Laryngopharyngeal reflux disease: Updated examination of mechanisms, pathophysiology, treatment, and association with gastroesophageal reflux disease.

Laryngopharyngeal reflux disease (LPRD) is an inflammatory condition in the laryngopharynx and upper aerodigestive tract mucosa caused by reflux of stomach contents beyond the esophagus. LPRD commonly presents with sym-ptoms such as hoarseness, cough, sore throat, a feeling of throat obstruction, excessive throat mucus. This complex condition is thought to involve both reflux and reflex mechanisms, but a clear understanding of its molecular mechanisms is still lacking. Currently, there is no standardized diagnosis or treatment protocol. Therapeutic strategies for LPRD mainly include lifestyle modifications, proton pump inhibitors and endoscopic surgery. This paper seeks to provide a comprehensive overview of the existing literature regarding the mechanisms, patho-physiology and treatment of LPRD. We also provide an in-depth exploration of the association between LPRD and gastroesophageal reflux disease.

Relationship between endoscopic gastroesophageal valve grading and mean nocturnal baseline impedance and postreflux swallow-induced peristaltic wave index in patients with gastroesophageal reflux disease.

This study aimed to investigate the relationship between endoscopic gastroesophageal valve grading and mean nocturnal baseline impedance (MNBI) and postreflux swallow-induced peristaltic wave index (PSPWI) in patients with gastroesophageal reflux disease (GERD). A total of 120 patients diagnosed with GERD disease were included in the study. According to the classification of endoscopic gastroesophageal valves, the patients were divided into 5 groups, group 1 as baseline group, and Group 2-4 as Hill grade I-IV. Basic information about the patients was collected, including age and gender. The mean nocturnal baseline impedance and creep wave index induced by swallowing after rumination were measured by high resolution creep measurement technique. Through statistical analysis, the relationship between valve classification and observation index was discussed. In terms of MNBI, impedance values gradually decreased with increasing valve classification. The average impedance of the Grade 1 group was 23.5 mm Hg/cm2, while the average impedance of the Grade 5 group was 15.2 mm Hg/cm2. This reduction showed a significant decreasing trend (P < .001). In addition, in terms of the peristaltic wave index caused by swallowing after regurgitation, the peristaltic wave index gradually increased with the increase of valve classification. The mean index in the Grade 1 group was 1.8 beats/min, while the mean index in the Grade 5 group was 3.6 beats/min. This increase showed a significant positive relationship (P < .001). Endoscopic gastroesophageal valve grading was significantly correlated with MNBI and PSPWI in patients with GERD. These observations can serve as useful tools for assessing the severity of GERD and monitoring disease progression.

Enhanced Runge-Kutta-driven feature selection model for early detection of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) profoundly compromises the quality of life, with prolonged untreated cases posing a heightened risk of severe complications such as esophageal injury and esophageal carcinoma. The imperative for early diagnosis is paramount in averting progressive pathological developments. This study introduces a wrapper-based feature selection model based on the enhanced Runge Kutta algorithm (SCCRUN) and fuzzy k-nearest neighbors (FKNN) for GERD prediction, named bSCCRUN-FKNN-FS. Runge Kutta algorithm (RUN) is a metaheuristic algorithm designed based on the Runge-Kutta method. However, RUN's effectiveness in local search capabilities is insufficient, and it exhibits insufficient convergence accuracy. To enhance the convergence accuracy of RUN, spiraling communication and collaboration (SCC) is introduced. By facilitating information exchange among population individuals, SCC expands the solution search space, thereby improving convergence accuracy. The optimization capabilities of SCCRUN are experimentally validated through comparisons with classical and state-of-the-art algorithms on the IEEE CEC 2017 benchmark. Subsequently, based on SCCRUN, the bSCCRUN-FKNN-FS model is proposed. During the period from 2019 to 2023, a dataset comprising 179 cases of GERD, including 110 GERD patients and 69 healthy individuals, was collected from Zhejiang Provincial People's Hospital. This dataset was utilized to compare our proposed model against similar algorithms in order to evaluate its performance. Concurrently, it was determined that features such as the internal diameter of the esophageal hiatus during distention, esophagogastric junction diameter during distention, and external diameter of the esophageal hiatus during non-distention play crucial roles in influencing GERD prediction. Experimental findings demonstrate the outstanding performance of the proposed model, with a predictive accuracy reaching as high as 93.824 %. These results underscore the significant advantage of the proposed model in both identifying and predicting GERD patients.

