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1.  Differences in Clinical Characteristics between Patients with Non-Erosive Reflux Disease and Erosive Esophagitis in Korea 
Journal of Korean Medical Science  2010;25(9):1318-1322.
Gastroesophageal reflux disease (GERD) is caused by abnormal reflux of gastric contents into the esophagus. GERD can be divided into two groups, erosive esophagitis and non-erosive reflux disease (NERD). The aim of this study was to compare the clinical characteristics of patients with erosive esophagitis to those with NERD. All participating patients underwent an upper endoscopy during a voluntary health check-up. The NERD group consisted of 500 subjects with classic GERD symptoms in the absence of esophageal mucosal injury during upper endoscopy. The erosive esophagitis group consisted of 292 subjects with superficial esophageal erosions with or without typical symptoms of GERD. Among GERD patients, male gender, high body mass index, high obesity degree, high waist-to-hip ratio, high triglycerides, alcohol intake, smoking and the presence of a hiatal hernia were positively related to the development of erosive esophagitis compared to NERD. In multivariated analysis, male gender, waist-to-hip ratio and the presence of a hiatal hernia were the significant risk factors of erosive esophagitis. We suggest that erosive esophagitis was more closely related to abdominal obesity.
PMCID: PMC2923803  PMID: 20808675
Erosive Esophagitis; Non-erosive Reflux Disease
2.  The Frequencies of Gastroesophageal and Extragastroesophageal Symptoms in Patients with Mild Erosive Esophagitis, Severe Erosive Esophagitis, and Barrett's Esophagus in Taiwan 
Background. Gastroesophageal reflux disease (GERD) may present with gastroesophageal and extraesophageal symptoms. Currently, the frequencies of gastroesophageal and extragastroesophageal symptoms in Asian patients with different categories of GERD remain unclear. Aim. To investigate the frequencies of gastroesophageal and extragastroesophageal symptoms in patients with mild erosive esophagitis, severe erosive esophagitis, and Barrett's esophagus of GERD. Methods. The symptoms of symptomatic subjects with (1) Los Angeles grade A/B erosive esophagitis, (2) Los Angeles grade C/D erosive esophagitis, and (3) Barrett's esophagus proven by endoscopy were prospectively assessed by a standard questionnaire for gastroesophageal and extragastroesophageal symptoms. The frequencies of the symptoms were compared by Chi-square test. Result. Six hundred and twenty-five patients (LA grade A/B: 534 patients; LA grade C/D: 37 patients; Barrett's esophagus: 54 patients) were assessed for gastroesophageal and extragastroesophageal symptoms. Patients with Los Angeles grade A/B erosive esophagitis had higher frequencies of symptoms including epigastric pain, epigastric fullness, dysphagia, and throat cleaning than patients with Los Angeles grade C/D erosive esophagitis. Patients with Los Angeles grade A/B erosive esophagitis also had higher frequencies of symptoms including acid regurgitation, epigastric acidity, regurgitation of food, nausea, vomiting, epigastric fullness, dysphagia, foreign body sensation of throat, throat cleaning, and cough than patients with Barrett's esophagus. Conclusion. The frequencies of some esophageal and extraesophageal symptoms in patients with Los Angeles grade A/B erosive esophagitis were higher than those in patients with Los Angeles grade C/D erosive esophagitis and Barrett's esophagus. The causes of different symptom profiles in different categories of GERD patients merit further investigations.
PMCID: PMC3753740  PMID: 23997765
3.  Association of Esophageal Inflammation, Obesity and Gastroesophageal Reflux Disease: From FDG PET/CT Perspective 
PLoS ONE  2014;9(3):e92001.
Gastroesophageal reflux disease (GERD) is associated with bothersome symptoms and neoplastic progression into Barrett's esophagus and esophageal adenocarcinoma. We aim to determine the correlation between GERD, esophageal inflammation and obesity with 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT).
We studied 458 subjects who underwent a comprehensive health check-up, which included an upper gastrointestinal endoscopy, FDG PET/CT and complete anthropometric measures. GERD symptoms were evaluated with Reflux Disease Questionnaire. Endoscopically erosive esophagitis was scored using the Los Angeles classification system. Inflammatory activity, represented by standardized uptake values (SUVmax) of FDG at pre-determined locations of esophagus, stomach and duodenum, were compared. Association between erosive esophagitis, FDG activity and anthropometric evaluation, including body mass index (BMI), waist circumference, visceral and subcutaneous adipose tissue volumes were analyzed.
