Functional Heartburn Research Articles

Personalized diagnosis of patients with gastroesophageal reflux disease using 24-hour pH-impedance testing and high-resolution esophageal manometry

To determine the phenotypic variants of patients with symptoms of gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), hypersensitive esophagus (HSE), functional heartburn (FH) using 24-hour pH-impedance testing and high-resolution esophageal manometry (HSEM). Fifty-five treatment-native symptomatic patients with newly diagnosed GERD and 48 control group subjects (CG) were examined. The mean age of the subjects was 45.0 years (95% confidence interval [CI] 41.0-48.9). Patients were grouped based on typical symptoms (heartburn, belching, regurgitation, odynophagy, dysphagia), medical history, endoscopy results, and 24-hour pH-impedance testing. Patients with typical symptoms of GERD and Grade B, C, D erosive esophagitis (EE) according to the Los Angeles Classification (LA) based on endoscopy were excluded from the further study. All patients without changes in the esophageal mucosa on endoscopy or with LA grade A EE (presumably NERD) underwent 24-hour pH-impedance testing and HSEM without proton pump inhibitors. Acid exposure, acid reflux count, symptom association with reflux (with symptom index and symptom association with reflux), mean nocturnal impedance, and post-reflux swallow-induced peristaltic wave index were assessed. The structure (presence or absence of a hiatal hernia) and function (presence or absence of the lower esophageal sphincter hypotonia) of the esophagogastric junction, as well as the motor function of the thoracic esophagus, were assessed using HSEM. The results of the HSEM were interpreted according to the Chicago Classification, 3rd edition (2015). The number of acid refluxes in patients with NERD was 71.0 (95% CI 58.4-83.7), in subjects with HSE - 38.5 (95% CI 28.3-49.0), with FH - 13.0 (95% CI 6.5-18.2), in CG - 16.5 (95% CI 9.0-21.0). The average nocturnal basal impedance was 1300 ohms (95% CI 1000-1986) in patients with NERD, 1725 ohms (95% CI 1338-2261) in patients with HSE, 2760 ohms (95% CI 2453-3499) in FH, 2515 ohms (95% CI 2283-2700) in CG. The index of post-reflux swallow-induced peristaltic wave in patients with NERD was 61% (95% CI 57-71), with HSE - 85% (95% CI 82-88), with FH - 71% (95% CI 64-78), in CG - 66% (95% CI 63-69). Hiatal hernia and/or hypotonia of the LES were more common in patients with NERD (23%) than in CG (13.3%). Ineffective motility was detected in 34% of patients with NERD, in 23% of subject with FH and in 66.7% of patients with HSE. The results support the hypothesis that patients with GERD symptoms represent a heterogeneous population. 24-hour pH-impedance testing and HSEM helps to differentiate endoscopically negative patients with GERD symptoms and patients with Grade A EE by LA to NERD, HSE and FH.

Functional Heartburn and Chest Pain: A Review of Esophageal Neuromodulation

Functional Heartburn and Chest Pain: A Review of Esophageal Neuromodulation

Spectrum of esophageal manometry and 24-h pH impedance findings in non-erosive gastroesophageal reflux disease and response to phenotype-based treatment-A prospective observational study.

Gastroesophageal reflux disease (GERD) is classified into erosive reflux disease (ERD) and non-erosive reflux disease (NERD). NERD includes three phenotypes: true NERD, functional heartburn (FH) and reflux hypersensitivity (RH). The management of these NERD phenotypes differs. We aimed at studying the spectrum of high-resolution manometry (HRM) and 24-hour impedance-pH findings in Indian patients with NERD, classifying the phenotypes and assessing the response to phenotype-based treatment. We prospectively studied the clinical characteristics, endoscopy, HRM, 24-hour impedance-pH findings, symptom association and response to phenotype-specific treatment in patients with NERD. Of 53 patients with NERD, the following phenotypes were diagnosed namely: 35(66%) true NERD, 12(22.7%) RH and six(11.3%) FH. The esophagogastric junction-contractile integral (EGJ-CI) was low in 60.4% and ineffective esophageal motility (IEM) was present in 53% of patients. The respective median values for true NERD, RH and FH groups were as follows: proximal mean nocturnal baseline impedance (P-MNBI) 2250Ω, 2241Ω, 2550Ω, (p = 0.592), distal (D-MNBI) 1431Ω, 2887.5Ω, 2516Ω (p < 0.001), post-reflux swallow-induced peristaltic wave index (PSPWI) 11.1%, 16%, 18.7% (p = 0.127). Receiver operating characteristic (ROC) curve analyses showed that D-MNBI and PSPWI discriminated FH and RH from true NERD, respectively, with a cut-off of 2376.5Ω (area under curve [AUC]:0.919, p < 0.001), 22.6% (AUC:0.671, p = 0.184) and 2318Ω (AUC:0.919, p = < 0.001), 16.2%(AUC:0.671, p = 0.079). The median P-MNBI was lower in patients with GERD-associated cough than other symptoms 1325 (1250, -). Fifty (94.3%) patients showed significant improvement in symptom severity scores (p < 0.001) following phenotype-specific treatment. In NERD patients, EGJ-CI and IEM were low. D-MNBI and PSPWI could effectively discriminate true NERD from FH and RH, whereas P-MNBI could help diagnose GERD-associated cough. The phenotype-specific treatment provides better symptom relief for patients.

