Epidemiology and Risk Factors of Eosinophilic Esophagitis in Japan: A Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) has been increasingly diagnosed globally. However, there have been few general population-based studies in Asia. The aim of this study was to investigate EoE epidemiology in the Japanese general population. METHODS: We analyzed an employer-based health insurance claim database from January 2005 to September 2022. EoE cases were identified on the basis of the International Statistical Classification of Diseases and Health-related Problems, 10th Revision code, K20.0. We calculated the incidence and prevalence of EoE using Poisson regression and binomial distribution, respectively. Using 10 matched controls for each EoE case, a nested case-control study was performed to identify potential risk factors for EoE. RESULTS: Of 15,200,895 individuals, 1010 EoE cases were identified. The incidence and prevalence of EoE were 2.82 (95% confidence interval [CI], 2.44-3.26) per 100,000 person-years and 10.68 (95% CI, 10.01-11.37) per 100,000 people in 2022, nearly 3 and 8 times as high as those in 2017, respectively. Smoking was associated with decreased risk of EoE (odds ratio [OR], 0.45, 0.36-0.56, P < .001), whereas alcohol consumption (OR, 1.51, 1.21-1.88, P < .001) was associated with increased risk of EoE along with several allergic conditions and psychiatric disorders. EoE was not related to either body mass index or lifestyle-related diseases such as hypertension, diabetes mellitus, hyperuricemia, and dyslipidemia. CONCLUSIONS: The incidence and prevalence of EoE in Japan have steadily increased over the past 2 decades. Nevertheless, EoE remains less common in Japan compared with the United States and Western Europe. Factors contributing to the epidemiology of EoE on a global basis may improve our understanding of the contribution of genetic and environmental risk factors.

Prevalence of Belching Disorders and Their Characteristics in the General Adult Population.

INTRODUCTION: Excessive bothersome belching is clinically problematic and the Rome IV classification categorizes belching disorders as gastroduodenal disorders. METHODS: A total of 10,000 Japanese adults participated in this web-based survey. We aimed to examine the prevalence of belching disorders and their characteristics. RESULTS: Belching disorders were found in 151 (1.5%) adults. The presence of reflux esophagitis, thyroid diseases, gastroesophageal reflux disease, functional dyspepsia, full eaters, or a small or large number of mastication was significantly associated with an increased odds ratio of belching disorders. DISCUSSION: A detailed epidemiology of belching disorders in adults was clarified.

Responses of Proton Pump Inhibitors and Potassium-Competitive Acid Blockers According to Outcomes of Symptom, Endoscopy, and Histology in Patients With Eosinophilic Esophagitis.

GOALS: We aimed to examine the response rate to proton pump inhibitors (PPIs) and potassium-competitive acid blockers and the prevalence of topical corticosteroid (TCS) therapy as the second-line treatment for eosinophilic esophagitis (EoE). BACKGROUND: Acid-suppressive drugs such as PPIs and potassium-competitive acid blockers are often used to treat EoE. Treatment response is based on outcomes including symptoms, endoscopy, and histology; however, the detailed response rate to PPI/P-CAB is unknown. STUDY: In total, 236 patients with histologically confirmed EoE who received PPI/P-CAB as the first-line treatment were included. We assessed the symptoms, endoscopic reference score (EREFS), and histology [eosinophils per high-power field (eos/hpf)] 8 weeks after PPI/P-CAB administration. Complete normalization was defined as the disappearance of symptoms, EREFS score 0, or 0-1 eos/hpf, and response as disappearance or improvement of symptoms, EREFS score ≤2, or <15 eos/hpf. The prevalence of TCS therapy in each response group was assessed. RESULTS: Complete normalization was achieved in 25%, 50%, 36%, and 8% of patients for symptoms, endoscopy, histology, and all 3 outcomes, respectively. The response rates were 81%, 87%, 87%, 75%, and 60% for symptoms, endoscopy, histology, and all 3 outcomes, respectively. TCS use was significantly lower (8%) in patients who achieved response of all 3 outcomes than in other groups and was dependent on the number of outcomes with nonresponse. CONCLUSIONS: Complete normalization of symptoms, endoscopy, and histology using PPI/P-CAB is uncommon. Based on treatment efficacy by response/nonresponse, TCS was the secondary treatment in cases with an increase in the number of nonresponse outcomes.

