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A review of the recent changes in understanding of laryngopharyngeal and extra-oesophageal reflux symptoms.
Literature search over 7 years (2008–2015) and relevant historical cited articles.
Modern investigation more clearly shows a subgroup of patients with intermittent full column oesophago-gastric-reflux-causing symptoms. Multiple other sites in the lung, head and neck may also be implicated in the reflux disease process.
Understanding of extra-oesophageal reflux symptomology is evolving. New equipment and techniques suggest further areas of research, and as yet effective therapy remains elusive for some.
To read the full-text of this research, you can request a copy directly from the authors.
... Gastroesophageal reflux disease (GERD) affects 20-30% of the population . In addition to the symptoms (heartburn, regurgitation, wheezing, asthma, etc.) , GERD may be complicated by Barrett's esophagus (BE) . ...
... Gastroesophageal reflux disease (GERD) affects 20-30% of the population . In addition to the symptoms (heartburn, regurgitation, wheezing, asthma, etc.) , GERD may be complicated by Barrett's esophagus (BE) . The presences of biopsy-proven goblet cell containing intestinal metaplasia (IM) within columnar lined esophagus (CLE) defines BE ( [1, 4, Fig. 1). ...
... GERD represents a lifestyle problem and results from the consumption of large meals, increased amount of carbohydrate-containing foods and beverages, and lack of physical activity . The study by Li et al.  clearly indicates the importance of including dietary treatment into the management of BE. ...
Barrett’s esophagus (BE) represents the premalignant morphology of gastroesophageal reflux disease (GERD). Evidence indicates a positive correlation between GERD vs. obesity and increased sugar consumption.
Here we analyzed recently published data (2006–2017) on the role of dietary sugar intake for BE development (main focus year 2017).
Recent investigations found a positive association between obesity, hip waist ratio and dietary sugar intake and Barrett’s esophagus.
Sugar intake positively associates with BE. A low carbohydrate diet should be recommended for persons with BE and GERD.
... the level of the esophagus and in the extraesophageal structures such as the laryngopharynx and lungs has been developed and validated [12,13]. As sulfur colloid is no longer available in Australia, the replacement agent, 99m Tc Phytate is currently in use for gastroesophageal studies such as reflux and gastric emptying. ...
Gastroesophageal reflux disease (GERD) is a common and growing problem in most western countries. It may present with the typical symptoms of heartburn and regurgitation or with the effects of extra-esophageal disease. We have developed and validated a scintigraphic test that evaluates reflux at both sites in patients at high risk of laryngopharyngeal reflux and lung aspiration. We hypothesized that the test may be able to separate physiologic reflux from pathological reflux and examined this possibility in normal asymptomatic volunteers. Asymptomatic volunteers were screened with the Belafsky reflux symptom index (RSI) and entered into the trial if scores were less than 13. 99mTc Phytate was ingested orally and dynamic studies from the pharynx to the stomach were obtained while upright and supine. A delayed study of the thorax was also obtained for lung aspiration of refluxate. Studies were semi-quantitated graphically as time-activity curves. A total of 25 volunteers were studied (13 M, 12 F) with a mean age of 57.5 yr (Range 40-85 yr). None gave a history of heartburn or regurgitation. Mean RSI was 4.1 (range 0-10). Testing showed upright gastroesophageal reflux to the mid-upper esophagus without pharyngeal contamination in 32%. None of the subjects showed supine reflux or lung aspiration. This result corresponds well with intraluminal impedance/pH monitoring in normal volunteers. The scintigraphic reflux test gives similar results to standard intraluminal impedance/pH studies in normal volunteers. A significant proportion of asymptomatic volunteers demonstrate upright reflux only.
... Laryngopharyngeal reflux disease (LPR) has long been difficult to diagnose and treat . This syndrome is considered to be caused by exposure of the upper aerodigestive tract to reflux of gastric content . ...
The diagnosis and management of laryngopharyngeal reflux (LPR) symptoms are made difficult by the lack of good standard tests for diagnosis and for assessment of responsiveness to medical therapy. Proximal esophageal 24‑h pH reading may help identify a group of patients likely to benefit from surgery. A consecutive cohort of patients from a prospective populated database were identified. Further review was undertaken by an independent investigator for symptomatic evaluation following fundoplication 24 months after surgery. There were 90 patients (70% female) treated by fundoplication. The 24‑h pH study was successful in 68 patients; abnormal test results were found in 62 patients. Two clinical groups of patients were identified (GORD predominant/LPR predominant) with better control of LPR symptoms in the mixed GOR/LPR cohort but improved overall (p < 0.01). Symptom control was incomplete. In selected patients with elevated proximal pH readings, symptom improvement of LPR can be achieved by fundoplication.
... A similar positive predictive value was observed for Peptest against symptomatic episodes (69%). Currently, there are well over 100 peer-reviewed publications describing the diagnostic potential of pepsin in LPR [7,19,. Many studies have incorporated the rapid simple pepsin spit saliva test into the battery of diagnostic procedures routinely used in ENT clinics such as questionnaires  like the RSI  and the RFS  together with a flexible transnasal laryngoscope. ...
Questionnaires and invasive diagnostic tests are established for diagnosing gastro-esophageal reflux disease (GERD) but shown not to be sensitive or specific for diagnosing laryngopharyngeal reflux (LPR) where vast majority of reflux events are weakly acidic or non-acidic. The research question addressed in the current multicentre study was to determine if the measurement of salivary pepsin is a sensitive, specific and reliable diagnostic test for LPR. Five UK voice clinics recruited a total of 1011 patients presenting with symptoms of LPR and a small group of subjects (n = 22) recruited as asymptomatic control group. Twenty-six patients failed to provide demographic information; the total patient group was 985 providing 2927 salivary pepsin samples for analysis. Study participants provided 3 saliva samples, the first on rising with two samples provided post-prandial (60 min) or post-symptom (15 min). The control group provided one sample on rising and two post-prandial providing a total of 66 samples. Pepsin analysis was carried out using Peptest as previously described. High prevalence of pepsin in patient groups (75%) represents a mean pepsin concentration of 131 ng/ml. The greatest prevalence for pepsin was in the post-prandial sample (155 ng/ml) and the lowest in the morning sample (103 ng/ml). The mean pepsin concentration in the control group was 0 ng/ml. Patients across all 5 clinics showed high prevalence of salivary pepsin (ranging from 69 to 86%), and the overall sensitivity was 76.4% and specificity 100%. Pepsin was shown to be an ideal biomarker for detecting airway reflux and LPR.
Gastroesophageal reflux disease (GERD) affects 20–30% of the population and impairs the life quality due to the symptoms and cancer risk in those with Barrett’s esophagus (BE). Due to the anatomical properties of the esophagus, GERD causes a large spectrum of symptoms including heartburn, wheezing, coughing, burning throat, nose, ears, and eyes. Here, we propose a novel multidisciplinary GERD and BE management to eliminate the two major causes for GERD-induced impairment of the life quality: symptoms and cancer risk. In addition, GERD-related management is related to the perspective of an ancient Greek concept of reasoning, as coined by Hesiod and others. Finally, the chapter may motivate a positive and cause-related management of GERD and BE.
