Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis.

Introduction: Eosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4+ T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing. Methods: In this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus. Results: Our results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4+ T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4+ and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4+ T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE. Discussion: Herein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models.

Obesity is associated with higher prevalence of gastroesophageal reflux disease and reflux related complications: A global healthcare database study.

BACKGROUND: Prior studies have demonstrated that obesity may be associated with the development of gastroesophageal reflux disease (GERD) and GERD-related complications. However, such association has never been assessed in a global-wide real-world patient population. METHODS: The TriNetX electronic health records network, which involves 92 healthcare organizations in 12 countries, was utilized for this multicenter global health research network study. The cohort with obesity comprised adult patients with body mass index (BMI) of more than 30 kg/m2. We performed 1:1 propensity score matching to decrease confounders effects. The prevalence of GERD and GERD-related complications including erosive esophagitis, Barrett's esophagus (BE), BE with dysplasia, and esophageal adenocarcinoma were assessed. RESULTS: A total of 2,356,548 patients were included in the obesity and non-obesity groups after propensity score matching. In the group with obesity, patients had a significantly higher prevalence of GERD (30% vs. 24%, OR 1.35, 95% CI 1.34-1.36) compared to the group without obesity. Further analysis showed a higher prevalence of GERD-related complications in the group with obesity with statistical significance: Erosive esophagitis (OR 1.07, 95% CI 1.05-1.08), Barrett's esophagus (1.08, 1.05-1.10), BE with dysplasia (1.11, 1.04-1.18), esophageal cancer (1.32, 1.15-1.51). CONCLUSION: Globally, obesity was associated with a higher prevalence of GERD and GERD-related complications.

Expression of epidermal growth factor receptor (EGFR) in systemic sclerosis patients (SSc) and gastro-oesophageal reflux disease (GORD).

INTRODUCTION: Systemic sclerosis (SSc) affects the connective tissue and leads to an abnormal fibrotic process in the skin and internal organs. Epidermal Growth Factor Receptor (EGFR) is able to induce cell proliferation and differentiation, and its expression is increased in SSc patients with pulmonary artery hypertension and in skin biopsies in patients with scleroderma. To date, no data on esophageal expression of EGFR are available in SSc patients. We aimed to evaluate whether the pro-fibrogenic pathways of SSc may affect EGFR expression in the esophagus. METHODS: A retrospective analysis included patients with SSc and control subjects suffering from gastroesophageal reflux symptoms. Endoscopic assessment and histopathologic analyses were performed in all subjects and the presence of microscopic esophagitis was used to distinguish patients with normal esophageal mucosa and subjects with non-erosive reflux disease. EGFR expression was measured in all subjects. RESULTS: A total of 35 patients with SSc were included, while the control group included 67 non-SSc patients. EGFR expression at the Z-line was higher in SSc patients than non-SSc patients in absence of microscopic esophagitis (median 65 %, IQR 56-71 % vs 42 %, IQR 37-54 %, p < 0.001). Microscopic esophagitis was found in 60 % of patients with SSc and 62.7 % of control patients, and EGFR expression was significantly higher in patients presenting microscopic esophagitis both in SSc and non-SSc patients. CONCLUSION: The EGFR hyperexpression may be due to SSc and/or reflux-related damage in patients with microscopic esophagitis. Further studies are warranted to answer open questions and provide a possible role of EGFR in terms of diagnosis, prognosis, and therapy.

Gastric juice analysis in clinical practice: why, how, and when. The experience with EndoFaster.

Gastric juice analysis may be useful for clinical purposes, including the detection of H. pylori infection and diffuse atrophic gastritis on gastric mucosa. EndoFaster is a novel device which performs real-time analysis of gastric juice revealing the infection and hypochlorhydria by measuring ammonium concentrations and pH levels. This review aimed to evaluate the clinical applications of such a tool. By considering data from overall 11 studies, the values of sensitivity, specificity, positive predictive value, negative predictive value, accuracy, positive likelihood ratio, and negative likelihood ratio were 90%, 86%, 67%, 96%, 87%, 8.5, and 0.13, respectively, for H. pylori diagnosis, and 83%, 92%, 58%, 97%, 91%, 9.9 and 0.2, respectively, for suspecting diffuse atrophic gastritis. The very high value of negative predictive values for both H. pylori and mucosal atrophy would allow avoiding to perform useless negative gastric biopsies when the results of the test are negative. Some promising data suggest that gastric juice analysis may be useful also to diagnose H. pylori infection in patients with chronic active gastritis without evidence of bacteria at histology, as well as in predicting persistent acid reflux in patients on proton pump inhibitor therapy for reflux disease.