Subjects with erosive esophagitis (n = 178, 38.9%) had significantly higher SUVmax at middle esophagus (2.69±0.74 vs. 2.41±0.57, P<.001) and esophagogastric junction (3.10±0.89 vs. 2.38±0.57, P<.001), marginally higher at upper esophageal sphincter (2.29±0.42 vs. 2.21±0.48, P = .062), but not in stomach or duodenum. The severity of erosive esophagitis correlated with SUVmax and subjects with Barrett's esophagus had the highest SUVmax at middle esophagus and esophagogastric junction. Heartburn positively correlated with higher SUVmax at middle oesophagus (r = .262, P = .003). Using multivariate regression analyses, age (P = .027), total cholesterol level (P = .003), alcohol drinking (P = .03), subcutaneous adipose tissue (P<.001), BMI (P<.001) and waist circumference (P<.001) were independently associated with higher SUVmax at respective esophageal locations.
Esophageal inflammation demonstrated by FDG PET/CT correlates with endoscopic findings and symptomatology of GERD. Obesity markers, both visceral and general, are independent determinants of esophageal inflammation.
PMCID: PMC3958434  PMID: 24642729
4.  Lifestyle factors affecting gastroesophageal reflux disease symptoms: a cross-sectional study of healthy 19864 adults using FSSG scores 
BMC Medicine  2012;10:45.
Gastroesophageal reflux disease (GERD) is a very common disorder worldwide, comprised of reflux esophagitis (RE) and non-erosive reflux disease (NERD). As more than half of GERD patients are classified into the NERD group, precise evaluation of bothersome epigastric symptoms is essential. Nevertheless, compared with many reports targeting endoscopic reflux esophagitis, large-scale studies focusing on GERD symptoms have been very scarce.
To elucidate lifestyle factors affecting GERD symptoms, 19,864 healthy adults in Japan were analyzed. Sub-analyses of 371 proton pump inhibitor (PPI) users and 539 histamine H2-receptor antagonist (H2RA) users were also performed. Using the FSSG (Frequency Scale for the Symptoms of GERD) score as a response variable, 25 lifestyle-related factors were univariately evaluated by Student's t-test or Pearson's correlation coefficient, and were further analyzed with multiple linear regression modelling.
Average FSSG scores were 4.8 ± 5.2 for total subjects, 9.0 ± 7.3 for PPI users, and 8.2 ± 6.6 for H2RA users. Among the total population, positively correlated factors and standardized coefficients (β) for FSSG scores are inadequate sleep (β = 0.158), digestive drug users (β = 0.0972 for PPI, β = 0.0903 for H2RA, and β = 0.104 for others), increased body weight in adulthood (β = 0.081), dinner just before bedtime (β = 0.061), the habit of midnight snack (β = 0.055), lower body mass index (β = 0.054), NSAID users (β = 0.051), female gender (β = 0.048), lack of breakfast (β = 0.045), lack of physical exercise (β = 0.035), younger age (β = 0.033), antihyperglycemic agents non-users (β = 0.026), the habit of quick eating (β = 0.025), alcohol drinking (β = 0.025), history of gastrectomy (β = 0.024), history of cardiovascular disease (β = 0.020), and smoking (β = 0.018). Positively correlated factors for PPI users are female gender (β = 0.198), inadequate sleep (β = 0.150), lack of breakfast (β = 0.146), antihypertensive agent non-users (β = 0.134), and dinner just before bedtime (β = 0.129), whereas those for H2RA users are inadequate sleep (β = 0.248), habit of midnight snack (β = 0.160), anticoagulants non-users (β = 0.106), and antihypertensive agents non-users (β = 0.095).
Among many lifestyle-related factors correlated with GERD symptoms, poor quality of sleep and irregular dietary habits are strong risk factors for high FSSG scores. At present, usual dose of PPI or H2RA in Japan cannot fully relieve GERD symptoms.
PMCID: PMC3353848  PMID: 22554226
gastroesophageal reflux disease (GERD); FSSG (Frequency Scale for the Symptoms of GERD); quality of sleep; dietary habits; proton pump inhibitor (PPI); histamine H2-receptor antagonist (H2RA)
5.  The Association Between Obesity and GERD: A Review of the Epidemiological Evidence 
Digestive diseases and sciences  2008;53(9):2307-2312.
