ABSTRACT Some patients with gastro-oesophageal reflux disease (GORD) experience symptoms despite proton pump inhibitor (PPI) treatment. In the early years of their availability, these drugs were thought to be a highly effective treatment for GORD and realisation that symptom relief was often incomplete came as a disappointment. This review considers the evolution of thinking with the aid of the Gartner hype cycle – a graphical depiction of the process of innovation, evolution and adoption of new technologies. Acknowledging that over-simplistic concepts of GORD have been largely responsible for inflated expectations of PPI therapy is an important step forward in establishing how patients with persistent symptoms, despite PPIs, should be assessed and treated.

OBJECTIVE:The objective of this study was to develop a self-administered questionnaire for upper gastrointestinal (GI) symptoms using lay vocabulary uninfluenced by established medical terminology or concepts and to conduct a survey of symptom occurrence among sufferers in four countries.METHODS:The questionnaire was designed by integrating information gained from the vocabulary used by 38 upper GI symptom sufferers. There was no medical input to its development. The questionnaire was then used, after appropriate translation, in Brazil, Russia, the UK and the USA. Details of 10 659 symptom episodes were obtained from 2665 individuals.RESULTS:Nine symptoms described in lay vocabulary were identified during questionnaire development. Of these, one corresponded to regurgitation, whereas two that were distinguished by survey participants might both be interpreted as heartburn. One chest symptom for which a corresponding medical term was uncertain occurred in ∼30% of the respondents. Five different 'stomach' or abdominal symptoms were identified. The predominant symptom and the pattern of concurrent symptoms often varied from one symptom episode to another. Use of the terms 'heartburn', 'reflux', 'indigestion' and 'burning stomach' to describe symptoms varied between countries.CONCLUSION:Some common upper GI symptoms described by those who suffer them have no clear counterpart in conventional medical terminology. Inadequacy of the conventional terminology in this respect deserves attention, first, to characterize it fully, and thereafter to construct enquiry that delivers more precise symptom identification. Our results suggest that improvement may require the use of vocabulary of individuals suffering the symptoms without imposing conformity with established symptom concepts.

Objectives/Hypothesis: The association between extraesophageal reflux (EER) and symptoms of gastroesophageal reflux disease (GERD) is inadequately understood. We used the Comprehensive Reflux Symptom Scale (CReSS) to evaluate EER and reflux-symptom prevalence in gastroenterology and otolaryngology outpatients and symptom awareness among UK gastroenterologists.Study Design: Cross-sectional cohort survey.Methods: Six hundred thirty-nine participants were surveyed: 103 controls, 359 patients undergoing esophagogastroduodenoscopy (EGD), and 177 otolaryngology clinic patients with throat symptoms. Participants completed the CReSS questionnaire. The study was undertaken in the Endoscopy Unit and the Department of Otolaryngology-Head and Neck Surgery, Newcastle upon Tyne Hospitals, Newcastle-upon-Tyne, United Kingdom. Registered members of the British Gastroenterology Society were asked to rate how frequently reflux patients might complain of each CReSS item.Results: The median CReSS total in volunteers (4) was significantly lower (P<.002) than in ear, nose, and throat (ENT) patients (26) or EGD patients with (42) or without (32) esophageal inflammation. All items were scored as >= 1 by >15% of ENT patients and 28% of EGD patients. Three major, robust CReSS factors: esophageal, pharyngeal, and upper airway emerged. Of 259 gastroenterologists, >20% scored 8 of the 34 symptoms as never being reported by reflux patients.Conclusions: Endorsement of each EER CReSS item by 28% to 58% of patients with endoscopic evidence of GERD supports the Montreal consensus on an EER-GERD continuum. Gastroenterologists vary considerably in their appreciation of EER symptom relevance. The advantages of CReSS include standardized, comprehensive capture of patient experience; discriminant validity of ENT and GERD patients from volunteers; and discrete esophageal, pharyngeal, and upper airway subscales.

