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Background: The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear., Aims: To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER., Methods: We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER., Results: We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies., Conclusions: The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study., (© 2021 John Wiley & Sons Ltd.)

Background: Proton pump inhibitors (PPI) have no effect on non-acid reflux events which can continue to provoke gastro-oesophageal reflux disease (GERD) symptoms. Baclofen, a γ-aminobutyric acid agonist, can decrease non-acid reflux but its symptomatic benefit in refractory GERD symptoms is understudied., Aims: To assess the efficacy of baclofen 10 mg t.i.d. vs placebo as add-on therapy in PPI-refractory GERD symptoms, in a randomised, double-blind, placebo-controlled study., Methods: Patients with persisting typical GERD symptoms on b.i.d. PPI therapy were randomised to 4 weeks of baclofen 10 mg or placebo t.i.d. Before and after treatment, patients underwent 24 h impedance-pH monitoring on-PPI. Throughout the study, patients filled out ReQuest diaries. Data were analysed using mixed models., Results: About 60 patients were included (age 47.5 years [range 19-73], 41f/19 m), 31 patients were randomised to baclofen. One patient withdrew consent and five in the baclofen group stopped treatment due to side effects. There was a trend towards a better response for general wellbeing in the baclofen-treated group compared to placebo (p = 0.06). When subdividing patients according to symptom association probability (SAP), only the SAP+ (n = 25) group improved significantly with baclofen (p corr  = 0.02), and worsened with placebo (p corr  = 0.008). The total number of reflux events decreased over time (p = 0.01), mainly due to the baclofen condition (p corr  = 0.1). The number of reflux events with a high proximal extent dropped significantly after baclofen (p corr  = 0.009), but not placebo., Conclusion: Baclofen decreases several reflux parameters in PPI refractory GERD symptoms, but pH-impedance monitoring is necessary before treatment as only SAP+ patients experience clinical benefit after 4 weeks., (© 2022 John Wiley & Sons Ltd.)

Background: Conflicting results exist on the association between Helicobacter pylori infection and gastro-oesophageal reflux (GOR), and its complications, such as erosive oesophagitis (EO) and Barrett's oesophagus (BO)., Aims: To explore the association of H. pylori infection with GOR symptoms and their complications METHODS: We searched Embase, PubMed, Web of Science and Scopus databases through December 2020 for relevant articles. Regarding the association between H. pylori and GOR symptoms (heartburn, regurgitation or reflux), we included observational studies comparing the prevalence of GOR symptoms between H. pylori-positive and -negative individuals. Concerning the association between H. pylori and complications of GOR, we included studies comparing the prevalence of EO or BO between H. pylori-positive and -negative individuals., Results: In total, 36 papers were eligible. Based on seven cross-sectional surveys, H. pylori infection was associated with a lower odds of GOR symptoms (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.61-0.90). However, in four case-control studies, H. pylori infection was not associated with odds of GOR symptoms (OR 1.10, 95% CI 0.85-0.1.43). In 26 cross-sectional studies in patients with GOR symptoms, the OR for EO was 0.70 (95% CI 0.58-0.84) in H. pylori-positive vs -negative cases. Based on nine cross-sectional studies in subjects with GOR complications, no significant association was found between H. pylori infection and either endoscopically-diagnosed (OR 1.84, 95% CI 0.67-5.02) or histologically confirmed (OR 0.85, 95% CI 0.60-1.20) BO., Conclusions: Helicobacter pylori infection appears to be associated with a decreased odds of GOR symptoms and EO. In contrast, H. pylori infection did not seem to affect the odds of BO in patients with GER complications., (© 2021 John Wiley & Sons Ltd.)

Background: The pathogenesis of gastro-oesophageal reflux disease (GERD) is complex and multifactorial. The oesophageal hypervigilance and anxiety scale (EHAS) is a novel cognitive-affective evaluation of visceral sensitivity., Aims: To investigate the interrelationship between EHAS and reflux symptom severity, psychological stress, acid reflux burden, phenotypes, and oesophageal mucosal integrity in patients with GERD., Methods: Patients with chronic reflux symptoms and negative endoscopy underwent 24-hour impedance-pH monitoring for phenotyping, acid reflux burden, and mucosal integrity with mean nocturnal baseline impedance (MNBI) calculation. Validated scores for patient-reported outcomes, including EHAS, GERD questionnaire (GERDQ), State-Trait Anxiety Inventory score, and Taiwanese Depression Questionnaire score, were recorded., Results: We enrolled 105 patients, aged 21-64 years (mean, 48.8), of whom 58.1% were female; 27 had non-erosive reflux disease, 43 had reflux hypersensitivity and 35 had functional heartburn. There were no significant differences in sex, EHAS, GERDQ, questionnaires of depression or anxiety among GERD phenotypes. EHAS was significantly correlated with GERDQ, questionnaires of depression and anxiety (P < 0.05). However, there were no significant correlations between GERDQ and questionnaires of depression or anxiety. Regarding patient-reported outcomes, GERDQ positively correlated with acid exposure time and negatively correlated with MNBI (P < 0.05)., Conclusions: EHAS associates with reflux symptom severity and psychological stress but not with acid reflux burden or mucosal integrity. Thus, EHAS assessment shows promise in assessment of subjective patient outcome and satisfaction with treatment, a hitherto unmet clinical need., (© 2021 John Wiley & Sons Ltd.)

Background: Gastro-oesophageal reflux is considered the main risk factor for Barrett's oesophagus. The role of other potential risk factors for the development of Barrett's oesophagus in patients with gastro-oesophageal reflux symptoms is controversial., Aims: To perform a systematic review and meta-analysis examining risk factors in development of Barrett's oesophagus., Methods: Medline, Embase and Embase Classic were searched (until December 2020) to identify cross-sectional studies reporting prevalence of Barrett's oesophagus based on presence of one or more proposed risk factors in individuals with gastro-oesophageal reflux symptoms. Prevalence of Barrett's oesophagus was compared according to presence or absence of each risk factor in individuals with gastro-oesophageal reflux symptoms., Results: Of 7164 citations evaluated, 13 studies reported prevalence of Barrett's oesophagus in 11 856 subjects. Pooled prevalence of histologically confirmed Barrett's oesophagus in individuals with gastro-oesophageal reflux symptoms in all studies was 7.0% (95% CI 4.8% to 9.6%). Prevalence was higher in subjects with hiatal hernia (OR 2.74; 95% CI 1.58 to 4.75) and in those who drank alcohol (OR 1.51; 95% CI 1.17 to 1.95). Other features including non-steroidal anti-inflammatory drugs and/or aspirin use (OR 1.19; 95% CI 1.00 to 1.42), smoking (OR 1.14; 95% CI 0.96 to 1.35) or obesity (OR 1.10; 95% CI 0.92 to 1.33) were not significantly associated with Barrett's oesophagus., Conclusions: The prevalence of Barrett's oesophagus in individuals with gastro-oesophageal reflux symptoms was higher in those who drank alcohol, although this association was modest. The strongest association found was between hiatal hernia and Barrett's oesophagus. Other potential risk factors assessed in this study did not appear to be associated with presence of Barrett's oesophagus among individuals with gastro-oesophageal symptoms., (© 2021 John Wiley & Sons Ltd.)

