Usefulness of baseline impedance in patients with proton pump inhibitor-refractory nonerosive reflux disease.

BACKGROUND AND AIM: Approximately more than half of patients with non-erosive reflux disease (NERD) do not respond to proton pump inhibitor (PPI) therapy. Although NERD is a heterogeneous entity, previous study showed that multichannel intraluminal impedance (MII)-pH monitoring could distinguish reflux-related disease from PPI-refractory NERD. The aim of this study was to examine the usefulness of baseline impedance in PPI-refractory NERD patients. METHODS: We used MII-pH monitoring to analyze reflux parameters, symptom index (SI), and baseline impedance in 37 PPI-refractory NERD patients on PPI. Reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified as having reflux-related disease based on abnormal reflux parameters or positive SI (≥ 50%), or non-reflux-related disease, including functional heartburn, based on negative SI with normal reflux parameters. RESULTS: A total of 26 of the 37 subjects were diagnosed with reflux-related disease, including eight with acid-reflux type and 18 with non-acid-reflux type, and nine with functional heartburn and two with pseudohypersalivation. There were no significant differences in the clinical characteristics of the acid-reflux type, non-acid-reflux type, and functional heartburn groups. The baseline impedance value in the acid-reflux type (1245 ± 392 Ω) was significantly lower than that in the non-acid-reflux type (2824 ± 1160 Ω) and functional heartburn (3546 ± 1353 Ω) groups. Baseline impedance values inversely correlated with reflux percent time, acid-reflux time, and acid exposure time. CONCLUSION: Among patients with PPI-refractory NERD, acid-reflux type was associated with lower baseline impedance compared with non-acid-reflux type and functional heartburn.

Rebamipide Alters the Esophageal Microbiome and Reduces the Incidence of Barrett's Esophagus in a Rat Model.

BACKGROUND: Barrett's esophagus (BE) is characterized by a distinct Th2-predominant cytokine profile. However, antigens that shift the immune response toward the Th2 profile are unknown. AIM: We examined the effects of rebamipide on the esophageal microbiome and BE development in a rat model. METHODS: BE was induced by esophagojejunostomy in 8-week-old male Wistar rats. Rats were divided into control and rebamipide-treated group receiving either a normal or a 0.225 % rebamipide-containing diet, respectively, and killed 8, 16, 24, and 32 weeks after the operation. PCR-amplified 16S rDNAs extracted from esophageal samples were examined by terminal-restriction fragment length polymorphism (T-RFLP) analysis to assess microbiome composition. The dynamics of four bacterial genera (Lactobacillus, Clostridium, Streptococcus, and Enterococcus) were analyzed by real-time PCR. RESULTS: The incidences of BE in the control and rebamipide group at 24 and 32 weeks were 80 and 100, and 20 and 33 %, respectively. T-RFLP analysis of normal esophagus revealed that the proportion of Clostridium was 8.3 %, while that of Lactobacillales was 71.8 %. The proportions of Clostridium increased and that of Lactobacillales decreased at 8 weeks in both groups. Such changes were consistently observed in the control but not in the rebamipide group. Clostridium and Lactobacillus expression was lower and higher, respectively, in the rebamipide group than in the control group. CONCLUSIONS: Rebamipide reduced BE development and altered the esophageal microbiome composition, which might play a role in BE development.

Intra-gastric pH following single oral administrations of rabeprazole and esomeprazole: double-blind cross-over comparison.