Belching Disorders and Rumination Syndrome: A Literature Review.

BACKGROUND: Belching disorders and rumination syndrome (RS) are disorders of gut-brain interaction (DGBIs) in Rome IV. Belching disorders are composed of excessive gastric belching (GB) and supragastric belching (SGB). Excessive GB is related to physiological phenomenon whereas excessive SGB and RS are behavioral disorders. SUMMARY: A recent large internet survey found that prevalence of belching disorders and RS were 1% and 2.8%, respectively. It has been recognized that not a few patients with two behavioral disorders, excessive SGB and RS, could be misdiagnosed as proton pump inhibitors (PPI)-refractory gastroesophageal reflux disease (GERD). In patients with reflux symptoms, distinguishing these conditions is essential because they need psychological treatment (i.e., cognitive behavioral therapy (CBT) rather than acid suppressants. Clinicians should take a medical history meticulously first to identify possible excessive SGB and/or RS. High-resolution impedance manometry and/or 24-h impedance-pH monitoring can offer an objective diagnosis of the disorders. Several therapeutic options are available for excessive SGB and RS. The first-line therapy should be CBT using diaphragmatic breathing that can stop the behaviors involving complex muscle contraction (e.g., abdominal straining) to generate SGB or rumination. Overlap with eating disorders and/or other DGBIs such as functional dyspepsia can make management of the behavioral disorders challenging since such coexisting conditions often require additional treatments. KEY MESSAGES: Excessive SGB and RS are not unusual conditions. It is important to raise awareness of the behavioral disorders for appropriate management.

Evidence-Based Clinical Guidelines for Chronic Constipation 2023.

The Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced bowel movement frequency type or defecation difficulty type. The first line of treatment includes the improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicines, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide.

Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023.

The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide.

How to recognize and treat rumination syndrome.

PURPOSE OF REVIEW: Rumination syndrome (RS) is a functional gastroduodenal disorder characterized by repeated effortless regurgitation or vomiting of recently ingested food without retching. RS generally has been considered a rare entity. However, it has been increasingly recognized that many RS patients are likely to be underdiagnosed. This review discusses how to recognize and manage RS patients in clinical practice. RECENT FINDINGS: A recent epidemiological study that included over 50,000 individuals found that the prevalence of RS around the world is 3.1%. In patients with proton pump inhibitor (PPI)-refractory reflux symptoms, postprandial high-resolution manometry combined with impedance (HRM/Z) reveals that RS accounts for up to 20% of those cases. HRM/Z can be a gold standard for objective RS diagnosis. In addition, off-PPI 24-h impedance pH monitoring can suggest the possibility of RS when it reveals frequent postprandial, non-acid reflux with a high symptom index. Modulated cognitive behavioral therapy (CBT) targeting secondary psychological maintaining mechanisms almost eliminates regurgitation. SUMMARY: The prevalence of RS is higher than generally thought. For patients suspected of RS, HRM/Z is useful to distinguish RS from gastroesophageal reflux disease. CBT can be a highly effective therapeutic option.