Objective. To investigate the risk factors associated with reflux esophagitis in patients undergoing esophageal cancer surgery and to provide reference for the prevention and treatment of reflux esophagitis. Methods. In the manner retrospective study, the data of 300 patients with esophageal cancer who received the surgical treatment in our hospital (January 2018–December 2020) were retrospectively reviewed. The 300 patients were divided into the occurrence group (n = 45) and nonoccurrence group (n = 255) depending on whether they had reflux esophagitis after surgery. The social demographic data and clinical data of the patients in the two groups were collected. These data were classified into the personal factors and surgical factors. The single-factor analysis method was adopted to analyze the effects of the personal and surgical factors on reflux esophagitis. The factors with statistically significant differences in the single-factor analysis were analyzed by logistic regression to verify the factors were the risk factors associated with reflux esophagitis in patients undergoing esophageal cancer surgery. Results. The differences in the bodyweight, body mass index (BMI), length of the resected esophagus, surgical approach, intraoperative blood loss, gastrointestinal decompression volume, and surgery time between the two groups were of statistical significance (P < 0.05). After being tested by the logistics multivariate analysis, length of the resected esophagus, whole stomach reconstruction, intraoperative blood loss, and surgery time were identified as the risk factors associated with reflux esophagitis in patients undergoing esophageal cancer surgery. Conclusion. The length of the resected esophagus, whole stomach reconstruction, intraoperative blood loss, and surgery time were the risk factors associated with reflux esophagitis in patients undergoing esophageal cancer surgery. It is necessary to choose the appropriate surgical approach according to the patients' conditions in practice and to strengthen the prevention and treatment of reflux esophagitis. [ABSTRACT FROM AUTHOR]

Background: Esophageal acid exposure time (AET) during 24 h pH monitoring is reproducible and predictive outcomes of treatment for gastroesophageal reflux disease. Several small Asian studies have investigated the normal range of the AET; the range may be different from that in Western populations. We evaluated its normal range in healthy Asian compared to Western subjects. Methods: We searched PubMed, Embase, Cochrane Library, and KoreaMed for studies that reported pH monitoring parameters in healthy subjects. Studies that reported the AET values of healthy subjects were eligible for the analyses. The upper limit of normal of the AET was obtained from the 95th percentile of the available raw data or calculated as the mean value +2 standard deviations. Key Results: Nineteen Asian and 49 Western studies were assessed. The estimated AET values were analyzed using a bootstrapping technique, weighted according to the sample size. The mean AET was 1.1% and 2.9% in the Asian and Western populations, respectively. The upper limit of the reference range was 3.2% (95% confidence interval [CI], 2.7–3.9%) and 8.2 (95% CI, 6.7–9.9) in the Asian and Western populations, respectively. The normal AET differed between the Asian and Western populations because the CI of the two groups did not overlap. Conclusions & Inferences: The upper limit of normal of the AET in healthy Asian subjects was 3.2% (95% CI, 2.7–3.9%), which was lower than that of healthy Western subjects. [ABSTRACT FROM AUTHOR]

Background High-resolution manometry ( HRM) has resulted in new revelations regarding the pathophysiology of gastro-esophageal reflux disease ( GERD). The impact of new HRM motor paradigms on reflux burden needs further definition, leading to a modern approach to motor testing in GERD. Methods Focused literature searches were conducted, evaluating pathophysiology of GERD with emphasis on HRM. The results were discussed with an international group of experts to develop a consensus on the role of HRM in GERD. A proposed classification system for esophageal motor abnormalities associated with GERD was generated. Key Results Physiologic gastro-esophageal reflux is inherent in all humans, resulting from transient lower esophageal sphincter ( LES) relaxations that allow venting of gastric air in the form of a belch. In pathological gastro-esophageal reflux, transient LES relaxations are accompanied by reflux of gastric contents. Structural disruption of the esophagogastric junction ( EGJ) barrier, and incomplete clearance of the refluxate can contribute to abnormally high esophageal reflux burden that defines GERD. Esophageal HRM localizes the LES for pH and pH-impedance probe placement, and assesses esophageal body peristaltic performance prior to invasive antireflux therapies and antireflux surgery. Furthermore, HRM can assess EGJ and esophageal body mechanisms contributing to reflux, and exclude conditions that mimic GERD. Conclusions & Inferences Structural and motor EGJ and esophageal processes contribute to the pathophysiology of GERD. A classification scheme is proposed incorporating EGJ and esophageal motor findings, and contraction reserve on provocative tests during HRM. [ABSTRACT FROM AUTHOR]

The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus ( BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium ( HET-1A) and BO ( QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α3, α4, α5, α6 and αν). Experimental findings were validated in human explant oesophageal biopsies, a rat model of gastroesophageal reflux disease ( GORD) and in patient tissue microarrays. The bile acid deoxycholic acid ( DCA) specifically reduced adhesion of HET-1A cells to vitronectin and reduced cell-surface expression of integrin-αν via effects on endocytic recycling processes. Increased expression of integrin-αv was observed in ulcerated tissue in a rat model of GORD and in oesophagitis and Barrett's intestinal metaplasia patient tissue compared to normal squamous epithelium. Increased expression of integrin-αν was observed in QH BO cells compared to HET-1A cells. QH cells were resistant to DCA-mediated loss of adhesion and reduction in cell-surface expression of integrin-αν. We demonstrated that a specific component of the gastric refluxate, DCA, affects the epithelial barrier through modulation of integrin αν expression, providing a novel mechanism for bile acid-mediated erosion of oesophageal squamous epithelium and promotion of BO. Strategies aimed at preventing bile acid-mediated erosion should be considered in the clinical management of patients with GORD. [ABSTRACT FROM AUTHOR]

Background Gastroesophageal reflux ( GER) has been associated with idiopathic pulmonary fibrosis ( IPF). Pathogenesis may be related to chronic micro-aspiration. We aimed to assess objective measures of GER on multichannel intraluminal impedance and pH study ( MII-pH) and their relationship with pulmonary function testing ( PFT) results, and to compare the performance of pH/acid reflux parameters vs corresponding MII/bolus parameters in predicting pulmonary dysfunction in IPF. Methods This was a retrospective cohort study of IPF patients undergoing prelung transplant evaluation with MII- pH off acid suppression, and having received PFT within 3 months. Patients with prior fundoplication were excluded. Severe pulmonary dysfunction was defined using diffusion capacity of the lung for carbon monoxide ( DLCO) ≤40%. Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were specified a priori. Multivariate analyses were applied using forward stepwise logistic regression. Predictive value of each parameter for severe pulmonary dysfunction was calculated by area-under-the-receiver-operating-characteristic-curve or c-statistic. Key Results Forty-five subjects (67% M, age 59, 15 mild-moderate vs 30 severe) met criteria for inclusion. Patient demographics and clinical characteristics were similar between pulmonary dysfunction groups. Abnormal total reflux episodes and prolonged bolus clearance time were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses. No pH parameters were significant. The c-statistic of each pH parameter was lower than its MII counterpart in predicting pulmonary dysfunction. Conclusions & Inferences MII/bolus reflux, but not pH/acid reflux, was associated with pulmonary dysfunction in prelung transplant patients with IPF. MII- pH may be more valuable than pH testing alone in characterizing GER in IPF. [ABSTRACT FROM AUTHOR]

Background The prevalence of gastroesophageal reflux disease ( GERD) has increased in the last decades and it is now one of the most common chronic diseases. Throughout time our insight in the pathophysiology of GERD has been characterized by remarkable back and forth swings, often prompted by new investigational techniques. Even today, the pathophysiology of GERD is not fully understood but it is now recognized to be a multifactorial disease. Among the factors that have been shown to be involved in the provocation or increase of reflux, are sliding hiatus hernia, low lower esophageal sphincter pressure, transient lower esophageal sphincter relaxation, the acid pocket, obesity, increased distensibility of the esophagogastric junction, prolonged esophageal clearance, and delayed gastric emptying. Moreover, multiple mechanisms influence the perception of GERD symptoms, such as the acidity of the refluxate, its proximal extent, the presence of gas in the refluxate, duodenogastroesophageal reflux, longitudinal muscle contraction, mucosal integrity, and peripheral and central sensitization. Understanding the pathophysiology of GERD is important for future targets for therapy as proton pump inhibitor-refractory GERD symptoms remain a common problem. Purpose In this review we provide an overview of the mechanisms leading to reflux and the factors influencing perception, in the light of historical developments. It is clear that further research remains necessary despite the recent advances in the understanding of the pathophysiology of GERD. [ABSTRACT FROM AUTHOR]

