The relationship between manometric subtype and symptom details in achalasia.

BACKGROUND: Although dysphagia and chest pain are the two most common symptoms in patients with achalasia, the mechanism of evoking symptoms is still unknown. The aim of this study was to reveal the relationship between symptoms and the subtypes of achalasia defined by the Chicago classification. METHODS: A total of 71consecutive patients with newly diagnosed achalasia were enrolled between March 2009 and December 2017. Esophageal motility was assessed by high-resolution manometry (HRM) with the Chicago classification v 3.0. and esophagograms. Their symptoms were evaluated with structured self-reported questionnaires focused on dysphagia and chest pain. Symptom profiles and radiographic findings according to the manometric subtypes were investigated. RESULTS: Among the total 71 patients, 69 patients (97%) had dysphagia and 39 patients (54%) had chest pain. Regarding dysphagia, type II patients reported dysphagia in the throat the most, while types I and III patients mostly felt it in the epigastrium. Type II patients often felt dysphagia at the time of swallowing (41%), but this was reported in only 8.7% of Type I and 33% of Type III patients (p = 0.02). Concerning chest pain, Type I patients rarely had pain during meals (14%), but more often while sleeping (43%) and in early morning (43%), while type III patients often had pain during meals (67%). Type III patients reported that solid food caused pain more often than other types (I/II/III 0/10/33%, p = 0.09). CONCLUSIONS: Detailed symptoms of achalasia, such as its site and timing, varied by subtypes. The status of the esophageal body might induce those differences in symptoms.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021.

In Japan, with the increasing prevalence of gastroesophageal reflux disease (GERD) and growing public interest, the Japanese Society of Gastroenterology issued Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009 and a revised 2nd edition in 2015. A number of studies on GERD were subsequently conducted in Japan and abroad, and vonoprazan, a potassium-competitive acid blocker (P-CAB), became available for the first time in Japan in February 2015. The revised 3rd edition (Japanese edition), which incorporates new findings and information, was published in April 2021. These guidelines are summarized herein, particularly sections related to the treatment of GERD. The important clinical issues addressed in the present revision are (i) the introduction of treatment algorithms that classify GERD into reflux esophagitis and non-erosive reflux disease, (ii) the clarification of treatment algorithms based on to the severity of reflux esophagitis, and (iii) the positioning of vonoprazan in the treatment for GERD. The present guidelines propose vonoprazan as the initial/maintenance treatment for severe reflux esophagitis. They also recommend vonoprazan or PPI as an initial treatment for mild reflux esophagitis and recommended PPI and proposed vonoprazan as maintenance treatment. These updated guidelines offer the best clinical strategies for GERD patients in Japan and hope that they will be of global use for the diagnosis and treatment for GERD.

High-Resolution Manometry Thresholds and Motor Patterns Among Asymptomatic Individuals.

OBJECTIVE: High-resolution manometry (HRM) is the current standard for characterization of esophageal body and esophagogastric junction (EGJ) function. We aimed to examine the prevalence of abnormal esophageal motor patterns in health, and to determine optimal thresholds for software metrics across HRM systems. DESIGN: Manometry studies from asymptomatic adults were solicited from motility centers worldwide, and were manually analyzed using integrated relaxation pressure (IRP), distal latency (DL), and distal contractile integral (DCI) in standardized fashion. Normative thresholds were assessed using fifth and/or 95th percentile values. Chicago Classification v3.0 criteria were applied to determine motor patterns across HRM systems, study positions (upright vs supine), ages, and genders. RESULTS: Of 469 unique HRM studies (median age 28.0, range 18-79 years). 74.6% had a normal HRM pattern; none had achalasia. Ineffective esophageal motility (IEM) was the most frequent motor pattern identified (15.1% overall), followed by EGJ outflow obstruction (5.3%). Proportions with IEM were lower using stringent criteria (10.0%), especially in supine studies (7.1%-8.5%). Other motor patterns were rare (0.2%-4.1% overall) and did not vary by age or gender. DL thresholds were close to current norms across HRM systems, while IRP thresholds varied by HRM system and study position. Both fifth and 95th percentile DCI values were lower than current thresholds, both in upright and supine positions. CONCLUSIONS: Motor abnormalities are infrequent in healthy individuals and consist mainly of IEM, proportions of which are lower when using stringent criteria in the supine position. Thresholds for HRM metrics vary by HRM system and study position.