Prevalence of elderly eosinophilic esophagitis and their clinical characteristics.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is predominantly found in middle-aged men among adults. There are few reports about EoE in the elderly, despite an ageing population. The study aimed to define the prevalence and clinical characteristics of EoE amongst older adults. METHODS: Elderly patients (defined as those ≥65 years) were compared to younger adults (18-64) in terms of clinical characteristics (age, gender, presenting symptoms, comorbidities), histological activity (eosinophil count), treatment modality and response to treatment. A pre- existing prospectively generated database of all EoE patients presenting to our department between February 2010 and December 2022 was interrogated. 309 patients who underwent endoscopy and esophageal biopsy and were found to have ≥15 eosinophils/HPF were defined as having EoE and were included for study. Statistical analyses were performed using Fisher's extract test or Mann-Whitney U test. RESULTS: 309 cases of EoE were recorded, mean age 45.7, range (21-88 years), of which20 patients were aged 65 years and over. Compared to younger patients, those aged ≥65 had more medical comorbidities (15 [75%] vs 111[38%], p = 0.002), and instead a non-significant trend toward less fibrosis (0.25 vs 0.46, p = 0.117). Although rate of cases required topical steroid (TCS) therapy was similar, none received repeated or maintenance TCS therapy in elderly. CONCLUSION: In our cohort, only 20 patients (6%) were aged 65 years or older, suggesting that EoE is uncommon in the elderly. The clinical characteristics of EoE in the older age group were similar to the younger patients. Future studies with prospective data collection may determine if EoE disappears with age, or if the younger mean age is reflective of an increasing prevalence in recent years, that may be realized in the elderly EoE population in the future.

Esophageal mast cells may be associated with the perception of symptoms in patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 helper T-cell (Th2)-mediated allergic disease that involves mast cells. This study aimed to clarify the relationship between perception of symptoms and mast cell levels in patients with EoE. METHODS: We enrolled patients with asymptomatic esophageal eosinophilia (aEE) and those with symptomatic EoE. Immunofluorescence staining was performed on esophageal biopsy specimens to quantify mast cell-related molecules, such as tryptase, proteinase-activated receptor (PAR)-2, and vasoactive intestinal peptide receptor (VPAC)-1. RESULTS: We evaluated 28 and 58 patients with aEE and EoE, respectively. There were no significant differences in clinical and endoscopic features and peak eosinophil counts between both groups. Mast cell tryptase-positive areas were significantly higher in EoE than in aEE (4.9 [3.5-6.2] vs. 2.0 [1.2-3.4] %, p < 0.01). The number of PAR-2-positive cells was significantly higher in EoE than in aEE (14 [8.8-20.0] vs. 4 [2.8-8.0] cells/high-power field [HPF], p < 0.01). The number of VPAC-1-positive cells was significantly higher in the EoE group than in the aEE group (13 [8.8-16.0] vs. 6 [3.0-9.3] cells/HPF, p < 0.01). A positive correlation was observed between the numbers of PAR-2-positive cells and VPAC-1-positive cells (r = 0.851, p < 0.01). Moreover, mast cell tryptase-positive areas positively correlated with the number of PAR-2- and VPAC-1-positive cells (r = 0.352, p < 0.01; r = 0.355, p < 0.01, respectively). CONCLUSIONS: Esophageal mast cells and their receptors, PAR-2 and VPAC-1, may contribute to the perception of symptoms in patients with EoE.

[Current real-world treatments for Japanese patients with eosinophilic esophagitis].

A total of 306 patients with eosinophilic esophagitis (EoE) were analyzed at our department. Proton pump inhibitors or potassium-competitive acid blockers were used as the first-line treatment in 286 (93.5%) patients. Fifty-five (18.0%) patients received topical steroid swallowing therapy. During 17.7-month mean follow-up, 46.4% of the patients were followed-up with no medications, 37.3% of the patients received maintenance or on-demand therapy using acid-suppressive drugs, and 9.8% of the patients received maintenance therapy with steroid swallowing. The majority of patients with EoE were treated using a therapeutic strategy similar to that used for gastroesophageal reflux disease. However, some patients were refractory to the treatment. Current real-world treatment strategies for Japanese patients with EoE are clarified.

Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors.

The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.

Identification of Different Phenotypes of Esophageal Reflux Hypersensitivity and Implications for Treatment.

