The Lyon Consensus provides conclusive criteria for and against the diagnosis of gastro-oesophageal reflux disease (GERD), and adjunctive metrics that consolidate or refute GERD diagnosis when primary criteria are borderline or inconclusive. An international core and working group was assembled to evaluate research since publication of the original Lyon Consensus, and to vote on statements collaboratively developed to update criteria. The Lyon Consensus 2.0 provides a modern definition of actionable GERD, where evidence from oesophageal testing supports revising, escalating or personalising GERD management for the symptomatic patient. Symptoms that have a high versus low likelihood of relationship to reflux episodes are described. Unproven versus proven GERD define diagnostic strategies and testing options. Patients with no prior GERD evidence (unproven GERD) are studied using prolonged wireless pH monitoring or catheter-based pH or pH-monitoring off antisecretory medication, while patients with conclusive GERD evidence (proven GERD) and persisting symptoms are evaluated using pH-impedance monitoring while on optimised antisecretory therapy. The major changes from the original Lyon Consensus criteria include establishment of Los Angeles grade B oesophagitis as conclusive GERD evidence, description of metrics and thresholds to be used with prolonged wireless pH monitoring, and inclusion of parameters useful in diagnosis of refractory GERD when testing is performed on antisecretory therapy in proven GERD. Criteria that have not performed well in the diagnosis of actionable GERD have been retired. Personalisation of investigation and management to each patient's unique presentation will optimise GERD diagnosis and management.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Up to 50% of patients with reflux symptoms do not manifest a satisfactory symptom response to proton pump inhibitor (PPI) therapy. Our primary aim in this study was to identify factors associated with symptom perception among PPI non-responder phenotypes.This prospective observational cohort study was performed from September 2014 to January 2017 at a single academic medical center and included PPI non-responders who underwent 24-h impedance-pH monitoring and completed a questionnaire set measuring patient-reported symptom severity, quality of life (QOL), and psychosocial distress. Participants were separated into cohorts based on impedance-pH results: on PPI: -acid exposure time (AET)/-symptom-reflux association (SRA), +AET, and -AET/+SRA; off PPI: functional (-AET/-SRA), gastroesophageal reflux disease (GERD) (+AET), and reflux hypersensitivity (RHS) (-AET/+SRA). The primary outcome was abnormal GERD symptom severity defined by GerdQ≥8.One hundred and ninety-two participants were included. Impedance-pH on PPI was performed on 125: 72 (58%) -AET/-SRA, 42 (34%) +AET, and 11 (9%) -AET/+SRA. Among the -AET/-SRA group, younger age, higher dysphagia scores, QOL impairment, and higher brief symptom index were associated with GerdQ≥8. Among the +AET group, higher number of reflux-associated symptoms and lower distal contractile integral was associated with GerdQ≥8. Impedance-pH off PPI was performed on 67 participants: 39 (58%) functional, 16 (24%) GERD, and 12 (18%) RHS. Among the functional group, higher QOL impairment and dysphagia scores were seen with GerdQ≥8.Perceptions of reflux symptoms are associated with psychosocial distress, reduced QOL, and sensation of dysphagia among PPI non-responders with normal impedance-pH. Among PPI refractory GERD patients, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors.

Visual Analog Scales (VAS) are simple, easy for patients to comprehend, and require limited translation. We evaluated the value of esophageal global symptom severity (GSS) measured using VAS in assessing initial reflux symptom burden as compared with other validated questionnaires, esophageal symptom burden, and outcome after reflux management.

Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.

Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, the degree to which the shared genetic determinants are involved in these associations underlying the GBA is unclear.