Comparisons between the acid inhibitory effects of rabeprazole and esomeprazole after single oral administration with standard doses have not been previously presented. We examined intra-gastric pH after oral administrations of these two proton pump inhibitors using 24-h pH monitoring. Fifty-four normal volunteers not infected by Helicobacter pylori were investigated. Using a cross-over design, we administered 10 mg of rabeprazole or 20 mg of esomeprazole in 27 at 30 min after supper and in the remaining 27 subjects at 15 min before supper, and performed 24-h pH monitoring. Intra-gastric pH data were nearly identical when the proton pump inhibitors were taken after meals. Even if the data were compared in different CYP2C19 genotypes, rabeprazole and esomeprazole did not show the difference. In poor metabolizer, both of the drugs showed stronger acid inhibition. When taken before meals, intra-gastric pH after esomeprazole administration was slightly but not significantly higher than that observed after rabeprazole administration not only in daytime but also in nighttime period. In conclusion, rabeprazole and esomeprazole were similarly effective when administered after a meal.

Pathogenesis of proton-pump inhibitor-refractory non-erosive reflux disease according to multichannel intraluminal impedance-pH monitoring.

BACKGROUND AND AIM: Proton-pump inhibitor (PPI) therapy is the first-line treatment for gastroesophageal reflux disease; however, there are some reports of PPI failure in cases of non-erosive reflux disease (NERD). Among the pathogenic factors associated with PPI-refractory NERD, reflux other than acid reflux can not be detected by conventional pH monitoring. The purpose of this study was to clarify the usefulness of multichannel intraluminal impedance-pH (MII-pH) monitoring for PPI-refractory NERD patients and examine the pathogenesis. METHODS: We used MII-pH monitoring to examine 29 PPI-refractory NERD patients on PPI treatment. Reflux parameters, symptom index (SI: positive if ≥ 50%), and proximal migration were analyzed. The acidity of the reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified into reflux-related disease (abnormal reflux parameters or positive SI) and non-reflux-related disease (normal reflux parameters and negative SI). RESULTS: Of the 29 subjects, 21 were diagnosed with reflux-related disease, including 6 with acid reflux type and 15 with non-acid reflux type, and 8 were diagnosed with non-reflux-related disease. Of the total 1816 liquid reflux episodes, 834 showed proximal migration, which was more common in symptomatic reflux than in asymptomatic reflux. CONCLUSIONS: MII-pH monitoring could distinguish reflux-related disease (especially non-acid type) from PPI-refractory NERD. Proximal migration was associated with symptomatic reflux in PPI-refractory NERD patients.

Association between left-handedness and gastrointestinal symptoms.

OBJECTIVE: Several studies have shown associations between left-handedness and several chronic diseases such as bronchial asthma and inflammatory bowel disease. Perceptual responses within the brain-gut axis play a crucial role in the development of the cardinal symptoms of functional gastrointestinal (GI) diseases, including dyspepsia and irritable bowel syndrome (IBS). The aim of this study was to determine the association between left-handedness and GI symptoms or diseases. METHODS: 2,447 Japanese who underwent a routine health check-up were asked to complete a self-report questionnaire regarding age, gender, writing handedness and GI symptoms experienced over the past 3 months, including heartburn, acid regurgitation, epigastric pain, postprandial fullness, abdominal pain/discomfort, nausea and/or chest pain. Symptoms were positive when their frequency was 2 to 3 days per month or more. Diagnosis of dyspepsia and IBS was performed according to the Rome III Integrative Questionnaire. RESULTS: Left-handedness was observed in 177 (7.2%) subjects. Early satiation, abdominal pain/fullness and postprandial fullness were less commonly observed in left-handed individuals. After adjustment for age and sex, left-handedness was found to be significantly associated with decreased OR for early satiation (OR = 0.43; 95% CI: 0.23-0.78). There were no significant associations between left-handedness and GERD (gastroesophageal reflux disease), dyspepsia or IBS. CONCLUSIONS: This study demonstrated a significant negative association between left-handedness and early satiation. The findings suggest that cerebral lateralization may affect the development of GI symptoms.

Prevalence of overlaps between GERD, FD and IBS and impact on health-related quality of life.

