ObjectiveGastroesophageal reflux disease comprises heterogeneous phenotypes, and symptom severity does not always correlate with endoscopic findings. This retrospective observational study aimed to characterize serum proteomic alterations in gastroesophageal reflux disease and to explore whether nonerosive reflux disease and reflux esophagitis exhibit distinct circulating protein signatures.MethodsSeventy individuals were included, comprising 26 controls, 14 patients with nonerosive reflux disease, and 30 with reflux esophagitis. For exploratory group-level proteomic discovery, pooled serum samples from each group were analyzed using liquid chromatography-tandem mass spectrometry. Clinical characteristics, upper gastrointestinal endoscopy, high-resolution manometry, and 24-h pH-impedance monitoring were assessed as appropriate. Differentially expressed proteins were identified using a fold change threshold of 1.3 together with nominal statistical significance, followed by functional annotation and enrichment analyses.ResultsAge and sex were comparable among the groups. Nonerosive reflux disease and reflux esophagitis showed no significant differences in gastroesophageal reflux disease questionnaire score, disease duration, body mass index, or most reflux-monitoring parameters. However, patients with reflux esophagitis had more gas reflux episodes, lower distal contractile integral values, and a higher frequency of esophageal motility disorders, suggesting impaired motor function. Proteomic profiling identified 872 proteins, including 666 quantified proteins. Differential expression analysis identified 48 proteins in nonerosive reflux disease versus controls, 43 in reflux esophagitis versus controls, and 7 in nonerosive reflux disease versus reflux esophagitis. The exploratory nonerosive reflux disease-associated protein profile was mainly characterized by cytoskeletal remodeling, adhesion-related regulation, redox adaptation, and selective immune rearrangement, whereas the exploratory reflux esophagitis-associated profile showed features related to actin remodeling, injury-defense responses, and alterations in lipid homeostasis.ConclusionsNonerosive reflux disease and reflux esophagitis exhibited distinct but partially overlapping serum proteomic profiles in this exploratory pooled serum analysis. These preliminary findings suggest phenotype-related biological differences beyond reflux burden alone; however, they should be interpreted as hypothesis-generating and require validation in independent, individual-level cohorts.

Idiopathic achalasia is a rare esophageal motility disorder characterized by the selective degeneration of inhibitory myenteric neurons. Its genetic basis remains poorly defined. We investigated whether rare coding variants may contribute to disease susceptibility. Exome sequencing was performed in 31 individuals with idiopathic achalasia and seven unaffected relatives. Candidate variants were prioritized using phenotype-driven filtering and assessed through in silico and structural analysis of publicly available gene expression and single-cell transcriptomic datasets. No pathogenic or likely pathogenic variants were identified in achalasia-associated genes. A gene-agnostic analysis identified two rare heterozygous missense variants in unrelated patients: AFG3L2 c.2105G>A (p.Arg702Gln) and POLG c.1760C>T (p.Pro587Leu). Both genes encode mitochondrial proteins involved in neuronal homeostasis. The variants affected conserved residues, mapped to functionally relevant protein regions, and were predicted by multiple computational approaches to affect protein stability and function. Both genes were highly expressed in esophageal tissue, with AFG3L2 showing enrichment in enteric neuronal populations. These exploratory findings support a potential link between mitochondrial dysfunction, enteric neurodegeneration, and idiopathic achalasia. Rare mitochondrial-related variants may contribute to disease susceptibility in selected individuals by increasing vulnerability of inhibitory enteric neurons, although functional validation and larger studies are required. Accordingly, our findings should be considered hypothesis-generating rather than evidence of causality.