We aimed to evaluate the prevalence of irritable bowel syndrome (IBS) in patients with typical reflux symptoms as distinguished into gastroesophageal reflux disease (GERD), hypersensitive esophagus (HE), and functional heartburn (FH) by means of endoscopy and multichannel intraluminal impedance (MII)-pH monitoring. The secondary aim was to detect pathophysiological and clinical differences between different sub-groups of patients with heartburn.Patients underwent a structured interview based on questionnaires for GERD, IBS, anxiety, and depression. Off-therapy upper-gastrointestinal (GI) endoscopy and 24 h MII-pH monitoring were performed in all cases. In patients with IBS, fecal calprotectin was measured and colonoscopy was scheduled for values >100 mg/kg to exclude organic disease. Multivariate logistic regression analysis was performed to identify independent risk factors for FH.Of the 697 consecutive heartburn patients who entered the study, 454 (65%) had reflux-related heartburn (GERD+HE), whereas 243 (35%) had FH. IBS was found in 147/454 (33%) GERD/HE but in 187/243 (77%) FH patients (P<0.001). At multivariate analysis, IBS and anxiety were independent risk factors for FH in comparison with reflux-related heartburn (GERD+HE).IBS overlaps more frequently with FH than with GERD and HE, suggesting common pathways and treatment. HE showed intermediate characteristic between GERD and FH.

Symptoms are inconsistently associated with esophageal motor findings on high-resolution manometry (HRM). We aimed to evaluate predictors of dysphagia severity, including esophageal hypervigilance and visceral anxiety, among patients evaluated with HRM.Adult patients undergoing HRM at 4 academic medical centers (United States and France) were prospectively evaluated. HRM was completed and analyzed per the Chicago Classification v3.0. Validated symptom scores, including the Brief Esophageal Dysphagia Questionnaire and Esophageal Hypervigilance and Anxiety Scale, were completed at the time of HRM.Two hundred thirty-six patients, aged 18-85 (mean 53) years, 65% female, were included. Approximately 59 (25%) patients had a major motor disorder on HRM: 19 achalasia, 24 esophagogastric junction outflow obstruction, 12 absent contractility, and 4 jackhammer. Approximately 177 (75%) patients did not have a major motor disorder: 71 ineffective esophageal motility and 106 normal motility. Having a major motor disorder was a significant predictor of dysphagia severity (Radj = 0.049, P < 0.001), but the Esophageal Hypervigilance and Anxiety Scale score carried a predictive relationship of Brief Esophageal Dysphagia Questionnaire that was 2-fold higher than having a major motor disorder: Radj = 0.118 (P < 0.001). This finding remained when evaluated by the major motor disorder group. HRM metrics were nonsignificant.In a prospective, international multicenter study, we found that esophageal hypervigilance and visceral anxiety were the strongest predictors of dysphagia severity among patients evaluated with HRM. Thus, an assessment of esophageal hypervigilance and visceral anxiety is important to incorporate when evaluating symptom severity in clinical practice and research studies.

Gastroesophageal reflux disease is an important and increasingly common condition. Both overweight and high fat food consumption have been implicated as causes of reflux disease. We examined the relationship of overweight, high dietary fat intake, and other factors with reflux disease hospitalization.We studied participants in the first National Health and Nutrition Examination Survey, a population-based sample examined in 1971-75 and followed through 1992-93. Persons with a physician-diagnosed hiatal hernia at baseline or reflux disease hospitalization within the first five years of study were excluded. A second analysis included follow-up of 9851 participants free of reflux disease in 1982-84. Ninety-six percent of the baseline cohort were recontacted. Reflux disease cases were persons hospitalized with a diagnosis of esophagitis or uncomplicated hiatal hernia. Hazard rate ratios for reflux disease hospitalization according to body mass index (BMI) (kg/m2), total daily servings of high fat foods and other factors were calculated using Cox proportional hazards analysis.A total of 12,349 persons were followed for a median of 18.5 years (range 5.0-22.1). Cumulative incidence of reflux disease hospitalization was 5.2% at 20 years. Multivariate survival analysis revealed higher reflux disease hospitalization rates with higher BMI (5 kg/m2) [hazard ratio (HR) = 1.22, 95% confidence interval (CI) = 1.13-1.32]. No relationship was found between higher fat intake and reflux disease hospitalization. Other factors associated with reflux disease hospitalization included age, low recreational activity, and history of doctor-diagnosed arthritis.Overweight, but not high dietary fat intake, increases risk of gastroesophageal reflux disease hospitalization.