Background Management of patients with gastro-oesophageal reflux disease (GORD) can be assisted by information predicting the likely response to proton pump inhibitor (PPI) treatment. The aim was to undertake a study of GORD patients designed to approximate ordinary clinical practice that would identify patient characteristics predicting symptomatic response to pantoprazole treatment. Methods 1888 patients with symptoms of GORD were enrolled in a multicentre, multinational, prospective, open study of 8 weeks pantoprazole treatment, 40 mg daily. Response was assessed by using the ReQuest™ questionnaire, by the investigator making conventional clinical enquiry and by asking patients about their satisfaction with symptom control. Factors including pre-treatment oesophagitis, gender, age, body mass index (BMI), Helicobacter pylori status, anxiety and depression, and concurrent IBS symptoms were examined using logistic regression to determine if they were related to response, judged from the ReQuest™-GI score. Results Poorer treatment responses were associated with non-erosive reflux disease, female gender, lower BMI, anxiety and concurrent irritable bowel syndrome symptoms before treatment. No association was found with age, Helicobacter pylori status or oesophagitis grade. Some reflux-related symptoms were still present in 14% of patients who declared themselves 'well-satisfied' with their symptom control. Conclusions Some readily identifiable features help to predict symptomatic responses to a PPI and consequently may help in managing patient expectation. ClinicalTrial.gov identifier: NCT00312806 .

AIM:To investigate the influence of irritable bowel syndrome (IBS)-like symptoms on treatment outcomes with pantoprazole in gastroesophageal reflux disease (GERD) in a real life setting.METHODS:For this prospective, open-label, multinational, multicentre study, 1888 patients assessed by the investigators as suffering from GERD were recruited. The patients were additionally classified as with or without IBS-like symptoms at baseline. They were treated with pantoprazole 40 mg once daily and completed the Reflux Questionnaire™ (ReQuest™) short version daily. Response rates and symptom scores were compared after 4 and 8 wk of treatment for subgroups defined by the subclasses of GERD [erosive (ERD) and non-erosive reflux disease (NERD)] and the presence of IBS-like symptoms.RESULTS:IBS-like symptoms were more prevalent in NERD than in ERD (18.3% vs 12.7%, P = 0.0015). Response rates after 4 and/or 8 wk of treatment were lower in patients with IBS-like symptoms than in patients without IBS-like symptoms in both ERD (Week 4: P < 0.0001, Week 8: P < 0.0339) and NERD (Week 8: P = 0.0088). At baseline, ReQuest™ "lower abdominal complaints" symptom scores were highest in NERD patients with IBS-like symptoms. Additionally, these patients had the strongest symptom improvement after treatment compared with all other subgroups.CONCLUSION:IBS-like symptoms influence treatment outcome and symptom burden in GERD and should be considered in management. Proton pump inhibitors can improve IBS-like symptoms, particularly in NERD.

The consensus meeting attempted to clarify concepts associated with the clinical entity often termed 'NERD' and to define it in a way that would permit physicians to communicate accurately amongst each other when they use the term, so that there may be a common understanding of the condition. In this paper, eight clinical case scenarios are presented that illustrate some points of potential uncertainty and ambiguity in the use of the term NERD and the clinical management of patients. They are discussed in relation to views reached by the consensus group.

PURPOSE OF REVIEW:To analyse the concept of nonerosive reflux disease (NERD), examining its evolving definition and its relationship to reflux disease and functional gastrointestinal disorders. RECENT FINDINGS:The advent of the Montreal definition of gastroesophageal reflux disease (GERD) and the Rome III definition of functional upper gastrointestinal disorders has refined the concept of NERD. The high prevalence of GERD symptoms and the strong overlap between GERD and irritable bowel syndrome is due to the influence of NERD. Subtle differences exist between patterns of acid exposure in NERD and erosive disease on pH testing. Symptom generation in NERD may be influenced by altered mucosal permeability. Improvements in endoscopic technology demonstrate esophageal mucosal changes in NERD which are not seen in controls. There is a general acknowledgement that the inferior symptomatic response to acid suppression reported in NERD is attributable, at least in part, to contamination of study populations by patients with functional heartburn. SUMMARY:NERD is common and its definition continues to evolve. For the present, however, this should be considered to be heartburn with and without regurgitation due to gastroesophageal reflux in the absence of esophageal mucosal erosions. Future studies examining treatment response of GERD subgroups must exclude functional heartburn if NERD is to be properly understood.