The utility of balloon-based and standard impedance technology to diagnose esophageal mucosal diseases in children.

BACKGROUND: Standard impedance catheters and balloon-based mucosal impedance catheters (BBMI) have been used to assess mucosal integrity and diagnose mucosal diseases. The goal of this study was to determine the age-related technical issues associated with mucosal balloon inflation, validate the BBMI measurement against a standard impedance probe, and compare software-generated diagnoses to histologic diagnoses. METHODS: We prospectively recruited patients undergoing endoscopy, during which patients underwent standard mucosal impedance catheters and BBMI measurements. Measurements were compared to each other, to the histologic diagnoses, and to the number of eosinophils per high power field. We then compared the patients' diagnosis to that assigned by the BBMI software. KEY RESULTS: Sixty-two patients (mean age: 62 ± 62 months) were recruited, including non-GERD (N = 40), GERD (N = 15), and EoE (N = 7) patients. There were significant differences between the impedance values measured by the two technologies at each esophageal height (p < 0.003). There were significant correlations between the mean impedance values taken by the two catheters in the distal (r2 = 0.272, p = 0.04), mid (r2 = 0.371, p < 0.001), and proximal (r2 = 0.259, p = 0.05) esophagus. There were significant differences in BBMI impedance values across diagnoses in the mid and proximal esophagus (p = 0.024 and 0.025, respectively). While not statistically significant (p = 0.061-0.073), the standard catheter showed similar trends by diagnosis. Using the BBMI diagnostic prediction software, 33%-72% of patients were misclassified. CONCLUSION AND INFERENCES: While there was significant variability in impedance values between technologies within patients, regional measurements were consistent across catheters. Automated analyses lacked the sensitivity to diagnose inflammatory disorders.

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

Introduction: 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. Methods: 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. Results: 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). Discussion: 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.

Colon micro- and macrooesofagisation in interposed pedicled colonic right half segments for esophagus reconstruction.

Treatment of esophageal burns may require surgical transplantation (interposition) of the colon or stomach. The interposed parts change their function and morphology. To investigate the macro- and microchanges in the transplanted colonic segment we analyzed in long-term follow-up (up to 29 years) the group of 21 patients in a retrospective study who underwent surgical interposition of pedicled colonic right half segments for esophageal burns. The data were analyzed statistically with the software package Statistica 13 (StatSoft Polska, Cracow). All calculations were performed with a significant level of P = .05. We evaluated the macro- and microanatomy of the grafts using radiology, endoscopy and histology. The adaptation of the transplanted tube was excellent. The diameter of the colonic tube was normal (35-60 mm) in 60% of females and 100% of males. Typical macrooesophagisation was found in all patients, while microoesophagisation involved inflammation, which gradually resolved over a period of about 5 years to be replaced by edema without fibrosis. Only in few patients persistent reflux was present, leading to erosions or ulcerations. All symptoms subsided after conservative treatment. We concluded macrooesophagization developed gradually after surgery, and was fully developed after 15 to 20 years. Microoesophagization appeared soon after interposition, and was obvious after 5 years. No metaplasia or dysplasia were observed (except in 1 patient), and the number of goblet cell remained constant.

The Role of Distal Mean Nocturnal Baseline Impedance in Differentiating GERD Phenotypes.