The current epidemics of obesity and gastroesophageal reflux disease (GERD)–related disorders, including symptoms, esophageal erosions, Barrett’s esophagus (BE), and esophageal adenocarcinoma, have generated much interest in studying the association between these two conditions. Results of multiple case-control and cohort studies indicate that obesity satisfies several criteria for a causal association with GERD and some of its complications, including a generally consistent association with GERD symptoms, erosive esophagitis, and esophageal adenocarcinoma. An increase in GERD symptoms has been shown to occur in individuals who gain weight but continue to have a body mass index (BMI) in the normal range, contributing to the epidemiological evidence for a possible dose-response relationship between increasing BMI and increasing GERD. However, data are less clear on the relationship between BE and obesity, with more recent investigations showing little association. However, when considered separately, abdominal obesity seems to explain a considerable part of the association with GERD, including BE. Overall, epidemiological data show that maintaining a normal BMI may reduce the likelihood of developing GERD and its potential complications.
PMCID: PMC2827866  PMID: 18651221
6.  Current Advances in the Diagnosis and Treatment of Nonerosive Reflux Disease 
Nonerosive reflux disease (NERD) is a distinct pattern of gastroesophageal reflux disease (GERD). It is defined as a subcategory of GERD characterized by troublesome reflux-related symptoms in the absence of esophageal mucosal erosions/breaks at conventional endoscopy. In clinical practice, patients with reflux symptoms and negative endoscopic findings are markedly heterogeneous. The potential explanations for the symptom generation in NERD include microscopic inflammation, visceral hypersensitivity (stress and sleep), and sustained esophageal contractions. The use of 24-hour esophageal impedance and pH monitoring gives further insight into reflux characteristics and symptom association relevant to NERD. The treatment choice of NERD still relies on acid-suppression therapy. Initially, patients can be treated by a proton pump inhibitor (PPI; standard dose, once daily) for 2–4 weeks. If initial treatment fails to elicit adequate symptom control, increasing the PPI dose (standard dose PPI twice daily) is recommended. In patients with poor response to appropriate PPI treatment, 24-hour esophageal impedance and pH monitoring is indicated to differentiate acid-reflux-related NERD, weakly acid-reflux-related NERD (hypersensitive esophagus), nonacid-reflux-related NERD, and functional heartburn. The response is less effective in NERD as compared with erosive esophagitis.
PMCID: PMC3725792  PMID: 23935610
7.  Relevance of Ultrastructural Alterations of Intercellular Junction Morphology in Inflamed Human Esophagus 
Detailed characterization of the ultrastructural morphology of intercellular space in gastroesophageal reflux disease has not been fully studied. We aimed to investigate whether subtle alteration in intercellular space structure and tight junction proteins might differ among patients with gastroesophageal reflux disease.
Esophageal biopsies at 5 cm above the gastroesophageal junction were obtained from 6 asymptomatic controls, 10 patients with reflux symptoms but without erosions, and 18 patients with erosions. The biopsies were morphologically evaluated by transmission electron microscopy, and by using immunohistochemistry for tight junction proteins (claudin-1 and claudin-2 proteins).
The expressions of tight junction proteins did not differ between asymptomatic controls and gastroesophageal reflux disease patients. In patients with gastroesophageal reflux disease, altered desmosomal junction morphology was only found in upper stratified squamous epithelium. Dilated intercellular space occurred only in upper stratified squamous epithelium and in patients with erosive esophagitis.
This study suggests that dilated intercellular space may not be uniformly present inside the esophageal mucosa and predominantly it is located in upper squamous epithelium. Presence of desmosomal junction alterations is associated with increased severity of gastroesophageal reflux disease. Besides dilated intercellular space, subtle changes in ultrastructural morphology of intercellular space allow better identification of inflamed esophageal mucosa relevant to acid reflux.
PMCID: PMC3714410  PMID: 23875099
Extracellular space; Gastroesophageal reflux; Microscopy, Electron, Transmission; Tight junctions
8.  Long-term management of gastroesophageal reflux disease with pantoprazole 
Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease that can progress to major complications. Affected patients have poorer health-related quality of life than the general population. As GERD requires continued therapy to prevent relapse and complications, most patients with erosive esophagitis require long-term acid suppressive treatment. Thus GERD results in a significant cost burden and poor health-related quality of life. The effective treatment of GERD provides symptom resolution and high rates of remission in erosive esophagitis, lowers the incidence of GERD complications, improves health-related quality of life, and reduces the cost of this disease. Proton pump inhibitors are accepted as the most effective initial and maintenance treatment for GERD. Oral pantoprazole is a safe, well tolerated and effective initial and maintenance treatment for patients with nonerosive GERD or erosive esophagitis. Oral pantoprazole has greater efficacy than histamine H2-receptor antagonists and generally similar efficacy to other proton pump inhibitors for the initial and maintenance treatment of GERD. In addition, oral pantoprazole has been shown to improve the quality of life of patients with GERD and is associated with high levels of patient satisfaction with therapy. GERD appears to be more common and more severe in the elderly, and pantoprazole has shown to be an effective treatment for this at-risk population.
