How reflux causes symptoms: Reflux perception in gastroesophageal reflux disease

In gastroesophageal reflux disease (GERD) symptoms arise due to reflux of gastric content into the oesophagus. However, the relation between magnitude and onset of reflux and symptom generation in GERD patients is far from simple; gastroesophageal reflux occurs several times a day in everyone and the majority of reflux episodes remains asymptomatic. This review aims to address the question how reflux causes symptoms, focussing on factors leading to enhanced reflux perception. We will highlight esophageal sensitivity variance between subtypes of GERD, which is influenced by peripheral sensitization of primary afferents, central sensitization of spinal dorsal horn neurons, impaired mucosal barrier function and genetic factors. We will also discuss the contribution of specific refluxate characteristics to reflux perception, including acidity, and the role of bile, pepsin and gas and proximal extent. Further understanding of reflux perception might improve GERD treatment, especially in current partial responders to therapy.     

Review of gastroesophageal reflux disease (GERD) in the diabetic patient

This article reviews the known pathophysiological mechanisms of comorbid gastroesophageal reflux disease (GERD) in the diabetic patient, discusses therapeutic options in care, and provides an approach to its evaluation and management. We searched for review articles published in the past 10 years through a PubMed search using the filters diabetes mellitus, GERD, pathophysiology, and management. The search only yielded a handful of articles, so we independently included relevant studies from these review articles along with related citations as suggested by PubMed. We found diabetic patients are more prone to developing GERD and may present with atypical manifestations. A number of mechanisms have been proposed to elucidate the connection between these two diseases. Studies involving treatment options for comorbid disease suggest conflicting drug–drug interactions. Currently, there are no published guidelines specifically for the evaluation and management of GERD in the diabetic patient. Although there are several proposed mechanisms for the higher prevalence of GERD in the diabetic patient, this complex interrelationship requires further research. Understanding the pathophysiology will help direct diagnostic evaluation. In our review, we propose a management algorithm for GERD in the diabetic patient.     

Focus on gastroesophageal reflux disease in patients with cystic fibrosis

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder in cystic fibrosis (CF), and based on various studies, its prevalence is elevated since childhood. There are several pathogenetic mechanisms on the basis of association between CF and GERD. However, there are no specific guidelines for GERD in CF patients, so diagnosis is based on guidelines performed on patients not affected by CF. The aim of this review is to provide the pathophysiology, diagnostic and therapeutic options, complications, and future directions in the management of GERD patients with CF.     

Gastroesophageal reflux disease related asthma: From preliminary studies to clinical practice

The diagnosis of asthma requires the presence of episodic respiratory difficulties characterized by variable and reversible airway obstruction. It has a high prevalence worldwide and is traditionally considered to be an allergic disease. Most cases are responsive to treatment with bronchodilators and anti-inflammatories, as recommended by national and international guidelines; however, approximately 10% of asthmatic patients are refractory even to optimal therapy. Gastroesophageal reflux disease (GERD) is a common disorder in asthmatic patients and the two disorders may be linked pathophysiologically. Here we review data from preliminary studies that suggest asthma could be induced or exacerbated by gastroesophageal reflux. The optimal strategies for the diagnosis of GERD-related asthma and its therapy are still debated. However, there is evidence to suggest that antireflux treatment is effective and practical for asthmatic patients with well-defined reflux disease.     

Endoscopic therapy for gastroesophageal reflux disease

Endoscopic therapies aimed to reduce gastroesophageal reflux have gained an enormous enthusiasm during the last 5 years when several of them were approved by the regulatory agencies and released on the market. These novel therapies comprise 3 types of techniques: injection/bulking, plicating/suturing and radiofrequency thermal injury. Open-labelled trials performed on proton pump inhibitors-responding patients with typical gastroesophageal reflux disease (GERD) symptoms have shown an improvement in reflux symptoms during short term follow-up. Longer-term data are now available and show disappointing results with partial-thickness plications of the cardia. Randomized sham-controlled trials, which are essential to proof the efficacy of GERD endotherapy because of a known high placebo effect in the management of GERD patients, have been conducted, one with radiofrequency and one with polymer injection, and have confirmed the clinical efficacy of both techniques, although the clinical benefit was less impressive than suggested in open-labelled trials. While mechanistic studies have suggested that the compliance of the gastroesophageal junction might be altered by GERD endotherapy, objective assessment of acid reflux with ambulatory pH-metry has shown, however, minimal or no modification by the treatment. Concerns about the safety of these new techniques have raised when complications were reported as the number of treated cases increased. Currently, no definite indication is established for each technique, but numerous potential indications exist and should be addressed in the setting of carefully designed clinical trials. Physicians should be patient and wait for proof of efficacy and safety of these techniques before using them in their clinical practice. Specific and extensive warning should be obtained before starting clinical application. The present review aims to provide a comprehensive and critical view of endoscopic therapy in GERD management.     