Esophagogastric junction morphology and contractile integral on high-resolution manometry in asymptomatic healthy volunteers: An international multicenter study.

BACKGROUND: Esophagogastric junction contractile integral (EGJ-CI) and EGJ morphology are high-resolution manometry (HRM) metrics that assess EGJ barrier function. Normative data standardized across world regions and HRM manufacturers are limited. METHODS: Our aim was to determine normative EGJ metrics in a large international cohort of healthy volunteers undergoing HRM (Medtronic, Laborie, and Diversatek software) acquired from 16 countries in four world regions. EGJ-CI was calculated by the same two investigators using a distal contractile integral-like measurement across the EGJ for three respiratory cycles and corrected for respiration (mm Hg cm), using manufacturer-specific software tools. EGJ morphology was designated according to Chicago Classification v3.0. Median EGJ-CI values were calculated across age, genders, HRM systems, and regions. RESULTS: Of 484 studies (28.0 years, 56.2% F, 60.7% Medtronic studies, 26.0% Laborie, and 13.2% Diversatek), EGJ morphology was type 1 in 97.1%. Median EGJ-CI was similar between Medtronic (37.0 mm Hg cm, IQR 23.6-53.7 mm Hg cm) and Diversatek (34.9 mm Hg cm, IQR 22.1-56.1 mm Hg cm, P = 0.87), but was significantly higher using Laborie equipment (56.5 mm Hg cm, IQR 35.0-75.3 mm Hg cm, P < 0.001). 5th percentile EGJ-CI values ranged from 6.9 to 12.1 mm Hg cm. EGJ-CI values were consistent across world regions, but different between manufacturers even within the same world region (P ≤ 0.001). Within Medtronic studies, EGJ-CI and basal LESP were similar in younger and older individuals (P ≥ 0.3) but higher in women (P < 0.001). CONCLUSIONS: EGJ morphology is predominantly type 1 in healthy adults. EGJ-CI varies widely in health, with significant gender influence, but is consistent within each HRM system. Manufacturer-specific normative values should be utilized for clinical HRM interpretation.

Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world.

OBJECTIVE: Limitations of existing impedance-pH thresholds include small sample size of normative studies, inclusion of artefactual pH drops and incorrect identification of impedance reflux events. We aimed to obtain new impedance-pH thresholds from expert consensus analysis of tracings from a large number of healthy subjects. DESIGN: Of 541 studies performed worldwide using two different systems (Diversatek, USA, and Laborie, Netherlands), 150 tracings with oesophageal diagnoses, behavioural disorders and study-related artefacts were excluded. The remainder studies were subject to two reviewer consensus analysis, in-person or through video conference, consisting of editing meals and pH drops, identification of impedance reflux and postreflux swallow-induced peristaltic wave (PSPW) using strict pre-established criteria and measurement of distal mean nocturnal baseline impedance (MNBI). RESULTS: Consensus analysis was performed in 391 tracings (age 32.7 years, range 18-71, 54.2% female). Normative thresholds were significantly different between Diversatek and Laborie (total acid exposure time: 2.8% and 5%; reflux episodes: 55 and 78; MNBI at 3 cm: 1400 and 1500 ohms, at 5 cm: 1400 and 1800 ohms). Males had higher acid exposure, more reflux episodes and lower MNBI. Significant regional differences were identified, including higher PSPW scores in Western countries, and higher MNBI in Asia using Diversatek, and higher acid exposure in the Netherlands, higher MNBI in Asia and South Africa, and lower MNBI in Turkey using Laborie. CONCLUSION: Normal impedance-pH monitoring thresholds have regional and system-related differences. Clinical interpretation needs to use normal thresholds valid for the system used and world region, following careful editing of the tracings.

Supragastric belching in Japan: lower prevalence and relevance for management of gastroesophageal reflux disease compared to United Kingdom.

