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Objective: An international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ., Design: Clinical questions relevant to the afore-mentioned major issues were drafted for which expert panels formulated relevant statements and textural explanations.A Delphi method using an anonymous system was employed to develop the consensus, the level of which was predefined as ≥80% of agreement. Two rounds of voting and amendments were completed before the meeting at which clinical questions and consensus were finalised., Results: Twenty eight clinical questions and statements were finalised after extensive amendments. Critical consensus was achieved: (1) definition for the GOJ, (2) definition of the GOJZ spanning 1 cm proximal and distal to the GOJ as defined by the end of palisade vessels was accepted based on the anatomical distribution of cardiac type gland, (3) chemical and bacterial ( Helicobacter pylori ) factors as the primary causes of inflammation, metaplasia and neoplasia occurring in the GOJZ, (4) a new definition of Barrett's oesophagus (BO)., Conclusions: This international consensus on the new definitions of BO, GOJ and the GOJZ will be instrumental in future studies aiming to resolve many issues on this important anatomic area and hopefully will lead to better classification and management of the diseases surrounding the GOJ., Competing Interests: Competing interests: KS serves as an advisor for Fujifilm Medical Co. and received a lecture fee from Fujifilm Medical Co. MF received lecture fee from Olympus Medical Systems Co. and Fujifilm Medical Co. He also received research grant from Olympus Medical Systems Co, Fujifilm Medical Co. and HOYA Pentax Co. HI serves as an advisor for Olympus Medical Systems Co. HM received a lecture fee from Fujifilm Medical Co. GT and HT received lecture fees from Olympus Medical Co. and Fujifilm Medical Co. Other authors have declared no competing interests regarding this manuscript, (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. The Author(s).)

Background: Although a third of gastroesophageal reflux disease (GERD) patients are refractory to proton pump inhibitor (PPI) therapy, the underlying mechanism of the refractoriness remains unclear. We compared the level of gastric acid suppression during PPI treatment between responders and non-responders by directly measuring gastric acid secretion in GERD patients taking PPIs., Methods: Seventy-five consecutive patients receiving standard-dose PPI therapy for GERD were prospectively recruited, irrespective of persistent GERD symptoms. They were asked about their GERD symptoms using a validated questionnaire, and simultaneously underwent both a routine endoscopic examination and a gastric acid secretory testing using an endoscopic gastrin test. Associations between residual gastric acid secretion during PPI treatment and persistent GERD symptoms were analyzed by a logistic regression analysis., Results: Overall, 26 of 75 (34.7%) patients were judged to be positive for persistent GERD symptoms. The patients with and without persistent symptoms showed similar gastric acid secretion levels (1.3 [1.3] mEq/10 min vs. 1.4 [2.0] mEq/10 min). Sufficient gastric acid suppression, defined as < 0.6, was not significantly associated with persistent GERD symptoms (odds ratio 1.1, 95% confidence interval 0.40-3.5)., Conclusions: This study provided solid evidence to support that the gastric acid suppression level during PPI treatment does not differ between patients with and without persistent GERD symptoms. The insignificant role of residual gastric acid in the persistent GERD symptoms suggests that the use of medications other than those that enhance gastric acid inhibitory effects would be an essential approach for the management of PPI-refractory GERD.

Background: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress., Aims: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide., Methods: Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17β-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17β-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array., Results: In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17β-estradiol than in male rats. 17β-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage., Conclusions: Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.