The diagnosis of laryngopharyngeal reflux (LPR) presents significant challenges despite its first being recognized as a distinct clinical entity decades ago. There remains considerable controversy over what the most reliable diagnostic criteria are and what diagnostic modality is preferred. There is no gold standard. Currently, a combination of clinical history, physical findings on laryngoscopy, and a variety of somewhat nonspecific tests are employed by practitioners to evaluate patients with suspected LPR. In this chapter, we will detail a variety of available diagnostic options for LPR, presenting the advantages and the disadvantages of each.
Barrett’s esophagus (BE) represents the premalignant manifestation of gastroesophageal reflux disease and includes columnar lined esophagus with intestinal metaplasia, low-grade dysplasia, high-grade dysplasia and cancer.
An Austrian panel of expert meeting was held at the Medical University Vienna, June 2015, to establish and define recommendations for the endoscopic treatment of BE with and without dysplasia and cancer. Recommendations are based on critical analysis of published evidence. Statistics were not applied.
Diagnosis of cancer and dysplasia is to be reconfirmed by a second expert pathologist. Advanced cancer (> T1a) requires surgical resection ± adjuvant therapies. Treatment of T1a early cancer, high- and low-grade dysplasia should include endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA). In the presence of increased cancer risk, BE without dysplasia should be treated by RFA within clinical studies only. Elimination of any early cancer, dysplasia and IM defines complete response, that is, post RFA histopathology shows squamous, cardiac or oxyntocardiac mucosa lined esophagus (Chandrasoma classification). Follow-up endoscopies are timed according to the base line histopathology. Down grade from cancer to dysplasia or from dysplasia to non-dysplastic BE defines partial response, respectively. Based on esophageal function testing, reflux is treated by medical or surgical therapy.
In Austria, RFA ± EMR is recommended for BE containing early cancer or dysplasia. Non-dysplastic BE with an increased cancer risk should be offered RFA within clinical trials to assess the efficacy for cancer prevention in this group of patients.
Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.
Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.
In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.
Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.
Laryngopharyngeal reflux (LPR) is an extraesophageal manifestation of gastroesophageal reflux disease (GERD). With the increase of GERD patients, the importance of LPR is acknowledged widely. However, the pathophysiology of LPR is not understood completely and the diagnostic criteria for LPR remain controversial. Unfortunately, a gold standard diagnostic test for reflux laryngitis is not available. Recently, an experimental animal model for reflux laryngitis was developed to investigate the pathophysiology of reflux laryngitis. An empirical trial of lifestyle modification and proton pump inhibitor therapy is a reasonable approach for LPR symptoms. Alternatives after failure with aggressive medical treatment are limited and multichannel intraluminal impedance and pH monitoring is currently the best alternative to detect nonacid reflux. Additional prospective and evidence-based research is anticipated.
Laryngopharyngeal reflux is defined as the reflux of gastric content into larynx and pharynx. A large number of data suggest the growing prevalence of laryngopharyngeal symptoms in patients with gastroesophageal reflux disease. However, laryngopharyngeal reflux is a multifactorial syndrome and gastroesophageal reflux disease is not the only cause involved in its pathogenesis. Current critical issues in diagnosing laryngopharyngeal reflux are many nonspecific laryngeal symptoms and signs, and poor sensitivity and specificity of all currently available diagnostic tests. Although it is a pragmatic clinical strategy to start with empiric trials of proton pump inhibitors, many patients with suspected laryngopharyngeal reflux have persistent symptoms despite maximal acid suppression therapy. Overall, there are scant conflicting results to assess the effect of reflux treatments (including dietary and lifestyle modification, medical treatment, antireflux surgery) on laryngopharyngeal reflux. The present review is aimed at critically discussing the current treatment options in patients with laryngopharyngeal reflux, and provides a perspective on the development of new therapies.
Approximately 30–40% of patients taking proton pump inhibitors (PPIs) for presumed gastro-oesophageal reflux (GOR) symptoms do not achieve adequate symptom control, especially when no oesophageal mucosal breaks are present at endoscopy and when extra-oesophageal symptoms are concerned. After failure of optimization of medical therapy, a careful work up is mandatory that aims at determining whether symptoms are related to GOR or not. Most patients with refractory symptoms do not have GOR-related symptoms. Some may have symptoms related to weakly acidic reflux and/or oesophageal hypersensitivity. Baclofen is currently the only antireflux compound available as add-on therapy to PPIs, but its poor tolerability limits its use in clinical practice. There is room for pain modulators in patients with hypersensitive oesophagus and functional heartburn. Antireflux surgery is a suitable option in patients responding to medical therapy who want to avoid taking medication or if persisting symptoms can be clearly attributed to poorly controlled GOR.
Abstract Background and aims. Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function. However, the influence of acid and/or bile acids on human esophageal epithelial barrier function and the tight junction (TJ) proteins has not been fully elucidated. The aim of the study is to investigate the esophageal barrier function and TJ expression in healthy subjects and patients with GERD. The functionality of esophageal mucosa exposed to bile salt deoxycholic acid (DCA) and trypsin has been studied in vitro. Material and methods. Endoscopic biopsies from healthy controls and patients with GERD-related symptom with endoscopic erosive signs, as well as esophageal mucosa taken from patients undergoing esophagectomy were evaluated in Ussing chambers and by western blot and immunohistochemistry. Results. The esophageal epithelium from GERD patients had lower electrical resistance and higher epithelial currents than controls. Claudin-1 and -4 were significantly decreased in GERD patients. The bile salt DCA in the low concentration of 1.5 mM and trypsin increased the resistance and claudin-1 expression, while the higher concentration of 2.5 mM DCA and trypsin decreased the resistance and the claudin-3, -4 and E-cadherin expressions. Conclusion. In addition to acidic reflux, duodenal reflux components, such as bile salts and trypsin, have the potential to disrupt the esophageal barrier function, partly by modulating the TJ proteins. However, the expression of TJ is dependent on both the refluxed material as well as the concentration of the bile salt.
Gastroesophageal reflux induced cough is a common cause of chronic cough, and proton pump inhibitors are a standard therapy. However, the patients unresponsive to the standard therapy are difficult to treat and remain a challenge to doctors. Here, we summarized the experience of successful resolution of refractory chronic cough due to gastroesophageal reflux with baclofen in three patients. It is concluded that baclofen may be a viable option for gastroesophageal reflux induced cough unresponsive to proton pump inhibitor therapy.
Gastro-oesophageal reflux disease is generally considered to be one of the commonest causes of chronic cough, however randomised controlled trials of proton pump inhibitors have often failed to support this notion. This article reviews the most recent studies investigating the mechanisms thought to link reflux and cough, namely laryngo-pharyngeal reflux, micro-aspiration and neuronal cross-organ sensitisation. How recent evidence might shed light on the failure of acid suppressing therapies and suggest new approaches to treating reflux related cough are also discussed.
Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function that is regulated by cell-cell contacts. The aim of the study was to investigate the expression pattern of selected components involved in the formation of tight junctions in relation to GERD.
Eighty-four patients with GERD-related symptoms with endoscopic signs (erosive: n = 47) or without them (non-erosive: n = 37) as well as 26 patients lacking GERD-specific symptoms as controls were included. Endoscopic and histological characterization of esophagitis was performed according to the Los Angeles and adapted Ismeil-Beigi criteria, respectively. Mucosal biopsies from distal esophagus were taken for analysis by histopathology, immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (RT-PCR) of five genes encoding tight junction components [Occludin, Claudin-1, -2, Zona occludens (ZO-1, -2)].