Proximal esophageal impedance baseline increases the yield of impedance-pH and is associated with response to PPIs in chronic cough patients.

BACKGROUND: Chronic cough significantly impairs the quality of life. Although various studies focused on MNBI as assessed in the distal esophagus, scarce data are available on the clinical value of proximal measurements. AIM: To investigate the role of proximal MNBI in the workup of patients with chronic cough and its ability to predict PPI response. METHODS: Demographic, clinical, endoscopy findings, impedance-pH and HRM tracings from consecutive cough patients were evaluated. MNBI was calculated at proximal and distal esophagus. RESULTS: One hundred and sixty four patients were included. In addition to traditional variables, when considering also the PSPW index or MNBI at 3 cm or 15 cm, the proportion of patients with pathological impedance-pH monitoring significantly increased. 70/164 patients were responders, while 94 (57.3%) were non-responder to double PPI dose (p < 0.05). Patients with pathologic MNBI at 3 cm and/or 15 cm as well as those with pathologic PSPW index were characterized by a significantly higher proportion of responders than that observed among patients with normal impedance-pH variables (p < 0.001). The proportion of responders with pathological MNBI at 15 cm was significantly higher than the proportion of responders with pathological MNBI at 3 cm (82.8% vs. 64.3%, p < 0.05). At multivariable model, pathological MNBI at both 3 cm and 15 cm as well as PSPW index were associated with PPI responsiveness. The strongest association with PPI response was observed for MNBI at 15 cm. CONCLUSIONS: The assessment of MNBI at proximal esophagus increases the diagnostic yield of impedance-pH monitoring and may represent a useful predictor of PPI responsiveness in the cumbersome clinical setting of suspected reflux-related cough.

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.

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.

Analysis of contractile segment impedance during straight leg raise maneuver using high-resolution impedance manometry increases diagnostic yield in reflux disease.

BACKGROUND: Contractile segment impedance (CSI) obtained from high-resolution impedance manometry (HRIM) is a measure of mucosal integrity that predicts gastroesophageal reflux disease (GERD). While straight leg raise (SLR) maneuver augments esophageal peristaltic vigor, it remains unclear whether SLR affects CSI values. This study was aimed to evaluate whether CSI with SLR is feasible and useful to complement the diagnosis of GERD. METHODS: We prospectively recruited 48 patients with typical GERD symptoms who underwent esophagogastroduodenoscopy, HRIM with SLR maneuver, and multichannel intraluminal impedance-pH (MII-pH) testing. The capability of mean nocturnal baseline impedance (MNBI), resting baseline impedance (RBI), CSI with or without SLR maneuver in predicting GERD was assessed using receiver operating characteristics (ROC) analysis. KEY RESULTS: Among 20 GERD patients and 28 non-GERD patients, all values of impedance-based metrics were lower in GERD patients compared to non-GERD patients (p < 0.001). For GERD identification, area under receiver operating characteristic curve (AUROC) values of CSI with SLR maneuver, CSI, MNBI, and RBI were 0.901, 0.858, 0.865, and 0.797. Particularly in ineffective esophageal motility (IEM) patients, SLR maneuver increased mean distal contractile integral from 436 to 828.7 mmHg.s.cm (p = 0.018) and enhanced AUROC values of CSI for GERD identification from 0.917 to 0.958. CONCLUSIONS & INFERENCES: CSI measurement during HRIM appears to be a reliable, time-saving, and less invasive tool for complementing GERD diagnosis. Our results also suggest a simple SLR maneuver during HRIM could enhance diagnostic accuracy of CSI for GERD identification especially in IEM patients.

Reduced masticatory function predicts gastroesophageal reflux disease and esophageal dysphagia in patients referred for upper endoscopy: A cross-sectional study.