PMCID: PMC1936305  PMID: 18360632
pantoprazole; proton pump inhibitor; erosive esophagitis; gastroesophageal reflux disease; tolerability; efficacy
9.  Halimeter ppb Levels as the Predictor of Erosive Gastroesophageal Reflux Disease 
Gut and Liver  2010;4(3):320-325.
In a previous issue published in Gut and Liver, we found that erosive changes in the esophagogastroduodenal mucosa were strongly correlated with increased levels of volatile sulfur-containing compounds (VSC), suggesting that halitosis could be a symptom reflecting the erosive status of the upper gut mucosa. Together with other studies showing a possible association between halitosis and gastroesophageal reflux disease (GERD), under the premise that halitosis could be one of extraesophageal manifestations of erosive GERD (ERD), we investigated the significance of Halimeter ppb levels on ERD compared to non-erosive gastroesophageal reflux disease (NERD).
Subjects were assigned to the NERD group if there was no evidence of esophageal erosive changes on endoscopy, despite reflux symptoms, and to the ERD group if they had GERD A, B, C, or D (according to the Los Angeles classification). The VSC levels were measured in all patients with either a Halimeter (before endoscopy) or by gas chromatography of the gastric juices aspirated during endoscopy.
The VSC level differed significantly between the NERD and ERD groups (p<0.0001), suggesting that this can be used to discriminate between NERD and ERD. However, the VSC level did not differ significantly with the severity of GERD. Even though hiatal hernia and a body mass index of >24 kg/m2 was significantly associated with ERD, there was no correlation with Halimeter ppb levels. Minimal-change lesions exhibited the highest VSC levels, signifying that minimal change lesions can be classified as ERD based on our finding that halimeter ppb levels were descrimitive of erosive change.
Erosive changes in the esophageal mucosa were strongly associated with VSC levels, supporting the hypothesis that halitosis can be a potential biomarker for the discrimination between ERD and NERD, reflecting the presence of erosive change in the lower esophagogastric junction.
PMCID: PMC2956342  PMID: 20981207
Volatile sulfur compound; H2S; Halitosis; Gastroesophageal reflux disease; Nonerosive gastroesophageal reflux disease; Hiatal hernia; Body mass index
10.  Esophageal intraluminal baseline impedance is associated with severity of acid reflux and epithelial structural abnormalities in patients with gastroesophageal reflux disease 
Journal of Gastroenterology  2012;48(5):601-610.
The esophageal intraluminal baseline impedance may be used to evaluate the status of mucosa integrity. Esophageal acid exposure decreases the baseline impedance. We aimed to compare baseline impedance in patients with various reflux events and with different acid-related parameters, and investigate the relationships between epithelial histopathologic abnormalities and baseline impedance.
A total of 229 GERD patients and 34 controls underwent 24-h multichannel intraluminal impedance and pH monitoring (MII–pH monitoring), gastroendoscopy, and completed a GERD questionnaire (GerdQ). We quantified epithelial intercellular spaces (ICSs) and expression of tight junction (TJ) proteins by histologic techniques.
Mean baseline values in reflux esophagitis (RE) (1752 ± 1018 Ω) and non-erosive reflux disease (NERD) (2640 ± 1143 Ω) were significantly lower than in controls (3360 ± 1258 Ω; p < 0.001 and p = 0.001, respectively). Among NERD subgroups, mean baselines in the acid reflux group (2510 ± 1239 Ω) and mixed acid/weakly acidic reflux group (2393 ± 1009 Ω) were much lower than in controls (3360 ± 1258 Ω; p = 0.020 and p < 0.001, respectively). The mean baseline in severe RE patients was significantly lower than in mild RE patients (LA-C/D vs. LA-A/B: 970 ± 505 Ω vs. 1921 ± 1024 Ω, p < 0.001). There was a significant negative correlation between baseline value and acid exposure time (AET) (r = −0.41, p < 0.001), and a weak but significant correlation (r = −0.20, p = 0.007) between baseline value and weakly AET. Negative correlations were observed between ICS and the baseline impedance (r = −0.637, p < 0.001) and claudin-1 and the baseline impedance (r = −0.648, p < 0.001).