Histopathology confirmed GERD-specific alterations as dilated intercellular spaces in the esophageal mucosa of patients with GERD compared to controls (P < 0.05). Claudin-1 and −2 were 2- to 6-fold upregulation on transcript (P < 0.01) and in part on protein level (P < 0.015) in GERD, while subgroup analysis of revealed this upregulation for ERD only. In both erosive and non-erosive reflux disease, expression levels of Occludin and ZO-1,-2 were not significantly affected. Notably, the induced expression of both claudins did not correlate with histopathological parameters (basal cell hyperplasia, dilated intercellular spaces) in patients with GERD.
Taken together, the missing correlation between the expression of tight junction-related components and histomorphological GERD-specific alterations does not support a major role of the five proteins studied in the pathogenesis of GERD.
To investigate the prevalence of gastroesophageal reflux disease (GERD) in patients with a laryngoscopic diagnosis of laryngopharyngeal reflux (LPR).
Between May 2011 and October 2011, 41 consecutive patients with laryngopharyngeal symptoms (LPS) and laryngoscopic diagnosis of LPR were empirically treated with proton pump inhibitors (PPIs) for at least 8 wk, and the therapeutic outcome was assessed through validated questionnaires (GERD impact scale, GIS; visual analogue scale, VAS). LPR diagnosis was performed by ear, nose and throat specialists using the reflux finding score (RFS) and reflux symptom index (RSI). After a 16-d wash-out from PPIs, all patients underwent an upper endoscopy, stationary esophageal manometry, 24-h multichannel intraluminal impedance and pH (MII-pH) esophageal monitoring. A positive correlation between LPR diagnosis and GERD was supposed based on the presence of esophagitis (ERD), pathological acid exposure time (AET) in the absence of esophageal erosions (NERD), and a positive correlation between symptoms and refluxes (hypersensitive esophagus, HE).
The male/female ratio was 0.52 (14/27), the mean age ± SD was 51.5 ± 12.7 years, and the mean body mass index was 25.7 ± 3.4 kg/m(2). All subjects reported one or more LPS. Twenty-five out of 41 patients also had typical GERD symptoms (heartburn and/or regurgitation). The most frequent laryngoscopic findings were posterior laryngeal hyperemia (38/41), linear indentation in the medial edge of the vocal fold (31/41), vocal fold nodules (6/41) and diffuse infraglottic oedema (25/41). The GIS analysis showed that 10/41 patients reported symptom relief with PPI therapy (P < 0.05); conversely, 23/41 did not report any clinical improvement. At the same time, the VAS analysis showed a significant reduction in typical GERD symptoms after PPI therapy (P < 0.001). A significant reduction in LPS symptoms. On the other hand, such result was not recorded for LPS. Esophagitis was detected in 2/41 patients, and ineffective esophageal motility was found in 3/41 patients. The MII-pH analysis showed an abnormal AET in 5/41 patients (2 ERD and 3 NERD); 11/41 patients had a normal AET and a positive association between symptoms and refluxes (HE), and 25/41 patients had a normal AET and a negative association between symptoms and refluxes (no GERD patients). It is noteworthy that HE patients had a positive association with typical GERD-related symptoms. Gas refluxes were found more frequently in patients with globus (29.7 ± 3.6) and hoarseness (21.5 ± 7.4) than in patients with heartburn or regurgitation (7.8 ± 6.2). Gas refluxes were positively associated with extra-esophageal symptoms (P < 0.05). Overall, no differences were found among the three groups of patients in terms of the frequency of laryngeal signs. The proximal reflux was abnormal in patients with ERD/NERD only. The differences observed by means of MII-pH analysis among the three subgroups of patients (ERD/NERD, HE, no GERD) were not demonstrated with the RSI and RFS. Moreover, only the number of gas refluxes was found to have a significant association with the RFS (P = 0.028 and P = 0.026, nominal and numerical correlation, respectively).
MII-pH analysis confirmed GERD diagnosis in less than 40% of patients with previous diagnosis of LPR, most likely because of the low specificity of the laryngoscopic findings.
Gastroesophageal reflux disease is mediated principally by acid. Today, we recognise reflux reaches beyond the esophagus, where pepsin, not acid, causes damage. Extraesophageal reflux occurs both as liquid and probably aerosol, the latter with a further reach. Pepsin is stable up to pH 7 and regains activity after reacidification. The enzyme adheres to laryngeal cells, depletes its defences, and causes further damage internally after its endocytosis. Extraesophageal reflux can today be detected by recognising pharyngeal acidification using a miniaturised pH probe and by the identification of pepsin in saliva and in exhaled breath condensate by a rapid, sensitive, and specific immunoassay. Proton pump inhibitors do not help the majority with extraesophageal reflux but specifically formulated alginates, which sieve pepsin, give benefit. These new insights may lead to the development of novel drugs that dramatically reduce pepsinogen secretion, block the effects of adherent pepsin, and give corresponding clinical benefit.
“For now we see through a glass, darkly.”
—First epistle, Chapter 13, Corinthians
The relationship between hiatal hernias and gastroesophageal reflux disease (GERD) has been greatly debated over the past decades, with the importance of hiatal hernias first being overemphasized and then later being nearly neglected. It is now understood that both the anatomical (hiatal hernia) and the physiological (lower esophageal sphincter) features of the gastroesophageal junction play important, but independent, roles in the pathogenesis of GERD, constituting the widely accepted "two-sphincter hypothesis." The gastroesophageal junction is an anatomically complex area with an inherent antireflux barrier function. However, the gastroesophageal junction becomes incompetent and esophageal acid clearance is compromised in patients with hiatal hernia, which facilitates the development of GERD. Of the different types of hiatal hernias (types I, II, III, and IV), type I (sliding) hiatal hernias are closely associated with GERD. Because GERD may lead to reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma, a better understanding of this association is warranted. Hiatal hernias can be diagnosed radiographically, endoscopically or manometrically, with each modality having its own limitations, especially in the diagnosis of hiatal hernias less than 2 cm in length. In the future, high resolution manometry should be a promising method for accurately assessing the association between hiatal hernias and GERD. The treatment of a hiatal hernia is similar to the management of GERD and should be reserved for those with symptoms attributable to this condition. Surgery should be considered for those patients with refractory symptoms and for those who develop complications, such as recurrent bleeding, ulcerations or strictures.
Background & Aims: There is growing evidence that gastroesophageal reflux disease (GERD) may cause typical pharyngeal/laryngeal findings secondary to tissue irritation. The prevalence of those findings in GERD patients, is not well established. The aim of this study was to evaluate the prevalence of GERD signs in the laryngopharyngeal area during routine upper gastrointestinal endoscopy. Methods: Between July 2000 and July 2001, 1209 patients underwent 1311 upper gastrointestinal endoscopies and were enrolled in this study. These patients underwent a careful structured examination of the laryngopharyngeal area during upper gastrointestinal endoscopy, which was videotaped for later blinded review. All videotapes were reviewed by three gastroenterologists and one otorhinolaryngologist, who were blinded to the gastroesophageal endoscopic findings. Of these 1209 patients, two groups were formed. Group I (n=132) included patients with typical endoscopical esophageal findings of GERD (Savary 1–4). The sex- and age-matched control group II (n=132) underwent upper gastrointestinal endoscopy for different reasons, had no reflux symptoms, and revealed no endoscopic pathologies. Results: 1079 videos of upper gastrointestinal endoscopy could be fully evaluated. Laryngopharyngeal signs of GERD like interarytenoid bar, arytenoid medial wall erythema, posterior pharyngeal wall cobblestoning, or posterior cricoid wall edema were similar in both groups (44% vs. 37%) and showed no statistical difference. The only laryngopharyngeal sign, which showed a tendency to be more common in GERD patients was posterior pharyngeal wall cobblestoning (72% vs. 65%, p=0.06). Conclusion: This study is the first large systematic investigation of GERD patients for the presence and prevalence of laryngopharyngeal findings attributed to gastroesophageal reflux. Our results challenge the published diagnostic specificity of typical GERD signs in the laryngopharyngeal region.