BACKGROUND: Supragastric belching (SGB) may play a role in the pathophysiology of proton pump inhibitors (PPIs)-refractoriness in gastroesophageal reflux disease (GERD). SGB may be present in up to 40% of reflux symptoms in PPI-refractory GERD. Most reports on SGB have come from Western countries, and little is known about the prevalence and relevance of SGB in Asian refractory GERD patients. This study aimed at comparing the role of SGB in GERD patients in Japan and the UK. METHODS: We re-analyzed impedance-pH monitoring tracings from patients who were referred to tertiary centers in Japan and the UK due to PPI-refractory reflux symptoms. The prevalence of excessive SGB and the impact of SGB on reflux symptoms were compared between the two countries. RESULTS: Impedance-pH tracings from124 Japanese and 83 British patients were re-analyzed. Japanese patients were significantly younger and had smaller body mass index than the British (P < 0.001). Japanese patients had significantly lower prevalence of excessive SGB (18.5%) than the UK (36.1%) irrespective of reflux phenotype (P = 0.006). Logistic regression analysis showed that the geographical/cultural difference was the only factor associated with the different prevalence of SGB (odds ratio; 2.91, 95% CI 1.09-7.73, P = 0.032). SGB were related to typical reflux symptoms very rarely in Japan [0% (0-4.9)] compared to the UK [35% (0-54.1)] (P = 0.071). CONCLUSIONS: The prevalence of SGB and their impact on reflux symptoms is significantly lower in Japan compared to the UK. The difference is not related to reflux parameters but might come from ethnic/cultural factors to be further characterized.

Randomised trial of acid inhibition by vonoprazan 10/20 mg once daily vs rabeprazole 10/20 mg twice daily in healthy Japanese volunteers (SAMURAI pH study).

BACKGROUND: Vonoprazan (V), a potassium-competitive acid blocker, has a more durable acid-inhibitory effect as compared with standard-dose proton pump inhibitors (PPIs) but has not been compared with 2-4 times higher daily PPI doses administered in two divided doses. AIMS: To evaluate the acid-inhibitory effect of V 10/20 mg once-daily (OD; V10/V20) vs rabeprazole (R) 10/20 mg twice-daily (BID; R20/R40) in healthy Japanese volunteers. METHODS: This multicentre, randomised, open-label, two-period, crossover study compared V10 or V20 vs R20, or V20 vs R40 using three cohorts of 10 healthy Japanese adults. Within each cohort, subjects were randomised to receive V or R for 7 days and, following a washout period ≥7 days, the other treatment for 7 days. On day 6 of each period, 24-hours multichannel gastric impedance-pH monitoring was performed. Percent times pH ≥ 3, ≥4 and ≥5 (pH 3, 4 and 5 holding time ratios [HTRs]) in 24 hours were evaluated as primary pharmacodynamic endpoints. RESULTS: Acid-inhibitory effect (24-hours pH 3 HTR) of V20 was greater than those of R20 (91.0% vs 65.3%; P = .0049) and R40 (98.5% vs 85.9%; P = .0073). Similar results were obtained for 24-hours pH 4 and 5 HTRs. V20 also achieved greater nocturnal pH 4 (91.5% vs 73.2%; P = .0319) and 5 HTRs (78.8% vs 62.2%; P = .0325) as compared with R40. One subject (20%) developed diarrhoea while receiving R40 which was considered treatment-related. CONCLUSIONS: Compared with 2-4 times the standard daily dose of R, V20 exerts a more potent and durable acid-inhibitory effect. Trial identifier: UMIN000022198 (www.umin.ac.jp/ctr/index.htm).

Efficacy of Vonoprazan, a Novel Potassium-Competitive Acid Blocker, in Patients with Proton Pump Inhibitor-Refractory Acid Reflux.