BACKGROUND & AIMS: Reflux hypersensitivity (RH), a functional esophageal disorder, is detected in 14%-20% of patients who present with typical esophageal symptoms. As many as 40% of patients with RH do not respond to treatment with pain modulators or proton pump inhibitors (PPIs); behavior disorders might contribute to lack of treatment efficacy. We aimed to assess the prevalence of behavioral disorders and their effects on typical reflux symptoms in patients with RH. METHODS: We performed a retrospective study of 542 patients with PPI-refractory esophageal symptoms (heartburn, regurgitation, or chest pain) or with symptoms that responded to PPI therapy, evaluated for anti-reflux surgery from January 2016 through August 2019 at a single center in London, United Kingdom. We collected data on symptoms, motility, and impedance-pH monitoring and assigned patients to categories of RH (n = 116), functional heartburn (n = 126), or non-erosive reflux disease (n = 300). RESULTS: Of the 116 patients with a diagnosis of RH, 59 had only hypersensitivity, whereas 57 patients (49.2%) had either excessive supragastric belching (SGB, 39.7%), based on 24-hour impedance-pH monitoring, or rumination (9.5%), based on postprandial manometry combined with impedance. The prevalence of SGB and rumination in patients with RH was significantly higher than in patients with functional heartburn (22%; P < .001). Patients with RH and rumination were significantly younger (P = .005) and had the largest number of non-acid reflux episodes (P = .023). In patients with RH with SGB, SGB episodes were associated with 40.6% of marked reflux symptoms (heartburn, regurgitation, or chest pain), based on impedance-pH monitoring. In patients with RH and rumination, 40% of reflux-related symptoms (mostly regurgitation) were due to possible rumination episodes. CONCLUSIONS: Almost half of patients with a diagnosis of RH have behavior disorders, including excessive SGB or rumination. Episodes of SGB or rumination are associated with typical reflux symptoms. Segregation of patients with diagnosis of RH into those with vs without behavioral disorders might have important therapeutic implications.

Vonoprazan shows efficacy similar to that of proton pump inhibitors with respect to symptomatic, endoscopic, and histological responses in patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic allergic disease with esophageal symptoms and intraepithelial eosinophil infiltration. Effects of potassium-competitive acid blockers (P-CABs) on EoE have not been elucidated. We aimed to examine and compare the effects of P-CABs and PPIs on symptomatic, endoscopic, and histological responses of patients with EoE. METHODS: We analyzed 118 EoE patients who received PPI or P-CAB therapy with rabeprazole 10 mg (RPZ10, N = 22), rabeprazole 20 mg (RPZ20, N = 34), esomeprazole 20 mg (EPZ20, N = 25), or vonoprazan 20 mg (VPZ20, N = 33). We evaluated symptomatic responses by classifying the patients into three groups: complete relief, partial relief, and no change. Endoscopic responses were evaluated using the endoscopic reference score (EREFS) following PPI or P-CAB therapy. Histological responses were evaluated by determining eosinophil counts in esophageal biopsy samples and classifying the patients into two groups: complete remission [0/1 eosinophil/high-power field (eos/HPF)] and remission (< 15 eos/HPF). RESULTS: There were no differences among the therapy groups in terms of clinical characteristics, endoscopic findings, and histological findings of the patients before treatment. The rate of complete relief in clinical symptoms was 54.5% in the RPZ10 group, 64.7% in the RPZ20 group, 72.0% in the EPZ20 group, and 75.7% in the VPZ20 group. There were no significant differences in the therapeutic effect among the therapy groups. Similarly, endoscopic and histological complete remission rates were not significantly different among the therapy groups. CONCLUSIONS: Vonoprazan showed similar efficacy to PPIs in EoE.

Effect of EP1 Receptor Antagonist on Transient Lower Esophageal Sphincter Relaxations in Humans.