The aim of this study was to determine whether the incidence of adenocarcinoma of the esophagus and esophagogastric junction in a well-defined population was higher than previously recognized.
Clinical records and original histological slides from patients residing in Olmsted County, Minnesota, were reviewed and compared with a previous study in the same population.
The incidence of esophageal adenocarcinoma rose from 0.13 for 1935-1971 to 0.74 for 1974-1989, and the incidence of adenocarcinoma of the esophagogastric junction rose from 0.25 to 1.34 per 100,000 person-years. Histological review of preserved surgical specimens showed associated intestinal metaplasia (Barrett's esophagus) in 2 of 2 esophageal and in 5 of 9 esophagogastric adenocarcinomas.
The incidence of adenocarcinoma in each location increased five to sixfold compared with the earlier study. This increase could not be explained by improved diagnostic methods or classification changes. The association with Barrett's esophagus and the parallel increased incidence of cancer in each location is evidence that adenocarcinoma of the esophagus and of the esophagogastric junction are related disorders.
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
Nowadays, benign inflammatory esophageal diseases represent a rising socioeconomic burden. Recently, novel therapeutic approaches have been introduced to enrich personalized surgical options.
A PubMed research was conducted and merged with institutional guidelines and data.
Magnetic sphincter augmentation strengthens the lower esophageal sphincter and therefore recreates the natural reflux barrier. Electrical sphincter stimulation offers the possibility to personalize minimal invasive treatment and considers even changing lifestyles. Endoscopic antireflux procedures try to mimic the outcome of laparoscopic fundoplication and aim to improve the angle of His. However, laparoscopic fundoplication remains the surgical treatment of choice in advanced reflux disease.
Reflux can also cause eosinophilic infiltration and therefore hinders diagnosis of eosinophilic esophagitis. Once diagnosis is established, dietary modifications and topical steroids offer relevant relief. Reflux produces Barrett’s esophagus, a neoplastic progression, which is commonly treated with radiofrequency ablation.
Novel therapeutic options are facing the rising incidence of benign inflammatory diseases.
Background: Weight loss is commonly recommended as part of first-line management of gastro-oesophageal reflux disease (GORD) despite the paucity of published clinical trials. The aim of this study was to prospectively assess the independent effect of weight loss on reflux symptoms in overweight individuals with either normal endoscopic findings or grade-I oesophagitis. Methods: Thirty-four patients were recruited on the basis of a body mass index (BMI) of greater than 23 and symptoms of GORD for at least 6 months. All patients were advised to lose weight. Symptoms of gastro-oesophageal reflux (GOR) were scored, using a modified DeMeester questionnaire at 0, 6, and 26 weeks. Patients who were unable to stop taking all medication for control of symptoms were excluded from the study. Changes in weight and symptom score were analysed by using a paired t test. Correlation between change in weight and symptom score was assessed with the Pearson correlation test. Results: Thirty-four patients were studied (18 me...
To determine whether there is an association between otitis media with effusion and laryngopharyngeal reflux in children.
This study included 31 children with otitis media with effusion. The pepsinogen level in the middle ear fluid of all patients was measured by sandwich enzyme-linked immunosorbent assay. Each patient's middle ear fluid was investigated for Helicobacter pylori (H. pylori) using the Campylobacter-like organism (CLO) test. The middle ear pepsinogen levels were compared with those in the serum. The correlation between pepsinogen levels and H. pylori positivity in the middle ear fluid was investigated.
The mean middle ear pepsinogen level (211.69 ng/mL) was significantly higher than that in the serum (24.18 ng/mL) in patients with otitis media with effusion. The middle ear aspirates of six patients (19%) were positive for H. pylori, and the correlation between H. pylori positivity and increased pepsinogen levels in the middle ear fluid was statistically significant in patients with otitis media with effusion.
We detected higher pepsinogen levels and H. pylori positivity rates in the middle ear fluid than in the serum of patients with otitis media with effusion. These results support the role of laryngopharyngeal reflux in the pathogenesis of otitis media with effusion.
Impedance monitoring for reflux evaluation does not have standardized scoring, which can confound interpretation between observers. We investigated the variability of impedance testing interpretation between physicians and computer software.
Raw impedance data from 38 patients that underwent impedance monitoring at a tertiary referral center between 2008 and 2013 were collected. Two physicians and computer software each analyzed the same impedance dataset for reflux activity and symptom-reflux correlation.
Normalized reflux activity interpretations did not differ between physicians and the computer for acid or non-acid reflux. However, for weakly acidic reflux, there was significant difference between physicians (p < 0.01) and between physician and computer (p < 0.01). In analyzing all reflux, significant variability existed between physicians (p < 0.01) but not between physician and computer. Variability in interpretation altered diagnosis in 24 % of patients when comparing between physicians, 18 % of patients when comparing both physicians to the computer, and an additional 24 % of cases when comparing a single physician to the computer. Symptom-reflux correlation differed in 7 % of physician-physician comparisons versus 8 % of computer-physician comparisons.
Impedance testing analysis is subject to marked variability between physicians and computer software, making impedance prone to interpretation error that can lead to differences in diagnosis and management.
To investigate the utility of scintigraphic studies in predicting response to laparoscopic fundoplication (LF) for chronic laryngopharyngeal reflux symptoms.
Patients with upper aero-digestive symptoms that remained undiagnosed after a period of 2 mo were studied with conventional pH and manometric studies. Patients mainly complained of cough, sore throat, dysphonia and globus. These patients were imaged after ingestion of 99m-technetium diethylene triamine pentaacetic acid. Studies were quantified with time activity curves over the pharynx, upper and lower oesophagus and background. Late studies of the lungs were obtained for aspiration. Patients underwent LF with post-operative review at 3 mo after surgery.
Thirty four patients (20 F, 14 M) with an average age of 57 years and average duration of symptoms of 4.8 years were studied. Twenty four hour pH and manometry studies were abnormal in all patients. On scintigraphy, 27/34 patients demonstrated pharyngeal contamination and a rising or flat pharyngeal curve. Lung aspiration was evident in 50% of patients. There was evidence of pulmonary aspiration in 17 of 34 patients in the delayed study (50%). Pharyngeal contamination was found in 27 patients. All patients with aspiration showed pharyngeal contamination. In the 17 patients with aspiration, graphical time activity curve showed rising activity in the pharynx in 9 patients and a flat curve in 8 patients. In those 17 patients without pulmonary aspiration, 29% (5 patients) had either a rising or flat pharyngeal graph. A rising or flat curve predicted aspiration with a positive predictive value of 77% and a negative predictive value of 100%. Over 90% of patients reported a satisfactory symptomatic response to LF with an acceptable side-effect profile.
Scintigraphic reflux studies offer a good screening tool for pharyngeal contamination and aspiration in patients with gastroesophageal reflux disease.