BACKGROUND: The role of mastication on gastroesophageal reflux disease (GERD) is unknown. AIMS: To assess whether reduced masticatory function predicts GERD and esophageal dysphagia in patients investigated with upper endoscopy. METHODS: In this cross-sectional study, 179 adult patients referred for elective upper gastrointestinal endoscopy agreed to participate. Before endoscopy, an expert dentist performed an oral examination and scored chewing function in three levels (normal, regular, and reduced). Patients replied questionnaires for assessment of GERD (heartburn, regurgitation, and dysphagia), xerostomia, and mastication (normal, regular, and reduced). Poor chewing was defined when either oral examination or mastication questionnaire rated the chewing function as reduced. Associations of mastication with GERD and dysphagia were estimated using Poisson regression. RESULTS: Eleven patients were excluded. Among 168 analyzed (aging 49.8 ± 15.5 years; 58.9% women), 46 had reduced masticatory function (27.4%), and 122 had regular/normal mastication (72.6%). Reduced mastication was associated with GERD [PR = 1.38 (95%CI 1.12 - 1.70)], adjusting for age, and with esophageal dysphagia [PR = 2.03 (95%CI 1.02 - 4.04)], adjusting for age and xerostomia. CONCLUSIONS: In outpatients referred for upper gastrointestinal endoscopy, reduced masticatory function defined by an expert dentist may be a risk factor for GERD and esophageal dysphagia.

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).

Response of Esophageal Epithelium to Acute and Chronic Stress in Rabbits.

We studied electrophysiological changes in rabbit esophageal epithelium following acute (AS) and chronic stress (CS). Esophageal tissue was placed in Ussing chamber and the potential difference U between the luminal and abluminal sides, the short-circuit current Isc, as well as the tissue resistance R were measured. The initial values of these parameters for each sample were determined after the samples were stabilized in Ringer solution. Then, the tissues were exposed for 1 h to normal Ringer solution or Ringer solution with pH 4.0 and pH 1.7 with or without pepsin (0.25 mg/ml). Fluorescein was added to the luminal side of the sample to measure its permeability. In the AS group, U at Ringer solution (pH 1.7)+pepsin was significantly decreased in comparison with the baseline and control values (by 46 and 22%, respectively, p<0.05). R decreased by 74% in comparison with baseline, which little differed from the decrease in control samples exposed to Ringer solution (pH 1.7)+pepsin (by 62%). CS did not change U relative to baseline values, while changes in R were similar to those in the AS group. In the AS group, the permeability of the esophageal tissue perfused with Ringer solution (pH 1.7)+pepsin was significantly higher than in both the control and CS groups. AS, but not CS, made the esophageal epithelium more sensitive to the effects of noxious agents, disrupted barrier properties, and increased permeability. The effects of stress on gastroesophageal reflux disease symptoms can be related to severe exposure to acid and/or pepsin; however, the mechanisms other than epithelial defense should be evaluated.

Influence of gastric morphology on gastroesophageal reflux in adults: An observational study.

ABSTRACT: The study's aim was to determine if there was an association between gastric morphology and gastroesophageal reflux (GER). Few published studies have investigated the relationship between gastric morphology and the risk of GER.A total of 777 patients were randomly selected from 3000 to 3300 patients who presented at a medical center in Taipei for annual health checkups from early 2008 through to late 2010 and underwent a series of radiographs of the upper gastrointestinal tract (UGI). GER was recorded during the real-time fluoroscopic study. Thirty-nine participants had a follow-up endoscopy, and another 164 participants were followed up by a second UGI series 12 +/ -1.5 months later, from late 2008 through to early 2022. All participants completed a lifestyle and symptom questionnaire. The variables included current smoking and alcohol consumption. Participants who had heartburn and dysphagia were included in the study. Additionally, all participants underwent a limited physical examination which recorded age, sex, body mass index, and total cholesterol and triglyceride levels.All participants were classified into types 1 to 6 based on the gastric morphology determined from the first UGI. Cascade stomach is recognized by characteristic findings on UGI. Gastric types 2 and 3 tend to appear as cascade stomachs and were significantly associated with GER (P < .05) compared with the other groups. Morphologic type 5 appeared as an elongated sac extending downward into the pelvic cavity and was less likely to develop GER (P < .001). The results of follow-up studies by UGI and endoscopy were similar to those of the first UGI. Gastric morphologic type 2 was significantly associated, and type 5 was usually not associated, with GER and erosive esophagitis (P < .05) compared with the other groups, by both UGI and endoscopy.Gastric morphologic types 2 and 3, with cascade stomach, might provide a relatively easy method for the development of the GER phenomenon. Gastric morphologic type 5 appeared as an elongated sac that might reduce the incidence of the GER phenomenon. The study suggested that gastric morphologic type could influence the occurrence of GER.

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.

Manual Cervical Traction and Trunk Stabilization Cause Significant Changes in Upper and Lower Esophageal Sphincter: A Randomized Trial.