<b>Introduction:</b> Acid suppression medications, such as proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists, are commonly prescribed for the treatment of gastroesophageal reflux disease and other gastrointestinal disorders. However, concerns regarding potential long-term side effects are brought up by the overuse of PPIs. This study aimed to investigate the relationship between PPI usage, allergy, and asthma in the general US population. <b>Methods:</b> Data of individuals aged ≥20 years who had information on PPI use and questionnaires on allergy and asthma in the US National Health and Nutrition Examination Survey (NHANES) 2005–2006 were analyzed. Univariate and multivariable logistic regression analyses were performed to determine the associations between PPI use, prevalent allergy, and asthma. <b>Results:</b> A total of 4,481 participants (representing 198,543,007 US individuals after weighting) were included in the analyses. PPI use was not significantly associated with the presence of allergy or asthma in the general study population after adjustment. However, in females without steroid exposure, PPI use was significantly associated with increased odds of allergy (adjusted odds ratio [aOR] = 1.69, 95% confidence interval [CI]: 1.002–2.86), among which esomeprazole use was significantly associated with increased odds of allergy (aOR = 2.68, 95% CI: 1.30–5.54) and lansoprazole with increased odds of asthma (aOR = 3.44, 95% CI: 1.50–7.87) as compared to no PPI use. Duration of PPI use was not significantly associated with allergy or asthma. <b>Conclusions:</b> In US women without steroid exposure, PPI use is associated with increased likelihood of prevalent allergy and asthma.

Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, the degree to which the shared genetic determinants are involved in these associations underlying the GBA is unclear.

In patients with non-erosive gastroesophageal reflux disease, heartburn can occur when acid reaches sensory nerve endings through oesophageal-mucosa-dilated intercellular spaces. Stressful life events may increase heartburn perception. In the rat, acute stress increases gastric and intestinal mucosa permeability. We investigated whether acute stress can also increase oesophageal mucosa permeability and contribute to the dilation of mucosa intercellular spaces.Male Sprague-Dawley rats were submitted to partial restraint stress. Oesophageal mucosa from stressed and control rats was mounted in diffusion chambers. The permeability to (51)Cr-EDTA (400 Da), fluorescein isothiocyanate (FITC)-dextran 4000 Da (FD4) and FITC-dextran 20 000 Da (FD20) was assessed after tissue incubation either with Krebs (control) or HCl pH 2.0+ pepsin 1 mg/ml. The diameter of intercellular spaces was assessed using transmission electron microscopy.Acute stress increased faecal output, small-intestinal permeability and glycaemia. Exposure of oesophageal mucosa from control rats to acid-pepsin did not increase permeability to any of the tested molecules. Stress increased the number of submucosal mast cells and, by itself, increased the permeability to the smallest molecule (22.8+/-7.1 pmol/cm(2) vs 5.8+/-2.1 pmol/cm(2)) (p<0.001). Exposure of mucosa from stressed rats to acid-pepsin significantly increased permeability to all molecules tested. Electron microscopy showed dilated intercellular spaces only in mucosa from stressed rats (with and without exposure to acid-pepsin).Acute stress can increase, by itself, oesophageal mucosa permeability. There is a potentiation between stress and exposure of the oesophageal mucosa to acid-pepsin, leading to increased permeability and dilated intercellular spaces.

Studies have demonstrated that gastroesophageal reflux disease (GERD) can cause sleep deprivation because of nighttime heartburn or short, amnestic arousals during sleep. Sleep deprivation has been associated with reports of increased GERD severity. Our aim was to determine whether sleep deprivation enhances perception of intraesophageal acid in patients with GERD vs healthy controls.Ten healthy controls and 10 patients with erosive esophagitis (grades B-D) were included in the study. All subjects were randomized to either sleep deprivation (1 night with </=3 hours of sleep) or sufficient sleep (3 days with >/=7 hours sleep/night). Patients crossed over to the other arm after a washout period of 1 week. To ensure proper sleep time, we objectively monitored subjects with an actigraph. The morning after sufficient sleep or sleep deprivation, patients underwent stimulus response functions to esophageal acid perfusion.Ten healthy controls and 10 GERD patients completed all stages of the study. GERD patients demonstrated a significant decrease in lag time to symptom report (91 +/- 21.6 vs 282.7 +/- 67 sec, respectively, P =.02), increase in intensity rating (9.3 +/- 1.4 vs 4.4 +/- 0.9 cm, respectively, P =.02), and increase in acid perfusion sensitivity score (48.3 +/- 8.5 vs 22.7 +/- 4.5 sec x cm/100, respectively, P =.02) after sleep deprivation as compared with nights of good sleep. Normal subjects did not demonstrate any differences in stimulus response functions to acid between sufficient sleep and sleep deprivation (578 +/- 164 vs 493.8 +/- 60.3 sec, 0.3 +/- 0.2 vs 0.45 +/- 0.2 cm, and 0.4 +/- 0.3 vs 2.4 +/- 1.4 sec x cm/100, respectively, all P = NS).Sleep deprivation is hyperalgesic in patients with GERD and provides a potential mechanism for increase in GERD symptom severity in sleep-deprived patients.