BACKGROUND/AIM: We evaluated the efficacy of vonoprazan (VPZ), a novel potassium-competitive acid blocker, in patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD), exhibiting continued pathological esophageal acid exposure (EAE). METHODS: Despite ≥8 weeks of appropriate PPI therapy, patients with -persistent reflux symptoms and pathological EAE times (EAETs ≥4%) were invited to switch to VPZ treatment. After an 8-week-course of once-daily VPZ (20 mg), multichannel intraluminal impedance-pH (MII-pH) monitoring was repeated to compare gastric acid exposure times (GAETs), EAETs, and other reflux parameters relative to the baseline values. Before each MII-pH study, reflux symptom severities were scored using the Gastrointestinal Symptom Rating Scale; erosive esophagitis and fasting plasma gastrin levels were also assessed. RESULTS: From among the 124 patients undergoing MII-pH monitoring, 13 patients (median age, 69 years; females, 64%) were monitored at baseline (while on PPI therapy) and after VPZ therapy. The median GAET associated with VPZ treatment (23.8%) was less than that for PPI treatment (41.1%; p = 0.01), including both daytime and nighttime measurements. VPZ therapy resulted in better median EAET values (4.5%) than did PPI therapy (10.6%) during the 24-h monitoring period (p = 0.055). EAE normalization was achieved in 46% of VPZ-treated patients and was associated with complete gastric acid suppression (p = 0.005). After switching to VPZ, reflux symptoms (p < 0.01) and erosive esophagitis (p = 0.01) improved. CONCLUSION: In patients with PPI-refractory GERD, VPZ provides more potent gastric acid suppression, more effective EAE control, enhanced symptom improvement, and better esophagitis healing than PPIs.

Clinical impact of different cut-off values in high-resolution manometry systems on diagnosing esophageal motility disorders.

BACKGROUND: The values of the parameters in the Chicago classification measured by a high-resolution manometry (HRM) system with the Unisensor catheter (Starlet) are significantly different from those measured by the ManoScan. The contraction vigor is categorized by values of the distal contractile integral (DCI) in the Chicago classification v3.0; however, reference values of the DCI in the Starlet and the clinical impact of the different reference values in the Starlet and ManoScan on diagnosing esophageal motility disorders are not known. METHODS: We evaluated data from a previous report in which ManoScan and Starlet were compared in the same subjects. The DCI values in each system were compared and reference DCI values were calculated. Moreover, diagnoses assessed by Starlet using reference values in ManoScan were compared with those using calculated reference values and those assessed by ManoScan. RESULTS: There was a significant positive correlation between the DCI values measured by ManoScan and those measured by Starlet (r = 0.80, p < 0.01). Based on a linear functional relationship considering measurement errors, the reference DCI values for diagnosing failed, weak and hypercontractile contraction vigor were calculated as 590.6, 1011.3 and 10,085.8 mmHg-s-cm, respectively, in the Starlet. Therefore, the proposed reference values in the Starlet were 500, 1000 and 10,000 mmHg-s-cm, respectively. When the reference values in the ManoScan were used in the Starlet data, approximately 30% of subjects were diagnosed inappropriately. This issue was resolved using the proposed reference values in the Starlet. CONCLUSION: Recognizing systemic differences in HRM systems is important.

Development of a Rapid and Versatile Method of Enzyme-Linked Immunoassay Combined with Immunoaffinity Column for Aflatoxin Analysis.

We combined immunoaffinity column (IAC) and enzyme-linked immunosorbent assay (ELISA) methods to develop a rapid method to analyze total aflatoxin (AF) in foods, using a large number of samples. Using newly developed monoclonal antibodies, with high cross-reactivity and high organic solvent tolerance, we developed the IAC-ELISA method. Our IAC-ELISA method showed a good correlation with the high-performance liquid chromatography method for corn samples spiked with total AF. Certain food samples, such as chili powder, chocolate, green coffee beans, and roasted coffee beans, are difficult to measure owing to their matrices, which affect ELISA adversely. Our IAC-ELISA method clearly improved the recovery rates (79 to 109%) compared with the ELISA method (97 to 164%) for four food samples. Our method is simple and quick; thus, it may be ideal for routine inspections.

Relationship between esophageal motility abnormalities and skin or lung involvements in patients with systemic sclerosis.