OBJECTIVES: Dysfunctions in the lower esophageal sphincter (LES) and the upper esophageal sphincter (UES) levels can occur owing to poor muscle coordination, contraction, or relaxation. Such condition can possibly be addressed by functional rehabilitation. The aim of this study was to measure pressure changes in the UES and LES at rest and during routine rehabilitation techniques, that is, cervical manual traction and trunk stabilization maneuver. METHODS: This study was conducted in a University Hospital Gastrointestinal Endoscopy Center. Cervical manual traction and a trunk stabilization maneuver were performed in a convenient group of 54 adult patients with gastroesophageal reflux disease. High-resolution manometry was used to measure pressure changes in the LES and UES at rest and during manual cervical traction and trunk stabilization maneuver. RESULTS: Average initial resting UES pressure was 90.91 mmHg. A significant decrease was identified during both cervical traction (average UES pressure = 42.13 mmHg, P < .001) and trunk stabilization maneuver (average UES pressure = 62.74 mmHg, P = .002). The average initial resting LES pressure was 14.31 mmHg. A significant increase in LES pressure was identified both during cervical traction (average LES pressure = 21.39 mmHg, P < .001) and during the trunk stabilization maneuver, (average pressure = 24.09 mmHg, P < .001). CONCLUSION: Cervical traction and trunk stabilization maneuvers can be used to decrease pressure in the UES and increase LES pressure in patients with gastroesophageal reflux disease.

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.

The mechanism of esophagus dysmotility in diabetes and research progress of relating treatments.

Introduction: Esophagus dysmotility is a crucial risk factor of gastroesophageal reflux disease (GERD), which is one of the most common diseases in digestive medicine globally. This review emphasizes the mechanisms of esophagus dysmotility in diabetes and summarizes more targeted treatments for these patients to avoid the overuse of proton pump inhibitors (PPIs).Areas covered: Diabetes mellitus (DM) is a clear factor that must not be neglected in the development of GERD. Previous studies have preliminarily researched the esophagus deterioration in diabetes. However, the multi-faceted mechanisms of esophagus dysmotility in diabetes need more studies. Besides, targeted treatments for these patients rather than conventional PPIs are urgently needed.Expert opinion: The treatments for GERD patients with diabetes should be further explored. Pharmacological approaches such as prokinetic agents, psychotherapy can be adopted. Meanwhile, it's feasible to explore non-drug treatments. For example, Electroacupuncture (EA) at Zusanli (ST-36) may be effective to protect the networks of intestinal cells of Cajal (ICCs) in diabetes. More effective approaches should be explored to achieve individualized treatment for these patients.

Increased visceral sensitivity, elevated anxiety, and depression levels in patients with functional esophageal disorders and non-erosive reflux disease.

BACKGROUND: Little is known about possible underlying psychological abnormalities and physiology of reflux hypersensitivity (RH) as defined in the recent Rome IV classification. We aimed to assess markers of psychological comorbidity as well as gastro-esophageal reflux measurements in RH patients compared to controls and also in patients with functional heartburn (FH) and non-erosive reflux disease (NERD) versus controls. METHODS: Data of 304 patients visiting our Functional Diagnostics Centre from 2016 to 2018 were analyzed. We focused on a psychological assessment using validated questionnaires (visceral sensitivity index; VSI, hospital anxiety and depression score; HADS) as well as multichannel intraluminal impedance (MII) and pH-metry data from the diagnostic work-up. KEY RESULTS: We found a decreased VSI of 57.8 ± 15.4 points (pts) among RH patients (n = 45) indicating higher visceral sensitivity compared to 85.7 ± 2.0 pts in the control group (n = 31, P < 0.001). Furthermore, a significant difference in VSI was found between the FH (60.8 ± 23.3 pts, n = 59, P < 0.001) and between the NERD (61.9 ± 20.8 pts, n = 67, P < 0.001) both compared to the control group. The HADS also displayed a significant difference between the RH (11.9 ± 6.0 pts, P < 0.001), FH (11.0 ± 7.4 pts, P < 0.001), respectively, NERD (11.3 ± 8.9 pts, P < 0.001) as compared to the control group (2.0 ± 1.4 pts). CONCLUSIONS AND INFERENCES: Increased sensation to visceral stimuli as well as anxiety and depression appears to play an important role not only in reflux hypersensitivity and functional heartburn as defined by Rome IV but also in NERD. These findings are in line with the disease concept of disorders of gut-brain interaction in which psychological comorbidities and visceral hypersensitivity play a major role.