Background Gastroesophageal reflux plays an important role in chronic cough ( CC). Whether disturbed esophageal motility contributes to increased esophageal reflux exposure or interferes with swallowed bolus clearance is unclear. This study used high resolution esophageal manometry and impedance ( HRIM) together with Chicago Classification, and 24-h impedance pH ( MII/pH) to address these questions in patients with CC compared with heartburn ( HB). Methods A retrospective review of 32 patients with CC (mean age 57 [95% CI: 52-62] years) and 32 patients with symptoms of HB (55 [52-62] years) referred for HRIM and MII/pH between September 2012 and September 2013 was undertaken. Key Results Weak peristalsis with large breaks ( WPLBs) was observed in 34% of CC patients compared with only 12% of HB patients ( p = 0.027). Pathological acid exposure time ( AET) was identified in 81% of CC patients with WPLBs compared with 29% without ( p = 0.011). Increased AET was associated with prolonged clearance time of refluxed events ( p = 0.006) rather than increased number of events. AET correlated with the percentage of peristaltic events with large breaks in CC ( ρ = 0.467, p = 0.007). Similar data were obtained for total bolus (acid and non-acid) exposure time. Only one of the CC patients with WPLBs exhibited complete bolus transit ( CBT) on swallowing compared with 81% without WPLBs ( p < 0.001). Moreover, the percentage of peristaltic events associated with CBT negatively correlated with the percentage of peristaltic events with large breaks ( r = −0.653, p < 0.001) in CC. Conclusions & Inferences One-third of CC patients exhibit WPLBs, which directly impacts on clearance of refluxed events and bolus's swallowed. These observations may have important implications for esophageal-bronchial interaction in CC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Baclofen, a GABAb agonist, has been shown to reduce episodes of gastroesophageal reflux (GER). To determine if baclofen would significantly reduce reflux during sleep, and also improve objective and subjective measures of sleep. Methods Twenty-one individuals with complaints of nighttime heartburn at least twice a week and a Carlsson GERD score of at least 5 were studied. Patients underwent polysomnography (PSG) and simultaneous esophageal pH monitoring on two occasions separated by approximately 1 week in a cross-over design. The night of each polysomnographic study, patients consumed a refluxogenic meal. Baclofen (40 mg) or placebo was given in random order 90 min prior to the start of the PSG. Key Results Baclofen significantly reduced the number of reflux events compared with placebo. Upright and recumbent acid contact times were both reduced by baclofen vs placebo, but the differences were not significant. Regarding sleep outcomes, several variables were significantly improved by baclofen. Total sleep time and sleep efficiency increased, and wake after sleep onset decreased in the baclofen condition compared with placebo. Proportion of Stage 1 sleep was also significantly decreased on baclofen. Conclusions & Inferences In addition to reducing the number of reflux events during sleep, baclofen significantly improved several measures of sleep in patients with documented GER and sleep disturbances. Baclofen could therefore be considered as a useful adjunct therapy to proton pump inhibitors (PPIs) in patients with nighttime heartburn and sleep disturbance who continue to have heartburn and/or sleep complaints despite PPI therapy. [ABSTRACT FROM AUTHOR]

Refractory gastroesophageal reflux disease may affect up to one-third of the patients that consume proton pump inhibitor (PPI) once daily. Treatment in clinical practice has been primarily focused on doubling the PPI dose, despite lack of evidence of its value. In patients who failed PPI twice daily, medical treatment has been primarily focused on reducing transient lower esophageal sphincter relaxation rate or attenuating esophageal pain perception using visceral analgesics. In patients with evidence of reflux as the direct trigger of their symptoms, endoscopic treatment or antireflux surgery may be helpful in remitting symptoms. The role of psychological interventions, as well as non-traditional therapeutic strategies remains to be further elucidated. [ABSTRACT FROM AUTHOR]

Background Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABAB), γ-aminobutyric acid type A (GABAA), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. Methods Using immunohistochemistry, we investigated the distribution of mGluR5, GABAA, GABAB, CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. Key Results MGluR5, GABAB, CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABAA receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. Conclusions & Inferences Human mGluR5, GABAA,B, and CB1,2 receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABAB receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective. [ABSTRACT FROM AUTHOR]

The lower esophageal sphincters (LES) together with the crural diaphragm are the major antireflux barriers protecting the esophagus from reflux of gastric content. However, reflux of gastric contents into the esophagus is a normal phenomenon in healthy individuals occurring primarily during episodes of transient lower esophageal sphincter relaxation (TLESR), defined as LES relaxation in the absence of a swallow. Transient lower esophageal sphincter relaxation is also the dominant mechanism of pathologic reflux in gastroesophageal reflux disorder (GERD) patients. Frequency of TLESR does not differ significantly between healthy individuals and those with GERD, but TLESRs are more likely to be associated with acid reflux in GERD patients. Understanding the mechanisms responsible for elicitation of a TLESR, using recently introduced novel technology is an area of intense interest. Pharmacologic and non-pharmacologic manipulation of receptors involved in the control of TLESR has recently emerged as a potential target for GERD therapy. [ABSTRACT FROM AUTHOR]

Non-specific esophageal dysmotility with impaired clearance is often present in patients with gastro-esophageal reflux disease (GERD), especially those with erosive disease; however the physio-mechanic basis of esophageal dysfunction is not well defined. Retrospective assessment of patients with erosive reflux disease (ERD; n = 20) and endoscopy negative reflux disease (ENRD; n = 20) with pathologic acid exposure on pH studies (>4.2% time/24 h) and also healthy controls (n = 20) studied by high resolution manometry. Esophageal motility in response to liquid and solid bolus swallows and multiple water swallows (MWS) was analyzed. Peristaltic dysfunction was defined as failed peristalsis, spasm, weak or poorly coordinated esophageal contraction (>3 cm break in 30 mmHg isocontour). Peristaltic dysfunction was present in 33% of water swallows in controls, 56% ENRD and 76% ERD respectively (P < 0.023 vs controls, P = 0.185 vs ENRD). The proportion of effective peristaltic contractions improved with solid compared to liquid bolus in controls (18% vs 33%, P = 0.082) and ENRD (22% vs 54%, P = 0.046) but not ERD (62% vs 76%, P = 0.438). Similarly, MWS was followed by effective peristalsis in 83% of controls and 70% ENRD but only 30% ERD patients (P < 0.017 vs controls and P < 0.031 vs ENRD). The association between acid exposure and dysmotility was closer for solid than liquid swallows (r = 0.52 vs 0.27). Peristaltic dysfunction is common in GERD. ERD patients are characterized by a failure to respond to the physiologic challenge of solid bolus and MWS that is likely also to impair clearance following reflux events and increase exposure to gastric refluxate. [ABSTRACT FROM AUTHOR]

Background Little is known about the contribution of bile and acid reflux to night-time symptoms generation in patients who failed PPI treatment. Aim To compare the degree of night-time oesophageal acid and bile [by the surrogate duodenogastroesophageal reflux (DGER)] exposure between gastrooesophageal reflux disease (GERD) patients who failed and those who fully responded to PPI once a day while on treatment. Methods Gastro-oesophageal reflux disease patients were assigned to the PPI failure group if they continued to report symptoms ⩾3 / week and to the PPI success group if they were asymptomatic for the last 3 months while on PPI once a day. All patients underwent upper endoscopy and subsequently simultaneous 24-h oesophageal Bilitec and pH testing while on PPI treatment. Results Twenty-three patients were enrolled into the PPI failure group and 24 patients into the PPI success group. The percentage of night-time pH < 4 and the number of night-time acid reflux episodes were significantly higher in the PPI failure group as compared with the PPI success group. All night-time DGER parameters were similar between the PPI failure and PPI success groups. Conclusions Night-time oesophageal acid exposure is significantly higher in the PPI failure group vs. PPI success group. The degree of night-time bile reflux is similar in the two groups of patients with GERD. [ABSTRACT FROM AUTHOR]