Objective: Barrett's metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype., Design: Oesophageal squamous cells from patients with Barrett's oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation., Results: In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets., Conclusions: In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett's pathogenesis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The incidence of esophageal adenocarcinoma (EAC) has risen sharply in western countries over the past 4 decades. This type of cancer is considered to follow a transitional process that goes from gastro-esophageal reflux disease (GERD) to Barrett's esophagus (BE, a metaplastic condition of the distal esophagus), a precursor lesion and ultimately adenocarcinoma. This spectrum of GERD is strongly predominant in males due to an unidentified mechanism. Several epidemiologic studies have described that the prevalence of GERD, BE and EAC in women is closely related to reproductive status, which suggests a possible association with the estrogen level. Recently, we revealed in an in vivo study that the inactivation of mast cells by the anti-inflammatory function of estrogen may account for the gender difference in the GERD spectrum. Other studies have described the contribution of female steroid hormones to the gender difference in these diseases. Estrogen is reported to modulate the metabolism of fat, and obesity is a main risk factor of GERDs. Moreover, estrogen could confer esophageal epithelial resistance to causative refluxate. These functions of estrogen might explain the approximately 20-year delay in the incidence of BE and the subsequent development of EAC in women compared to men, and this effect may be responsible for the male predominance. However, some observational studies demonstrated that hormone replacement therapy exerts controversial effects in GERD patients. Nevertheless, the estrogen-related endocrine milieu may prevent disease progression toward carcinogenesis in GERD patients. The development of innovative alternatives to conventional acid suppressors may become possible by clarifying the mechanisms of estrogen.

Aim: To clarify the pathogenesis of gastroesophageal reflux disease symptoms in non-erosive reflux disease (NERD) patients., Methods: Thirty-five NERD patients with persistent symptoms, despite taking rabeprazole 10 mg twice daily for at least 8 wk, were included in this study. All patients underwent 24 h combined impedance - pH on rabeprazole. The symptom index (SI) was considered to be positive if ≥ 50%, and proximal reflux episodes were determined when reflux reached 15 cm above the proximal margin of the lower esophageal sphincter., Results: In 14 (40%) SI-positive patients, with liquid weakly acid reflux, the occurrence rate of reflux symptoms was significantly more frequent in proximal reflux episodes (46.7%) than in distal ones (5.7%) (P < 0.001). With liquid acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (38.5%) and distal ones (20.5%) (NS). With mixed liquid-gas weakly acid reflux, the occurrence rate of reflux symptoms in proximal reflux episodes was significantly more frequent (31.0%) than in distal reflux ones (3.3%) (P < 0.001). With mixed liquid-gas acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (29.4%) and distal ones (14.3%) (NS)., Conclusion: The proximal extent of weakly acidic liquid and mixed liquid-gas reflux is a major factor associated with reflux perception in SI-positive patients on proton pump inhibitor therapy.

Acid-related diseases (ARD) including gatroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) are treated by acid suppression drugs, especially proton pump inhibitor (PPI). Use of PPI as a first line therapy for ARD is recommended in various guidelines. Recently, vonoprazan, a new class of acid secretion inhibitor called potassium-competitive acid blocker (P-CAB) developed in Japan for the treatment of ARD. The drug is covered by the Japanese medical insurance for the treatment of ARD, and it is reported that Helicobacter pylori (HP) eradication rate with it is more than 90%.

Background: The features of proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) are similar to those of eosinophilic oesophagitis (EoE), but PPI-REE demonstrates symptomatic and histological responses to PPI therapy. Several studies have shown that basophils play a crucial role in the pathogenesis of allergic diseases., Aim: To identify and compare basophil infiltration in the oesophageal epithelium in patients with EoE, PPI-REE, gastroesophageal reflux disease (GERD) and normal oesophagus (controls)., Methods: Biopsy specimens from 43 patients, including 12 with EoE, 11 with PPI-REE, 10 with GERD and 10 normal oesophagus, were analysed. Immunohistochemistry was performed to quantify the number of basophils and mast cells in the oesophageal epithelium. Double immunofluorescence staining for thymic stromal lymphopoietin (TSLP) and basophils was performed. Patients with EoE were treated with swallowed fluticasone., Results: There were no differences in clinical, endoscopic or histological features between patients with EoE and PPI-REE. There were more basophils and mast cells in patients with EoE and PPI-REE than in patients with GERD and control subjects. Basophil infiltration of the oesophageal epithelium in patients with EoE was higher than that in patients with PPI-REE (3.6 ± 2.8 per high power field vs. 1.2 ± 0.9 per high power field respectively; P = 0.02); however, there was no significant difference in mast cell infiltration between the two groups. TSLP was highly expressed in the oesophageal epithelium in areas infiltrated by basophils. Steroid therapy significantly decreased intraepithelial basophils in patients with EoE., Conclusion: Basophils may play an important role in the pathogenesis of eosinophilic oesophagitis., (© 2015 John Wiley & Sons Ltd.)