BACKGROUND AND AIMS: Gastroesophageal reflux disease (GERD) is one of the most frequent digestive pathologies. The current diagnosis of GERD either by trial of proton pump inhibitors (PPIs), endoscopy or by multichannel impedance pH study (MII/pH) has limitations. Our study aims to show if mean nocturnal baseline impedance (MNBI) can differentiate between the GERD phenotypes. METHODS: We recruited 62 patients who underwent upper digestive endoscopy and MII/pH, with some patients undergoing esophageal manometry to exclude motility disorders. Patients were separated into 4 GERD phenotypes: erosive reflux disease (ERD), non-erosive reflux disease (NERD), reflux hypersensitivity (RH) and functional heartburn (FH). Proximal MNBI was calculated as the mean value of the proximal 2 channels (Z1 and Z2), and distal MNBI was calculated as the mean value of the distal 4 channels (Z3, Z4, Z5, Z6). RESULTS: Distal MNBI can help distinguish the abnormal acid exposure time (AET) phenotypes (ERD, NERD) from normal AET phenotypes (RH, FH) with a decent performance (AUROC 0.857). Distal MNBI has good accuracy in separating ERD from other phenotypes (AUROC 0.872). Furthermore, distal MNBI can differentiate FH from ERD, NERD, RH with good accuracy (AUROC 0.879), and on top of that is able to separate FH from RH (AUROC 0.817). CONCLUSIONS: Our study showed that distal MNBI is a good method of differentiating GERD phenotypes and should be taken into consideration in future studies to assess its validity in helping physicians make the correct diagnosis.

Pancreatic acinar metaplasia at the gastroesophageal junction is associated with protective effect against intestinal metaplasia in patients with gastroesophageal reflux disease.

Anecdotal evidence suggests that pancreatic acinar metaplasia (PAM) and intestinal metaplasia (IM) overlap infrequently at the gastroesophageal junction/distal esophagus (GEJ/DE). The goal of this study was to evaluate the significance of PAM at GEJ/DE in relation to IM in patients with gastroesophageal reflux disease (GERD). Group 1 comprised 230 consecutive patients with GEJ/DE biopsies (80.6% with GERD symptoms). Group 2 comprised 151 patients with established GERD and GEJ/DE biopsies taken before Nissen fundoplication. Group 3 comprised 540 consecutive patients used for a follow-up study of PAM. PAM was present in 15.7%-15.9% and IM in 24.8%-31.1% of patients in groups 1 and 2, respectively. PAM-IM overlap was present in 2.2%-3.3%, respectively. Patients with PAM were, on average, 6-12 years younger than patients with IM, and were predominantly female (72.2%-75%), in contrast to patients with IM (47.3%-32%). In the unadjusted logistic regression model, patients with PAM were 69%-65% less likely to also have IM, as compared to patients without PAM. In the fully adjusted model, patients with PAM were 35%-61% less likely to also have IM, although the P-value was not significant. Follow-up analysis of patients with PAM from group 3 (n = 28) demonstrated the prevalence of IM and PAM in subsequent biopsies at 7.1% and 60.7%, respectively. No cases showed PAM-IM overlap on follow-up. The data suggests that PAM at the GEJ/DE is associated with protective effect against IM and thus could be useful as a marker of decreased susceptibility to IM.

Gelatin-Based Ingestible Impedance Sensor to Evaluate Gastrointestinal Epithelial Barriers.

Low-profile and transient ingestible electronic capsules for diagnostics and therapeutics can replace widely used yet invasive procedures such as endoscopies. Several gastrointestinal diseases such as reflux disease, Crohn's disease, irritable bowel syndrome, and eosinophilic esophagitis result in increased intercellular dilation in epithelial barriers. Currently, the primary method of diagnosing and monitoring epithelial barrier integrity is via endoscopic tissue biopsies followed by histological imaging. Here, a gelatin-based ingestible electronic capsule that can monitor epithelial barriers via electrochemical impedance measurements is proposed. Toward this end, material-specific transfer printing methodologies to manufacture soft-gelatin-based electronics, an in vitro synthetic disease model to validate impedance-based sensing, and tests of capsules using ex vivo using porcine esophageal tissue are described. The technologies described herein can advance next generation of oral diagnostic devices that reduce invasiveness and improve convenience for patients.