Background Transient lower oesophageal sphincter relaxations (TLOSR) are considered the physiological mechanism that enables venting of gas from the stomach and appear as sphincter relaxations that are not induced by swallowing. It has become increasingly clear that most reflux episodes occur during TLOSRs and therefore play a key role in gastro-oesophageal reflux disease (GERD). Aim To describe the current knowledge about TLOSRs and its clinical implications. Methods Search of the literature published in English using the PubMed database and relevant abstracts presented at international conventions. Results Several factors influence the rate of TLOSRs including anti-reflux surgery, meal, body position, nutrition, lifestyle and a wide array of neurotransmitters. Ongoing insights in the neurotransmitters responsible for the modulation of TLOSRs, as well as the neural pathways involved in TLOSR induction, have lead to novel therapeutic targets. These therapeutic targets can serve as an add-on therapy in patients with an unsatisfactory response to proton pump inhibitor by inhibiting TLOSRs and its associated reflux events. However, the TLOSR-inhibiting drugs that are currently available still have significant side effects. Conclusion It is likely that in the future, selected GERD patients may benefit from transient lower oesophageal sphincter relaxation inhibition when compounds are found without significant side effects. [ABSTRACT FROM AUTHOR]

Alcoholic beverages are known to increase acidic gastro-esophageal reflux (GER) and the risk of esophagitis. Moreover, duodenogastro-esophageal reflux (DGER), containing bile acids, was shown to harmfully alter the esophageal mucosa, alone and synergistically with HCl and pepsin. However, studies directly addressing potential effects of different low proof alcoholic beverages on DGER in health and disease are missing. Bilitec readings for beer and white, rose, and red wine were obtained in vitro from pure and from mixtures with bile. One-hour DGER monitoring and pH-metry were performed in 12 healthy subjects and nine reflux patients with DGER after ingestion of a standardized liquid meal together with 300 mL of water, white wine, and in the volunteers, beer and rose wine. Bilitec measurement was found to be feasible in the presence of beer, white wine, and using a threshold of 0.25, rose wine. However, the presence of red wine resulted in extinction values above this threshold. The consumption of all investigated alcoholic beverages, especially of white wine, triggered increased acidic GER, both in healthy participants and patients with reflux disease. In contrast, no relevant DGER was found after intake of alcoholic beverages. Fiber-optic bilirubin monitoring can be used for DGER monitoring in combination with alcoholic beverages, except with red wine. Low-proof alcoholic beverages are a strong trigger of GER, but not of DGER, both in healthy subjects and patients with reflux disease. [ABSTRACT FROM AUTHOR]

Background Gastro-esophageal reflux is considered a major culprit in the pathogenesis of Barrett’s esophagus (BE). Still, there is controversy on the role of weakly acidic and weakly alkaline reflux in BE. To compare characteristics of reflux episodes patients with BE, erosive esophagitis (EE), and healthy volunteers (HV). Methods One hundred consecutive patients with BE (75 short-segment BE, 25 long-segment BE), 50 with EE and 48 HV underwent multichannel intraluminal impedance-pH off-therapy. We quantified esophageal acid exposure, characteristics, and proximal extension of reflux episodes. Key Results Total and acid reflux episodes gradually increased from HV [28 (17.5–43) and 18 (8–31)] to EE [73.5 (54–96) and 52 (39–68)], short-segment BE (SSBE) [83 (73.2–131) and 65 (43.3–95)] and long-segment BE (LSBE) [105 (102–187) and 77 (75–107)]. Weakly acidic reflux episodes were significantly higher ( P < 0.05) in LSBE [36 (27.5–50.5)] and SSBE [34 (18.5–41)] compared to EE [21.5 (15–37)] and HV [19 (14–25)]. No differences in terms of proportion of acid, weakly acidic and weakly alkaline reflux were found [HV (49%–49%–2%) vs EE (68%–32%–1%) vs SSBE (65%–34%–1%) vs LSBE (69%–30%–1%); P = ns]. In LSBE, a higher percentage of reflux episodes ( P < 0.05) reached the proximal esophagus (59%) compared with SSBE (43%). Conclusions & Inferences Barrett esophagus patients have more severe reflux as shown by the number of acid and weakly acidic reflux episodes, re-reflux episodes and proximal migration. Given that PPI change only the pH of the refluxate, the role of weakly acidic reflux in Barrett’s patients on acid suppressive therapy warrants further investigation. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 443–447 Background In patients with Los Angeles (LA) grade C or D oesophagitis, a positive relationship has been established between the duration of intragastric acid suppression and healing. Aim To determine whether there is an apparent optimal time of intragastric acid suppression for maximal healing of reflux oesophagitis. Methods Post hoc analysis of data from a proof-of-concept, double-blind, randomized study of 134 adult patients treated with esomeprazole (10 or 40 mg od for 4 weeks) for LA grade C or D oesophagitis. A curve was fitted to pooled 24-h intragastric pH (day 5) and endoscopically assessed healing (4 weeks) data using piecewise quadratic logistic regression. Results Maximal reflux oesophagitis healing rates were achieved when intragastric pH >4 was achieved for approximately 50–70% (12–17 h) of the 24-h period. Acid suppression above this threshold did not yield further increases in healing rates. Conclusion After 4 weeks’ acid-suppressive therapy for LA grade C or D oesophagitis, successful healing appears to reach a threshold above which improvements are unlikely to be achieved despite an increase in number of hours with intragastric pH >4. [ABSTRACT FROM AUTHOR]

Refractory gastro-esophageal reflux disease (GERD), defined as persistent symptoms despite proton pump inhibitor (PPI) therapy, is an increasingly prevalent condition and is becoming a major challenge for the clinician. Since non-acidic reflux may be associated with symptoms persisting during PPI treatment, the lower esophageal sphincter (LES), the most important barrier protecting against reflux, has become an important target for the treatment of (refractory) GERD. Preclinical research has identified several receptors that are involved in the control of transient lower esophageal sphincter relaxations (TLESRs), the predominant mechanism of both acid and non-acidic reflux events, and several drugs have now been tested in humans. The GABAB agonist baclofen has demonstrated to effectively reduce the rate of TLESRs and the amount of reflux in both GERD patients and healthy volunteers. Nevertheless, the occurrence of central side effects limits its clinical use for the treatment of GERD. Several analogues are being developed to overcome this limitation and have shown promising results. Additionally, metabotropic glutamate receptor 5 (mGluR5) receptor antagonists have shown to reduce both acid and non-acidic reflux in GERD patients and several molecules are currently being evaluated. Although CB1 antagonists have been shown to reduce TLESRs, they are also associated with central side effects, limiting their clinical applicability. Despite the identification of several potentially interesting drugs, the main challenge for the future remains the reduction of central side effects. Moreover, future studies will need to demonstrate the efficacy of these treatments in patients with refractory GERD. [ABSTRACT FROM AUTHOR]

Background Rumination is an eating disorder clinically suspected in the presence of chronic regurgitation of recently ingested food with subsequent re-mastication and swallowing. Oesophageal manometry is currently used to confirm the diagnosis, however, it is difficult to distinguish rumination from postprandial belching-regurgitation, being the manometric pattern identical in both situations. Oesophageal impedance allows recognition between liquid and gas gastro-oesophageal reflux. Our aims were (i) to improve diagnosis of rumination using combined impedance–manometry (ii) to assess the gastro-oesophageal pressure-flow pattern in rumination events. Methods Sixteen patients with clinically suspected rumination underwent impedance–manometry monitoring for 1 h after a solid liquid meal. Manometry was first analysed blindly to the impedance pattern. All events marked by the patients and straining episodes were identified. After the manometric analysis, impedance tracings were unblinded and each straining episode was analysed for presence of liquid and/or gas oesophageal retrograde flow. Only rumination events were included for additional evaluation. Key results Postprandial manometry showed a pattern compatible with rumination in 12/16 patients. In total, impedance–manometry confirmed the clinical diagnosis of rumination in eight of the 16 patients with clinical suspicion of rumination. In 102 clearly identified rumination events, the onset of gastric strain (manometry) occurred before the onset of oesophageal liquid retroflow (impedance) in 58% of cases or simultaneously in 37% of cases. In most cases (86%), oesophageal retrograde flow started after an initial increase in abdominal pressure but before the peak gastric strain pressure. Conclusions & Inferences Postprandial impedance–manometry monitoring improves diagnosis of rumination because it allows distinction between rumination and postprandial belching and regurgitation. During rumination, oesophageal liquid retrograde flow is first driven by an early small rise in intragastric pressure preceding the peak pressure observed during straining. [ABSTRACT FROM AUTHOR]