Mean nocturnal baseline impedance in gastro-esophageal reflux disease diagnosis: Should we strictly follow the Lyon 2 Consensus?

Clinical practice guidelines drive clinical practice and clinicians rely to them when trying to answer their most common questions. One of the most important position papers in the field of gastro-esophageal reflux disease (GERD) is the one produced by the Lyon Consensus. Recently an updated second version has been released. Mean nocturnal baseline impedance (MNBI) was proposed by the first Consensus to act as supportive evidence for GERD diagnosis. Originally a cut-off of 2292 Ohms was proposed, a value revised in the second edition. The updated Consensus recommended that an MNBI < 1500 Ohms strongly suggests GERD while a value > 2500 Ohms can be used to refute GERD. The proposed cut-offs move in the correct direction by diminishing the original cut-off, nevertheless they arise from a study of normal subjects where cut-offs were provided by measuring the mean value ± 2SD and not in symptomatic patients. However, data exist that even symptomatic patients with inconclusive disease or reflux hypersensitivity (RH) show lower MNBI values in comparison to normal subjects or patients with functional heartburn (FH). Moreover, according to the data, MNBI, even among symptomatic patients, is affected by age and body mass index. Also, various studies have proposed different cut-offs by using receiver operating characteristic curve analysis even lower than the one proposed. Finally, no information is given for patients submitted to on-proton pump inhibitors pH-impedance studies even if new and extremely important data now exist. Therefore, even if MNBI is an extremely important tool when trying to approach patients with reflux symptoms and could distinguish conclusive GERD from RH or FH, its values should be interpreted with caution.

Utility of the Post-Reflux Swallow-Induced Peristaltic Wave Index and Mean Nocturnal Baseline Impedance for the Diagnosis of Gastroesophageal Reflux Disease Phenotypes in Children.

(1) Objectives: Assessment of novel impedance parameters such as the post-reflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) have been proposed to enhance the accuracy of gastroesophageal reflux disease (GERD) diagnosis. We aimed to evaluate the clinical value of MNBI and the PSPW index in discerning different phenotypes of GERD in children. (2) Methods: We conducted a prospective, observational study that included 49 children aged 5-18 years, referred for MII-pH monitoring due to negative endoscopy and persisting gastroesophageal reflux symptoms despite acid-suppressant treatment. The PSPW index and MNBI were assessed along with conventional metrics. (3) Results: Using a receiver operating characteristic (ROC) curve analysis, MNBI (AUC 0.864) and the PSPW index (AUC 0.83) had very good performance in differentiating between non-erosive reflux disease (NERD) and functional phenotypes. The PSPW index (AUC 0.87) discriminated better between functional heartburn (FH) and reflux hypersensitivity (RH) compared to the MNBI (AUC 0.712). A PSPW cut-off value of 65% provided a sensitivity of 76.9% and a specificity of 90% in distinguishing FH and RH. The PSPW index (AUC 0.87) proved to have better performance than the MNBI (AUC 0.802) in differentiating between FH and non-FH patients. MNBI diagnosed FH with a sensitivity of 84% and a specificity of 80.6% at a cut-off value of 2563 Ω. (4) Conclusions: The PSPW index and MNBI are useful to distinguish between GERD phenotypes in pediatric patients.