BACKGROUND/AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal reflux. Recently, an EP1 receptor antagonist, ONO-8539, showed the reduction of TLESRs in monkeys. However, its effect on TLESRs in humans remains unclear. This study investigated the effect of ONO-8539 on postprandial TLESRs in healthy male subjects. METHODS: Twenty-seven subjects participated in this placebo-controlled, cross-over study. The subjects received either placebo or ONO-8539 (450 mg) after a standardized breakfast. A 30-min basal recording was performed 4 h after drug administration. Subsequently, TLESR recordings were performed after a high-fat test meal for 3 h. The examination was repeated at least 7 days from the first evaluation for washout. RESULTS: Thirteen patients were ultimately analyzed. The basal lower esophageal sphincter pressure was not different between the 2 groups (16.3 and 18.0 mm Hg for placebo and ONO-8539, respectively; p = 0.88). ONO-8539 significantly reduced the number of TLESRs from 15.0 to 12.0 for 3 h (p < 0.05). The proportion of terminating events of TLESRs was significantly different between the 2 groups (p < 0.05). No events and swallowing terminated more TLESRs with ONO-8539 than with placebo. CONCLUSIONS: ONO-8539 suppressed TLESRs mildly. EP1 receptor may be involved with the mechanism of human TLESRs.

[A case of excessive supragastric belching treated with cognitive behavioral therapy].

A 52-year-old woman had a 6-month history of frequent belching;however, esophagogastroduodenoscopy revealed no abnormal findings. She presented to our department with belching refractory to several medications. Abdominal radiography revealed no massive gas in the stomach and intestine. She had frequent belching during the medical interview but no belching during speaking. Findings from high-resolution esophageal manometry and esophageal impedance pH monitoring confirmed supragastric belching. Thus, she was diagnosed as having excessive supragastric belching, which improved with cognitive behavioral therapy.

Persistent Postprandial Regurgitation vs Rumination in Patients With Refractory Gastroesophageal Reflux Disease Symptoms: Identification of a Distinct Rumination Pattern Using Ambulatory Impedance-pH Monitoring.

OBJECTIVES: Up to 20% of patients with refractory gastroesophageal reflux disease (GERD) might have postprandial rumination. The aim of this study was to distinguish persistent GERD-related postprandial regurgitation from rumination in patients with refractory GERD undergoing ambulatory multichannel intraluminal impedance-pH (MII-pH) monitoring. METHODS: We first characterized 24-hour and postprandial MII-pH patterns in 28 consecutive patients with confirmed rumination syndrome (positive clinical and high-resolution manometry/impedance). We compared such MII-pH patterns with those from 30 patients with typical GERD symptoms (10 nonerosive reflux disease, 10 hyperactive esophagus, and 10 functional heartburn) and 27 healthy controls. Using ROC curves, we selected the best MII-pH parameters to prepare an MII-pH rumination score. We prospectively tested the performance of the new MII-pH rumination score in 26 consecutive patients with refractory GERD (predominant regurgitation). RESULTS: Compared with GERD controls, patients with rumination were more often females, younger, and had significantly more postprandial early nonacid reflux episodes with high proximal extent. Postprandial reflux in ruminators had a distinct nadir pH profile over time (from nonacid to acid). Despite increased reflux events, baseline impedance in ruminators was similar to that in healthy subjects. Ruminators marked postprandial symptoms earlier and much more often than patients with GERD. An MII-pH-based rumination score (using postprandial nonacid reflux/hour and Symptom Index) diagnosed rumination in 46% of patients with refractory GERD and persistent regurgitation (sensitivity 91.7% and specificity 78.6%). DISCUSSION: Postprandial rumination is very common in refractory GERD with persistent regurgitation. A simple MII-pH score detects rumination in these patients with high sensitivity and specificity.

Optimal Biopsy Protocol to Evaluate Histological Effectiveness of Proton Pump Inhibitor Therapy in Patients with Eosinophilic Esophagitis.