Over the last 3 decades, the incidence of esophageal adenocarcinoma has dramatically increased in Western countries; a similar increase may be observed in Asian countries in the near future. Esophageal adenocarcinoma arises from a sequential gastroesophageal reflux disease (GERD) spectrum from reflux erosive esophagitis, to Barrett's esophagus, and finally to esophageal adenocarcinoma. At present, gastric acid and bile are assumed to be primarily involved in the etiology of the GERD spectrum. We reported in 2002 that, at the gastroesophageal junction in humans, abundant amounts of nitric oxide (NO) are generated luminally through the entero-salivary re-circulation of dietary nitrate. Since then, we have carried out a series of experiments to demonstrate that NO diffuses into the adjacent epithelium at cytotoxic levels. This diffusion results in disruption of the epithelial barrier function, exacerbation of inflammation, acceleration of columnar transformation in the esophagus (Barrett's esophagus) via the induction of caudal-type homeobox 2, and the shifting of carcinogenic N-nitroso compound formation from the luminal to epithelial compartment. These results suggest that, in addition to conventionally recognized causative factors, luminal NO could also be involved in the pathogenesis of the GERD spectrum. In addition, we recently showed that there is a prominent gender-related difference in NO-related cytotoxicity in the esophagus and that estrogen attenuated the esophageal tissue damage via the estrogen receptor in female rats. The role of estrogen in attenuating the esophageal tissue damage in NO-related esophageal damage could explain the well-recognized male predominance in the GERD spectrum in humans., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: We recently encountered patients with localized esophageal eosinophilia in a small area of the esophagus. However, this condition remains to be described in detail, and its clinical significance has not been established. We investigated the clinical, endoscopic and histological features of localized esophageal eosinophilia in comparison with diffuse esophageal eosinophilia., Methods: We investigated 10 patients with localized esophageal eosinophilia, and compared them with 23 who had diffuse esophageal eosinophilia. Whether esophageal eosinophilia was localized or diffuse was determined on the basis of endoscopic findings. Localized esophageal eosinophilia was defined endoscopically as a focal area of esophageal eosinophilia, whereas diffuse esophageal eosinophilia was defined as a widespread area of esophageal eosinophilia involving more than one of three locations: the upper, middle and lower esophagus. Histological esophageal eosinophilia in the mucosa showing endoscopic abnormality was confirmed by biopsy with a peak of ≥ 15 eosinophils/high-power field., Results: There were no significant differences in age, gender distribution, allergic conditions or peripheral eosinophilia between the two groups. In all cases but one, localized esophageal eosinophilia was observed in a small area above the esophagogastric junction. Esophageal symptoms such as dysphagia, heartburn or chest pain were present in 20% of the localized group and in 65% of the diffuse group, the difference being statistically significant (P<0.05). The maximum amounts of eosinophils infiltrating the esophageal mucosa did not differ between the groups., Conclusions: Esophageal eosinophilia can be localized in a small area, especially above the esophagogastric junction. Gastric acid reflux or contact may influence this condition in addition to its allergic pathogenesis., (© 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.)

Objective: There is a strong male predominance of oesophageal adenocarcinoma, which might be related to the higher prevalence of precursor lesions such as erosive reflux oesophagitis in men compared with women. This experiment investigated the gender difference in a reflux oesophagitis model of rats and explored the potential role of oestrogen in controlling oesophageal tissue damage., Design: An acid-reflux oesophagitis model was surgically produced in male and female rats, and ascorbic acid in the diet and sodium nitrite in the drinking water were administered to half of either group to provoke luminal exogenous nitric oxide (NO) as an exacerbating agent. Seven days after the surgery, the oesophagus was excised, and the injury area, myeloperoxidase activity and pro-inflammatory cytokine levels were measured. Furthermore, 17β-oestradiol was administered to ovariectomised female rats or male rats, which then underwent reflux oesophagitis surgery., Results: While there was no gender difference in oesophageal damage in the baseline model, oesophageal damage was more intensively observed in males than in females in the presence of exogenous NO administration. While oesophageal damage was increased in ovariectomised rats compared with sham ovariectomised, exacerbated oesophageal damage was attenuated by the replacement of 17β-oestradiol. In addition, exacerbated oesophageal damage in male rats was suppressed by 17β-oestradiol., Conclusion: This is the first study showing the prominent gender difference in the severity of oesophageal tissue damage in a gastro-oesophageal reflux disease-related animal model, highlighting the critical involvement of oestrogen in controlling gastro-oesophageal reflux disease-related oesophageal epithelial injury.