Prevalence of functional esophageal disorders and associated clinical characteristics in patients with proton-pump-inhibitor-unresponsive reflux symptoms.

Patients with proton-pump-inhibitor (PPI)-unresponsive reflux symptoms, often caused by functional esophageal disorders (FED), are frequently encountered in clinical practice. We aimed to investigate the prevalence of FED and its associated clinical characteristics in patients with PPI-unresponsive reflux symptoms. We retrospectively identified patients who were evaluated for persistent typical reflux symptoms, despite ≥8weeks of PPI treatment, at the National Taiwan University Hospital from 2014 to 2023. All patients underwent a comprehensive evaluation comprising validated gastroesophageal reflux disease (GERD) symptom questionnaires, 5-item Brief Symptom Rating Scale (BSRS-5), Pittsburgh Sleep Quality Index (PSQI), esophagogastroduodenoscopy, high-resolution impedance manometry, and 24-h impedance-pH monitoring off PPI therapy. Diagnosis of FED and non-erosive reflux disease (NERD) was based on the Rome IV criteria. We analyzed 190 patients [46.8% male, median age 52 (interquartile range, 42-61) years], of whom 32 (16.8%) had NERD and 158 (83.2%) had FED (57.9% with functional heartburn and 25.3% with reflux hypersensitivity). Patients with FED had a lower body mass index than those with NERD and a higher prevalence of psychological comorbidities and poor sleep quality than healthy volunteers. The severity of reflux symptoms among FED patients was significantly associated with the severity of psychological comorbidities and sleep quality. A notably high prevalence (83.2%) of FED was observed among patients experiencing PPI-unresponsive reflux symptoms. Patients with FED had a higher level of psychological distress and diminished sleep quality, both of which were associated with reflux symptom severity.

The Utility of Novel pH-Impedance Monitoring Parameters (PSPW Index and MNBI) in Pediatric Gastroesophageal Reflux Disease Phenotypes-A Systematic Review.

Background/Objectives: Researchers have proposed two novel impedance-pH parameters, mean nocturnal baseline impedance (MNBI) and the post-reflux swallow-induced peristaltic wave (PSPW) index, to enhance the diagnosis of gastroesophageal reflux disease (GERD) and enable better predictions of the effectiveness of anti-reflux therapies. This systematic review aims to synthesize the available evidence on the utility of the PSPW index and MNBI as diagnostic tools for pediatric GERD. Methods: A systematic search of studies reporting PSPW index and MNBI values in patients with GERD was performed in PubMed, Embase, Clarivate, Scopus, Cochrane and Google Scholar databases from their beginning until April 2024. The following terms were used: GERD, children, pediatric, PSPW and MNBI. Results: Eight studies were included, describing 479 patients ranging from 2 months to 17 years old over an 8-year period in 12 pediatric centers. Four studies demonstrated that children with pathological acid exposure have a significantly lower MNBI, with a good discriminatory ability to diagnose GERD. The PSPW index showed lower values in patients with reflux hypersensitivity (RH) compared to those with functional heartburn (FH). Conclusions: Patients with pathological acid exposure tend to exhibit lower MNBI and PSPW index values compared to those with normal acid exposure. MNBI and the PSPW index show promise as diagnostic tools in distinguishing between different GERD phenotypes. Further research is needed to establish standardized diagnostic criteria and optimize the clinical applicability in GERD diagnosis and management.

Diagnostic value associated with the combination of saliva pepsin and microorganisms in functional heartburn and gastroesophageal reflux disease.

Heartburn is a common symptom shared by both gastroesophageal reflux disease (GERD) and functional heartburn (FHB), which can make it challenging to differentiate between the two conditions. However, examining oral manifestations of GERD can be a cost-effective and readily available method to aid in this differentiation process. It may serve as a valuable tool in distinguishing GERD from FHB.

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

BackgroundVonoprazan, 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.MethodsThis 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.ResultsThe 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]).ConclusionPatients 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.

Risk factors associated with functional esophageal disorders (FED) versus gastroesophageal reflux disease (GERD).