BACKGROUND: Esophageal motility abnormalities (EMAs) and interstitial lung diseases (ILDs) are often seen in patients with systemic sclerosis (SSc). Gastroesophageal reflux disease (GERD) could be associated with ILDs, but it is not fully understood if ILDs are caused by GERD or SSc itself. METHODS: A total of 109 patients with SSc who underwent high-resolution manometry were enrolled. Esophageal motility was diagnosed with the Chicago classification v3.0. The severity of skin thickness was evaluated by the modified Rodnan total skin thickness score (mRSS). The severity of ILDs was assessed with the chest high-resolution computer tomography (HRCT) scoring system. Relationships between EMAs, GERD, autoantibodies, skin thickness and ILDs were evaluated. RESULTS: 44 patients had normal esophageal motility, eight had esophago-gastric junction outflow obstruction, one had distal esophageal spasm, 27 had ineffective esophageal motility and 29 had absent contractility (AC). Patients with AC had more GERD than those with normal esophageal motility (p < 0.05). The mRSS score in patients with AC was significantly higher than that in those with normal esophageal motility (p < 0.05). The HRCT score in patients with AC tended to be higher than that in those with normal esophageal motility (p = 0.05). A multivariable analysis showed that severe skin thickness was a significant predictor of AC. GERD was not a significant predictor for ILDs. CONCLUSIONS: There were significant correlations between EMAs and severe skin thickness. GERD is not an etiology of ILDs.

Impact of a Single Oral Acute Dose of Aflatoxin B1 on Liver Function/Cytokines and the Lymphoproliferative Response in C57Bl/6 Mice.

Aflatoxin B1 (AFB1), a mycotoxin found in food and feed, exerts harmful effects on humans and animals. The liver is the earliest target of AFB1, and its effects have been evaluated in animal models exposed to acute or chronic doses. Considering the possibility of sporadic ingestion of AFB1-contaminated food, this study investigated the impact of a single oral dose of AFB1 on liver function/cytokines and the lymphoproliferative response in mice. C57BL/6 mice were treated with a single oral AFB1 dose (44, 442 or 663 µg AFB1/kg of body weight) on the first day. Liver function (ALT, γ-GT, and total protein), cytokines (IL-4, IFN-γ, and IL-17), histopathology, and the spleen lymphoproliferative response to mitogens were evaluated on the 5th day. Although AFB1 did not produce any significant changes in the biochemical parameters, 663 µg AFB1/kg-induced hepatic upregulation of IL-4 and IFN-γ, along with liver tissue injury and suppression of the lymphoproliferative response to ConA (p < 0.05). In conclusion, a single oral dose of AFB1 exposure can induce liver tissue lesions, liver cytokine modulation, and immune suppression in C57BL/6 mice.

Increase of transient lower esophageal sphincter relaxation associated with cascade stomach.

We previously reported that cascade stomach was associated with reflux symptoms and esophagitis. Delayed gastric emptying has been believed to initiate transient lower esophageal sphincter relaxation (TLESR). We hypothesized that cascade stomach may be associated with frequent TLESR with delayed gastric emptying. Eleven subjects with cascade stomach and 11 subjects without cascade stomach were enrolled. Postprandial gastroesophageal manometry and gastric emptying using a continuous 13C breath system were measured simultaneously after a liquid test meal. TLESR events were counted in early period (0-60 min), late period (60-120 min), and total monitoring period. Three parameters of gastric emptying were calculated: the half emptying time, lag time, and gastric emptying coefficient. The median frequency of TLESR events in the cascade stomach and non-cascade stomach groups was 6.0 (median), 4.6 (interquartile range) vs 5.0, 3.0 in the early period, 5.0, 3.2 vs 3.0, 1.8 in the late period, and 10.0, 6.2 vs 8.0, 5.0 in the total monitoring period. TLESR events were significantly more frequent in the cascade stomach group during the late and total monitoring periods. In contrast, gastric emptying parameters showed no significant differences between the two groups. We concluded that TLESR events were significantly more frequent in persons with cascade stomach without delayed gastric emptying.

New endoscopic classification of cascade stomach, a risk factor for reflux esophagitis.