Objectives: Recent studies have consistently reported a significant association between gastric atrophy and esophageal squamous cell carcinomas (ESCCs). However, causative factors responsible for the linkage remain to be clarified. Multichannel intraluminal impedance monitoring in conjunction with a pH sensor (MII-pH) is a reliable technique to evaluate gastroesophageal reflux (GER) episodes, independent of the acidity. We investigated the potential roles of GER in the pathogenesis of ESCC with MII-pH., Methods: From August 2008 to May 2010, 14 consecutive inpatients with superficial ESCCs (ESCC group) and 14 age- and sex-matched inpatients without any esophageal dysplastic lesions (non-ESCC group) were enrolled. Twenty-four hour portable MII-pH monitoring was performed under standard hospitalized conditions. The data of MII-pH were used to identify acid reflux (AR: pH drop below 4.0 during a reflux episode) and non-AR (NAR: pH drop above 4.0 during a reflux episode)., Results: The median intragastric pH of the ESCC group was 4.7 (2.3-6.4), implying hypochlorhydria in this patient group. The numbers of total reflux and NAR episodes in the ESCC group were significantly higher than those in the non-ESCC group (56 (43-87) vs. 35.5 (18-47), P=0.016 for total reflux and 46.5 (32-84) vs. 24.5 (8-37), P=0.012 for NAR), whereas the numbers of AR were similar in both groups. In addition, there was significance in the category of percentage time of bolus reflux episodes., Conclusions: Using MII-pH monitoring, we revealed the clinical significance of GER, especially NAR, in ESCCs. NAR may be a key factor in the link between gastric atrophy and ESCCs.

Exposure of the esophageal mucosa to refluxed gastroduodenal contents is recognized to be an important risk factor for Barrett's esophagus (BE). At the human gastroesophageal junction, nitric oxide is generated luminally through the enterosalivary recirculation of dietary nitrate, and in cases with gastroesophageal reflux, the site of luminal nitric oxide generation could shift to the distal esophagus. The aim of this study is to investigate whether exogenous luminal nitric oxide could promote the development of BE in rats. Sodium nitrite plus ascorbic acid were administered to a rat surgical model of BE, in which the gastroduodenal contents were refluxed into the esophagus to generate exogenous luminal nitric oxide in the esophagus by the acid-catalyzed chemical reaction between the 2 reagents. The emergence of BE was evaluated histologically in the early phase (several weeks) after the surgery with or without exogenous nitric oxide administration. To elucidate the histogenesis of BE, CDX2, MUC2 and MUC6 expressions were investigated immunohistochemically. Coadministration of sodium nitrite plus ascorbic acid significantly accelerated the timing of emergence and increased the area of BE compared with controls. Administration of either reagent alone did not show any promotive effects on BE formation. Immunohistochemically, the columnar epithelium thus induced was similar to the specialized intestinal metaplasia in human BE. The results of this animal model study suggest that exogenous luminal nitric oxide could be involved in the pathogenesis of the columnar transformation of the esophagus. Further studies in human are warranted.

Objective: Dilatation of the intercellular space (DIS) of the esophageal epithelium is recognized as one of the earliest histological changes in gastroesophageal reflux disease patients. At the human gastroesophageal junction, reactive nitrogen oxide species (RNOS) are generated luminally through the entero-salivary re-circulation of dietary nitrate. In cases with gastroesophageal reflux, the site of luminal RNOS generation may shift to the distal esophagus. The aim of this study was to investigate whether luminal RNOS exposure could be involved in the pathogenesis of DIS., Material and Methods: Rat esophageal mucosa was studied with an Ussing chamber model. On the luminal side of the chamber, RNOS were generated by the acidification of physiologic concentrations of sodium nitrite (1.0 or 5.0 mM). Esophageal barrier function was assessed by means of electrophysiological transmembrane resistance and membrane permeability by means of (3)H-mannitol flux. The dimensions of the intercellular spaces were assessed by using transmission electron microscopy., Results: Administration of acid plus sodium nitrite induced DIS of the esophageal epithelium, and this ultrastructural morphological change was accompanied by a concomitant decrease in the transmembrane resistance and an increase in the epithelial permeability. The DIS induced by luminal RNOS was also confirmed in an in vivo exposure model., Conclusions: The present animal study indicates that the RNOS generated by the acidification of salivary nitrite in the presence of refluxed gastric acid in the esophagus could be a luminal factor that is responsible for the induction of DIS. Further studies are warranted to investigate the clinical relevance of the present findings to the human situation.