Aspiration of foreign matter into the airways and lungs can cause a wide spectrum of pulmonary disorders with various presentations. The type of syndrome resulting from aspiration depends on the quantity and nature of the aspirated material, the chronicity, and the host responses. Aspiration is most likely to occur in subjects with a decreased level of consciousness, compromised airway defense mechanisms, dysphagia, gastroesophageal reflux, and recurrent vomiting. These aspiration-related syndromes can be categorized into airway disorders, including vocal cord dysfunction, large airway obstruction with a foreign body, bronchiectasis, bronchoconstriction, and diffuse aspiration bronchiolitis, or parenchymal disorders, including aspiration pneumonitis, aspiration pneumonia, and exogenous lipoid pneumonia. In idiopathic pulmonary fibrosis, aspiration has been implicated in disease progression and acute exacerbation. Aspiration may increase the risk of bronchiolitis obliterans syndrome in patients who have undergone a lung transplant. Accumulating evidence suggests that a causative role for aspiration is often unsuspected in patients presenting with aspiration-related pulmonary diseases; thus, many cases go undiagnosed. Herein, we discuss the broadening spectrum of these pulmonary syndromes with a focus on presenting features and diagnostic aspects.
Gastro-oesophageal reflux disease (GERD) is poorly defined at best. Symptoms can be variable, ranging from none to heartburn, regurgitation and chest pain. When the reflux extends to the oropharynx [laryngopharyngeal reflux (LPR)], the symptoms can be protean and include cough and sore throat. We present the scintigraphic findings in two broad groups classified by symptoms as either GERD or LPR.
Patients with an established diagnosis of GERD or LPR by standard methods (95%) or high clinical pretest probability (5%) were scanned in the upright and supine position after swallowing Tc-DTPA. A delayed image was obtained at 2 h to evaluate the possibility of lung aspiration.
Studies were obtained in 285 patients (168 females, 117 males), with a mean age of 54 years. Of these, 80 had typical symptoms of GERD and 205 had LPR. The group with GERD had pharyngeal contamination in 49 and 14% showed pulmonary aspiration. The group with LPR had pharyngeal contamination in 65 and 23% had lung aspiration. Pharyngeal contamination was more common in the supine than in the upright position (P=0000). Lung aspiration was correlated with upper oesophageal activity.
Scintigraphic reflux studies are a good screening test for GERD and LPR as they can detect oropharyngeal reflux and lung aspiration in an unsuspected proportion of patients in both groups. The oropharynx and lung are sites that are out of reach of the current standards of investigation such as pH studies, manometry and impedance monitoring.
Gastroesophageal reflux disease affects at least 10 % of people in Western societies and produces troublesome symptoms and impairs patients’ quality of life. The effective management of GERD is imperative as the diagnosis places a significant cost burden on the United States healthcare system with annual direct cost estimates exceeding 9 billion dollars annually. While effective for many patients, 30–40 % of patients receiving medical therapy with proton pump inhibitors experience troublesome breakthrough symptoms, and recent evidence suggests that this therapy subjects patients to increased risk of complications. Given the high cost of PPI therapy, patients are showing a decrease in willingness to continue with a therapy that provides incomplete relief; however, due to inconsistent outcomes and concern for procedure-related side effects following surgery, only 1 % of the GERD population undergoes anti-reflux surgery annually. The discrepancy between the number of patients who experience suboptimal medical treatment and the number considered for anti-reflux surgery indicates a large therapeutic gap in the management of GERD. The objective of the SSAT State-of-the-Art Conference was to examine technologic advances in the diagnosis and treatment of GERD and to evaluate the ways in which we assess the outcomes of these therapies to provide optimal patient care.
Background and aim: Increased esophageal sensitivity and impaired mucosal integrity have both been described in gastroesophageal reflux disease (GERD) patients, but their relationship is unclear. Aim of this study was to investigate acid sensitivity in patients with erosive and non-erosive reflux disease and controls, to determine the relation with functional esophageal mucosal integrity changes, as well as to investigate cellular mechanisms of impaired mucosal integrity in these patients. Methods: In this prospective study 12 non-erosive reflux disease (NERD) patients, 12 patients with esophagitis grade A or B and 11 healthy controls underwent an acid perfusion test and upper endoscopy. Mucosal integrity was measured during endoscopy by electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance and transepithelial permeability, and for gene expression of tight junction proteins and filaggrin. Results: NERD and esophagitis patients were more sensitive to acid perfusion compared to controls. In reflux patients enhanced acid sensitivity was associated with impairment of in vivo and vitro esophageal mucosal integrity. Mucosal integrity was significantly impaired in patients with esophagitis, displaying higher transepithelial permeability and lower extracellular impedance. Although no significant differences in the expression of tight junction proteins were found in biopsies among patient groups, mucosal integrity parameters in reflux patients correlated negatively with the expression of filaggrin. Conclusions: Sensitivity to acid is enhanced in patients with GERD, irrespective of the presence of erosions, and is associated with impaired esophageal mucosal integrity. Esophageal mucosal integrity is associated with the expression of filaggrin.
Our objective was to systematically identify and evaluate prospective studies providing evidence for and against the use of prokinetic agents in the treatment of laryngopharyngeal reflux (LPR) disease. Data SourcesOur data sources were PubMed, Embase, BIOSIS, and Web of Science databases. Review MethodsA systematic literature review was conducted to identify studies prospectively evaluating the effectiveness of prokinetic agents in the treatment of LPR. Data from eligible studies were independently extracted from each study by two authors. The primary outcome of interest was the improvement of LPR symptoms among study participants. Secondary outcomes included resolution of LPR physical signs and the development of side effects from therapy. ResultsAmong 724 unique articles identified, four studies met inclusion criteria. These four investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. The studies included in the review were deemed to be at high risk of bias. Three of the four investigations demonstrated a statistically significant difference in patient symptoms that favored the use of prokinetics in the management of LPR. The investigations were mixed in their report of improvement in physical examination findings among patients receiving and those not receiving prokinetic medical therapy. No significant adverse effects were described in any of these trials. Conclusions
Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a recommendation for their use in this disease process. Further research should be conducted to assess the use of prokinetic medications in the management of LPR. Level of EvidenceNA Laryngoscope 124:2375-2379, 2014
The aim of this study was to assess the performance of the gastroesophageal reflux disease questionnaire (GerdQ) self-assessment questionnaire, 24-hour impedance monitoring, the proton pump inhibitor (PPI) test and intercellular space of esophageal mucosal epithelial cells in the diagnosis of gastroesophageal reflux disease (GERD).
Patients with symptoms suggestive of GERD received the GerdQ questionnaires, endoscopy (measurement of intercellular space in the biopsy specimens sampled at 2 cm above the z-line), 24-h impedance-pH monitoring and underwent a two-weeks experimental treatment with esomeprazole.
A total of 636/670 (94.9%) subjects were included for the final analysis, including 352 cases with a diagnosis of GERD. The sensitivity and specificity of GerdQ for a diagnosis of GERD were 57.7% and 48.9% respectively and 66.4% and 43.3% respectively for 24-hour impedance monitoring and the sensitivity of 24-hour impedance-pH monitoring increased to 93.7%. The sensitivity and specificity of dilated intercellular spaces (DIS) for a diagnosis of GERD were 61.2% and 56.1%, respectively and were 70.5% and 44.4% respectively for the PPI test.