The aim of the study is to compare the characteristics of reflux episodes in controls and in patients with various degrees of oesophagitis and Barrett’s oesophagus. Ambulatory 24-h impedance-pH tracings were analysed from healthy volunteers, patients with non-erosive reflux disease (NERD), patients with grade A oesophagitis, grade B oesophagitis, grade C or D oesophagitis and patients with a short segment (<2 cm) of Barrett’s metaplasia. The number of acid and weakly acidic reflux episodes increased from 25.9 ± 3.9 to 17.9 ± 1.5 in the controls, 39.9 ± 6.3 to 33.4 ± 5.7 in the patients with NERD, 46.6 ± 6.2 to 40.4 ± 9.2 in grade A, 68.2 ± 9.2 to 49.2 ± 12.3 in grade B, 79.8 ± 15.6 to 47.4 ± 4.6 in grade C/D and 75.1 ± 7.9 to 37.3 ± 8.5 in the patients with Barrett. The proportion of reflux episodes that is acidic or alkaline was similar all groups. Comparison with normal values revealed that none of the controls, 40% of the patients with NERD, 50% of the patients with grade A, 80% of the patients with grade B and all patients with grade C/D or Barrett’s oesophagus had an abnormally high total number of reflux episodes. In the patients with severe oesophagitis a significantly higher percentage of reflux episodes reached the proximal oesophagus (43.8%) compared to the patients with Barrett’s oesophagus (19.2%). With increasing degrees of oesophagitis, patients have more reflux episodes but a large overlap between the groups exists making comparison with normal values of limited relevance. In patients with Barrett’s oesophagus fewer reflux episodes reach the proximal oesophagus which might explain their low sensitivity to reflux. [ABSTRACT FROM AUTHOR]

The mechanisms underlying symptoms in non-erosive reflux disease (NERD) remain to be elucidated. Non-erosive reflux disease patients appear to be more sensitive to intraluminal stimula than erosive patients, the proximal oesophagus being the most sensitive. In order to assess regional oesophageal changes in reflux acidity and sensitivity to reflux, according either to the acidity or the composition of the refluxate, combined multiple pH and multiple pH-impedance (pH-MII) was performed in 16 NERD patients. According to multiple pH-metry, 29% and 12% of reflux events reached the middle and proximal oesophagus respectively, and 35% and 19% according to conventional pH-MII ( P < 0.05). The per-individual analysis confirmed the difference between the two techniques. According to combined distal and proximal pH-MII, approximately 30% of distal acid reflux became weakly acidic at the proximal oesophagus. In all patients, the frequency of symptomatic refluxes, both acid and weakly acidic, was significantly higher at the proximal, compared with distal oesophagus (25 ± 8% vs 11 ± 2% for acid reflux and 27 ± 8% vs 8 ± 2% for weakly acidic reflux; P < 0.05). Compared with multiple pH-metry, pH-MII shows a higher sensitivity in the detection of proximal reflux. As approximately 30% of acid reflux becomes weakly acidic along the oesophageal body, to better characterize proximal reflux, in clinical practice, combined proximal pH-impedance monitoring should be used. In NERD patients, the proximal oesophagus seems to be more sensitive to both acid and weakly acidic reflux. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the role of bile and acid reflux in the pathogenesis of reflux oesophagitis (RE) in children. Methods: A total of 44 patients aged 5–17 years with gastro-oesophageal reflux symptoms were enrolled. Simultaneous 24-h oesophageal Bilitec 2000 (Medtronic Instruments, Minneapolis, MN, USA) bilirubin monitoring and pH monitoring, in biopsy of oesophageal mucosa by gastro-endoscopy, were performed in all patients. Results: According to the diagnostic criteria of pathological acid reflux and pathological bile reflux, 10 of 44 cases (22.7%) had acid reflux, 10 (22.7%) had isolated bile reflux, 16 (36.4%) had mixed acid and bile reflux, and the other eight (18.2%) had no reflux. Significant difference was observed in the ratio of different patterns of reflux between the RE group (26 cases) and the non-erosive reflux disease (NERD) group (18 cases) (χ2 = 9.096, P < 0.01). All the parameters of acid reflux in the RE group were higher significantly than that in the NERD group ( P < 0.05 or P < 0.01). A total of 20 out of 26 cases (76.9%) with RE had oesophageal acid reflux as against six out of 18 cases (33.3%) in patients with NERD ( P < 0.01). The difference of each parameter of bile reflux had not reached significance between the two groups. Conclusions: Mixed reflux is the predominant form of reflux in the causation of oesophageal mucosal injury in children. Isolated bile reflux also plays a role in the development of RE, although only in patients without acid reflux. [ABSTRACT FROM AUTHOR]

Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB1/CB2 receptor agonist Δ9-tetrahydrocannabinol (Δ9-THC) on TLESRs in dogs. Based on these findings, the effect of Δ9-THC was studied in healthy volunteers. Experimental approach: In dogs, manometry was used to evaluate the effect of Δ9-THC in the presence and absence of the CB1 receptor antagonist SR141716A on TLESRs induced by gastric distension. Secondly, the effect of 10 and 20 mg Δ9-THC was studied in 18 healthy volunteers in a placebo-controlled study. Manometry was performed before and for 3 h after meal ingestion on three occasions. Key results: In dogs, Δ9-THC dose-dependently inhibited TLESRs and reduced acid reflux rate. SR141716A significantly reversed the effects of Δ9-THC on TLESRs. Similarly, in healthy volunteers, Δ9-THC significantly reduced the number of TLESRs and caused a non-significant reduction of acid reflux episodes in the first postprandial hour. In addition, lower oesophageal sphincter pressure and swallowing were significantly reduced by Δ9-THC. After intake of 20 mg, half of the subjects experienced nausea and vomiting leading to premature termination of the study. Other side-effects were hypotension, tachycardia and central effects. Conclusions and implications: Δ9-THC significantly inhibited the increase in meal-induced TLESRs and reduced spontaneous swallowing in both dogs and humans. In humans, Δ9-THC significantly reduced basal lower oesophageal sphincter pressure. These findings confirm previous observations in dogs and indicate that cannabinoid receptors are also involved in the triggering of TLESRs in humans. Mandarin translation of abstract [ABSTRACT FROM AUTHOR]

The morbidity and mortality of anastomotic complications after esophagectomy have gradually decreased in recent years. However, swallowing difficulties and reflux continue to burden patients jeopardizing their quality of life. In the present study we performed endoscopic evaluation of the outcomes of esophagogastrostomy by analyzing the presence of anastomotic stenosis and reflux esophagitis. A retrospective analysis was carried out on 74 patients who underwent esophagogastrostomy after esophagectomy by one surgeon between January 1995 and December 2004. Fifty-three patients had an endoscopic examination during follow-up (29 ± 23.6 months, range = 5–111 months). Reflux esophagitis and stenosis at the anastomostic site were analyzed according to the surgical technique used and the location of the esophagogastrostomy. The mean age at the time of repair was 60.3 ± 8.87 (range = 39–81) years. Cervical anastomosis was performed in 26 patients and intrathoracic anastomosis in 27 patients. No significant statistical difference in the frequency of anastomotic stenosis was observed between the two groups ( p = 0.829); reflux esophagitis was noted in three patients in the cervical anastomosis group and in 14 patients in the intrathoracic anastomosis group ( p = 0.041). For all patients, 23 received a hand-sewn esophagogastric anastomosis and 30 a circular stapled one. There was no significant statistical difference in anastomotic stenosis ( p = 0.689) and reflux esophagitis ( p = 0.879) in comparisons between the two groups. Cervical anastomosis resulted in a better outcome for esophagogastrostomy by lowering the risk of reflux esophagitis; this outcome might improve the patient’s quality of life. [ABSTRACT FROM AUTHOR]