Background: On-demand PPI has been shown to be an effective step-down therapy for GERD.But data on comparison with regular PPI is lacking.Aim: To compare the efficacy, quality of life (QoL) and cost-effectiveness of on-demand and daily PPI regimens in long-term management of mild GERD.Methods: Consecutive patients with weekly reflux symptoms for >6 months were prospectively recruited for assessment of reflux symptom score (0-3) and validated disease-specific GERD-QOL questionnaire (0-400).EGD defined esophagitis by LA classification.Exclusion criteria included NSAID use, peptic ulcer, esophagitis ≥ grade B, stricture or Barrett's esophagus.Eligible patients were given esomeprazole (Eso) 20 mg daily for 8 weeks as initial treatment.Patients with complete symptom resolution to Eso were randomized to (1) On-demand (OD) group: daily placebo + on-demand Eso 20 mg, or (2) Regular (R) group: daily Eso 20mg + on-demand placebo for 26 weeks.Treatment failure was defined as inadequate relief of reflux symptom by patient-reported global symptom assessment.Primary measure was treatment failure at 26 weeks.Results: 250 patients (Male= 87, Mean age: 51+/-11, NERD=205) were randomized (N=125 in each group).37 (29.6%)patients in OD and 22 (17.6%) in R group had treatment failure at 26 weeks (p=0.025).The probability of treatment failure at 26 weeks was 31.6% (mean remission time: 21 weeks) for OD and 19.0% (mean remission time: 24 weeks) for R group, respectively (p=0.018, log rank).Among OD patients without treatment failure, PPI was taken in 20.5% of time and there was no significant difference in symptom severity (Median symptom score: 1, p= 0.34) or GERD-specific QoL measures (OD: 210.8 +/-91.4Vs R: 196.0 +/-101.1,p=0.43) at 26 weeks compared to R patients.The cost-effectiveness ratio was US$15,144 for OD group and US$59,289 for R group.The incremental cost to achieve an additional patient with adequate symptom relief by switching from OD group to R group was US$318,272.Conclusion: On-demand PPI regimen is inferior to daily PPI regimen for long-term management of mild GERD.However, on-demand PPI strategy is much more cost-effective.Probability of treatment failure over 26 weeks

a linear combination of symptoms: ES (sialorrhea, globus, dysphagia, odinophagia, retching, eructs, and halitosis), UA (upper abdominal discomfort, early satiety, postprandial fullness, nausea and flatulence), EX (non-cardiac chest pain, disnea, chronic cough, hoarseness, sleep disturbances).Scores from the extracted variance (UA 48%, ES 40%, EX 46%) were used in a general linear model (GLM) adjusted by geographical distribution, medical specialty, age, sex, BMI, severity of heartburn and regurgitation.RESULTS: Severities of ES, UA, and EX symptoms were positively associated with the severity of heartburn and regurgitation.EX symptoms scores were higher in the NS group compared with diurnal complains group (p<0.001),but for UA, the symptoms score was higher in the diurnal group (p<0.03).We tested the effect of NS over ES, UA and EX scores using a GLM for repeated measurements (adjusted by geographical distribution, medical specialty, age, sex, and BMI).Improvements in the scores for all symptoms were found after treatment with PMg.The EX symptoms in NS group had particularly relevant improvement (p<0.001).CONCLUSIONS: PMg showed an important improvement for all symptoms scores.This effect was markedly superior for EX symptoms in the NS group.

determinant of QoL in both genders, other upper GI symptoms also contribute to GERD related QoL impairment in female patients.Gender difference in symptom determinants of different domains of GERD-QoL M1030

Objective To determine the relative benefits and risks of laparoscopic fundoplication surgery as an alternative to long term drug treatment for chronic gastro-oesophageal reflux disease (GORD). Design Multicentre, pragmatic randomised trial (with parallel preference groups). Setting 21 hospitals in the United Kingdom. Participants 357 randomised participants (178 surgical, 179 medical) and 453 preference participants (261, 192); mean age 46; 66% men. All participants had documented evidence of GORD and symptoms for >12 months. Intervention The type of laparoscopic fundoplication used was left to the discretion of the surgeon. Those allocated to medical treatment had their treatment reviewed and adjusted as necessary by a local gastroenterologist, and subsequent clinical management was at the discretion of the clinician responsible for care. Main outcome measures The disease specific REFLUX quality of life score (primary outcome), SF-36, EQ-5D, and medication use, measured at time points equivalent to three and 12 months after surgery, and surgical complications. Main results Randomised participants had received drugs for GORD for median of 32 months before trial entry. Baseline REFLUX scores were 63.6 (SD 24.1) and 66.8 (SD 24.5) in the surgical and medical randomised groups, respectively. Of those randomised to surgery, 111 (62%) actually had total or partial fundoplication. Surgical complications were uncommon with a conversion rate of 0.6% and no mortality. By 12 months, 38% (59/154) randomised to surgery (14% (14/104) among those who had fundoplication) were taking reflux medication versus 90% (147/164) randomised medical management. The REFLUX score favoured the randomised surgical group (14.0, 95% confidence interval 9.6 to 18.4; P<0.001). Differences of a third to half of 1 SD in other health status measures also favoured the randomised surgical group. Baseline scores in the preference for surgery group were the worst; by 12 months these were better than in the preference for medical treatment group. Conclusion At least up to 12 months after surgery, laparoscopic fundoplication significantly increased measures of health status in patients with GORD. Trial registrationISRCTN15517081.