Background/aims: Little is known about the correlation between clinical symptoms in daily life and the endoscopic features of gastroesophageal reflux disease (GERD). The study aim is to evaluate the correlation between clinical symptoms in daily life and endoscopic findings in reflux esophagitis (RE), and endoscopically suspected esophageal metaplasia (ESEM) in a large number of Japanese non-clinical cases., Methodology: A total of 6504 subjects who underwent an endoscopy for their annual medical check-up at Miyagi cancer society were enrolled in this study. If esophagitis was present, it was graded according to the Los Angeles classification. ESEM describes endoscopic findings consistent with BE that await histological evaluation. It was also investigated the symptom of heartburn as a "typical symptom" of GERD, and dysphagia as an "atypical symptom" of GERD., Results: The prevalence of heartburn and dysphagia significantly increased concomitantly with endoscopic the esophagitis grading. The prevalence of heartburn was significantly higher in subjects with long segment ESEM than those without it., Conclusion: The prevalence of heartburn and dysphagia were closely associated with RE grading. Long segment ESEM is strongly associated with the reflux symptom and RE. The more frequent the GERD symptoms, the greater the risk for the development of severe RE, and ESEM.

Aim: To test this hypothesis of barrett esophagus (BE) classified into two types and to further determine if there was any correlation between the shape of endoscopically suspected esophageal metaplasia (ESEM), prevalence of reflux esophagitis (RE) and heartburn., Methods: A total of 6504 Japanese who underwent endoscopy for their annual stomach check-up were enrolled in this study. BE was detected without histological confirmation that is ESEM. We originally classified cases of ESEM into 3 types based on its shape: Tongue-like (T type), Dome-like (D type) and Wave-like (W type) ESEM. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a one-month period., Results: ESEM was observed in 10.3% of 6504 subjects (ESEM < 1 cm, 9.4%; 1 cm < or = ESEM < 3 cm, 1.7%; ESEM > or = 3 cm, 0.5%). The frequency of ESEM was significantly higher in males compared with female subjects. Statistical analysis showed that the prevalence of heartburn and RE were significantly higher in the T type ESEM than in the W type ESEM (P < 0.05)., Conclusion: The T type ESEM was strongly asso-ciated with reflux symptoms and RE whereas the W type ESEM was not associated with GERD.

Aim: To examine the prevalence of gastroesophageal reflux disease (GERD) symptoms in a large unselected general population in Japan., Methods: In Japan, mature adults are offered regular check-ups for the prevention of gastric cancer. A notice was sent by mail to all inhabitants aged>40 years. A total of 160983 Japanese (60774 male, 100209 female; mean age 61.9 years) who underwent a stomach check up were enrolled in this study. In addition, from these 160983 subjects, we randomly selected a total of 82894 (34275 male, 48619 female; mean age 62.4 years) to evaluate the prevalence of abdominal pain. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a 1 mo period., Results: The respective prevalences of the symptoms in males and females were: heartburn, 15.8% vs 20.7%; dysphagia, 5.4% vs 7.8%; and abdominal pain, 6.6% vs 9.6%. Among these symptoms, heartburn was significantly high compared with the other symptoms, and the prevalence of heartburn was significantly more frequent in females than in males in the 60-89-year age group. Dysphagia was also significantly more frequent in female patients., Conclusion: The prevalence of typical GERD symptoms (heartburn) was high, at about 20% of the Japan population, and the frequency was especially high in females in the 60-89 year age group.