GerdQ score or the PPI test alone cannot accurately diagnose GERD in a Chinese population suspected of GERD. A definitive diagnosis of GERD is still dependent on endoscopy or 24-h pH monitoring. pH-impedance monitoring may increase the sensitivity for a diagnosis of GERD by 20%, however, when used alone, it results in poor specificity in patients without acid suppressive therapy.
This article reviews the evaluation and management of patients with suspected extraesophageal manifestations of gastroesophageal reflux disease, such as asthma, chronic cough, and laryngitis, which are commonly encountered in gastroenterology practices. Otolaryngologists and gastroenterologists commonly disagree upon the underlying cause for complaints in patients with one of the suspected extraesophageal reflux syndromes. The accuracy of diagnostic tests (laryngoscopy, endoscopy, and pH- or pH-impedance monitoring) for patients with suspected extraesophageal manifestations of gastroesophageal reflux disease is suboptimal. An empiric trial of proton pump inhibitors in patients without alarm features can help some patients, but the response to therapy is variable.
Background & Aims
Combined pH and impedance monitoring can detect all types of reflux episodes within the esophageal lumen and the pharynx. We performed a multicenter study to establish normal values of pharyngeal and esophageal pH-impedance monitoring in individuals on and off therapy and to determine the interobserver reproducibility of this technique.
We collected ambulatory 24-hour pH-impedance recordings from 46 healthy subjects by using a bifurcated probe that allowed for detection of reflux events in the distal and proximal esophagus and pharynx. Data were collected when subjects had not received any medicine (off therapy) and after receiving 40 mg esomeprazole twice daily for 14 days (on therapy). The interobserver agreement for the detection of reflux events was determined in 20 subjects off and on therapy. Results were expressed as median (interquartile range).
Off therapy, subjects had a median of 32 reflux events (17–45) in the distal esophagus and 3 (1–6) in the proximal esophagus; they had none in the pharynx. On therapy, subjects had a median number of 21 reflux events (6–37) in the distal esophagus and 2 (0–5) in the proximal esophagus; again, there were none in the pharynx. Interobserver agreement was good for esophageal reflux events but poor for pharyngeal events.
We determined normal values of pharyngeal and gastroesophageal reflux events by 24-hour pH-impedance monitoring of subjects receiving or not receiving esomeprazole therapy. Analyses of esophageal events were reproducible, but analyses of pharyngeal events were not; this limitation should be taken into account in further studies. Eudract.ema.europa.eu, Number: 2010-022845-48.
Gastroesophageal reflux disease (GERD) is a very prevalent disorder. Medical therapy improves symptoms in some but not all patients. Antireflux surgery is an excellent option for patients with persistent symptoms such as regurgitation, as well as for those with complete symptomatic resolution on acid-suppressive therapy. However, proper patient selection is critical to achieve excellent outcomes.
A panel of experts was assembled to review data and personal experience with regard to appropriate preoperative evaluation for antireflux surgery and to construct an evidence and experience-based consensus that has practical application.
The presence of reflux symptoms alone is not sufficient to support a diagnosis of GERD before antireflux surgery. Esophageal objective testing is required to physiologically and anatomically evaluate the presence and severity of GERD in all patients being considered for surgical intervention. It is critical to document the presence of abnormal distal esophageal acid exposure, especially when antireflux surgery is considered, and reflux-related symptoms should be severe enough to outweigh the potential side effects of fundoplication. Each testing modality has a specific role in the diagnosis and workup of GERD, and no single test alone can provide the entire clinical picture. Results of testing are combined to document the presence and extent of the disease and assist in planning the operative approach.
Currently, upper endoscopy, barium esophagram, pH testing, and manometry are required for preoperative workup for antireflux surgery. Additional studies with long-term follow-up are required to evaluate the diagnostic and therapeutic benefit of new technologies, such as oropharyngeal pH testing, multichannel intraluminal impedance, and hypopharyngeal multichannel intraluminal impedance, in the context of patient selection for antireflux surgery.
Gastroesophageal reflux (GER) is frequently found in association with asthma. Successful control of GER in these patients may improve in their asthma symptoms. The present retrospective analysis was undertaken to find out the incidence of GER in asthmatic children not responding to routine antiasthmatic medications and to find out if there is a clinical correlation between the symptoms of GER and scintigraphic evidence of GER in these patients. A total of 126 children with a mean age of 2.31 years and range 6 months to 6 years were evaluated. The children were divided into two groups. Group I (n=100) consisted of children with asthma but no clinical symptoms of GER. Group II (n=26) consisted of those children with asthma and clinical symptoms of GER. Radionuclide scintigraphy was performed with 100–200 μCi (3.7–7.4 MBq) of Tc99m-sulphur colloid. All 33 out of 126 (26%) children had GER on scintigraphy. In Group I, only 23 (23%) had reflux while in Group II, 10 (38.5%) had reflux. In conclusion, esophageal scintiscanning can be used to detect GER in asthmatic children refractory to routine antiasthmatic medication irrespective of the presence or absence of symptoms suggestive of GER.
Background. Antireflux surgery can reduce respiratory symptoms associated with gastroesophageal reflux. However, there is a paucity of data on the durability of this benefit. To evaluate the long-term effects of antireflux surgery on respiratory complaints associated with gastroesophageal reflux, we reviewed our experience.Methods. Retrospective review of 2,123 antireflux procedures completed between 1986 and 1998 identified 65 patients (3.1%) with associated respiratory symptoms. There were 32 men and 33 women, ranging in age from 20 to 80 years (median 59 years). Respiratory symptoms included wheezing in 43 patients, sputum production in 37, cough in 30, choking episodes in 24, and hoarseness in 17. Preoperative medication use included steroids in 23 patients and bronchodilators in 18.Results. Antireflux operations included the uncut Collis-Nissen fundoplication in 29 patients, Belsy Mark IV repair in 13, open Nissen fundoplication in 13, and laparoscopic Nissen fundoplication in 10. Perioperative complications occurred in 19 patients who underwent open procedures and in none who had laparoscopic procedures. There was one death in the open-operation group and none in the laparoscopic group. Median follow-up was 65 months (range 1 to 174 months) and was complete in 62 patients (96.9%). Improvement in respiratory symptoms (83%) and reduction in respiratory medication use (78%) were significant as compared to a calculated 33% placebo-effect improvement (p < 0.05).Conclusions. Antireflux operations significantly reduce respiratory complaints associated with gastroesophageal reflux. This benefit appears to be long term.
Background & aims:
Patients with Barrett's esophagus (BE) and high-grade dysplasia (HGD) or early neoplasia increasingly receive endoscopic mucosal resection and radiofrequency ablation (RFA) therapy. We analyzed data from a UK registry that follows the outcomes of patients with BE who have undergone RFA for neoplasia.
We collected data on 335 patients with BE and neoplasia (72% with HGD, 24% with intramucosal cancer, 4% with low-grade dysplasia [mean age, 69 years; 81% male]), treated at 19 centers in the United Kingdom from July 2008 through August 2012. Mean length of BE segments was 5.8 cm (range, 1-20 cm). Patients' nodules were removed by endoscopic mucosal resection, and the patients then underwent RFA every 3 months until all areas of BE were ablated or cancer developed. Biopsies were collected 12 months after the first RFA; clearance of HGD, dysplasia, and BE were assessed.