Prevalence and risk factors of barrett's esophagus in lynch syndrome.

Lynch syndrome (LS), the most common hereditary cause of colorectal cancer, predisposes to upper gastrointestinal neoplasia. The prevalence of Barrett's esophagus (BE) is elevated in some hereditary gastrointestinal cancer syndromes but has not been systematically evaluated in LS. We assessed the prevalence of BE, BE-related dysplasia, esophageal adenocarcinoma (EAC), and factors associated with BE in LS. Asymptomatic patients with a germline pathogenic variant (PV) in the DNA mismatch repair (MMR) genes undergoing EGD for LS surveillance were identified from a hereditary colorectal cancer registry. We assessed the prevalence of BE and compared demographic, clinical, and endoscopic factors in LS patients with and without BE by logistic regression analysis. 323 patients were included. 21 patients (6.5%) were diagnosed with BE including 38% of females and 33% without gastroesophageal reflux disease (GERD). Dysplasia was diagnosed in two patients (9.5%) and EAC in one (4.8%) patient. Factors associated with BE included male gender (OR 3.00, 1.21-7.46), age at last LS EGD (OR 1.04, 1.01-1.08), presence of hiatal hernia (OR 20.09, 4.57-88.23), hiatal hernia > 3 cm (OR 11.25, 2.41-51.94), and GERD (OR 3.39, 1.32-8.67). No MMR PV was associated with BE. BE was diagnosed in 1 of 15 patients undergoing EGD surveillance for LS and nearly 10% had dysplasia including one EAC. Risk factors associated with BE in LS are similar to those established for BE in the general population. More studies are needed to evaluate if an association between BE and LS exists.

Improving the Diagnostic Yield of High-Resolution Esophageal Manometry for GERD: The "Straight Leg-Raise" International Study.

BACKGROUND & AIMS: The straight leg raise (SLR) maneuver during high-resolution manometry (HRM) can assess esophagogastric junction (EGJ) barrier function by measuring changes in intraesophageal pressure (IEP) when intra-abdominal pressure is increased. We aimed to determine whether increased esophageal pressure during SLR predicts pathologic esophageal acid exposure time (AET). METHODS: Adult patients with persistent gastroesophageal reflux disease (GERD) symptoms undergoing HRM and pH-impedance or wireless pH study off proton pump inhibitor were prospectively studied between July 2021 and March 2022. After the HRM Chicago 4.0 protocol, patients were requested to elevate 1 leg at 45º for 5 seconds while supine. The SLR maneuver was considered effective when intra-abdominal pressure increased by 50%. IEPs were recorded 5 cm above the lower esophageal sphincter at baseline and during SLR. GERD was defined as AET greater than 6%. RESULTS: The SLR was effective in 295 patients (81%), 115 (39%) of whom had an AET greater than 6%. Hiatal hernia (EGJ type 2 or 3) was seen in 135 (46%) patients. Compared with patients with an AET less than 6%, peak IEP during SLR was significantly higher in the GERD group (29.7 vs 13.9 mm Hg; P < .001). Using receiver operating characteristic analysis, an increase of 11 mm Hg of peak IEP from baseline during SLR was the optimal cut-off value to predict an AET greater than 6% (area under the receiver operating characteristic curve, 0.84; sensitivity, 79%; and specificity, 85%), regardless of the presence of hiatal hernia. On multivariable analysis, an IEP pressure increase during the SLR maneuver, EGJ contractile integral, EGJ subtype 2, and EGJ subtype 3, were found to be significant predictors of AET greater than 6% CONCLUSIONS: The SLR maneuver can predict abnormal an AET, thereby increasing the diagnostic value of HRM when GERD is suspected. CLINICALTRIALS: gov ID: NCT04813029.

Value of 96-hour ambulatory esophageal pH monitoring in the assessment of patients with refractory acid reflux symptoms and their response to anti-reflux diet.