Background: The efficacy of lansoprazole (LPZ) at inhibiting gastric acid secretion is influenced by cytochrome P450 2C19 (CYP2C19) polymorphism. The purpose of the present study was to investigate whether CYP2C19 polymorphism had an influence on the remission of erosive reflux esophagitis (RE) during maintenance therapy with LPZ., Methods: Eighty-two Japanese patients with initial healing of erosive RE by 8 weeks of LPZ therapy were enrolled. As maintenance therapy, the patients were treated with LPZ (15 mg/day) for 6 months. The CYP2C19 genotype, Helicobacter pylori infection status, and serum pepsinogen (PG) I/II ratio were assessed before treatment. The patients were investigated for relapse by endoscopy at 6 months or when symptoms recurred., Results: The proportion of patients in remission after 6 months was 61.5%, 78.0%, and 100% among homozygous extensive metabolizers (homo-EM), heterozygous EM (hetero-EM), and poor metabolizers (PM), respectively. The percentage of PM patients who remained in remission was significantly higher than that of homo-EM or hetero-EM., Conclusions: The efficacy of LPZ (15 mg/day) as maintenance therapy for erosive RE is influenced by CYP2C19 polymorphism.

Background and Aims: When saliva, with its high nitrite content derived from the enterosalivary recirculation of dietary nitrate, meets acidic gastric juice, the nitrite is converted to nitrous acid, nitrosative species, and nitric oxide. In healthy volunteers this potentially mutagenic chemistry is focused at the gastric cardia. We have studied the location of this luminal chemistry in Barrett's patients during acid reflux., Methods: Ten Barrett's patients were studied before and after administration of 2 mmol nitrate. Using microdialysis probes we measured nitrite, ascorbic acid, total vitamin C, and thiocyanate concentrations and pH simultaneously in the proximal oesophagus, Barrett's segment, hiatal sac, proximal stomach, and distal stomach. In a subgroup, real time nitric oxide concentrations were also measured., Results: During acid reflux, Barrett's segment was the anatomical site with maximal potential for acid catalysed nitrosation, with its median concentration of nitrite exceeding that of ascorbic acid in two of 10 subjects before nitrate and in four of nine after nitrate. Thiocyanate, which catalyses acid nitrosation, was abundant at all anatomical sites. On entering the acidic Barrett's segment, there was a substantial fall in nitrite and the lowest ascorbic acid to total vitamin C ratio, indicative of reduction of salivary nitrite to nitric oxide at this anatomical site. Episodes of acid reflux were observed to generate nitric oxide concentrations of up to 60 muM within the Barrett's segment., Conclusion: The interaction between acidic gastric refluxate and nitrite rich saliva activates potentially mutagenic luminal nitrosative chemistry within Barrett's oesophagus.

Recent advancement in the research of GERD has revealed that endoscopy negative GERD may not be a milder form of erosive GERD and may have different pathogenesis. We have previously proven that hypersensitivity to the acid of the esophageal mucosa plays an important role in its pathogenesis. Regarding the mechanisms for the esophageal hypersensitivity, we hypothesized that the tight junction proteins of the esophageal mucosa are fully or partially impaired in GERD patients. Accordingly, we immunohistologically studied the expression of various tight junction proteins using the rat reflux esophagitis model. The results demonstrated that the several kinds of tight junction proteins are expressed differently in the various parts of esophagus and their expression altered according to the development of reflux esophagitis.

Background: The acid suppressive effect of lansoprazole is influenced by the P450 2C19 (CYP2C19) polymorphism., Aim: To investigate whether the CYP2C19 genotype is related to the healing of erosive reflux oesophagitis during treatment with lansoprazole., Methods: Eighty-eight Japanese patients with erosive reflux oesophagitis were treated with a daily oral dose of 30 mg lansoprazole for 8 weeks. The CYP2C19 genotype, Helicobacter pylori infection status and serum pepsinogen I/II ratio were assessed before treatment. At 4 and 8 weeks, the healing of erosive reflux oesophagitis was evaluated endoscopically., Results: The healing rates were 57.1%, 69.2% and 72.7% at 4 weeks and 77.4%, 95.0% and 100% at 8 weeks in homozygous extensive metabolizers, heterozygous extensive metabolizers and poor metabolizers, respectively. At 8 weeks, the healing rate of erosive reflux oesophagitis was significantly lower in homozygous extensive metabolizers than in the other two groups (P < 0.05). The H. pylori status and serum pepsinogen I/II ratio had less influence than CYP2C19 polymorphism on the healing rate of erosive reflux oesophagitis., Conclusions: The therapeutic effect of lansoprazole on erosive reflux oesophagitis is influenced by the CYP2C19 genotype status. Therefore, a test of CYP2C19 genotype may be useful for the medical treatment of reflux oesophagitis with lansoprazole.