HGD was cleared from 86% of patients, all dysplasia from 81%, and BE from 62% at the 12-month time point, after a mean of 2.5 (range, 2-6) RFA procedures. Complete reversal dysplasia was 15% less likely for every 1-cm increment in BE length (odds ratio = 1.156; SE = 0.048; 95% confidence interval: 1.07-1.26; P < .001). Endoscopic mucosal resection before RFA did not provide any benefit. Invasive cancer developed in 10 patients (3%) by the 12-month time point and disease had progressed in 17 patients (5.1%) after a median follow-up time of 19 months. Symptomatic strictures developed in 9% of patients and were treated by endoscopic dilatation. Nineteen months after therapy began, 94% of patients remained clear of dysplasia.
We analyzed data from a large series of patients in the United Kingdom who underwent RFA for BE-related neoplasia and found that by 12 months after treatment, dysplasia was cleared from 81%. Shorter segments of BE respond better to RFA; http://www.controlled-trials.com, number ISRCTN93069556.
Gastroesophageal reflux disease (GERD) can present with a wide variety of extraesophageal symptoms that are usually difficult to diagnose because of the absence of typical GERD symptoms (ie, regurgitation or heartburn). The diagnostic process is further complicated by the lack of a definitive test for identifying GERD as the cause of extraesophageal reflux symptoms. Due to the low predictive value of upper endoscopy and pH testing-as well as the lack of reliability of the symptom index and symptom association probability-extraesophageal reflux disease is still an area of investigation. This paper discusses recent developments in this field, with special emphasis on new diagnostic modalities and treatment options.
Barrett's esophagus (BE) and gastroesophageal reflux disease are the strongest risk factors for esophageal adenocarcinoma. To reduce the clinical impact of this disease, endoscopic screening to detect BE has been proposed and nonendoscopic diagnostic techniques are under investigation. Because screening would result in new diagnoses of BE and additional costs related to endoscopic surveillance, novel tools for risk stratification are also warranted. Dysplasia is the gold standard for risk stratification. Molecular biomarkers may provide a more objective and reproducible estimation of the individual risk, and further prospective studies are required as a prelude to introducing biomarkers into routine clinical practice.
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
To determine the patterns and proximity of reflux events in patients with adult-onset asthma (AOA) using hypopharyngeal multichannel intraluminal impedance (HMII) and to assess outcomes of antireflux surgery (ARS) in patients with AOA. DESIGN Retrospective review of prospectively collected data.
University hospital. PATIENTS, INTERVENTIONS, AND OUTCOMES: All patients with AOA referred to our testing center underwent HMII, and those with abnormal proximal exposure, defined as laryngopharyngeal reflux at least once a day and/or high esophageal reflux at least 5 times a day, subsequently underwent ARS.
From October 1, 2009, through June 30, 2011, a total of 31 patients with AOA (4 men and 27 women; mean age, 53 years) underwent HMII. Of 27 patients with available information, 11 (41%) had objective evidence of reflux disease. Nineteen patients (70%) had concomitant typical reflux symptoms. Despite a frequently negative DeMeester score, abnormal proximal exposure, which occurred in the upright position, was observed in 19 patients (70%). Of 20 patients who subsequently underwent ARS, asthma symptoms improved in 18 (90%), and 6 of them discontinued or reduced pulmonary medications at a mean (range) follow-up of 4.6 (0.6-15.2) months. Pulmonary function test results before and after ARS revealed that of 5 patients, 4 (80%) had improvement of the forced expiratory volume in the first second of expiration and/or the peak expiratory flow rate, which correlated with symptomatic improvement.
Adult-onset asthma is associated with abnormal proximal exposure of the aerodigestive tract to refluxate; these patients respond to ARS despite negative pH test results. Patients with AOA should undergo testing with HMII because they would not be detected with conventional pH testing.
This is one of a series of statements discussing the use of GI endoscopy in common clinical situations. The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy prepared this text. In preparing this guideline, a search of the medical literature was performed using PubMed. Additional references were obtained from the bibliographies of the identified articles and from recommendations of expert consultants. When limited or no data exist from well-designed prospective trials, emphasis is given to results of large series and reports from recognized experts. Guidelines for appropriate use of endoscopy are based on a critical review of the available data and expert consensus at the time the guidelines are drafted. Further controlled clinical studies may be needed to clarify aspects of this guideline. This guideline may be revised as necessary to account for changes in technology, new data, or other aspects of clinical practice. The recommendations were based on reviewed studies and were graded on the strength of the supporting evidence (Table 1).(1) The strength of individual recommendations is based on both the aggregate evidence quality and an assessment of the anticipated benefits and harms. Weaker recommendations are indicated by phrases such as "we suggest," whereas stronger recommendations are typically stated as "we recommend." This guideline is intended to be an educational device to provide information that may assist endoscopists in providing care to patients. This guideline is not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment. Clinical decisions in any particular case involve a complex analysis of the patient's condition and available courses of action. Therefore, clinical considerations may lead an endoscopist to take a course of action that varies from these guidelines.
Microaspiration is often considered a potential cause of cough. The aim of this study was to investigate the relationship between microaspiration, the degree and type of gastroesophageal reflux, and the frequency of coughing in patients with chronic cough.
One hundred patients with chronic cough (mean [± SD] age, 55.8 years [± 11.0 years]; 65 women) and 32 healthy volunteers (median age, 43.5 years [interquartile range (IQR), 30-50.8 years]; 16 women) were recruited. Patients with chronic cough performed 24-h objective cough frequency with simultaneous esophageal impedance/pH monitoring and measurement of pepsin concentrations in sputum and BAL. Twelve healthy volunteers underwent bronchoscopy/BAL, and 20 underwent impedance/pH monitoring.
Patients with chronic cough had significantly more reflux episodes than healthy volunteers (median, 63.5 reflux episodes [IQR, 52.5-80.0] vs 59.0 [IQR, 41.8-66.0]; P = .03), although the absolute difference was small, and there was no difference in numbers of events extending into the proximal esophagus (median, 17.2% [IQR, 8.0%-26.0%] vs 20.3% [IQR, 5.1%-32.1%]; P = .36). BAL pepsin levels were also similar in chronic cough to control subjects (median, 18.2 ng/mL [range, 0-56.4 ng/mL] vs 9.25 ng/mL [range, 0-46.9 ng/mL]; P = .27). Sputum but not BAL pepsin weakly correlated with the number of proximally occurring reflux events (r = 0.33, P = .045) but was inversely related to cough frequency (r = −0.52, P = .04). Sputum pepsin was, therefore, best predicted by combining the opposing influences of cough and proximal reflux (r = 0.50, P = .004).
Proximal gastroesophageal reflux and microaspiration into the airways have limited roles in provoking chronic cough. Indeed, coughing appears to be protective, reducing pepsin concentration in the larger airways of patients with chronic cough.
Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251).
In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥ 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline.
In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels.
In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.
Background Gastro-oesophageal reflux disease (GERD) is one of the commonest diseases of Western populations, affecting 20 to 30% of adults. GERD is multifaceted and the classical oesophageal symptoms such as heartburn and regurgitation often overlap with atypical symptoms that impact upon the respiratory system and airways. This is referred to as extra-oesophageal reflux disease (EERD), or laryngopharyngeal reflux (LPR), which manifests as chronic cough, laryngitis, hoarseness, voice disorders and asthma.
Aim The ‘Reflux and its consequences’ conference was held in Hull in 2010 and brought together a multidisciplinary group of experts all with a common interest in the many manifestations of reflux disease to present recent research and clinical progress in GERD and EERD. In particular new techniques for diagnosing reflux were showcased at the conference.
