admittance may be more closely related to basal zone hyperplasia than dilatation of intercellular spaces. Thus, BAM may be able to detect abnormalities in the subepithelial layer of the esophagus.NEW & NOTEWORTHY Bioelectrical admittance measurement is a new method to evaluate esophageal mucosal permeability vertically during upper gastrointestinal endoscopy. Measurement of low-grade inflammation of the esophageal mucosa with electrical conductivity shows promise in assessing proton pump inhibitor responsiveness in patients with gastroesophageal reflux disease. As various gastrointestinal diseases are associated with changes in mucosal permeability, bioelectrical admittance measurement is expected to be clinically applied to therapeutic decision-making for these diseases in the future.

Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors.

The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.

Esophageal Mucosa Innervation in Children With Nonerosive Reflux Disease.

INTRODUCTION: Esophageal mucosa innervation in adults with nonerosive reflux disease (NERD) is more superficial compared with healthy volunteers. We delineated the esophageal mucosal innervation in pediatric NERD and controls. METHODS: Distal and proximal pediatric esophageal biopsies were immunohistochemically stained with calcitonin gene-related peptide and transient receptor potential cation channel subfamily V member 1. RESULTS: Mucosal innervation was assessed in 18 controls (9M:9F, median age: 9 years) and 11 NERD patients (6M:5F, median age: 5 years). Calcitonin gene-related peptide positive nerve fibers were lying deep in the mucosa in both groups, P > 0.05 and did not coexpress transient receptor potential cation channel subfamily V member 1. DISCUSSION: The pediatric esophageal mucosa in NERD displays deep lying nerve fibers, in contrast to adults.

Effects of Diaphragmatic Breathing on the Pathophysiology and Treatment of Upright Gastroesophageal Reflux: A Randomized Controlled Trial.

INTRODUCTION: Uncontrolled results suggest that diaphragmatic breathing (DB) is effective in gastroesophageal reflux disease (GERD) but the mechanism of action and rigor of proof is lacking. This study aimed to determine the effects of DB on reflux, lower esophageal sphincter (LES), and gastric pressures in patients with upright GERD and controls. METHODS: Adult patients with pH proven upright GERD were studied. During a high-resolution impedance manometry, study patients received a standardized pH neutral refluxogenic meal followed by LES challenge maneuvers (Valsalva and abdominal hollowing) while randomized to DB or sham. After that, patients underwent 48 hours of pH-impedance monitoring, with 50% randomization to postprandial DB during the second day. RESULTS: On examining 23 patients and 10 controls, postprandial gastric pressure was found to be significantly higher in patients compared with that in controls (12 vs 7 mm Hg, P = 0.018). Valsalva maneuver produced reflux in 65.2% of patients compared with 44.4% of controls (P = 0.035). LES increased during the inspiratory portion of DB (42.2 vs 23.1 mm Hg, P < 0.001) in patients and healthy persons. Postprandial DB reduced the number of postprandial reflux events in patients (0.36 vs 2.60, P < 0.001) and healthy subjects (0.00 vs 1.75, P < 0.001) compared with observation. During 48-hour ambulatory study, DB reduced the reflux episodes on day 2 compared with observation on day 1 in both the patient and control groups (P = 0.049). In patients, comparing DB with sham, total acid exposure on day 2 was not different (10.2 ± 7.9 vs 9.4 ± 6.2, P = 0.804). In patients randomized to DB, esophageal acid exposure in a 2-hour window after the standardized meal on day 1 vs day 2 reduced from 11.8% ±6.4 to 5.2% ± 5.1, P = 0.015. DISCUSSION: In patients with upright GERD, DB reduces the number of postprandial reflux events pressure by increasing the difference between LES and gastric pressure. These data further encourage studying DB as therapy for GERD.

Integrative Effects and Vagal Mechanisms of Transcutaneous Electrical Acustimulation on Gastroesophageal Motility in Patients With Gastroesophageal Reflux Disease.

INTRODUCTION: Impaired esophageal and gastric motilities are known to contribute to symptoms of gastroesophageal reflux disease (GERD). However, there is a lack of GERD therapy, targeting both gastric and esophageal functions. This study was designed to investigate the effects of transcutaneous electrical acustimulation (TEA) on symptoms of GERD and gastroesophageal functions and possible mechanisms in patients with GERD. METHODS: Thirty patients with GERD with ineffective esophageal motility were equally divided and randomized into a 4-week sham-TEA or 4-week TEA treatment. The GERD questionnaire (GerdQ), GERD health-related quality-of-life questionnaire, high-resolution esophageal manometry, a nutrient drink test, the electrogastrogram, and ECG were performed to assess the severity of reflux symptoms, low esophageal sphincter (LES) pressure, distal contractile integral (DCI), gastric accommodation, gastric slow waves (GSW), and autonomic functions, respectively. RESULTS: Compared with sham-TEA, the 4-week TEA treatment significantly decreased the GerdQ score (P = 0.011) and GERD health-related quality of life (P = 0.028) and improved nutrient drink-induced fullness (P < 0.001) and belching (P < 0.001) in patients with GERD. Although only acute TEA significantly enhanced LES pressure (P < 0.05), both acute and chronic TEA remarkedly increased DCI (P < 0.05) and reduced the incidence of ineffective esophageal contractions during wet swallows (P = 0.02). In addition, chronic TEA significantly increased gastric accommodation and the percentage of postprandial normal GSW compared with sham-TEA and baseline. Concurrently, TEA-enhanced vagal activity (P = 0.02) and the vagal activity positively correlated with LES pressure (r = 0.528; P = 0.003) and DCI (r = 0.522; P = 0.003). DISCUSSION: The TEA treatment performed in this study improves reflux-related symptoms, increases DCI, reduces the incidence of ineffective esophageal contractions during wet swallows, and improves gastric accommodation and slow waves. The improvement in GERD symptoms might be attributed to the integrative effects of TEA on these gastroesophageal functions mediated via the vagal mechanism.

Optimal management of severe symptomatic gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a common disorder, and empirical proton pump inhibitor (PPI) treatment is often the first step of management; however, up to 40% of patients remain symptomatic despite PPI treatment. Refractory reflux refers to continued symptoms despite an adequate trial of PPI, and management remains challenging. The differential diagnosis is important; other oesophageal (e.g. eosinophilic oesophagitis) and gastroduodenal disorders (e.g. functional dyspepsia) should be ruled out, as this changes management. A combination of clinical assessment, endoscopic evaluation and in selected cases oesophageal function testing can help characterize patients with refractory reflux symptoms into oesophageal phenotypes so appropriate therapy can be more optimally targeted. Medical options then may include adding a H2 receptor antagonist, alginates, baclofen or antidepressant therapy, and there is emerging evidence for bile acid sequestrants and diaphragmatic breathing. The demonstration of a temporal association of symptoms with reflux events on pH-impedance testing (reflux hypersensitivity) serves to focus the management on modulating oesophageal perception and reducing the reflux burden, or identifies those with no obvious pathophysiologic abnormalities (functional heartburn). Anti-reflux surgery based on randomized controlled trial evidence has a role in reflux hypersensitivity or continued pathological acid reflux despite PPI in carefully considered, fully worked up cases that have failed medical therapy; approximately two of three cases will respond but there is a small risk of complications. In patients with persistent volume reflux despite medical therapy, given the lack of alternatives, anti-reflux surgery is a consideration. Promising newer approaches include endoscopic techniques. This review aims to summarize current diagnostic approaches and critically evaluates the evidence for the efficacy of available treatments.