Ambulatory esophageal pH monitoring is a diagnostic tool in patients with heartburn and regurgitation. The aim of this study is to evaluate 96-hour esophageal pH monitoring in patients with gastroesophageal reflux disease (GERD), at baseline and under diet that impedes GER. We hypothesized that diet would potentially reduce pathologic acid exposure time (AET). Retrospective series of 88 patients with GERD undergoing wireless 96-hour pH monitoring. Two-day (48 hours) tandem periods, one on liberal, followed by another on restricted diet assessed esophageal AET. Primary end point was >30% reduction in AET while on anti-GER diet. Of the 88 patients, 16 were excluded because of probe migration. Endoscopy and biopsies assessed erosive esophagitis (EE) and Barrett's esophagus (BE), or normal esophagus. Abnormal AET (% pH < 4.0 ≥ 6) further defined nonerosive reflux disease (NERD), whereas normal AET (% pH < 4.0 < 6) with normal endoscopy defined patients as functional heartburn (FH). There were 6 patients with EE (n = 5) and BE (n = 1), 23 with NERD and 43 with FH. Anti-GER diet led to >30% reduction in AET in EE and NERD patients, but not in those with FH. Most patients (n = 43/72; 60%) had FH and could have avoided acid suppression. Furthermore, (14/23; 61%) of patients with NERD completely normalized AET with diet, potentially negating acid suppression. Ninety-six-hour esophageal pH distinguishes GERD patients from those with FH. Fifty percent of EE/BE patients and 61% of those with NERD completely normalize AET with diet. If pathologic AET occurs despite diet, acid suppression is indicated.

Association of Symptoms of Gastroesophageal Reflux, Esophageal Dilation, and Progression of Systemic Sclerosis-Related Interstitial Lung Disease.

OBJECTIVE: To investigate whether symptoms of gastroesophageal reflux disease and radiographic measures of esophageal dilation are associated with radiographic progression of systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: Participants of the Scleroderma Lung Study II, which compared mycophenolate versus cyclophosphamide for SSc-ILD, completed the reflux domain of the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 at baseline. The diameter and area of the esophagus in the region of maximum dilation was measured by quantitative image analysis. Univariate and multivariable linear regression analyses were created to evaluate the relationship between these measures of esophageal involvement and progression of SSc-ILD over 2 years, based on the radiologic quantitative interstitial lung disease (QILD) and quantitative lung fibrosis (QLF) in the lobe of maximum involvement (LM). All multivariable models controlled for the treatment arm, baseline ILD severity, and proton-pump inhibitor use. RESULTS: The baseline mean patient-reported reflux score was 0.57, indicating moderate reflux (n = 141). Baseline mean maximal esophageal diameter and area were 22 mm and 242 mm2 , respectively. Baseline reflux scores were significantly associated with the change in QLF-LM and QILD-LM in the univariate and multivariable models. Neither radiographic measure of esophageal dilation was associated with the change in radiographic measures of lung involvement. CONCLUSION: Severity of reflux symptoms as measured by an SSc-specific questionnaire was independently associated with the change in the radiographic extent of ILD and fibrosis over 2 years in patients with SSc-ILD. Two objective measures of esophageal dilation were not associated with radiographic progression of ILD, highlighting the need for improved objective measures of esophageal dysfunction in SSc.

Augmented CPT1A Expression Is Associated with Proliferation and Colony Formation during Barrett's Tumorigenesis.

Obesity is a known risk factor for the development of gastroesophageal reflux disease (GERD), Barrett's Esophagus (BE) and the progression to esophageal adenocarcinoma. The mechanisms by which obesity contributes to GERD, BE and its progression are currently not well understood. Recently, changes in lipid metabolism especially in the context of a high fat diet have been linked to GERD and BE leading us to explore whether fatty acid oxidation plays a role in the disease progression from GERD to esophageal adenocarcinoma. To that end, we analyzed the expression of the rate-limiting enzyme, carnitine palmytoyltransferase 1A (CPT1A), in human tissues and cell lines representing different stages in the sequence from normal squamous esophagus to cancer. We determined uptake of palmitic acid, the most abundant fatty acid in human serum, with fluorescent dye-labeled lipids as well as functional consequences of stimulation with palmitic acid relevant to Barrett's tumorigenesis, e.g., proliferation, characteristics of stemness and IL8 mediated inflammatory signaling. We further employed different mouse models including a genetic model of Barrett's esophagus based on IL1ß overexpression in the presence and absence of a high fat diet and deoxycholic acid to physiologically mimic gastrointestinal reflux in the mice. Together, our data demonstrate that CPT1A is upregulated in Barrett's tumorigenesis and that experimental palmitic acid is delivered to mitochondria and associated with increased cell proliferation and stem cell marker expression.