Methods Both clinical and non-clinical key opinion leaders were invited to write a review on key areas presented at the `Reflux and its consequences' conference for inclusion in this supplement.
Results and conclusion Eleven chapters contained in this supplement reflected the sessions of the conference and included discussion of the nature of the refluxate (acid, pepsin, bile acids and non-acid reflux); mechanisms of tissue damage and protection in the oesophagus, laryngopharynx and airways. Clinical conditions with a reflux aetiology including asthma, chronic cough, airway disease, LPR, and paediatric EERD were reviewed. In addition methods for diagnosis of reflux disease and treatment strategies, especially with reference to non-acid reflux, were considered.
Aliment Pharmacol Ther 2011; 33 (Suppl. 1), 1–71
Laparoscopic fundoplication controls heartburn and regurgitation, but the effects on the respiratory symptoms of gastroesophageal
reflux disease (GERD) are unclear. Confusion stems from difficulty preoperatively in determining whether cough or wheezing
is actually caused by reflux when reflux is found on pH monitoring. To date, there is no proven way to pinpoint a cause-and-effect
relationship. The goals of this study were to assess the following: (1) the value of pH monitoring in establishing a correlation
between respiratory symptoms and reflux; (2) the predictive value of pH monitoring on the results of surgical treatment; and
(3) the outcome of laparoscopic fundoplication on GERD-induced respiratory symptoms. Between October 1992 and October 1998,
a total of 340 patients underwent laparoscopic fundoplication for GERD. From the clinical findings alone, respiratory symptoms
were thought possibly to be caused by GERD in 39 patients (11 %). These 39 patients had been symptomatic for an average of
134 months. They were all taking H-blocking agents (21 %) or proton pump inhibitors (79%). Seven patients (18%) were also
being treated with bronchodilators, alone (3 patients) or in combination with prednisonc (4 patients). Median length of postoperative
follow-up was 28 months. In 23 patients (59%) a temporal correlation was found during 24-hour pH monitoring between respiratory
symptoms and episodes of reflux. Postoperatively heartburn resolved in 91% of patients, regurgitation in 90% of patients,
wheezing in 64% of patients, and cough in 74% of patients. Cough resolved in 19 (83%) of 23 patients in whom a correlation
between cough and reflux was found during pH monitoring, but in only 8 (57%) of 14 of patients when this correlation was absent.
Cough persisted postoperatively in the two patients who did not cough during the study. These data show that pH monitoring
helped to establish a correlation between respiratory symptoms and reflux, and it helped to identify the patients most likely
to benefit from antircflux surgery. Following laparoscopic surgery, respiratory symptoms resolved in 83% of patients when
a temporal correlation between cough and reflux was found on pH monitoring; heartburn and regurgitation resolved in 90%.
Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.
Baclofen, a GABAB agonist, has been shown to reduce transient lower oesophageal sphincter relaxations (TLESRs), a major cause of gastro-oesophageal reflux disease (GERD).
To examine the effect and tolerability of baclofen in GERD patients over a 2-week period.
Forty-three GERD patients with abnormal 24-h pH tests were prospectively randomised to receive baclofen or placebo in a double-blind fashion for 2 weeks. Oesophageal manometry, 24-h pH monitoring, and a standard questionnaire was administered, before and after treatment.
Thirty-four patients completed the study. In the baclofen group there were significant decreases in 24-h pH score (P = 0.020), percent of upright reflux episodes (P = 0.016), percent total time pH <4 (P = 0.003), number of reflux episodes (P = 0.018), number of reflux episodes longer than 5 min (P = 0.016), number of postprandial reflux episodes (P = 0.045), and percentage of time pH <4 (P = 0.003). No significant changes in reflux parameters were noted in the placebo group. Patients receiving baclofen had significantly less belching (P = 0.038), regurgitation (P = 0.036) and overall symptom score (P = 0.004) whereas placebo patients had less heartburn (P = 0.001), chest pain (P = 0.002), regurgitation (P = 0.017) and overall symptom score (P = 0.000). However, there were no significant differences in changes of reflux parameters or symptoms when comparing the two groups. Drowsiness did not limit baclofen use.
Baclofen was associated with a significant decrease in percent upright reflux by 24-h pH monitoring and a significant improvement in belching, regurgitation and overall symptom score. Baclofen may be more effective in patients with predominantly upright reflux and belching.
Up to 80% of patients with cystic fibrosis (CF) may have increased gastroesophageal reflux and aspiration of duodenogastric contents into the lungs. We aimed to assess aspiration in patients with CF by measuring duodenogastric components in induced sputum and to investigate whether the presence of bile acids (BAs) in sputum was correlated with disease severity and markers of inflammation.
In 41 patients with CF, 15 healthy volunteers, 29 patients with asthma, and 28 patients with chronic cough, sputum was obtained after inhalation of hypertonic saline. Sputum supernatant was tested for BA and neutrophil elastase. Spirometry and BMI were assessed on the day of sputum collection.
Two of 15 healthy patients (13%), eight of 29 patients (28%) with asthma, four of 28 patients (14%) with chronic cough, and 23 of 41 patients (56%) with CF had BA in sputum. BA concentrations were similar in patients who are positive for BA with genotype F508del homozygote, F508del heterozygote, and other CF mutations and were not related with BMI and age. Patients with CF with BA in sputum had a higher concentration of neutrophil elastase compared with patients without BA in sputum (31.25 [20.33-54.78] μg/mL vs 14.45 [7.11-27.88] μg/mL, P < .05). There was a significant correlation between BA concentrations and dynamic lung volumes (FEV(1) % predicted [r = -0.53, P < .01], FVC% [r = -0.59, P < .01]) as well as with number of days of antibiotic IV treatment (r = 0.58, P < .01).
BAs are present in the sputum of more than one-half of patients with CF, suggesting aspiration of duodenogastric contents. Aspiration of BA was associated with increased airway inflammation. In patients with BA aspiration, the levels of BA were clearly associated with the degree of lung function impairment as well as the need for IV antibiotic treatment.
Gastroesophageal reflux disease (GERD) is common in patients with end-stage lung disease (ESLD). GERD may cause obliterative bronchiolitis after lung transplantation (LTx), represented by a decline in forced expiratory volume in 1 second (FEV(1)).
To identify the patterns of reflux in patients with ESLD and to determine whether antireflux surgery (ARS) positively impacts lung function.
Retrospective review of prospectively collected data.
Tertiary care university hospital.
Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24).
Reflux patterns including laryngopharyngeal reflux as measured by esophageal impedance, and FEV(1), and episodes of pneumonia and acute rejection before and after ARS.
Before ARS, 19 of 43 patients (44%) were minimally symptomatic or asymptomatic. Laryngopharyngeal reflux events, which occurred primarily in the upright position, were common in post-LTx (56%) and pre-LTx (31%) patients. At 1 year after ARS, FEV(1) significantly improved in 91% of the post-LTx patients (P < .01) and 85% of the pre-LTx patients (P = .02). Of patients with pre-ARS declining FEV(1), 92% of post-LTx and 88% of pre-LTx patients had a reversal of this trend. Episodes of pneumonia and acute rejection were significantly reduced in post-LTx patients (P = .03) or stablilized in pre-LTx patients (P = .09).
There should be a low threshold for performing objective esophageal testing including esophageal impedance because GERD may be occult and ARS may improve or prolong allograft and native lung function.