Functional esophageal disorders (functional chest pain, functional heartburn, reflux hypersensitivity, globus, and functional dysphagia) are the disorders of gut‐brain interactions (DGBI) and present with esophageal symptoms not associated with a structural, major motility or underlying inflammatory condition. Notably, many patients with the latter conditions may still experience esophageal symptoms beyond what could be attributed to their underlying disorders. Esophageal visceral hypersensitivity and hypervigilance are the two pathways which drive functional esophageal disorders and symptoms. These functional esophageal symptoms may be severe, leaving patients with impaired quality of life and inadequate treatment outcomes. Neuromodulators are the foundation of the pharmacologic approach of many of the functional esophageal disorders and symptoms, modulating both peripheral and central hyperalgesia. There is also emerging evidence for brain‐gut behavioral therapies (BGBT) such as gut‐directed hypnotherapy and cognitive behavior therapy for the treatment of a variety of DGBIs. In this issue of Neurogastroenterology and Motility, Hurtte et al. add to the literature on the effectiveness of BGBT in treating functional esophageal symptoms, showing multimodal therapy with pharmacologic and non‐pharmacologic approaches led to improvement in health‐related quality of life. In this review, we outline the mechanistic underpinnings of BGBT and review the existing evidence for BGBT for functional esophageal disorders and symptoms. We also highlight the future research directions and challenges for scaling these therapies.

There is a need to identify factors outside of abnormal reflux that contribute to gastroesophageal reflux disease (GERD). Esophageal hypervigilance is a psychological process impacting symptom experience in esophageal disease. However, little is known about the presence of hypervigilance in GERD phenotypes, especially in those with abnormal acid exposure or symptom index scores. The primary aim was to assess differences in self‐reported esophageal hypervigilance across different GERD presentations. The secondary aim was to evaluate esophageal hypervigilance as a predictor of symptom severity.

Up to 50% of patients with reflux symptoms do not manifest a satisfactory symptom response to proton pump inhibitor (PPI) therapy. Our primary aim in this study was to identify factors associated with symptom perception among PPI non-responder phenotypes.This prospective observational cohort study was performed from September 2014 to January 2017 at a single academic medical center and included PPI non-responders who underwent 24-h impedance-pH monitoring and completed a questionnaire set measuring patient-reported symptom severity, quality of life (QOL), and psychosocial distress. Participants were separated into cohorts based on impedance-pH results: on PPI: -acid exposure time (AET)/-symptom-reflux association (SRA), +AET, and -AET/+SRA; off PPI: functional (-AET/-SRA), gastroesophageal reflux disease (GERD) (+AET), and reflux hypersensitivity (RHS) (-AET/+SRA). The primary outcome was abnormal GERD symptom severity defined by GerdQ≥8.One hundred and ninety-two participants were included. Impedance-pH on PPI was performed on 125: 72 (58%) -AET/-SRA, 42 (34%) +AET, and 11 (9%) -AET/+SRA. Among the -AET/-SRA group, younger age, higher dysphagia scores, QOL impairment, and higher brief symptom index were associated with GerdQ≥8. Among the +AET group, higher number of reflux-associated symptoms and lower distal contractile integral was associated with GerdQ≥8. Impedance-pH off PPI was performed on 67 participants: 39 (58%) functional, 16 (24%) GERD, and 12 (18%) RHS. Among the functional group, higher QOL impairment and dysphagia scores were seen with GerdQ≥8.Perceptions of reflux symptoms are associated with psychosocial distress, reduced QOL, and sensation of dysphagia among PPI non-responders with normal impedance-pH. Among PPI refractory GERD patients, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors.