Despite the high prevalence of typical symptoms of gastroesophageal reflux disease (GERD), approximately 30% of patients have functional esophageal disorders (FED) on ambulatory reflux monitoring, which may include reflux hypersensitivity (RH; defined as physiologic acid exposure but temporally correlated symptoms of reflux), or functional heartburn (FH; defined as physiologic acid exposure and negative symptom correlation). There are limited epidemiological data characterizing these conditions. We investigated demographic and socioeconomic factors as well as medical comorbidities which may predispose to FED versus pathologic GERD. Adult patients with reflux symptoms for at least 3months were studied with 24-h pH-impedance testing from 11/2019 to 3/2021. Participants were categorized into pathologic GERD, FH, or RH using pH-impedance data and reported symptom correlation. Demographic data, including age, gender, race/ethnicity, zip code, insurance status, and medical comorbidity data were retrospectively retrieved from the electronic medical record on all participants. 229 patients were included. Non-Hispanic Asian ethnicity (OR 5.65; p = 0.01), underweight BMI (OR 7.33; p = 0.06), chronic pain (OR 2.33; p < 0.01), insomnia (OR 2.83; p = 0.06), and allergic rhinitis (OR 3.90; p < 0.01) were associated with a greater risk for FED. Overweight BMI (OR 0.48; p = 0.03) and alcohol use (OR 0.57; p = 0.06) were associated with a decreased risk for FED. This is the first report of a greater risk of FED in patients with underweight BMI, insomnia, chronic pain, allergic rhinitis, or of Asian or Hispanic ethnicities. The weak associations between female gender and anxiety are corroborated in other studies. Our findings enable clinicians to better screen patients with reflux for this disorder.

Behavioral Therapy for Functional Heartburn: Recommendation Statements

Brain-gut behavior therapies (BGBT) are increasingly recognized as effective therapeutic interventions for functional heartburn. However, recommendations regarding candidacy for treatment, initial treatment selection, and navigating treatment non-response have not been established for functional heartburn specifically. The aim of this study was to establish expert-based recommendations for behavioral treatment in patients with functional heartburn. The validated RAND/University of California, Los Angeles Appropriateness Method was applied to develop recommendations. A 15-member panel composed of 10 gastrointestinal psychologists and 5 esophageal specialists ranked the appropriateness of a series of statements on a 9-point interval scale over 2 ranking periods. Statements were within the following domains: pre-therapy evaluation, candidacy criteria for BGBT, selection of initial BGBT, role of additional therapy for initial non-response to BGBT, and role of pharmacologic neuromodulation. The primary outcome was appropriateness of each intervention based on the recommendation statements. Recommendations for psychosocial assessment (eg, hypervigilance, symptom-specific anxiety, health-related quality of life), candidacy criteria (eg, motivated for BGBT, acknowledges the role of stress in symptoms), and treatment were established. Gut-directed hypnotherapy or cognitive behavioral therapy were considered appropriate BGBT for functional heartburn. Neuromodulation and/or additional BGBT were considered appropriate in the context of non-response. Gut-directed hypnotherapy and/or cognitive behavioral therapy are recommended as appropriate behavioral interventions for heartburn symptoms, depending on clinical indication, specific gut-brain targets, and preferred treatment modality (pharmacologic vs non-pharmacologic). Pre-therapy evaluation of psychosocial processes and candidacy for BGBT are important to determine eligibility for referral to psychogastroenterology services.

Prevalence, types, and risk factors of functional gastrointestinal diseases in Hainan Province, China

To investigate the prevalence, types, and risk factors of functional gastrointestinal diseases (FGIDs) in Hainan Province, China, in order to provide insights for future prevention and treatment strategies. A questionnaire survey was conducted from July 2022 to May 2023, using stratified sampling to sample local residents in five cities (20 townships) in Hainan Province. Out of 2057 local residents surveyed, 659 individuals (32.0%) reported experiencing at least one FGID. The most prevalent FGIDs were functional dyspepsia (FD) (10.7%), functional constipation (FC) (9.3%), irritable bowel syndrome (IBS) (6.8%), functional bloating (2.2%), belching disorder (2.2%), functional diarrhea (FDr) (1.5%), functional heartburn (1.5%), and fecal incontinence (0.98%). The study revealed significant associations between FGIDs and factors such as age, sleep quality, anxiety, smoking, alcohol consumption, and the consumption of pickled food (P < 0.05). Older age, poor sleep quality, anxiety, and the consumption of pickled food were identified as independent risk factors for the prevalence of FGIDs (P < 0.05). In Hainan Province, the overall prevalence of FGIDs was found to be 32.0%, with higher prevalences of FC and FD. Older age, poor sleep quality, anxiety, and the consumption of pickled food were identified as risk factors for FGIDs.