Diagnostic tests for gastroesophageal reflux disease

A range of tests is available to the physician pursuing the diagnosis of gastroesophageal reflux disease (GERD). Many times, these studies are unnecessary because the history is sufficiently revealing to identify the presence of troubling reflux disease. 1 However, this may not be the case and the clinician must decide which tests to choose to arrive at a diagnosis in a reliable, timely, and cost-effective manner (Table 1). Furthermore, the various esophageal tests need to be selected carefully depending upon the information desired. For example, identifying the presence of gastroesophageal reflux disease is different from proving that the patient's symptoms are caused by reflux episodes. Additionally, defining that acid reflux exists may not be enough. To tailor appropriate medical or surgical therapy requires knowing whether complications of GERD are present as well as possible mechanisms by which abnormal GER occurs. A thorough and well-devised investigation strategy requires knowledge of testing procedures ranging from radiology and pathology to physiology and endoscopy. An informed background in these areas allows the clinician and investigator to address not only the presence of reflux and its correlation to patient symptoms but also the severity of esophageal injury and even the mechanisms by which the damage is done. By using the available tests judiciously, one can increase the opportunity of making a correct diagnosis of GERD and simultaneously limit the potential inconveniences or cost to the patient.     

Twice‐daily proton pump inhibitor therapy does not decrease the frequency of reflux episodes during nocturnal recumbency in patients with refractory GERD: analysis of 200 patients using multichannel intraluminal impedance–pH testing

Over half of patients with gastroesophageal reflux disease (GERD) report nocturnal symptoms. Proton pump inhibitors (PPIs) are the main medications used to treat GERD. Multichannel intraluminal impedance with pH (MII‐pH) monitoring is the most sensitive method for detection and characterization of GERD. The aim of this study was to assess and compare reflux frequency in patients with refractory GERD symptoms on and off PPI therapy during the nocturnal recumbent period, as assessed by MII‐pH testing. We analyzed 24‐hour MII‐pH studies performed in 200 patients monitored either on twice‐daily (n = 100) or off (n = 100) PPI therapy. Demographic analysis of the on‐therapy group revealed a mean age of 52 years (24–78 years) with 37% males, and the off‐therapy group revealed a mean age of 49 years (18–84 years) with 40% males. All studies were interpreted to assess and characterize the number of acid and nonacid reflux episodes in the nocturnal recumbent period identified by each patient on an overnight recorder (Zephyr, Sandhill Scientific, Inc., Highlands Ranch, CO, USA). The nocturnal recumbent period was the period documented by patients during which they lie in the recumbent period at night to sleep with average periods lasting 456 and 453 minutes for patients on and off PPI therapy. There were more mean recumbent reflux episodes in the on‐therapy group in comparison with the off‐therapy group (3.76 mean reflux episodes [mre] per patient in the recumbent vs. 2.82 mre); the difference was not statistically significant (P = 0.187). When the reflux events are classified into acid and non‐acid reflux episodes, the relative occurrence of acid reflux events is less in the on‐therapy group (P = 0.047), while the off‐therapy group have fewer nonacid reflux episodes (P = 0.003). PPIs decrease the acidity of esophageal refluxate but do not decrease the relative frequency of reflux episodes in the recumbent position in patients with refractory GERD despite twice‐a‐day treatment with PPI therapy. The explanation for the finding of numerically increased, although not statistically significant, amount of reflux episodes in the PPI treatment group in this study, and previous studies is unclear and warrants further evaluation.     

Medical therapy for gastroesophageal reflux disease in 2007

Maximizing therapy for the patient with symptomatic gastroesophageal reflux disease (GERD) and optimizing efficacy of available agents in the difficult or refractory patient requires an understanding of antisecretory pharmacology and pharmacodynamics. Recent studies raise issues related to potential side effects of proton pump inhibitors (PPIs). Non-acid reflux and its potential association with symptoms must be considered in the management of refractory patients. Medical therapy of GERD is discussed, emphasizing optimizing antisecretory therapy, reviewing recent studies addressing potential side effects of PPIs and options for treatment of non-acid reflux.     

Management of gastroesophageal reflux disease in primary care: results of a survey in 2 areas in Germany.