Background The development of well-tolerated acid suppressant drugs has stimulated substantial growth in the number of trials assessing therapy options for gastro-oesophageal reflux disease (GERD). Aim To develop consensus statements to inform clinical trial design in adult patients with GERD. Methods Draft statements were developed employing a systematic literature review. A modified Delphi process including three rounds of voting was used to reach consensus. Between voting, statements were revised based on feedback from the Working Group and additional literature reviews. The final vote was at a face-to-face meeting that included discussion time. Voting was conducted using a six-point scale. Results At the last vote, 93% of the final 102 statements achieved consensus (defined a priori as being supported by ≥75% of the votes). The Working Group strongly supported the development of validated patient-reported outcome instruments. Symptom assessments carried out by the investigator were considered unacceptable. There was agreement that exclusion from clinical trials should be minimized to improve generalizability, that prospective evaluation ideally requires electronic timed/dated methods and that endoscopists should be blinded to patient symptom status. Conclusions Implementation of the consensus statements will improve the quality and comparability of trials, and make them compatible with regulatory requirements. [ABSTRACT FROM AUTHOR]

Better understanding of the mechanisms that lead to reflux disease is an important area for future research, given the very high prevalence of this problem. During the lifetime of this journal, much has been learnt about the pathophysiology of reflux disease. Abnormally, frequent acid reflux plays a key role in pathogenesis: this reflux occurs predominantly during transient lower oesophageal sphincter relaxations. Analysis of the literature suggests that the importance of transient relaxations as the major permissive event for occurrence of acid reflux is currently substantially underestimated. ‘Transient relaxation’ is an inexact descriptor, as this motor programme includes inhibition of the diaphragmatic hiatus and distal oesophageal body circular muscle and contraction of the oesophageal longitudinal muscle. Laxity of the diaphragmatic hiatus and hiatus hernia are probably important factors that increase the probability for acid reflux to occur during transient relaxations and in allowing strain-induced reflux episodes. The importance of straining and low basal tone of the lower oesophageal sphincter in causing abnormal reflux has probably been overestimated, but these need more investigation. High resolution manometry is the key method for acquisition of important new insights into the normal and disordered mechanics of the antireflux function of the gastro-oesophageal junction, but as yet, the potential of this technique has been tapped relatively little. In the future, improved understanding of the mechanics of the gastro-oesophageal junction should lead to improved physical antireflux procedures. Much progress has been made in defining the control of transient relaxations and this has been translated into several promising options for a new class of drug that treats reflux disease by inhibition of transient relaxations. Clinical trials on these agents appear imminent. [ABSTRACT FROM AUTHOR]

Background and Purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are triggered by activation of mechanosensitive gastric vagal afferents and are the major cause of gastroesophageal reflux and therefore an important target for therapeutic intervention in gastroesophageal reflux disease (GERD). Activation of the metabotropic GABA(B) receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABA(A) receptor in the regulation of TLESRs.Experimental Approach: TLESRs were quantified using Dentsleeve manometry in dogs, and GABA(A) agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABA(A) receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs.Key Results: The prototypical GABA(A) agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABA(A) agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABA(A) positive allosteric modulator diazepam, had no major effects on TLESRs. Evaluation of higher doses was limited by emesis (THIP and isoguvacine) or restlessness/sedation (diazepam). Of the predominant GABA(A) receptor subunits (alpha, beta and gamma components), alpha and beta but not gamma were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the gamma subunit.Conclusions and Implications: The present observations demonstrate that GABA(A) receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABA(A) isoform-selective agonists to define the identity of receptors involved. [ABSTRACT FROM AUTHOR]

Background Over the last 10 years a number of endoscopic procedures for treating gastro-oesophageal reflux disease (GORD) have been developed (suturing, injections, implants and radiofrequency ablation), thus obviating the need for long-term proton pump inhibitors (PPI) and the potential morbidity of laparoscopic fundoplication. Aim To present an update of the literature studying the clinical efficacy of endoscopic antireflux procedures, and to discuss further developments. Methods A PubMed search was performed for endoscopic suturing, antireflux treatment, endoscopic gastroplication, polymer injection, radiofrequency ablation of GORD. Own recent research was compared with existing data. Information concerning GORD endotherapy were gathered. Results Uncontrolled studies have reported promising clinical results on the short to intermediate term for most endoscopic GORD procedures, but the placebo effect remained unknown. It is, therefore, commendable that the three main procedures (Endocinch, Stretta and Enteryx) have now all been tested against a sham procedure. Although all three techniques were able to improve symptoms, quality of life and PPI use, oesophageal acid reduction was unremarkable. Endocinch and Stretta are safe outpatient procedures. Concerns about the durability of Endocinch have risen. Polymer injection (Enteryx) and gel prosthesis implantation (Gatekeeper) were recalled for severe complications and lack of efficacy, respectively. Conclusions Endotherapy has shown the potential to treat (uncomplicated) GORD. However, some early procedures have failed or proven unsafe. Further developments and studies are necessary to determine what modifications to these techniques are required to produce optimal efficacy and durability. Until then, widespread clinical use of endotherapy for GORD should probably be avoided. [ABSTRACT FROM AUTHOR]

Background Gastro-oesophageal reflux disease (GERD) is a common condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Aim To review the current knowledge on the underlying factors contributing to GERD, with particular emphasis on the most recent research. Methods Literature searches were conducted in Medline and EMBASE. The abstracts from recent large congresses were also reviewed to ensure coverage of the latest findings. Results The pathophysiological factors causing GERD can be split into those inducing greater exposure of the oesophagus to stomach contents, and those that provide increased perception of reflux or increased mucosal damage. Transient lower oesophageal sphincter relaxations, which are likely to be triggered by gastric distension, appear to be a key physiological cause of GERD. Excessive reflux may also be provoked by impaired oesophageal or gastric clearance mechanisms. Pre-epithelial, epithelial and post-epithelial defences all normally protect the oesophagus from injury, and may be compromised in individuals with GERD. Heartburn could also be caused by oesophageal hypersensitivity as a result of visceral neural pathway dysfunction. Conclusion The pathophysiology of GERD is multifactorial, and abnormalities in the gastro-oesophageal junction, the stomach, the oesophagus and the nervous system may all contribute to this disease state. [ABSTRACT FROM AUTHOR]

Background A number of mechanisms, other than acid reflux, may be responsible for the symptoms of gastro-oesophageal reflux disease. Aim To assess the importance of non-acid reflux mechanisms. Methods This review is based on presentations and discussion at a workshop, where specialists in the field analysed data relating to these mechanisms. Results Weakly acidic reflux, pH (4–7), detected with impedance–pHmetry is associated with regurgitation and atypical gastro-oesophageal reflux disease symptoms. It is not clear whether pepsin and trypsin can elicit symptoms, but bile can elicit heartburn. The magnitude of reflux-induced oesophageal distension can be determined by high frequency ultrasonography and is not reduced by proton pump inhibition, suggesting that persisting symptoms ‘on’ a proton pump inhibitor may still be due to oesophageal distension by non-acidic reflux. Exaggerated longitudinal muscle contraction can induce non-acid-related heartburn. Preliminary studies showed a positive effect of baclofen, surgery or endoscopic procedures to reduce weakly acidic reflux. Conclusion Mechanisms other than acid reflux are involved in some of the symptoms of gastro-oesophageal reflux disease. Controlled outcome studies are needed to clarify their roles and the indications for antireflux procedures in patients with persistent symptoms whilst ‘on’ a proton pump inhibitor. [ABSTRACT FROM AUTHOR]