BACKGROUND: We recently demonstrated that cascade stomach detected by barium studies was correlated with upper gastrointestinal symptoms. We developed a new endoscopic classification of cascade stomach and examined its relationship with reflux esophagitis. METHODS: Study 1: the classification (grades 0-3) was based on detecting a ridge that runs from the cardia toward the anterior wall crossing the greater curvature. Inter-observer variation was evaluated by kappa statistics when ten experienced endoscopists used this classification three times each. Study 2: in 710 consecutive subjects (500 men and 210 women) undergoing endoscopic screening, the grade of cascade stomach and incidence of reflux esophagitis were compared. RESULTS: In study 1, the kappa values at the third assessment were 0.85, 0.58, 0.50, and 0.78 for each grade, respectively, while overall agreement was 0.68. In study 2, the incidence of reflux esophagitis in men was 20 % in grade 0, 17 % in grade 1, 25 % in grade 2, and 30 % in grade 3, showing significant differences. Among women, the incidence of reflux esophagitis in each grade was 9, 3, 6, and 35 %, respectively, also showing significant differences. Multivariate analysis showed that independent risk factors for reflux esophagitis were cascade stomach (odds ratio = 2.20), body mass index, and hiatus hernia in men, as well as cascade stomach (odds ratio = 9.01) and smoking tobacco in women. CONCLUSIONS: This endoscopic classification of cascade stomach showed acceptable inter-observer variation. Cascade stomach is a risk factor for reflux esophagitis.

Exposure Assessment of Infants to Aflatoxin M1 through Consumption of Breast Milk and Infant Powdered Milk in Brazil.

Aflatoxin M1 (AFM1) is an important biomarker that can be used to evaluate aflatoxin exposure in both humans and animals. The aim of this study was to evaluate the exposure degree of infants to AFM1 through consumption of breast milk and infant powdered milk in Brazil. For this purpose, the estimated daily intake (EDI) for infants was calculated based on the AFM1 levels analyzed in 94 breast milk (BM) samples collected in Southern Brazil, and 16 infant powdered milk (IPM) samples commonly commercialized in Brazil. AFM1 was detected in 5.3% (n = 5) and 43.8% (n = 7) of BM and IPM samples, with mean levels of 0.003 ng/g and 0.011 ng/g, respectively. All the IPM samples showed AFM1 levels lower than those established by the Brazilian guidelines (5 ng/g), and in most of the samples (81.25%) levels were below the maximum limit tolerated by the European Commission (0.025 ng/g). The EDI of AFM1 for infants aged zero to 12 months old showed values from 0.018 to 0.069 ng/kg body weight/day for BM, and 0.078 to 0.306 ng/kg body weight/day for IPM. Hazard index (HI) values for BM and IPM were less than one, except for IPM intended for infants up to one month. In conclusion, the exposure of infants to AFM1 was low, but continuous monitoring of mycotoxin levels is essential to minimize infant health risk.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015.

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

Liquid-containing Refluxes and Acid Refluxes May Be Less Frequent in the Japanese Population Than in Other Populations: Normal Values of 24- hour Esophageal Impedance and pH Monitoring.

BACKGROUND/AIMS: Twenty-four-hour esophageal impedance and pH monitoring allows detection of all types of reflux episodes and is considered the best technique for identifying gastroesophageal refluxes. However, normative data for the Japanese population are lacking. This multicenter study aimed to establish the normal range of 24-hour esophageal impedance and pH data both in the distal and the proximal esophagus in Japanese subjects. METHODS: Forty-two healthy volunteers (25 men and 17 women) with a mean ± standard deviation age of 33.3 ± 12.4 years (range: 22-72 years) underwent a combined 24-hour esophageal impedance and pH monitoring. According to the physical and pH properties, distal or proximal esophageal reflux events were categorized. RESULTS: Median 45 reflux events occurred in 24 hours, and the 95th percentile was 85 events. Unlike previous reports, liquid-containing reflux events are median 25/24 hours with the 95th percentile of 62/24 hours. Acidic reflux events were median 11/24 hours with the 95th percentile of 39/24 hours. Non-acidic gas reflux events were median 15/24 hours with the 95th percentile of 39/24 hours. Proximal reflux events accounted for 80% of the total reflux events and were mainly non-acidic gas refluxes. About 19% of liquid and mixed refluxes reached the proximal esophagus. CONCLUSIONS: Unlike previous studies, liquid-containing and acidic reflux events may be less frequent in the Japanese population. Non-acidic gas reflux events may be frequent and a cause of frequent proximal reflux events. This study provides important normative data for 24-hour impedance and pH monitoring in both the distal and the proximal esophagus in the Japanese population.