BACKGROUND: The incidence of gastroesophageal reflux disease (GERD) is increasing. Although guidelines have been issued on the diagnosis and treatment of GERD, the way in which these should be applied in everyday practice is unclear. The aim of the present survey was to interview private-practice physicians on their personal opinions concerning the management of GERD. METHODS: A questionnaire based on the case of a typical patient with reflux was sent out to a total of 918 private-practice physicians. The questions concerned general measures for avoiding reflux symptoms (dietary and lifestyle modifications), the diagnosis of GERD, and the type and dosage of antireflux treatment. RESULTS: A total of 255 questionnaires were evaluated (28 %), which had been returned by 151 family doctors, 63 internal medicine specialists, and 41 gastroenterologists. 70 % of the respondents carry out specific diagnostic tests (endoscopy in 98 % of cases) prior to treatment. Altering specific dietary and lifestyle factors (such as sleeping position) was considered useful by the majority of respondents. 99 % of the physicians administer some form of GERD therapy, and 88 % of the internists/gastroenterologists and 74 % of family doctors (P = 0.006) do so using a "step-down" approach (with proton-pump inhibitors as the initial strategy). With the "step-up" procedure, the initial recommendation includes primarily antacids, with a change to more effective drugs only when symptomatic relief is not achieved. CONCLUSIONS: The current guidelines on the diagnosis and treatment of GERD are largely adhered to, particularly by specialists. In addition to the well-established drug treatment, empirical recommendations on dietary and lifestyle measures still form part of the management of GERD, despite the lack of scientific evidence to support them.     

GERD evaluation: time for a new paradigm?

In the past there has been reliance on heartburn and acid regurgitation as the cardinal symptoms of gastro-esophageal reflux. Now it is recognized that diverse additional symptoms including extraesophageal manifestations are essential components of gastroesophageal reflux disease (GERD). Furthermore, previous reliance in mucosal damage at endoscopy as evidence of therapeutic success in the management of GERD has proven of only limited value in the diverse world of GERD symptoms. Indeed is now apparent that the relationship between symptoms and lesions is modest at best. Most patients with GERD have no overt erosions or ulceration at endoscopy and they frequently suffer from a wide array of complaints other than heartburn that contribute to their diminished perception of life's quality. To address these problems, multidimensional questionnaires designed to encompass the diverse symptomatology of GERD have been investigated, principally, to provide a reproducible metric of change in the subjective response to pharmacologic therapy during trials for patients with nonerosive reflux disease. The most promising of these instruments is The ReQuest questionnaire, because it has been extensively validated in multiple patient groups and cultures, appears highly promising in this regard and for erosive disease too and may ultimately prove to be of value for the initial evaluation of patients with GERD. We propose that accurate symptom delineation complemented with endoscopy performed in selected groups of patients will become the mainstay in diagnosis of GERD and the assessment of therapy efficacy.     

An updated review on gastro-esophageal reflux in pediatrics

Comprehensive guidelines for the diagnosis and management of gastro-esophageal reflux (GER) and GER disease (GERD) were developed by the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. GERD is reflux associated with troublesome symptoms or complications. The recognition of GER and GERD is relevant to implement best management practices. A conservative management is indicated in infants with uncomplicated physiologic reflux. Children with GERD may benefit from further evaluation and treatment. Since the publications of the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in 2009, no important novelties in drug treatment have been reported. Innovations are mainly restricted to the management of regurgitation in infants. During the last 5 years, pros and cons of multichannel intraluminal impedance have been highlighted. However, overall ‘not much has changed’ in the diagnosis and management of GER and GERD in infants and children.     

Extra-esophageal gastroesophageal reflux disease and asthma: understanding this interplay

Gastroesophageal reflux disease (GERD) is a condition that develops when there is reflux of stomach contents, which typically manifests as heartburn and regurgitation. These esophageal symptoms are well recognized; however, there are extra-esophageal manifestations of GERD, which include asthma, chronic cough, laryngitis and sinusitis. With the rising incidence of asthma, there is increasing interest in identifying how GERD impacts asthma development and therapy. Due to the poor sensitivity of endoscopy and pH monitoring, empiric therapy with proton pump inhibitors (PPIs) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. If unresponsive, diagnostic testing with pH monitoring off therapy and/or impedance/pH monitoring on therapy, may be reasonable in order to assess for baseline presence of reflux with the former and exclude continued acid or weakly acid reflux with the latter tests. PPI-unresponsive asthmatics, without overt regurgitation, usually have either no reflux or causes other than GERD. In this group, PPI therapy should be discontinued. In those with GERD as a contributing factor acid suppressive therapy should be continued as well as optimally treating other etiologies requiring concomitant treatment. Surgical fundoplication is rarely needed but in those with a large hiatal hernia, moderate-to-severe reflux by pH monitoring surgery might be helpful in eliminating the need for high-dose acid suppressive therapy.     