Transnasal esophagogastroscopy (TNE) may provide clinically relevant information on gastroesophageal junction morphology in patients with globus sensation and reflux disease. This prospective single-arm interventional cohort study with a pre-post design evaluated the association between TNE findings and treatment response in patients with objectively confirmed reflux disease. Ninety-two patients with globus sensation underwent dual-probe pH monitoring; reflux disease was detected in 59 patients. These patients underwent TNE and completed the German version of the Glasgow Edinburgh Throat Scale (GETS-G) before and after 12 weeks of antireflux treatment. Pathological TNE findings were identified in 25 patients, with sliding hiatal hernia being the most frequent abnormality (18 patients). The mean GETS-G score decreased significantly from 38.5 ± 7.1 to 24.0 ± 8.1 after treatment. Using the ≥ 20% GETS-G reduction threshold, 48 of 59 patients met the study-defined response criterion. Sliding hiatal hernia was not significantly associated with reflux subtype but was independently associated with poorer symptom improvement. Hill grades I-II were associated with greater improvement than Hill grades III-IV. Endoscopic assessment of hiatal hernia and Hill classification may support individualized management of reflux-associated globus sensation.

Gastroesophageal reflux disease (GERD) is implicated as a potential cause of chronic laryngopharyngeal symptoms, including laryngitis, cough, dysphonia, and throat clearing, often grouped under laryngopharyngeal reflux (LPR). This study aimed to assess the predictive value of clinical and demographic factors for GERD in patients with LPR symptoms using multichannel intraluminal impedance-pH monitoring. Analytical cross-sectional study of 2688 adults with upper airway symptoms and suspected LPR undergoing pH-impedance monitoring between January 2019 and December 2022. Pathological GERD was defined as acid exposure time (AET) >6%, or AET 4%-6% with abnormal reflux parameters (total reflux events >80 and/or positive symptom association). Proximal reflux episodes were recorded but not used diagnostically. Multivariable logistic regression analyses identified independent predictors. Among 2688 patients (73.6% female; mean age 54.5 years), only 8.4% had pathological GERD. Independent predictors included higher body mass index, male sex, older age, heartburn, and hiatal hernia. The final model demonstrated moderate discrimination area under the curve (AUC) 0.676. Only a small proportion of patients with suspected LPR have objective GERD. Pathological reflux is better predicted by traditional GERD-related factors than by isolated laryngopharyngeal symptoms, supporting a more cautious interpretation of LPR and consideration of alternative diagnoses.

A 96-hour ambulatory pH testing is a practical tool for diagnosing gastroesophageal reflux disease (GERD) and for concurrently evaluating two conditions: dietary variation and its effect on measured acid exposure time (AET) and reported symptoms. To date, it is unknown how consuming a diet of either low or high acidity can influence pathologic GERD. This study aimed to assess the effects of high- and low-acid diets on AET and the occurrence of laryngopharyngeal symptoms (LPS) during prolonged wireless pH monitoring. A retrospective review of 208 patients who underwent 96-hour wireless pH monitoring for GERD evaluation was completed. Patients consumed a primarily high-acid diet on 1 day and a primarily low-acid diet on a separate day during the 96-hour period. Patients were considered to have pathologic GERD if esophageal AET was >6% for the time with pH <4, and were considered normal on an individual day if the AET was <4%. Pathologic GERD was found in 78 patients (37.5%), of whom the majority (55%) recorded their lowest AET during the study on their low-acid day. Only 24.7% achieved normal AET on a low-acid diet day. Mean AET on a high-acid diet, compared with a low-acid diet, decreased by 41%, from 12.51 to 7.33, with a similarly proportional decrease in patients negative for GERD. There was no significant difference between patients with and without LPS with regard to esophageal acid exposure on high- and low-acid diet days (P = 0.73, P = 0.81). A low-acid diet may be a viable lifestyle modification when used as monotherapy or adjunctively with proton pump inhibitor in patients with or without pathologic GERD.