OBJECTIVE: Gastroesophageal reflux disease (GERD), functional dyspepsia (FD), and irritable bowel syndrome (IBS) are common, and have negative impacts on health-related quality of life (HR-QOL). Several studies demonstrated a significant overlap between two of these three diseases. The purpose of this study was to examine the prevalence of GERD, FD, and IBS, their overlap rates, and HR-QOL for each disease and each overlap compared with healthy controls in the Japanese general population. METHODS: We performed a cross-sectional study of Japanese workers who visited a clinic for a routine health check-up, and asked them to fill out a self-report questionnaire. Prevalence and overlap rate of GERD defined as heartburn and/or acid regurgitation at least weekly, FD and IBS based on Rome III criteria, and HR-QOL by SF-8 were examined. RESULTS: Of the 2680 eligible subjects, 207 (7.7%) were diagnosed as having GERD, 269 (10.0%) as FD, and 381 (14.2%) as IBS. Overlaps were found in 46.9% in GERD, 47.6% in FD, and 34.4% in IBS. Prevalence of overlaps in subjects with IBS was significantly lower compared with those among GERD or FD. Sufferers from GERD, FD, or IBS reported significantly poorer HR-QOL across all domains compared with controls. Overlaps significantly worsened HR-QOL in most domains except in the 'role emotional' domain. HR-QOL was particularly poor in the physical component summary for overlapping GERD and in the mental component summary for overlapping IBS. CONCLUSION: Overlaps among GERD, FD and IBS were common and worsened HR-QOL in Japanese general population.

Sleep dysfunction in Japanese patients with gastroesophageal reflux disease: prevalence, risk factors, and efficacy of rabeprazole.

BACKGROUND AND AIM: Several studies performed in Western countries demonstrate the association between sleep dysfunction and gastroesophageal reflux disease (GERD), especially when nighttime heartburn is present. The purpose of this study was to examine the prevalence and risk factors of sleep dysfunction, and the effect of rabeprazole on reflux symptoms and sleep dysfunction in Japanese GERD patients. METHODS: A total of 134 GERD patients, including 82 patients with non-erosive reflux disease (NERD), were enrolled. Patients received rabeprazole 10 mg daily for 8 weeks. Patients were asked to complete both a frequency scale for symptoms of GERD (FSSG) questionnaire and a Pittsburgh Sleep Quality Index (PSQI) questionnaire at baseline and 8 weeks after treatment. RESULTS: Sleep dysfunction defined as a PSQI score >5.5 was found in 70 (52.2%) of the GERD patients. NERD was significantly associated with sleep dysfunction compared to erosive reflux disease (OR 2.18, 95% CI 1.05-4.53). However, other factors, including nighttime heartburn, were not associated with sleep dysfunction. Rabeprazole treatment significantly decreased both the FSSG and the PSQI score. CONCLUSION: The prevalence of sleep dysfunction was high among GERD patients. NERD was identified as a risk factor for sleep dysfunction. Use of a proton-pump inhibitor led to an effective decrease in sleep dysfunction. These results suggest a different pathogenesis of sleep dysfunction in Japanese GERD patients compared to GERD patients in Western countries. However, acid plays an important role in sleep dysfunction in all patients with GERD.

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.

Long-Term Benefits of Smoking Cessation on Gastroesophageal Reflux Disease and Health-Related Quality of Life.

OBJECTIVE: Smoking is associated with gastroesophageal reflux disease (GERD). Varenicline, a nicotinic receptor partial agonist, is used to aid smoking cessation. The purpose of this study was to prospectively examine the long-term benefits of smoking cessation on GERD and health-related quality of life (HR-QOL). METHODS: Patients treated with varenicline were asked to fill out a self-report questionnaire about their smoking habits, gastrointestinal symptoms, and HR-QOL before and 1 year after smoking cessation. The prevalence of GERD, frequency of symptoms, and HR-QOL scores were compared. We also investigated associations between clinical factors and newly-developed GERD. RESULTS: A total of 141 patients achieved smoking cessation (success group) and 50 did not (failure group) at 1 year after the treatment. The GERD improvement in the success group (43.9%) was significantly higher than that in the failure group (18.2%). The frequency of reflux symptoms significantly decreased only in the success group. There were no significant associations between newly developed GERD and clinical factors including increased body mass index and successful smoking cessation. HR-QOL significantly improved only in the success group. CONCLUSIONS: Smoking cessation improved both GERD and HR-QOL. Smoking cessation should be recommended for GERD patients.