Patients with dominant acid reflux events and with longer AET have low baseline impedance. Baseline values are correlated with esophageal mucosal histopathologic changes such as dilated ICS and TJ alteration.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-012-0689-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3654188  PMID: 23076541
Baseline impedance; Acid reflux; Intercellular spaces; Tight junction
11.  Barrett’s esophagus: Prevalence and risk factors in patients with chronic GERD in Upper Egypt 
AIM: To determine the prevalence and possible risk factors of Barrett’s esophagus (BE) in patients with chronic gastroesophageal reflux disease (GERD) in El Minya and Assuit, Upper Egypt.
METHODS: One thousand consecutive patients with chronic GERD symptoms were included in the study over 2 years. They were subjected to history taking including a questionnaire for GERD symptoms, clinical examination and upper digestive tract endoscopy. Endoscopic signs suggestive of columnar-lined esophagus (CLE) were defined as mucosal tongues or an upward shift of the squamocolumnar junction. BE was diagnosed by pathological examination when specialized intestinal metaplasia was detected histologically in suspected CLE. pH was monitored in 40 patients.
RESULTS: BE was present in 7.3% of patients with chronic GERD symptoms, with a mean age of 48.3 ± 8.2 years, which was significantly higher than patients with GERD without BE (37.4 ± 13.6 years). Adenocarcinoma was detected in eight cases (0.8%), six of them in BE patients. There was no significant difference between patients with BE and GERD regarding sex, smoking, alcohol consumption or symptoms of GERD. Patients with BE had significantly longer esophageal acid exposure time in the supine position, measured by pH monitoring.
CONCLUSION: The prevalence of BE in patients with GERD who were referred for endoscopy was 7.3%. BE seems to be associated with older age and more in patients with nocturnal gastroesophageal reflux.
PMCID: PMC2715977  PMID: 19630106
Barrett’s esophagus; Gastrointestinal; Endoscopy; Gastroesophageal reflux; Risk factors
12.  Lifestyle Change Influences on GERD in Japan: A Study of Participants in a Health Examination Program 
Digestive Diseases and Sciences  2011;56(10):2857-2864.
Though gastroesophageal reflux disease (GERD) has been a prevalent disease in Western countries, the incidence of GERD has only just started to increase in Japan.
The aim of this study was to determine which lifestyle factors may be associated with GERD in Japan.
A total of 2,853 participants who took part in a health examination program between July 2004 and March 2005 were enrolled. GERD symptoms were assessed using the Japanese version of the Carlsson-Dent self-administered questionnaire (QUEST). The GERD group consisted of participants with a QUEST score ≥6 and/or endoscopic findings. The GERD group was divided into asymptomatic ERD (erosive reflux disease with no symptoms), symptomatic ERD (erosive reflux disease with symptoms) and NERD (non-erosive reflux disease) groups. Associated factors for these diseases were analyzed by logistic regression analysis.
GERD was diagnosed in 667 (23.4%) participants. Among the subjects placed in the GERD group, asymptomatic ERD, symptomatic ERD and NERD were diagnosed in 232 (8.1%), 91 (3.2%) and 344 (12.1%) participants, respectively. Factors associated with GERD included a high BMI (body mass index), hiatus hernia, fewer hours of sleep, lack of exercise, and drinking green tea.
Relationships between lifestyle, gender and GERD were investigated in the present study. Both lifestyle improvements and consideration of gender differences can be used to help prevent GERD development.
PMCID: PMC3179841  PMID: 21487772
Gastroesophageal reflux disease (GERD); Japanese; Lifestyle; Gender
13.  Endoscopic Experience Improves Interobserver Agreement in the Grading of Esophagitis by Los Angeles Classification: Conventional Endoscopy and Optimal Band Image System 
Gut and Liver  2013;8(2):154-159.
Interobserver variation by experience was documented for the diagnosis of esophagitis using the Los Angeles classification. The aim of this study was to evaluate whether interobserver agreement can be improved by higher levels of endoscopic experience in the diagnosis of erosive esophagitis.
Endoscopic images of 51 patients with gastroesophageal reflux disease (GERD) symptoms were obtained with conventional endoscopy and optimal band imaging (OBI). Endoscopists were divided into an expert group (16 gastroenterologic endoscopic specialists guaranteed by the Korean Society of Gastrointestinal Endoscopy) and a trainee group (individuals with fellowships, first year of specialty training in gastroenterology). All endoscopists had no or minimal experience with OBI. GERD was diagnosed using the Los Angeles classification with or without OBI.
The mean weighted paired κ statistics for interobserver agreement in grading erosive esophagitis by conventional endoscopy in the expert group was better than that in the trainee group (0.51 vs 0.42, p<0.05). The mean weighted paired k statistics in the expert group and in the trainee group based on conventional endoscopy with OBI did not differ (0.42, 0.42).