Spectrum of histopathological changes and its quantification using a scoring system in patients with gastroesophageal reflux disease.

Aim: The aim of this study was to evaluate the role of histopathological and histomorphometric features in oesophageal biopsy of patients presenting with symptoms of Gastroesophageal Reflux Disease (GERD). Material and Methods: Present study included 42 patients and 12 controls. Complete clinical evaluation followed by endoscopic examination of the patients was done and multipleoesophageal biopsies were taken. Biopsies were processed routinely and stained with Hematoxylin and Eosin and examined for any changes related to GERD. Morphometric assessment was done by using Leitz optical micrometer. The histological scoring was done based on the parameters: basal cell hyperplasia, stromal papillae elongation, cells with irregular nuclear contour (CINC), eosinophilic infiltrate, gastric and intestinal metaplasia. A numerical score was assigned to each parameter and sum of these scores represented the total score. Statistics: The statistical analysis was done using graph pad prism, Medcalc software and Windows MS office. P value and mean standard deviation (SD) was calculated. Results: The endoscopic findings of all the controls and 83.33% of patients were normal. Only 16.67% of patients had reflux associated changes of varying grades on endoscopy. Oesophageal biopsy of all patients had changes related to GERD on histology. Immunohistochemistry confirmed that cells with irregular nuclear contour were T- lymphocytes. The mean (SD) histological scoring of control and patients were 1.75 (0.62) and 5.66 (1.31) respectively. The difference was considered to be statistically significant (P < 0.001). Thus, it was suggested that a cut-off of histological score > 3 can be used to indicate GERD. Conclusion: Patients with gastroesophageal reflux symptoms can have normal endoscopic findings but can be diagnosed on the basis of histological changes in the squamous epithelium. Scoring of the histopathological parameters along with the cut-off value can give a definitive diagnosis of GERD.

Distal esophageal wall thickness correlates with dysphagia in adult patients with eosinophilic esophagitis.

BACKGROUND: Thickening of the esophageal wall in patients with eosinophilic esophagitis (EoE) and gastro-esophageal reflux disease (GERD) has been shown in studies using endoscopic ultrasound (EUS). We hypothesise that transmural inflammation in EoE results in prominent esophageal wall thickening compared with the mucosal inflammation in GERD. The aim of this study was to compare the relationship among dysphagia, endoscopic appearance, wall thickness, histology, and motility in EoE and GORD. METHODS: EoE and GERD patients were prospectively studied between February 2012 and April 2021. Patients were studied on 2 separate occasions with endoscopy, EUS and mucosal biopsies, followed by high-resolution manometry. Epidemiology and dysphagia data were obtained. RESULTS: A total of 45 patients (31 EoE, 14 GERD) were included. There were no significant differences in age, sex, duration of disease and presence of esophageal motility disorders. EoE patients had a higher dysphagia score (P < 0.001), EREFS score (P < 0.001) and peak eosinophil count (P < 0.001) compared with GERD patients. Thickness of the submucosa in the distal esophagus in EoE was significantly higher than GERD (P = 0.003) and positively correlated with duration of disease (P = 0.01, R = 0.67). Positive correlation was also found between dysphagia score and distal total esophageal wall thickness (P = 0.03, R = 0.39) in EoE patients. No correlation was found between these variables in GERD patients. CONCLUSION: Distal esophageal wall thickness positively correlates with dysphagia score in EoE but not GERD. This appears to be related to the composition of the submucosa which can be identified using EUS.

Effect of hiatus hernia on reflux patterns and mucosal integrity in patients with non-erosive reflux disease.