Функциональная изжога: проблемы диагностики и лечения

Введение. Функциональная изжога относится к широко распространенным заболеваниям желудочно-кишечного тракта. Для этой патологии характерна рефрактерная изжога, т. е. отсутствие ее купирования при оптимальном применении ингибиторов протонной помпы, что требует проведения дифференциальной диагностики с другими заболеваниями верхних отделов пищеварительного тракта. Функциональную изжогу связывают с частыми обращениями за медицинской помощью, необходимостью повторных обследований и, как следствие, увеличением страховых расходов. Однако существуют проблемы недостаточной информированности врачей о данном ззаболевании и отсутствия широкодоступного метода диагностики, что приводит к неэффективности лечения и снижению качества жизни пациентов. Болезнь нередко сопряжена с тревожными и депрессивными расстройствами, рост которых отмечается в последнее время, что требует своевременной диагностики и коррекции данных состояний. Ключевой частью патофизиологии функциональной изжоги является висцеральная гиперчувствительность, а психосоциальные факторы влияют на взаимодействия между нервной системой желудочно-кишечного тракта и головным мозгом, что определяет тяжесть симптомов у пациентов. Врачам рекомендуется подробно рассказывать пациентам о сути заболевания, направлениях возможного эффективного лечения для лучшей приверженности терапии, рекомендовано использование антидепрессантов, когнитивно-поведенческой терапии, гипнотерапии и методов релаксации. На данный момент стандартом диагностики функциональной изжоги является pН-импедансометрия с первичным исключением органической патологии при эндоскопическом исследовании пищевода со взятием биопсии и проведением гистологического исследования и исключением нарушений моторики пищевода при проведении манометрии. Необходимы неинвазивные, доступные и экономически эффективные диагностические инструменты, чтобы избежать гипердиагностики гастроэзофагеальной рефлюксной болезни и неправильного использования игибиторов протонной помпы, перспективно исследование пепсина слюны и обследование пациента у стоматолога. Цель работы. Обобщение данных проведенных исследований о распространенности функциональной изжоги, влиянии на ее течение психологических факторов, актуальных методах диагностики и лечения данной патологии. Чтобы выявить исследования, посвященные проблемам диагностики и лечения функциональной изжоги, был проведен поиск литературы в базах данных PubMed и eLibrary до ноября 2023 г., были просмотрены оригинальные статьи, метаанализы и соответствующие запросу обзоры. Background. Functional heartburn is one of the disorders of the gastrointestinal tract that is widespread in modern society. The disease is characterized by refractory symptoms of heartburn, lack of relief of symptoms with optimal use of proton pump inhibitors, which requires differential diagnosis with a number of diseases of the esophagus. Functional heartburn is associated with frequent medical treatment, repeated examinations, and increased insurance costs. At the same time, there is a problem of insufficient awareness of doctors about this disease, the lack of a widely available diagnostic method, which leads to a failure to receive effective treatment and a decrease in the quality of life of patients. The disease is often associated with anxiety and depressive disorders, the growth of which has been noted recently, which requires timely diagnosis and correction of these conditions. Visceral hypersensitivity is a key part of the pathophysiology of functional heartburn, and psychosocial factors influence interactions between the gastrointestinal nervous system and the brain, which determines the severity of symptoms in patients. Doctors are recommended to tell patients in detail about the essence of the diagnosis, directions in possible effective treatment, for better adherence to therapy, the use of antidepressants, cognitive behavioral therapy, hypnotherapy and relaxation methods is recommended. At the moment, the standard for the diagnosis of functional heartburn is pH-impedance measurement, with the primary exception of organic pathology during endoscopic examination of the esophagus with biopsy and histological examination, and the exclusion of esophageal motility disorders during manometry. Non-invasive, affordable and cost-effective diagnostic tools are needed to avoid overdiagnosis of gastroesophageal reflux disease and improper use of proton pump inhibitors, saliva pepsin examination and dental examination are promising. Objective. The purpose of the review is to summarize the existing research data on the prevalence of functional heartburn, the influence of psychological factors on its course, and current methods of diagnosis and treatment of this pathology. In order to identify studies on the problems of diagnosis and treatment of functional heartburn, a literature search was conducted in the PubMed and eLibrary databases until November 2023, original articles, meta-analyses and relevant reviews were reviewed.