Background: The role of acid secretion in reflux oesophagitis which may develop after H. pylori eradication is not well known., Aim: To investigate the participation of altered gastric acid secretion and the presence of hiatal hernia in the development of reflux oesophagitis after eradication therapy for H. pylori., Subjects and Methods: A total of 105 patients with H. pylori infection, but without reflux oesophagitis at the time of eradication therapy, were followed prospectively for 7 months after the clearance of this microorganism. Gastric acid secretion was assessed by endoscopic gastrin test, and the presence of hiatal hernia by endoscopy., Results: Reflux oesophagitis developed in 11 out of 105 (10.5%) patients when examined at 7 months after the eradication therapy. The incidence was correlated significantly with the increase in gastric acid secretion after the eradication of H. pylori, and was significantly higher in the patients with hiatal hernia (20%) than in those without it (0%)., Conclusions: Increased acid secretion after H. pylori eradication is an important risk factor of reflux oesophagitis, especially in patients with hiatal hernia.

Objective: The human gastro-oesophageal junction is exposed to abundant amounts of luminal reactive nitrogen oxide species (RNOS) derived from the enterosalivary recirculation of dietary nitrate. The aim of this study is to investigate the direct effects of luminal RNOS on the adjacent gastric barrier function using an ex vivo chamber model. Methods: A chamber model in which the rat gastric mucosal membrane was mounted between the two halves of a chamber was designed to simulate the microenvironment of the lumen and the adjacent mucosa of the gastro-oesophageal junction. On the mucosal side of the chamber, RNOS were generated by the acidification of physiological concentrations of sodium nitrite. The epithelial barrier function was evaluated by electrophysiological transmembrane resistance, and membrane permeability with [³H]mannitol flux. The expression of occludin was evaluated by immunohistochemistry and immunoblotting. Dinitrosyl dithiolato iron complex (DNIC) was also measured by means of electron paramagnetic resonance spectroscopy to confirm the diffusion of RNOS from the mucosal lumen into the mounted mucosa. Results: The administration of acidified nitrite to the mucosal lumen caused both a decrease in transmembrane resistance and an increase in epithelial permeability, suggesting a disturbance of the gastric barrier function. These changes were accompanied by a derangement of the expression of occludin. The diffusion of luminal RNOS into the mounted membrane was confirmed by showing the generation of DNIC within the tissue. Conclusions: Simulating the microenvironment of the human gastro-oesophageal junction, this study demonstrated that RNOS generated luminally at the human gastro-oesophageal junction can derange the barrier function of the adjacent tissue by disrupting the tight junction. [ABSTRACT FROM AUTHOR]

We have previously reported that H. pylori infection prevents reflux esophagitis (RE) and Barrett’s esophagus (BE) by decreasing gastric acid secretion. Gastroesophageal (GE) junction adenocarcinoma, including Barrett’s adenocarcinoma, has been thought to be a complication of gastroesophageal reflux disease. However, the relationship between H. pylori infection, gastric acid secretion and GE junction adenocarcinoma had not yet been investigated in Japan. We demonstrated that the status of gastric acid secretion was higher in patients with GE junction adenocarcinoma than in patients with early gastric cancer (EGC), and that the level was the same in patients with RE and those with BE. We also found that the prevalence of H. pylori infection in patients with GE junction adenocarcinoma was significantly lower than that in patients with EGC, although not as low as that in patients with RE and BE, suggesting that preservation of gastric acid secretion may be important for the development of GE junction adenocarcinoma in Japanese people, regardless of the presence of H. pylori infection. [ABSTRACT FROM AUTHOR]