Interobserver agreement in the expert group using conventional endoscopy was better than that in the trainee group. Endoscopic experience can improve the interobserver agreement in the grading of esophagitis using the Los Angeles classification.
PMCID: PMC3964265  PMID: 24672656
Gastroesophageal reflux; Agreement; Experience
14.  Improvement of clinical parameters in patients with gastroesophageal reflux disease after radiofrequency energy delivery 
AIM: To evaluate the efficacy of Stretta procedure with gastroesophageal reflux disease (GERD) based on symptom control, medication changes and oesophagitis grade.
METHODS: Ninety patients with a history of GERD underwent Stretta procedure from June 2007 to March 2010. All patients with GERD diagnosed by the presence of endoscopically evidenced oesophagitis or abnormal esophageal pH testing. We evaluated GERD-health-related quality of life, satisfaction, medication use and endoscopy at baseline, 6, 12 mo after treatment. Complications of the procedure were analyzed.
RESULTS: We found that patients experienced significant changes in symptoms of GERD after Stretta procedure. The onset of GERD symptom relief was less than 2 mo (70.0%) or 2 to 6 mo (16.7%). The mean GERD-HRQL score was 25.6 (baseline), 7.3 (6 mo, P < 0.01), and 8.1 (12 mo, P < 0.01).The mean heartburn score was 3.3 (baseline), and 1.2 (12 mo, P < 0.05). The percentage of patients with satisfactory GERD control improved from 31.1% at baseline to 86.7% after treatment, and patient satisfaction improved from 1.4 at baseline to 4.0 at 12 mo (P < 0.01). Medication usage decreased significantly from 100% of patients on proton pump inhibitors therapy at baseline to 76.7% of patients showing elimination of medications or only as needed use of antacids/H2-RA at 12 mo. An improvement in endoscopic grade of oesophagitis was seen in 33 of the 41 patients. All patients had either no erosions or only mild erosive disease (grade A) at 6 mo.
CONCLUSION: The experience with Stretta procedure confirms that it is well tolerated, safe, effective and durable in the treatment of GERD. The Stretta procedure provides the drug-refractory patients with a new minimally invasive method.
PMCID: PMC3218158  PMID: 22110270
Gastroesophageal reflux disease; Clinical parameters; Stretta procedure; Radiofrequency
15.  Meta-Analyses of the Effect of Symptoms of Gastroesophageal Reflux on the Risk of Barrett's Esophagus 
Esophageal adenocarcinoma (EAC) is a devastating disease that has risen in incidence over the past several decades. Barrett's esophagus (BE) is an associated premalignant lesion. Current preventative efforts rely on endoscopic screening of individuals with gastroesophageal reflux disease (GERD) symptoms and surveillance endoscopy for those with BE. However, some recent studies have found a high prevalence of BE in patients without GERD, and others have found little or no association with GERD. We hypothesized that studies of higher-quality design show weaker associations of GERD with BE, and that GERD is only weakly associated with short-segment Barrett's esophagus (SSBE).
We performed a systematic literature search in multiple online electronic databases regardless of language. Eligible studies required visualization of columnar mucosa and histological confirmation of intestinal metaplasia, and GERD symptoms ascertained by questionnaire or interview. The highest-quality sampling design was defined a priori by both cases and controls identified among unselected research volunteers (“research design”) rather than by patients selected for endoscopy for clinical indications (“clinical design”), which introduces selection and ascertainment bias. A priori, heterogeneity was defined by Cochrane's Q P < 0.20 and the inconsistency index (I2; 25% low, 50% moderate, and 75% high). Heterogeneity of results can reflect significant differences in study design or effect modification by strata of outcomes.
Systematic review identified 13,392 citations. Evaluation identified 108 potentially relevant journal articles, of which 26 met eligibility. Of these, 14 studies identified cases of BE and controls based on clinical indication (“clinical design”), and 6 used the “research design.” The remaining six studies identified cases of BE from patients undergoing endoscopy for clinical indication and controls among patients without known BE (“cases clinical/controls research”). The summary odds ratio (OR) for the association of GERD with BE from all studies was 2.90 (95% confidence interval (CI), 1.86–4.54), but the results were very heterogeneous (P = 0.0001; I2 = 89%). When stratified by BE length and sampling design, the studies with clinical design showed substantial, but heterogeneous, associations with SSBE (OR, 2.38; 95% CI, 1.21–4.70; P = 0.02; I2 = 62%), and stronger and homogeneous association with long-segment BE (LSBE; fixed effects OR, 2.96; 95% CI, 1.69–5.19; P = 0.25; I2 = 25%). In the research study design, stratifying by length of BE resolved the heterogeneity and showed a strong association between GERD and LSBE (fixed effects OR, 4.92; 95% CI, 2.01–12.0; P = 0.30; I2 = 19%) and no association with SSBE (fixed effects OR, 1.15; 95% CI, 0.763–1.73; P = 0.84; I2 = 0%). Funnel plots showed potential evidence for bias against dissemination of small negative studies.