Role of Th-2 cytokines in the development of Barrett's esophagus in rats.

BACKGROUND: Barrett's esophagus is characterized by a distinct Th-2-predominant cytokine profile, unlike the pro-inflammatory nature of reflux esophagitis. The aim of this study was to examine the role of Th-2 cytokines during the development of Barrett's esophagus, using a rat model. METHODS: Barrett's esophagus was induced by Levrat's esophagojejunostomy technique in Brown-Norway (BN) rats. Rats were killed at 8, 15, 30, and 50 weeks after the operation. We studied the incidences of esophagitis and Barrett's esophagus, and the mRNA expression of cytokines and CDX2 by real-time reverse transcriptase-polymerase chain reaction and immunohistochemical staining. Finally, we compared the incidence of Barrett's esophagus in BN rats with that in Sprague-Dawley (SD) rats. RESULTS: Esophagitis was found in all rats. Barrett's esophagus appeared 8 weeks after the operation, and its incidence and length increased over time. Levels of Th-2 cytokines such as interleukin (IL)-4, IL-10, and IL-13 were significantly increased in Barrett's esophagus as compared to those in non-Barrett's esophagus, while there were no differences in the levels of pro-inflammatory cytokines. The peak of elevated IL-4 mRNA was observed before that of CDX2 mRNA. IL-4 was co-localized in CD4-positive cells and CDX2-positive goblet cells. The incidence of Barrett's esophagus was more common in BN rats (8/10, 80%) than in SD rats (2/7, 28%) at 30 weeks. CONCLUSION: Th-2 cytokines, especially IL-4, may play a crucial role in the development of Barrett's esophagus in an early phase. These results provide understanding of the pathogenesis of Barrett's esophagus from the aspect of the Th-2 immune response.

Cigarette smoking and its association with overlapping gastroesophageal reflux disease, functional dyspepsia, or irritable bowel syndrome.

BACKGROUND: Gastroesophageal reflux disease (GERD), functional dyspepsia (FD), and irritable bowel syndrome (IBS) are common gastrointestinal diseases. Several studies have shown a significant occurrence of overlap among these 3 diseases. The purpose of this study was to examine the factors associated with such disease overlap in Japanese adults. METHODS: We performed a cross-sectional study on Japanese workers who visited a clinic for a routine health check-up and asked them to fill out a self-report questionnaire. GERD was defined as episodes of heartburn and/or acid regurgitation at least once a week, and the diagnosis of FD and IBS was based on Rome III criteria. A logistic regression model was used to identify risk factors, and odds ratio (OR) was calculated with 95% confidence intervals (CIs). RESULTS: Disease overlaps were found in 160 (6.0%) of the 2680 eligible subjects. Female gender was associated with GERD + IBS (OR=1.99; 95% CI, 1.06-3.75), and FD + IBS (OR=1.72; 95% CI, 1.03-2.85), and lower body mass index was negatively associated with FD + IBS (OR=0.54; 96% CI, 0.34-0.87). Cigarette smoking was a common factor associated with the overlaps: GERD + FD (OR=2.14; 95% CI, 1.22-3.76), GERD + IBS (OR=3.16; 95% CI, 1.75-3.71), FD + IBS (OR=2.26; 95% CI, 1.40-3.66), and GERD + FD + IBS (OR=4.08; 95% CI, 1.66-10.07). The associations between smoking habits and overlaps were stronger in smokers who smoked ≥1 pack per day as compared to those who smoked <1 pack per day. CONCLUSION: Cigarette smoking was significantly associated with overlaps among GERD, FD, and IBS in Japanese adults.