With the widespread use of proton pump inhibitors (PPIs), the frontier of treating reflux disease has shifted from refractory esophagitis to PPI‐refractory symptoms. However, symptoms are inherently less specific than mucosal disease and, as noted by Herregods et al. in their contribution appearing in this issue of Neurogastroenterology and Motility, patients with refractory gastroesophageal reflux disease (GERD) symptoms often do not have GERD. This review discusses potential etiologies for PPI‐refractory symptoms. Three major concepts are explored: subendoscopic esophagitis, weakly acidic reflux events, and alternative explanations for persistent symptoms. With respect to subendoscopic esophagitis and unsuppressed reflux, ample evidence exists that these are present in PPI‐refractory patients. The problem is that these findings are also often present in substantial numbers of individuals with a satisfactory response to PPI therapy. Hence, the emphasis shifts to determinants of symptom perception. The major conclusion of the review is that psychogenic factors such as hyperalgesia, allodynia, hypervigilance, and heightened anxiety are the most plausible explanations as the dominant determinants of PPI‐refractory symptoms.

Oesophageal hypervigilance and anxiety can drive symptom experience in chronic oesophageal conditions, including gastro‐oesophageal reflux disease, achalasia and functional oesophageal disorders. To date, no validated self‐report measure exists to evaluate oesophageal hypervigilance and anxiety.

The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.Copyright © 2021 Elsevier Inc. All rights reserved.

Laryngopharyngeal reflux (LPR) is a clinical conundrum without a diagnostic gold standard. The Esophageal Hypervigilance and Anxiety Scale (EHAS) is a questionnaire designed for cognitive-affective evaluation of visceral sensitivity. We hypothesized that esophageal hypervigilance and symptom-specific anxiety have an etiopathological role in generation of LPR symptoms, especially when gastroesophageal reflux disease (GERD) cannot explain these symptoms.

Positive symptom association probability (SAP) with physiologic esophageal acid exposure time (AET) on pH‐impedance monitoring defines reflux hypersensitivity (RH), a correlate of acid sensitivity on pH monitoring. We evaluated prevalence, clinical characteristics, and symptomatic outcomes of RH in a prospective observational cohort with reflux symptoms undergoing pH‐impedance monitoring.

Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.

BEST PRACTICE ADVICE 1: A diagnosis of functional heartburn should be considered when retrosternal burning pain or discomfort persists despite maximal (double-dose) proton pump inhibitor (PPI) therapy taken appropriately before meals during a 3-month period. BEST PRACTICE ADVICE 2: A diagnosis of functional heartburn requires upper endoscopy with esophageal biopsies to rule out anatomic and mucosal abnormalities, esophageal high-resolution manometry to rule out major motor disorders, and pH monitoring off PPI therapy (or pH-impedance monitoring on therapy in patients with proven gastroesophageal reflux disease [GERD]), to document physiologic levels of esophageal acid exposure in the distal esophagus with absence of reflux-symptom association (ie, negative symptom index and symptom association probability). BEST PRACTICE ADVICE 3: Overlap of functional heartburn with proven GERD is diagnosed according to Rome IV criteria when heartburn persists despite maximal PPI therapy in patients with history of proven GERD (ie, positive pH study, erosive esophagitis, Barrett's esophagus, or esophageal ulcer), and pH impedance testing on PPI therapy demonstrates physiologic acid exposure without reflux-symptom association (ie, negative symptom index and symptom association probability). BEST PRACTICE ADVICE 4: PPIs have no therapeutic value in functional heartburn, the exception being proven GERD that overlaps with functional heartburn. BEST PRACTICE ADVICE 5: Neuromodulators, including tricyclic antidepressants, selective serotonin reuptake inhibitors, tegaserod, and histamine-2 receptor antagonists have benefit as either primary therapy in functional heartburn or as add-on therapy in functional heartburn that overlaps with proven GERD. BEST PRACTICE ADVICE 6: Based on available evidence, acupuncture and hypnotherapy may have benefit as monotherapy in functional heartburn, or as adjunctive therapy combined with other therapeutic modalities. BEST PRACTICE ADVICE 7: Based on available evidence, anti-reflux surgery and endoscopic GERD treatment modalities have no therapeutic benefit in functional heartburn and should not be recommended.Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.