Reflux monitoring: on or off therapy?

The role of esophageal pH (or impedance) monitoring in diagnosing gastroesophageal reflux disease (GERD) has evolved over the years. In the era of empiric therapy with potent acid-suppressive agents such as proton pump inhibitors (PPIs), esophageal reflux monitoring is often reserved for patients with PPI-refractory symptoms (1, 2). Given the complexity of patient presentations, technological advancement, and emerging data in the field of GERD, two essential questions need to be addressed: (i) What are the indications for esophageal pH testing in patients suspected to have GERD? (ii) If patients do not respond to aggressive acid suppression, what is the likelihood that they still have reflux; and should the testing be performed at baseline (i.e., off therapy), or is it more important to know whether there is continued reflux despite therapy (i.e., on therapy)?     

Surgical Management of Gastroesophageal Reflux Disease in Obesity

Bariatric surgery is ubiquitous today. In the obese patient with comorbid gastroesophageal reflux disease (GERD), it is increasingly being used as an alternative to fundoplication because it not only has an effect on GERD but also on other comorbid illnesses. Traditional GERD surgery is designed to augment the mechanical barriers against reflux, decrease acid production in the stomach, improve gastric emptying, or divert bile from the stomach. Roux-en-Y gastric bypass addresses these issues in addition to resulting in profound weight loss in patients. Banding may have a positive influence in patients' GERD, though to a lesser extent. The duodenal switch provides excellent control for patients with alkaline reflux. A revision of the 1991 National Institutes of Health guidelines for determining bariatric surgical candidates is overdue, and it may be feasible to consider expanding the body mass index and comorbidity requirements to reflect the benefits offered by these techniques for GERD patients.     

Diagnostic approach to gastro-oesophageal reflux disease

It is neither practical nor necessary to embark on a diagnostic evaluation of every patient with classic symptoms of gastroesophageal reflux disease (GERD). In most cases a well-taken history is usually sufficient to confirm the diagnosis of GERD and begin therapy. However, some patients may present with atypical symptoms; and many with classic symptoms are refractory to standard medical therapy. In these cases one must rely on diagnostic studies to confirm that abnormal acid reflux is present and potentially responsible for the symptoms in question. Modern technology has given us many different modalities to quantify esophageal acid exposure and determine whether symptoms are correlated to reflux events. Unfortunately, these studies are not perfect and the work-up of refractory patients typically requires more than one test. The goal of the following review will be to summarize the currently available techniques for diagnosis of GERD and also discuss the possible impact of new techniques, such as intraluminal impedance monitoring and wireless ambulatory pH monitoring.     

Management of reflux disease in clinical praxis in hungary

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is a chronic condition that affects a large proportion of the population. The majority of patients are treated in the primary care but effective management of the disease still remains a challenge for specialists as well. A recent survey - based on the case of a typical GERD patient - conducted in Germany indicated that mainly specialists adhered to the guidelines. AIM: The purpose of this study was to conduct a survey among specialists and primary care physician members of the Hungarian Society of Gastroenterology about the practical management of GERD using the same questionnaire as in the German study. METHODS: A questionnaire based on the case of a typical patient with GERD was sent out to a total of 1090 members of the society. The questions concerned general measures for avoiding reflux symptoms (dietary and life-style modifications), diagnosis of GERD and the type of treatment. Answers were compared with those in the German study. RESULTS: A total of 421 questionnaires were evaluated (38 %), which had been returned by 174 general practitioners (GP), 173 gastroenterologists (GE), 41 paediatricians, and 33 surgeons. Only 9 % (38/421) of the responders think that there is no necessity to carry out specific diagnostic approaches before starting any treatment. In 91 % of the cases (25 % always and 66 % only if symptoms persist) doctors carry out specific diagnostic tests (75 % endoscopy, 13 % 24 hours pH-metry, and 12 % X-ray). 47 % of responders start drug treatment at once while 35 % start medications only after getting the results of the requested examinations. 18 % of Hungarian doctors do start with a non-medical therapy. Almost all responders feel that it is important to advise a reduction of weight and a cessation of smoking for GERD patients. Altering specific dietary and life-style habits was considered useful by more than 85 % of our responders. Hungarian physicians were more concerned about different alcoholic drinks and spicy, fatty or bloating meals and less about sweets than their German counterparts. More than 85 % of GPs administer some kind of drug therapy as first choice. Over 65 % of GPs are using the step-down approach with proton pump inhibitors as the initial strategy and 78 %, 76 %, and 81 % of GEs, paediatricians, and surgeons, respectively, do the same. Almost one-third of GPs and paediatricians are willing to continue therapy and almost two-thirds of GPs will reduce the dose of current medical therapy if the GERD patient is responding well to the initial therapy. CONCLUSIONS: Irrespective of the country, specialists are adhering more strictly to the guidelines on the diagnosis and treatment of GERD than general practitioners. The majority of responders, however, ask for endoscopy prior to initiation of any medication and use the step-down approach. Despite the lack of scientific evidence, reduction of weight, cessation of smoking, dietary and life-style modifications are still part of the treatment of GERD in both Germany and Hungary.     