It seems self-evident that complete remission should be a goal of therapy for any disease that cannot be cured. Remission itself is easy to define: it denotes that a disease or disorder has become quiescent or suppressed to a point that it no longer causes morbidity. However, recent recognition that gastroesophageal reflux disease (GERD) may be associated with symptoms of irritable bowel and with other disorders raises questions about the specification of the “reflux symptoms” for which remission will be sought. Moreover, the fact that many GERD patients are content to take their acid-suppressing medication prn is evidence that total abolition of reflux symptoms is not what they seek in any case. Therefore, to consider remission in GERD it is necessary to first consider “what is GERD?” GERD is now often described as a family or spectrum of disorders, but the distinction is not always made between the spectrum of GERD symptoms, the spectrum of GERD pathology, and the spectrum of underlying pathophysiology of GERD. The 3 are linked, of course, but they overlap. The well accepted Genval definition of GERD is a pragmatic definition rather than one based on scientific principles, but it seems to have served the clinical and scientific community well. Its limitations are inherent in its focus on clinical features related to gastroesophageal reflux. Now that more is known of GERD pathophysiology, it is clear that the underlying abnormalities of GERD are not fully embraced by the Genval definition. Clarity about remission requires that the definition of remission and the specification of criteria for its attainment should be considered in sequence and separately. Consequently, no attempt is made in this paper to suggest criteria. However, notwithstanding the limitations of the Genval definition of GERD, there is merit in defining remission in similar terms and thus the following definition is proposed: “GERD patients are in remission when they are no longer exposed to the risk of physical complications from gastroesophageal reflux and have no clinically significant impairment of health-related well being (quality of life) due to reflux-related symptoms.”

SUMMARY Concepts of the spectrum of gastroesophageal reflux disease (GERD) continue to evolve as researchers and clinicians chal- lenge conceptual frameworks and explore new paradigms aided by innovative technologies and novel developments in symptom assessment. In this review, the deliberations of a meeting of experts in gastroenterology (Athens, 2006) are presented as a critical evaluation of the current understand- ing of GERD and its symptoms, and an exploration of future directions. Consensus statements from Genval, Marrakesh and Montreal present working definitions of GERD; these will, inevitably, continue to be refined as our understanding of the spectrum of GERD-associated symptoms evolves and our appreciation of differences among non-erosive reflux disease (NERD), erosive GERD and Barrett's esophagus, as well as the overlap between GERD and functional gastro- intestinal disorders (FGIDs), grows. Currently, we lack an independent basis by which to determine whether particu- lar symptoms are a manifestation of GERD per se or should be attributed to associated FGIDs. Furthermore our under- standing of the etiology of atypical manifestations and ex- traesophageal symptoms is poor. It is possible that, in the future, acid-related NERD will become identifiable in terms of a microscopic inflammatory or ultrastructural change in the esophageal epithelium, thereby allowing a diagnosis of microscopic erosive reflux disease. It is likely that the natu- ral history of GERD will be confirmed as largely benign and biomarkers will identify the minority who may be destined for a more sinister outcome. Finally, developments in symp-

There is a continuing increase in gastroesophageal reflux disease (GERD), its diverse manifestations and complications worldwide. Indeed the substantial increase in Asia remains is a major epidemiologic and a developing health care issue. This manifesto provides a contemporary review of the current status of areas of uncertainty and in particular highlights the lack of knowledge and unmet needs in the field of GERD biology and especially management. There seems to be no widely accepted rationale for the increasing incidence and prevalence of GERD globally. Although consideration has been given to the decline in Helicobacter pylori infection, others consider the steadily growing problem of obesity as the most likely etiologic factor. What actually comprises the disease entity of GERD continues to confound physicians, and the steady increase in new definitions suggests that a clear picture is still emerging. Of note, however, is the rising awareness of its protean systemic manifestations and the fact that while erosive reflux disease is easily recognizable endoscopically, nonerosive disease (NERD) comprises the majority of presentations in many populations. In view of this, GERD-specific questionnaires and other evaluative tools have been designed to capture the multidimensional nature of the symptom complexes in GERD patients who for the most part may have no endoscopic evidence of disease. Such tools have obvious utility in the evaluation of changes with treatment, especially because there is no endoscopic abnormality detectable. The recognition that NERD is becoming a major clinical entity that requires substantial further investigation is now clearly apparent. At this time, however, little is known of the cellular barrier mechanisms of the esophagus and what is responsible for their reconstitution after injury. Similarly, the neural basis of esophageal pain appreciation, or its relation to the visceral sensory mechanisms that may link NERD with aspects of functional bowel disease are as yet ill understood. Apart from the clinical concern with symptom-focused issues, it is the specter of Barrett esophagus, the most-feared complication of GERD that mostly continues to drive endoscopic practice in GERD. At this time, however, current surveillance strategies remain severely limited in their ability to adequately detect or prevent most esophageal adenocarcinoma. Although considerable effort has been directed at defining the neural circuitry of the esophagus in terms of both motility and sensation, the topography and function of the esophagealbrain-gut axis in respect of the generation of esophageal symptoms remains terra incognita. At this time therefore acid suppression remains the mainstay of therapy in terms of treating the GERD/NERD disease process. Despite the efficacy of the currently available proton pump inhibitor class of drugs, there are clearly unmet needs in this area and agents with a more rapid onset of action and prolonged effect, particularly at night remain important goals in the future advance of pharmacotherapy.