In the highest-quality studies, GERD symptoms are not associated with SSBE, but increased the odds of LSBE by fivefold. GERD symptoms can serve as a reliable predictor of LSBE, but not SSBE. If SSBE is considered worthy of identification, then current screening practices do not select patients at risk for endoscopy, and alternative methods of selection for screening need to be developed.
PMCID: PMC2916949  PMID: 20485283
16.  Impact of PPIs on patient focused symptomatology in GERD 
About half of patients with gastroesophageal reflux disease (GERD) have a normal endoscopy, so symptom assessment is the only appropriate outcome measure for these persons. Symptom assessment is also of great importance in persons with erosive esophagitis. There is currently no fully validated questionnaire to compare symptom response to treatment of patients with GERD. The aim of this review is to consider ReQuest™ assessment tool to evaluate esophageal, supra-esophageal, and infra-esophageal symptoms, as well as any modification of the patient’s quality of life. The ReQuest™ may be combined with the Los Angeles classification of esophagitis (LA A–D), to include the normal endoscopic finding in normal endoscopy reflux disease. The ReQuest™ score declines rapidly towards normal with patient treatment with a proton pump inhibitor. A proportion of patients need more than the usual 8 weeks of therapy. For example, in GERD patients with Los Angeles B–D, the ReQuest™ score falls more with pantoprazole 40 mg than with esomoprazole 40 mg after 12 weeks of therapy. Now that the simplified ReQuest in Practice™ is available, this validated brief questionnaire has potential as an instrument for use in GERD patients seen in everyday clinical practice.
PMCID: PMC2643100  PMID: 19337426
complete healing; dyspepsia; erosive esophagitis; GERD symptoms; pH; ReQuest™
17.  Clinical Significance of Hiatal Hernia 
Gut and Liver  2011;5(3):267-277.
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.
PMCID: PMC3166665  PMID: 21927653
Hiatal hernia; Gastroesophageal reflux disease; Lower esophageal sphincter
18.  Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome 
Gastroenterology  2009;137(2):588-597.
Background & Aims
Gastroesophageal reflux causes inflammation, intestinal metaplasia and its downstream sequelum adenocarcinoma in the distal esophagus. The incidence of esophageal adenocarcinoma has increased approximately 6-fold in the U.S. since the 1970s, accompanied with a significant increase in prevalence of gastroesophageal reflux disease (GERD). Despite extensive epidemiological study, the cause for GERD and the unexpected increases remain unexplainable. Microbes are among the environmental factors that may contribute to the etiology of GERD but very little research has been done on the esophageal microbiome, particularly in its relation to GERD. This is the first reported correlation between a change in the esophageal microbiome and esophageal diseases.
Biopsies of the distal esophagus were collected from 34 patients. Host phenotypes were histologically defined as normal, esophagitis, or Barrett’s esophagus (intestinal metaplasia). Microbiomes from the biopsies were analyzed by bacterial 16S rRNA gene survey and classified into types using unsupervised cluster analysis and phenotype-guided analyses. Independence between host phenotypes and microbiome types were analyzed by Fisher Exact test.
Esophageal microbiomes can be classified into two types. The type I microbiome was dominated by the genus Streptococcus and concentrated in the phenotypically normal esophagus. Conversely, the type II microbiome contained a greater proportion of Gram-negative anaerobes/microaerophiles and primarily correlated with esophagitis (Odds Ratio: 15.4) and BE (Odds Ratio: 16.5).
In the human distal esophagus, inflammation and intestinal metaplasia are associated with global alteration of the microbiome. These findings raise the issue of a possible role for dysbiosis in the pathogenesis of reflux-related disorders.
PMCID: PMC2963147  PMID: 19394334
19.  Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: A meta-analysis 
AIM: To investigate the efficacy of adding prokinetics to proton pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD).
METHODS: PubMed, Cochrane Library, and Web of Knowledge databases (prior to October 2013) were systematically searched for randomized controlled trials (RCTs) that compared therapeutic efficacy of PPI alone (single therapy) or PPI plus prokinetics (combined therapy) for GERD. The primary outcome of those selected trials was complete or partial relief of non-erosive reflux disease symptoms or mucosal healing in erosive reflux esophagitis. Using the test of heterogeneity, we established a fixed or random effects model where the risk ratio was the primary readout for measuring efficacy.