Refractory Gastroesophageal Reflux Disease: Diagnosis and Management.

Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett's esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.

Clinical diagnostic value of mean nocturnal baseline impedance and post-reflux swallow-induced peristaltic wave index for distinguishing functional heartburn from non-erosive reflux disease

Clinical diagnostic value of mean nocturnal baseline impedance and post-reflux swallow-induced peristaltic wave index for distinguishing functional heartburn from non-erosive reflux disease

Association between Mean Nocturnal Baseline Impedance (MNBI) and Post-Reflux Swallow-Induced Peristaltic Wave Index (PSPW) in GERD Patients.

Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders in the world. Two parameters, mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave index (PSPW), have been recently proposed to help differentiate GERD phenotypes. Our study aimed to assess whether there is any correlation between the two parameters, while also taking a look at their ability to distinguish between GERD phenotypes. We recruited 81 patients who were divided into 4 groups based on their GERD phenotype: erosive reflux disease (ERD), non-erosive reflux disease (NERD), reflux hypersensitivity (RH), and functional heartburn (FH). Both MNBI (AUROC 0.855) and PSPW (AUROC 0.835) had very good performances in separating ERD patients from non-ERD patients. PSPW (AUROC 0.784) was superior to MNBI (AUROC 0.703) in distinguishing NERD patients from patients with RH or FH. The PSPW index (AUROC 0.762) was more effective than MNBI (AUROC 0.668) in separating RH from FH. We found that PSPW and MNBI have a strong statistical correlation (Pearson correlation coefficient, r = 0.722, p < 0.001). Furthermore, PSPW predicted pathological MNBI (<2292 Ω) with good performance (AUROC 0.807). MNBI and PSPW are useful in distinguishing GERD phenotypes, with a strong correlation between the two parameters.

Identification of novel immune cell signature in gastroesophageal reflux disease: altered mucosal mast cells and dendritic cell profile.

Heartburn pathogenesis in GERD remains incompletely understood. We aimed to identify differences in the immune cell signature and sensory mucosal markers between reflux phenotypes and healthy asymptomatic subjects. Thirty-seven patients with heartburn symptoms were phenotyped endoscopically and with objective reflux studies into erosive reflux disease (ERD) (N=10), nonerosive reflux disease (NERD) (N=9), functional heartburn (FH) (N=9), and Barrett's esophagus (BO) (N=9). Bulk mRNA-sequencing(RNA-seq) was conducted on RNA extracted from endoscopic biopsies, and immune cell deconvolution analysis was performed using CIBERSORT. RNA-seq findings were validated by immunofluorescent staining for CD1a, nerve growth factor (NGF), and mast cell tryptase in corresponding patient biopsies. Transcriptomic analysis detected higher mast cell abundance in BO, ERD, and NERD compared to healthy controls (p<0.05), with decreased dendritic cell infiltration in BO, ERD, and NERD patients compared to healthy controls and FH patients. CD1a-positive dendritic cell infiltration was significantly higher in the healthy esophageal mucosa at protein level compared to BO (p=0.0005), ERD (p=0.0004), and FH patients (p=0.0096). Moreover, NGF co-expression on mast cells in GERD patients was significantly higher than in healthy controls (p=0.0094). The mucosa in patients with GERD had a significant increase in NGF expression on mast cells, suggesting an upregulation of signalling for neuronal sprouting in GERD. Moreover, decreased dendritic cell abundance in GERD esophageal mucosa may play a role in reduced oral tolerance and development of subsequent immune responses which may participate in esophageal sensitivity.

Roles of Cytokines in Pathological and Physiological Gastroesophageal Reflux Exposure.