BACKGROUND: Hiatus hernia (HH) contributes to development of gastroesophageal reflux disease, Barrett's esophagus and esophageal adenocarcinoma. This study was aimed to investigate the influence of HH on reflux patterns and distal esophageal mucosal integrity in non-erosive reflux disease (NERD). METHODS: We retrospectively analyzed PPI-refractory NERD patients referred to three tertiary referral centers who underwent high-resolution manometry and off-PPI 24-h impedance-pH monitoring (with or without bile spectrophotometry). Patients with HH ≥2 cm (HH group, n = 42) or no HH (non-HH group, n = 40) with similar esophageal acid exposure time (AET 6%-12%) were included. KEY RESULTS: Age, gender, BMI, esophageal motility, AET, and esophageal clearance were similar between the two groups. The HH group had higher numbers of total reflux episodes (p = 0.015) with similar proportion of acid/non-acid reflux compared with the non-HH group. Mean nocturnal baseline impedance (MNBI) in the distal esophagus was significantly lower in the HH group than the non-HH group at both 5 cm (p = 0.002) and 3 cm (p = 0.015) above the lower esophageal sphincter. Multivariable regression analysis showed that HH, less non-acid reflux and lower post-reflux swallow-induced peristaltic wave index (PSPWI) were independently associated with lower MNBI. Among 31 patients tested with bile spectrophotometry, the HH group had significantly longer bile exposure time than the non-HH group (p = 0.011), and bile reflux inversely and significantly correlated with MNBI (rho = -0.75, p < 0.001). CONCLUSIONS AND INFERENCES: Hiatus hernia, less non-acid reflux and lower PSPWI were associated with lower MNBI. HH impairs distal esophageal mucosal integrity, the mechanism of which we speculate to be through excessive bile reflux.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Presenting with Area Postrema Syndrome-Like Symptoms without Medulla Oblongata Lesions.

INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described steroid-responsive meningoencephalomyelitis positive for cerebrospinal fluid (CSF) anti-GFAP antibody. Area postrema syndrome (APS) involves intractable hiccups, nausea, and vomiting, which is caused by medulla oblongata (MO) impairment. APS is a characteristic symptom of aquaporin-4 (AQP4) autoimmunity, and it helps to differentiate between AQP4 and GFAP autoimmunity. Conversely, although 6 cases of autoimmune GFAP astrocytopathy with APS and MO lesions have been reported, the association between GFAP autoimmunity and APS is unclear. We report the case of a patient with autoimmune GFAP astrocytopathy presenting with APS-like symptoms without MO lesions and discuss the mechanisms underlying the symptoms. METHODS: CSF anti-GFAP antibody was detected using cell-based assays and immunohistochemical assays. RESULTS: A 54-year-old Japanese man developed persistent hiccups, intermittent vomiting, fever, anorexia, and inattention. Brain magnetic resonance imaging (MRI) showed periventricular lesions with radial linear periventricular enhancement, suggesting autoimmune GFAP astrocytopathy. However, no obvious MO lesions were identified on thin-slice images. Spinal cord MRI revealed hazy lesions with patchy enhancement along the cervical and thoracic cord. CSF analysis demonstrated inflammation, with positive results for anti-GFAP antibodies. Anti-AQP4 antibodies in the serum and CSF were negative. Esophagogastroduodenoscopy revealed gastroparesis and gastroesophageal reflux disease, and vonoprazan, mosapride, and rikkunshito were effective only against persistent hiccups. Steroid therapy was initiated, allowing clinical and radiological improvements. Repeated MRIs demonstrated no obvious MO lesions. CONCLUSION: This report suggests that autoimmune GFAP astrocytopathy presents with APS-like symptoms without obvious MO lesions. The possible causes of hiccups were gastroparesis and cervical cord lesions. Gastroesophageal reflux disease was not considered a major cause of the hiccups. Intermittent vomiting appeared to be associated with gastroparesis, cervical cord lesions, and viral-like symptoms. Testing for anti-GFAP antibodies should be considered in patients with APS-like symptoms in the context of typical clinical-MRI features of autoimmune GFAP astrocytopathy.