Endoscopic therapy for GERD: Does it have a future?

Approximately 20% of patients with gastroesophageal reflux disease (GERD) have symptoms refractory to long-term proton pump inhibitor (PPI) therapy. Furthermore, PPI therapy is expensive. Fundoplication is considered the gold standard of GERD therapy in terms of normalization of esophageal acid exposure and symptom control; however, this exposes the patient to the risks of surgery and anesthesia. Therefore, an endoscopic approach to treating GERD that obviates the need for PPIs and avoids surgical morbidity is desirable. Several endoscopic methods have been used, including radiofrequency ablation, implantation of foreign substances as bulking agents, and various tissue apposition strategies. The emerging field of GERD endotherapy is promising, but more rigorous, sham-controlled, long-term studies are required to elucidate its exact role in clinical practice. This review discusses the evolution of these concepts, describes specific endoscopic devices that have been developed, and explores the future of endotherapies as viable treatment alternatives for GERD.     

Development and validation of a patient-reported outcome instrument in partial responders to proton pump inhibitors

Abstract

Objective. The Reflux Symptom Questionnaire 7-day recall (RESQ-7) was developed, in line with the US Food and Drug Administration (FDA) guidelines, to address the need for a patient-reported outcome (PRO) instrument assessing symptoms specifically in patients with gastroesophageal reflux disease (GERD) who are only partially responsive to proton pump inhibitor (PPI) therapy. Materials and methods. The RESQ-7 was constructed using patient interviews and expert consensus. The instrument was psychometrically validated in a clinical trial setting in patients with persistent GERD symptoms despite PPI therapy. Results. Evaluation of content validity yielded a 13-item structure for the RESQ-7, incorporating symptoms overlooked by existing GERD questionnaires, such as hoarseness, cough, difficulty swallowing and burping. Principal component analysis suggested a four-domain structure. All domains had a high inter-item correlation (Cronbach's α lower 95% confidence limits: 0.77–0.87 for intensity; 0.72–0.82 for frequency). Test–retest reliability was fair-to-good or excellent (intraclass correlation coefficient lower 95% confidence limits: 0.70–0.78 for intensity; 0.65–0.75 for frequency). Convergent and discriminant validity were confirmed by correlation comparisons with the Gastrointestinal Symptom Rating Scale. Discussion. The RESQ-7 demonstrated good content validity and psychometric properties in patients with GERD and a partial response to PPIs. The weekly recall makes the RESQ-7 appropriate for use in routine clinical care. The authors believe that it is the first instrument to be developed specifically for patients with a partial response to PPI therapy in line with FDA guidelines on PROs (ClinicalTrials.gov identifier: NCT00703534).     

A Causal Relationship Between Cough and Gastroesophageal Reflux Disease (GERD) has been Established: A Pro/Con Debate

Along with upper airway cough syndrome (formerly, postnasal drip syndrome) and eosinophilic airway inflammation (asthma, nonasthmatic eosinophilic bronchitis), gastroesophageal reflux disease (GERD) is generally considered among the most common etiologies of chronic cough. Indeed, cough management guidelines published by numerous respiratory societies worldwide recommend evaluation and treatment of GERD as an integral component of the diagnostic/therapeutic algorithm for the management of chronic cough. However, a significant number of patients with chronic cough presumed due to GERD do not report improvement despite aggressive acid-suppressive therapy. Some of these refractory cases may be due to the recently appreciated entity of nonacid or weakly acidic reflux. Further contributing to the controversy are recent studies that demonstrate that patients with chronic cough do not have excessive reflux events relative to healthy volunteers. Although a temporal relationship between cough and reflux events has been suggested by studies utilizing impedance-pH monitoring of reflux events and objective cough recording, consensus is lacking in terms of whether this temporal relationship proves a causal link between reflux and cough. The fourth American Cough Conference (New York, June 2013) provided an ideal forum for the debate of this issue between two internationally recognized experts in the field of reflux and chronic cough.