Esomeprazole, a proton pump inhibitor (PPI), is widely approved for gastroesophageal reflux disease (GERD) in adults and pediatrics globally, but prior to December 2022, its oral tablets (20 and 40 mg) were approved only for adults in China. To address unmet needs in Chinese adolescents aged 12-17 years, physiologically based pharmacokinetic (PBPK) modeling was employed to extrapolate data and support label extension, leveraging similarities in GERD pathophysiology and PK/PD relationships across ages and ethnicities. A PBPK model was developed for esomeprazole to capture the enteric-coated formulation's pharmacokinetics. The model was validated against clinical PK studies in Caucasian, Japanese, and Chinese adults and/or adolescents, demonstrating good predictions of concentration-time profiles and area under the curve (AUC) for CYP2C19-specific genotypes as well as overall populations across these ethnic groups. All predicted-to-observed ratios for AUC fell within 0.5- to 2.0-fold, with 14 out of 18 predictions within the 0.67- to 1.5-fold. This robust validation enabled the model's application to predict PK in Chinese adolescents. PBPK predictions for Chinese adolescents indicated that steady-state AUC for 20- and 40-mg doses was comparable to that in Japanese adolescents and slightly higher than in Caucasian adolescents. By integrating an established PK/PD relationship between AUC and the percentage of time with intragastric pH >4, once-daily doses of 20 or 40 mg were justified, achieving adequate acid suppression with a favorable safety profile. This PBPK-informed extrapolation was accepted by China's National Medical Products Administration (NMPA), enabling GERD indication extension to adolescents.

Peroral endoscopic myotomy (POEM) is an effective and safe treatment for achalasia, but short-term follow-up studies suggest an increased risk of gastroesophageal reflux after treatment. The aim of this study was to evaluate the risk of reflux esophagitis and the long-term complications in achalasia patients more than 5 years after POEM. This prospective cohort study included achalasia patients who underwent POEM between August 2011 and December 2019 and were scheduled for follow-up upper gastrointestinal endoscopy at least five years after treatment. Multivariate regression was used to assess predictive factors for reflux esophagitis after POEM. In total 161 achalasia patients were included of whom 153 completed questionnaires. Median age at follow-up was 56 years and 49.7% were female. Reflux esophagitis was diagnosed in 67 patients (41.6%, 95%-CI 34.0%-49.2%), with 22 of these cases classified as severe (grade C/D, 32.8%). Prior laparoscopic Heller myotomy (OR 0.44, 95%-CI 0.20-0.98) and retreatment with PD (OR 0.36, 95%-CI 0.17-0.75) were associated with lower observed rates of reflux esophagitis. Factors associated with severe reflux esophagitis (grade C/D) included BMI (OR 1.13, 95%-CI 1.04-1.23) and PD after POEM (OR 0.12, 95%-CI 0.02-0.93). Barrett esophagus was observed in five patients (3.1%). Peptic strictures were seen in three patients (1.9%) necessitating dilation and no cases of esophageal adenocarcinoma were identified. Reflux esophagitis remains a common long-term finding in achalasia patients more than 5 years after POEM and is classified as severe in nearly one-third of these cases.

Patient-healthcare provider communication is optimized when patients' goals, preferences, and values are at the forefront of the communication. Traditional communication styles, however, often meant providers unilaterally made medical decisions without the cooperation of patients' preferences into medical decision making. This communication style in which patients are at the center of decision making and actively partake and think about their care is referred to as shared decision making. Engaging in shared decision making requires the provider to seek the patients' goals, preferences, and values from the beginning, before presenting treatment options, particularly in gastroesophageal reflux disease (GERD) management. Therefore the 'one size fits all' approach no longer applies when applying shared decision making. We aim to present three key elements when applying shared decision making in GERD clinical management, with the emphasis on: (1) effective communication, (2) patient autonomy, and (3) customized approach.

High-resolution manometry (HRM), the gold standard for diagnosing esophageal motility disorders, remains constrained by inter-rater variability, limited access to expert esophagologists, and inadequate training infrastructure. Many gastroenterology fellowship programs provide insufficient motility training, and dedicated expert centers remain geographically concentrated. Emerging Artificial intelligence (AI) tools have the potential to automate diagnosis, and augment clinician interpretive capacity and democratizing expert-level motility assessment.