Gastroesophageal reflux disease (GERD) is now the most common diagnosis made in gastroenterology outpatient practice. Increasing time and resources are spent on its management each year. Many conditions associated with, or the result of, GERD also appear to be on the rise-the most worrisome, esophageal adenocarcinoma, is steadily increasing in incidence, although it remains an uncommon cancer. Now that proton pump inhibitors (PPIs) are widely available, including over the counter in some countries, patients seen in consultation by gastroenterologists are becoming ever more challenging. In view of these trends, a meeting was convened in Whistler, British Columbia, Canada, in the fall of 2006 to review the current state-of-the-art approach to GERD, and to highlight areas of uncertainty in this field. The aim was to focus attention on patient needs, in an effort to provide better symptomatic care. The discussions were free ranging, on a variety of the most difficult problems, and the chairmen were instructed to lead the discussions into the unmet needs. The following pages highlight a summary of these discussions.

Purpose:ReQuest in Practice™ (RiP™), a shortened form of the fully validated ReQuest™ questionnaire, was designed to allow patients' self-assessment of GERD symptoms in day-to-day clinical practice. Methods: Data from previous studies showing a high correlation of symptom frequency x intensity with resultant distress was used to devise an abbreviated questionnaire, RiP™. Visual analogue scales were used to assess 5 symptom dimensions plus the patients' general well-being. Acid complaints, upper abdominal/stomach complaints, lower abdominal/digestive complaints, and nausea form the subscale RiP™-GI; general well-being and sleep disturbance form the subscale RiP™-WS. 120 patients with GERD were studied to determine the construct validity, internal consistency and the intra-class correlation coefficient (ICC) of RiP™. Half the patients completed RiP™ followed by ReQuest™. The other half completed the same questionnaires in reverse order to avoid a sequence bias. Before and after endoscopy all patients completed the health-related quality of life questionnaire GERDyzer™. A high Spearman correlation coefficient (SCC) of >0.75 of ReQuest™ and RiP™ would establish the applicability of all validation parameters of the former (Cronbach's alpha: 0.9; ICC: 0.86; test-retest reliability: 0.85; responsiveness index: 165.3) to the latter. Consequently, construct validity was assessed by correlating RiP™ with ReQuest™ and with GERDyzer™. In addition, Cronbach's alpha and ICC were calculated directly for RiP™ and its subscales. Results: The SCC of ReQuest in Practice™ and ReQuest™ was 0.9, indicating that the two are parallel forms. Internal consistency was high (Cronbach's alpha: 0.9) establishing the suitability of RiP™ to assess and monitor individual patients. Psychometric evaluation revealed an ICC of 0.99. The RiP™-WS subscale correlated well with the different dimensions of GERDyzer™ (SCC: 0.65) and with the GERDyzer™ total score (SCC: 0.80). Conclusion:ReQuest in Practice™ is a valid and reliable instrument for symptom assessment in GERD. It may be used by individual patients in day-to-day clinical practice and thus can potentially assist the physician in monitoring response to treatment.

The case of a 56-year-old man with recurrent retrosternal heartburn no longer relieved by antacids is discussed. Arguments for and against conducting endoscopy in this patient are presented. Initial therapy with a standard dose proton pump inhibitor, without endoscopy is the suggested treatment strategy. The main purpose of conducting an endoscopy in a patient with chronic gastrointestinal reflux is to detect the presence of Barrett's esophagus. However, data indicate that the presence of Barrett's esophagus is unrelated to symptoms and that it is not significantly associated with heartburn. Additionally, there is no certainty that survival is improved by the detection of Barrett's esophagus. Nonetheless, many clinical practice guidelines support conducting endoscopy in patients with GERD.