OBJECTIVE: Recent guidelines propose that both proton pump inhibitor (PPI) responders and nonresponders are included in eosinophilic esophagitis (EoE). Although multiple biopsies should be required to diagnose EoE because of patchy distribution of esophageal eosinophils, it is unclear whether multiple biopsies are required to evaluate histological effectiveness of PPI therapy. This study aimed to determine the optimal biopsy protocol after PPI therapy in patients with EoE. METHODS: Of 110 EoE patients, 22 PPI nonresponders were enrolled. Intraepithelial eosinophils were counted in areas of high density in multiple biopsy specimens after PPI therapy. The prevalence of esophageal eosinophilia and peak eosinophil counts after PPI therapy was analyzed according to the biopsy sites and endoscopic findings. Positive predictive value (PPV) was calculated according to the number of biopsies. RESULTS: Of 124 biopsies, 59 (47.6%) specimens showed esophageal eosinophilia (≥15 per high-power field). Eosinophil counts were significantly higher in specimens from the lower esophagus than in those from the upper esophagus but not in those from the middle esophagus. Prevalence of esophageal eosinophilia was 76.2, 40.9, and 24.3% in the lower, middle, and upper esophagus respectively. PPI nonresponders were diagnosed in all cases with 4 biopsy specimens obtained from the lower and middle esophagus, showing that PPV for non-effectiveness of PPI therapy was 0.910 (95% CI 0.773-1.000). The prevalence of esophageal eosinophilia and peak eosinophil counts was higher in cases with white plaques and linear furrows. CONCLUSION: Multiple biopsies should be required to evaluate histological effectiveness of PPI therapy in patients with EoE. Four biopsies from the lower and middle esophagus may be sufficient.

Changes in Clock Genes Expression in Esophagus in Rat Reflux Esophagitis.

BACKGROUND: Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Clock genes harmonize circadian rhythms by their periodic expression and regulate several physiological functions. However, the association between clock genes and GERD is still unknown. AIMS: We investigated whether reflux esophagitis affects circadian variability of clock genes in the esophagus and other organs using a rat reflux esophagitis model. METHODS: Reflux esophagitis was induced in 7-week-old male Wistar rats. Sham-operated rats were used as controls. Rats were killed at 09:00 (light period) and 21:00 (dark period) 3 days (acute phase) and 21 days (chronic phase) after induction of esophagitis. The expression levels of clock gene mRNAs such as Per1, Per2, Per3, Cry1, Cry2, Arntl, and Clock in the esophagus were investigated by qPCR. Arntl expression was examined in stomach, small intestine, colon, and liver tissues. Serum melatonin and IL-6 levels were measured by ELISA. RESULTS: Histological examination of reflux esophagitis mainly revealed epithelial defects with marked inflammatory cell infiltration in the acute phase and mucosal thickening with basal cell hyperplasia in the chronic phase. Circadian variability of clock genes, except Cry1, was present in the normal esophagus and was completely disrupted in reflux esophagitis during the acute phase. The circadian variability of Per2, Per3, and Arntl returned to normal, but disruption of Per1, Cry2, and Clock was present in the chronic phase. Disruption of circadian variability of Arntl was observed in the esophagus, as well as in the stomach, small intestine, and liver tissues in reflux esophagitis during the acute phase. There were no significant differences in serum melatonin and IL-6 levels between control and reflux esophagitis animals in both acute and chronic phases. CONCLUSIONS: Disruption to circadian variability of clock genes may play a role in the pathogenesis of GERD.

Expression of Serum Exosomal and Esophageal MicroRNA in Rat Reflux Esophagitis.

Gastroesophageal reflux disease (GERD) is a common upper gastrointestinal disease. However, the role of exosomal microRNAs (miRNAs) and esophageal miRNAs in GERD has not been studied. A rat model of acid reflux esophagitis was used to establish a novel diagnosis marker for GERD and examine dynamics of miRNA expression in GERD. Rats were sacrificed 3 (acute phase), 7 (sub-acute phase) and 21 days (chronic phase) after induction of esophagitis. Exosomes were extracted from serum, and the expression patterns of serum miRNAs were analyzed. Four upregulated miRNAs (miR-29a-3p, 128-3p, 223-3p and 3473) were identified by microarray analysis. The expression levels of exosomal miR-29a-3p were significantly higher in the chronic phase of reflux esophagitis compared with controls, and increased expression of miR-29a-3p was specific to chronic reflux esophagitis. Esophageal miR-223-3p expression was higher compared with controls, and gradually decreased from acute to chronic phase in esophagitis. In conclusion, exosomal miR-29a-3p and esophageal miR-223-3p might play roles in GERD.