Proton-pump inhibitor (PPI) failure has become more prevalent with the increasing use of PPI as the first-line agent in the treatment of gastroesophageal reflux disease (GERD). The underlying mechanisms are diverse and may overlap. The commonly available investigations are limited in their capacity in identifying the underlying cause for PPI failure. Multichannel intraluminal impedance with 24-h pH sensors may be useful to identify non-acid or duodenogastroesophageal reflux in selected cases. The management strategy for PPI failure is largely empirical. Patients who have symptomatic failure on normal dose of PPI shall try double dose PPI. Failing that, empirical treatment with transient lower esophageal sphincter relaxation reducers or pain modulators can be tried. Better understanding of the pathophysiology and mechanisms for PPI failure will help to improve the management of this rising problem. [ABSTRACT FROM AUTHOR]

Some transient lower oesophageal sphincter relaxations (TLOSRs) are accompanied by gastro-oesophageal reflux and others are not. We aimed to investigate what factors determine the occurrence and type of reflux during TLOSRs. In 12 healthy subjects prolonged high-resolution manometry was performed. Reflux was detected using pH-impedance monitoring. A total of 219 TLOSRs were detected; no differences were observed between the duration of TLOSRs with liquid-containing reflux (20.2 ± 1.0 s), gas reflux (17.0 ± 1.0 s) and no reflux (19.0 ± 1.0 s). Trans-sphincteric pressure gradient was similar in TLOSRs with liquid reflux (1.6 ± 0.1 kPa), gas reflux (1.5 ± 0.1 kPa) and no reflux (1.7 ± 0.3 kPa). Prevalence, duration and amplitude of oesophageal pre-contractions and sphincteric after-contractions were not different for TLOSRs with and without reflux. The total number of TLOSRs decreased significantly from 8.2 ± 0.8 in the first to 5.7 ± 0.5 in the second and 4.4 ± 0.6 in the third 70-min recording period. The number of TLOSRs accompanied by liquid-containing reflux decreased from 4.7 ± 0.9 to 3.0 ± 0.4 to 1.6 ± 0.4, while the numbers of TLOSRs with gas reflux remained unchanged (2.1 ± 0.6–2.1 ± 0.7–2.2 ± 0.6). Besides, time after the meal, no differences were observed in the characteristics of TLOSRs with and without gastro-oesophageal reflux. We conclude that factors, other than TLOSR characteristics, are important of whether or not a TLOSR is reflux-related. [ABSTRACT FROM AUTHOR]

Gastro-oesophageal reflux disease is a multifaceted and multifactorial disorder which results from the reflux of gastric contents into the oesophagus. Animal studies suggest that synergism between acid and pepsin and conjugated bile acids have the greatest damaging potential for oesophageal mucosa, although unconjugated bile acids may be caustic at more neutral pH. Human studies are compatible with a synergistic action between acid and duodenogastric reflux in inducing lesions. During prolonged monitoring studies, typical gastro-oesophageal reflux symptoms are more related to acid reflux events than to non-acid reflux events. However, symptoms that persist during acid suppressive therapy are often related to non-acid reflux events. The therapeutic options for the non-acid component of the refluxate, including acid suppression, prokinetics, baclofen, surgery and mucosal protective agents like alginates, are discussed. [ABSTRACT FROM AUTHOR]

Ambulatory pH monitoring detects abnormal levels of acid reflux in the oesophagus and can be used to correlate patients’ symptoms with oesophageal acid exposure. Catheter-based pH testing has several limitations, including issues of sensitivity, specificity, tolerability and the inability to record non-acid reflux events. In an effort to improve upon these drawbacks, several devices have been introduced, including the Bilitec system for measuring duodenogastro-oesophageal reflux; intraluminal impedance monitoring, which detects the distribution, composition and clearing of both acid and non-acid oesophageal reflux; and a wireless pH monitoring device, the Bravo capsule. Initial investigations using the Bilitec system demonstrated that duodenogastro-oesophageal reflux tracked very closely with acid reflux and decreased with proton-pump inhibitor (PPI) therapy, casting doubt on the clinical utility of Bilitec monitoring. Recent evidence revealed a possible role for duodenogastro-oesophageal reflux in a subset of patients who continue to report reflux symptoms in the setting of normalized oesophageal acid exposure on high-dose PPI therapy. When combined with pH monitoring, impedance monitoring enhances the detection and characterization of gastro-oesophageal reflux and may have a role in the evaluation of certain specific gastro-oesophageal reflux disease (GERD) symptoms that persist despite acid suppression therapy. The utility of the Bravo wireless technology for GERD diagnosis has been validated in several studies, with improvements over catheter-based pH monitoring in tolerability, accuracy and sensitivity, as well as the ability to record periods both off and on PPI therapy in a single study. All three diagnostic modalities have advanced the understanding of GERD pathogenesis, but their impact on the clinical management of GERD is still the focus of active investigation. [ABSTRACT FROM AUTHOR]

This study investigated the relationship between the oesophageal acid exposure time and the underlying manometric motor events in patients with gastro-oesophageal reflux disease (GORD). In 31 patients, 3-hour oesophageal motility and pH were measured after a test meal. Ten patients underwent 24-hour ambulatory manometry and pH recording. In the 3-hour postprandial study, of 367 reflux episodes 79% was associated with a transient lower oesophageal sphincter relaxation (TLOSR), 14% with absent basal lower oesophageal sphincter (LOS) pressure and the remaining 7% with other mechanisms, representing 62, 28 and 10% of the acid exposure time, respectively. Acid reflux duration per motor mechanism was longer for absent basal LOS pressure than for TLOSR (189 ± 23 s and 41 ± 5 s, respectively, P < 0.001). In the 24-hour ambulatory study, the contribution of TLOSRs to reflux frequency vs acid exposure time were 65 vs 54% interprandially and 74 vs 53% after the meal. During the night, absence of basal LOS pressure accounted for 36% of reflux events representing 71% of acid exposure time. In conclusion, the duration of oesophageal acid exposure following a TLOSR is shorter than reflux during absent basal LOS pressure. TLOSRs are, the major contributor to oesophageal acid exposure during the day. At night, however, reflux during absent basal LOS pressure is the major contributor to acid exposure. [ABSTRACT FROM AUTHOR]

Gastro-oesophageal reflux disease (GERD) is a condition in which the gastro-oesophageal reflux provokes symptoms or complications. Since the majority of patients with heartburn do not have mucosal breaks, expressions such as ‘endoscopy-negative reflux disease’ (ENRD), ‘non-erosive reflux disease’ (NERD), or even ‘reflux-like dyspepsia’ and ‘functional heartburn’ are frequently employed despite the lack of consensus concerning their exact meaning. Moreover, definition of a disease does not mean that precise diagnostic criteria exist. Diagnostic approaches to GERD differ considerably between primary and secondary care. The primary care physician's role is to decide, on the basis of symptoms and clinical examination, if it is likely that the patient has some serious problem which requires urgent investigation and intervention. In practice, a symptom-based diagnosis can often be made reliably because heartburn and regurgitation are very specific for GERD. The secondary care physician has to make a full evaluation of an already highly-selected patient and, as far as possible, to make a comprehensive, accurate diagnosis, using whatever investigative tools are required. However, there is no ‘gold standard’ for the diagnosis of GERD and 24-hour pH monitoring lacks sensitivity in NERD. Recently, impedance-pH monitoring has been introduced and promising results have been reported. However, this new technology needs further validation and technical improvement before being employed in routine clinical investigation. [ABSTRACT FROM AUTHOR]

Gastro-oesophageal reflux disease is defined as the presence of symptoms or lesions that can be attributed to the reflux of gastric contents into the oesophagus. Aspiration and prolonged monitoring studies in humans have shown that reflux of gastric contents is comprised of both acid and non-acid components, in healthy as well as diseased people. Methods to monitor the non-acid component of the refluxate are described in detail. Experimental models suggest that synergism between acid and pepsin and conjugated bile acids have the greatest damaging potential for oesophageal mucosa, although unconjugated bile acids may be caustic at a more neutral pH. Human studies are compatible with a synergistic action between acid and duodenogastric reflux in inducing lesions. During prolonged monitoring studies, typical gastro-oesophageal reflux disease symptoms are more related to acid reflux events than to non-acid reflux events. However, symptoms that persist during acid-suppressive therapy are often related to non-acid reflux events. The therapeutic options for the non-acid component of the refluxate, including acid suppression, prokinetics, baclofen and surgery, are discussed. [ABSTRACT FROM AUTHOR]