Gastroesophageal reflux disease is frequently observed and has no definitive treatment. There are 2 main views on the pathogenesis of gastroesophageal reflux disease. The first is that epithelial damage starts from the mucosa by acidic-peptic damage and the inflammatory response of granulocytes. The other view is that T-lymphocytes attract chemoattractants from the basal layer to the mucosa, and granulocytes do not migrate until damage occurs. We aim to investigate the inflammatory processes occurring in the esophageal epithelium of the phenotypes at the molecular level. We also examined the effects of these changes on tissue integrity. Patients with mild and severe erosive reflux, nonerosive reflux, reflux hypersensitivity, and functional heartburn were included. Inflammatory gene expressions (JAK/STAT Signaling and NFKappaB Primer Libraries), chemokine protein levels, and tissue integrity were examined in the esophageal biopsies. There was chronic inflammation in the severe erosion group, the acute response was also triggered. In the mild erosion group, these 2 processes worked together, but homeostatic cytokines were also secreted. In nonerosive groups, T-lymphocytes were more dominant. In addition, the inflammatory response was highly triggered in the reflux hypersensitivity and functional heartburn groups, and it was associated with physiological reflux exposure and sensitivity. "Microinflammation" in physiological acid exposure groups indicates that even a mild trigger is sufficient for the initiation and progression of inflammatory activity. Additionally, the anti-inflammatory cytokines were highly increased. The results may have a potential role in the treatment of heartburn symptoms and healing of the mucosa.

Revisiting the Role of Esophageal Mucosal Dilated Intercellular Spaces in the Diagnosis and Pathophysiology of Heartburn.

Dilated intercellular spaces (DISs) facilitate the diffusion of noxious agents into the deep layers of the esophageal epithelium. The role of DIS in heartburn pathogenesis is still controversial. Therefore, we aim to reinvestigate DIS in an extensively evaluated group of patients and healthy controls (HCs). We classified 149 subjects into the following groups: 15 HC, 58 mild erosive reflux disease (ERD), 17 severe ERD, 25 nonerosive reflux disease (NERD), 15 reflux hypersensitivity (RH), and 19 functional heartburn (FH). A total of 100 length measurements were performed for each patient's biopsy. The overall intercellular spaces (ISs) value of gastroesophageal reflux disease (GERD) patients was higher than that of HC (P = 0.020). In phenotypes, mild ERD (vs HC [P = 0.036], NERD [P = 0.004], RH [P = 0.014]) and severe ERD (vs HC [P = 0.002], NERD [P < 0.001], RH [P = 0.001], FH [P = 0.004]) showed significantly higher IS. There was no significant difference between the HC, NERD, RH, and FH groups. The 1.12 μm DIS cutoff value had 63.5% sensitivity and 66.7% specificity in the diagnosis of GERD. There was a weak correlation (r = 0.302) between the IS value and acid exposure time, and a weak correlation (r = -0.359) between the IS value and baseline impedance. A strong correlation was shown between acid exposure time and baseline impedance (r = -0.783). Since the IS length measurement had better discrimination power only in erosive groups, it is not feasible to use in daily routine to discriminate other nonerosive phenotypes and FH. The role of DIS in heartburn in nonerosive patients should be reconsidered.

Frequency of functional esophageal disorders in patients with refractory reflux symptoms in Lima, Peru

Gastroesophageal reflux disease (GERD) is a clinical condition in which gastric reflux causes symptoms or damage to the esophageal mucosa. It is managed with proton pump inhibitors, however, up to 45% of patients with suspected GERD are refractory to treatment. It is necessary to establish a true GERD diagnosis by means of a digestive endoscopy, which does not show lesions in approximately 70% of patients. In this scenario, it is necessary to perform an esophageal pH-impedance measurement, a procedure that allows to determine whether exposure to gastric acid is pathological. Of this group, patients with pathological acid exposure are diagnosed as true non-erosive reflux disease (NERD). If, in addition to not presenting esophageal lesions, they have a physiological exposure to gastric acid, they suffer from esophageal hypersensitivity or functional heartburn, which are functional disorders. These require a different approach from that of GERD or NERD, as the symptoms are not due to pathological exposure to gastric acid. The aim was to calculate the frequency of esophageal hypersensitivity and functional heartburn in patients with suspected NERD. This was a cross-sectional study. Data was collected by reviewing pH-impedance and manometry reports, 166 patients were selected. The frequency for functional disorders was 86.15%, being 46.9% for functional heartburn and 39.2% for esophageal hypersensitivity. The frequency of functional disorders was higher than that reported in previous studies. In conclusion, age, psychological conditions, dietary, cultural, ethnic or lifestyle factors inherent to our environment might play important roles in the development of functional disorders.