Proton-pump inhibitor failure has become a common clinical dilemma in gastrointestinal clinics and has been increasingly encountered at the primary care level as well. Underlying mechanisms are diverse and may overlap. Most patients who have proton-pump inhibitor failure are likely to originate from the non-erosive reflux disease phenotype. Currently, available diagnostic modalities provide limited clues to the exact underlying cause. Treatment relies primarily on escalating dosing of proton-pump inhibitors. However, new insights into the pathophysiology of proton-pump inhibitor failure are likely to provide alternative therapeutic options. [ABSTRACT FROM AUTHOR]

Recent studies suggest that duodeno-gastro-oesophageal reflux (DGER) contributes to the occurrence of reflux oesophagitis and Barrett's oesophagus. The mechanisms underlying duodeno-gastric reflux (DGR), a prerequisite for DGER, are poorly understood.To study the occurrence of DGR in relation to interdigestive and postprandial gastroduodenal motility.Ten healthy subjects underwent stationary gastroduodenal manometry with simultaneous duodenal and antral Bilitec® recording 4 h before and 5 h after ingestion of a liquid meal. Eight volunteers underwent the same study, with administration of erythromycin postprandially.During the interdigestive phase II, all volunteers had short DGR episodes. Postprandially, DGR occurred in all subjects, on average 39 ± 28 min after the start of the meal, and was cleared from the stomach after 242 ± 23 min. Induction of increased antral motility and of a premature phase III, by administration of erythromycin, was associated with faster gastric DGR clearance. However, there was no direct temporal relationship between erythromycin-induced gastric phase III and erythromycin-induced DGR clearance.In healthy subjects, duodenogastric reflux occurs sporadically in the interdigestive state and is a normal phenomenon in the postprandial period. Erythromycin induces faster clearance of DGR from the stomach, which depends on enhanced antral contractile activity rather than premature phase III. [ABSTRACT FROM AUTHOR]

Treatment of gastro-oesophageal reflux disease (GERD) with lifestyle changes to avoid the conditions that make the symptoms worse and medication to lower the acid content of the refluxed material are generally very effective therapies. However, some individuals do not benefit enough from these approaches, and surgical intervention is warranted. Laparoscopic surgery is the procedure of choice among surgeons performing operations for reflux disease. This surgical technique allows for shorter hospitalization, fewer post surgical complications and less pain than open surgery while maintaining a high success rate. Data from Japan confirms that laparoscopic fundoplication is a safe and effective technique for controlling both typical and atypical symptoms of GERD. Recently, several endoscopic or luminally delivered techniques have been developed as an alternative to laparoscopic surgery. These new surgical options, currently under evaluation in Japan, may offer a valuable alternative to patients who are not responsive to, or who do not wish to persist with lifelong medical therapy for GERD. [ABSTRACT FROM AUTHOR]

Reflux of duodeno-gastric fluid is a significant problem after oesophagectomy with gastric conduit reconstruction. It can impact considerably upon the patient's quality of life and can induce oesophagitis and Barrett's metaplasia in the remnant oesophagus. The aim of the present study was to describe the use of a modified fundoplication in controlling reflux after oesophagectomy. Patients undergoing subtotal oesophagectomy at the Royal Adelaide Hospital were identified. Clinical and operative details were obtained from hospital records. All patients had an end oesophagus to side stomach anastomosis. Two cohorts were identified − one with a standard anastomosis only and the other in whom a modified fundoplication had been added. A structured phone interview was used to assess reflux in the two groups with a minimum of 6 months follow up. The interviewer was blinded to the operative details. The operative technique is described. A total of 44 patients were assessed, 33 having the fundoplication type anastomosis and 11 the standard anastomosis. Operative morbidity was not different between the groups. Symptoms of reflux were better controlled in patients with the fundoplication anastomosis than in patients with a standard anastomosis. Of those with a fundoplication, 14 of 33 patients (42%) were asymptomatic with respect to reflux compared to only one of 11 patients (9%) in the standard anastomosis group. Only four of the 33 patients (12%) with a fundoplication anastomosis had symptoms of severe reflux while seven of the 11 patients (63%) with a standard anastomosis had severe reflux symptoms. This initial evaluation of a modified fundoplication as an antireflux manoeuvre after oesophagectomy suggests that the technique is effective in controlling post-oesophagectomy reflux in the majority of patients. It is simple to perform and may have benefits in improving quality of life and preventing oesophagitis and metaplastic changes in the remnant oesophagus. A more detailed prospective study of the technique is warranted. [ABSTRACT FROM AUTHOR]

Endoscopic-negative reflux disease (ENRD) is the most common presentation of gastro-oesophageal reflux disease (GERD)—affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD-related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high-dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial. [ABSTRACT FROM AUTHOR]

Summary Background: The majority of patients with gastro-oesophageal reflux disease do not present with erosive oesophagitis and make up a heterogeneous group. Patients with non-erosive gastro-oesophageal reflux disease are less responsive than patients with oesophagitis to acid-suppressive therapy. Aim: To assess the role of acid reflux in gastro-oesophageal reflux disease symptoms. Methods: The spatio-temporal characteristics of reflux events were analysed and related to reflux perception in 45 patients with non-erosive gastro-oesophageal reflux disease and 20 patients with erosive oesophagitis. Results: Compared with healthy controls, all patients showed a higher intra-oesophageal proximal spread of acid, which was prominent in patients with non-erosive gastro-oesophageal reflux disease (> 50% of events lasting for 1–2 min). Irrespective of mucosal injury, the risk of reflux perception was very high when acid reached proximal sensors (odds ratio, 7.6; 95% confidence interval, 4.6–12.5), being maximal in patients with non-erosive gastro-oesophageal reflux disease with normal acid exposure time (odds ratio, 11; 95% confidence interval, 5.2–22.3). Conclusions: Patients with non-erosive gastro-oesophageal reflux disease are characterized by a significantly higher proportion of proximal acid refluxes and a higher sensitivity to short-lasting refluxes when compared with patients with oesophagitis. The highest proximal acid exposure and highest perception occurred in patients with non-erosive gastro-oesophageal reflux disease presenting with a normal pH-metric profile. The assessment of acid distribution and its perception in the oesophageal body can better identify reflux patients who should benefit from acid-suppressive treatment. [ABSTRACT FROM AUTHOR]

Abstract Background. Development of reflux esophagitis is one of the adverse effects that cause concern in relation to curative treatment of Helicobacter pylori infection. However, recent studies present a rather negative association between curative treatment and development of reflux esophagitis or reflux symptoms. Therefore, this issue has remained controversial. Accordingly, we investigated the long-term adverse effects of H. pylori eradication treatment in special reference to development of reflux symptoms. Patients and Methods. We conducted a case controlled study by mailing structured questionnaires on past (before curative treatment or 3 years previously) and current status. A case was an endoscopically confirmed peptic ulcer patient with confirmed cure of the infection after eradication treatment 3 years previously and a control was one who had not undergone the eradication treatment during the same period. We studied 241 pairs who matched for age, gender, and type of ulcer disease (GU, DU or GDU). Of these pairs, 81.3% were male and the mean age was 52.6 ± 9.6 year (range 23–76). Results. The rates of patients with improved reflux symptoms in the case and control groups were 65.4% and 30.4%, respectively, with the rate being significantly greater in the case group. On the contrary, the rates of those with worsened reflux symptoms were similar (5.1% and 7.6%). Regarding general events, the rate of patients with decreased frequency of hospital visits and of those who regularly used antiacid medications were significantly decreased in the case group. Furthermore, the case group experienced significantly fewer hospital admissions for various diseases in this 3-year period. However, a significantly greater number of case group patients than control subjects gained weight. Conclusion. Reflux symptoms as well as general well-being were significantly improved after cure of H. pylori infection. [ABSTRACT FROM AUTHOR]