RESULTS: Twelve RCTs including 2403 patients in total were enrolled in this study. Combined therapy was not associated with significant relief of symptoms or alterations in endoscopic response relative to single therapy (95%CI: 1.0-1.2, P = 0.05; 95%CI: 0.66-2.61, P = 0.44). However, combined therapy was associated with a greater symptom score change (95%CI: 2.14-3.02, P < 0.00001). Although there was a reduction in the number of reflux episodes in GERD [95%CI: -5.96-(-1.78), P = 0.0003] with the combined therapy, there was no significant effect on acid exposure time (95%CI: -0.37-0.60, P = 0.65). The proportion of patients with adverse effects undergoing combined therapy was significantly higher than for PPI therapy alone (95%CI: 1.06-1.36, P = 0.005) when the difference between 5-HT receptor agonist and PPI combined therapy and single therapy (95%CI: 0.84-1.39, P = 0.53) was excluded.
CONCLUSION: Combined therapy may partially improve patient quality of life, but has no significant effect on symptom or endoscopic response of GERD.
PMCID: PMC3942846  PMID: 24605040
Gastroesophageal reflux diseases; Proton pump inhibitors; Prokinetics; GABA-B receptor agonists; Treatment; Meta-analysis
20.  Esophageal epithelial surface in patients with gastroesophageal reflux disease: An electron microscopic study 
AIM: To investigate the intercellular spaces between the most superficially located esophageal epithelial cells in patients with gastroesophageal reflux disease (GERD).
METHODS: Eighteen patients with erosive esophagitis, 10 patients with non-erosive reflux disease (NERD), and 18 normal asymptomatic volunteers were enrolled. Biopsy specimens were obtained from the lower esophageal mucosa without ulcer or erosion. Scanning electron microscopy was employed to investigate the tightness of the superficial cellular attachment.
RESULTS: The intercellular space between the most superficially located epithelial cells in patients with erosive esophagitis or NERD was not different from that in asymptomatic healthy individuals.
CONCLUSION: Widened luminal intercellular spaces of esophageal superficial epithelium are not responsible for the induction of reflux symptoms in patients with GERD.
PMCID: PMC2748207  PMID: 18837089
Reflux esophagitis; Non-erosive gastroesophageal reflux diseases; Electron microscopy; Questionnaire
21.  Current Pharmacological Management of Gastroesophageal Reflux Disease 
Gastroesophageal reflux disease (GERD), a common disorder with troublesome symptoms caused by reflux of gastric contents into the esophagus, has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose PPI. Antacids, alginate, histamine type-2 receptor antagonists, and prokinetic agents are usually used as add-on therapy to PPI in clinical practice. Development of novel therapeutic agents has focused on the underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxation, motility disorder, mucosal protection, and esophageal hypersensitivity. Newer formulations of PPI with faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, have also been investigated in clinical trials. In this review, we summarize the current and developing therapeutic agents for GERD treatment.
PMCID: PMC3710614  PMID: 23878534
22.  Endoscopic evaluation of gastro-esophageal reflux disease. 
Endoscopy is, currently, the initial investigation of choice for the investigation of gastroesophageal reflux disease (GERD) in clinical practice and clinical research. Erosion severity is predictive of a patient's response to therapy and of the likelihood of relapse after therapy. It is, therefore, important to grade the severity of erosive reflux esophagitis, particularly in the context of clinical trials. The Savary-Miller endoscopic classification system is used widely but usage and interpretation are very variable. The "MUSE" (metaplasia [M], ulceration [U], stricturing [S] and erosions [E]) classification provides clear definitions of the relevant endoscopic features, and it is based on a standardized report form, which allows the endoscopist to make a clear record of esophagitis severity. Recent studies confirm that endoscopists can identify erosions or mucosal breaks, ulcers, strictures, and metaplasia reproducibly. The "L.A." (Los Angeles) classification describes four grades of esophagitis severity (A to D), based on the extent of esophageal lesions known as "mucosal breaks," but it does not record the presence or severity of other GERD lesions. Thus, for patients with "complicated" reflux disease, the "MUSE" classification offers a more comprehensive description of esophagitis severity. Endoscopy is not universally applicable: 40 to 60 percent of patients with typical reflux symptoms do not have esophageal erosions and are now considered to have "endoscopy negative reflux disease" (ENRD). Thus, endoscopy is not the final arbiter as to a diagnosis of reflux disease, and it is not, therefore, a necessary prerequisite to therapy. Endoscopy is indicated at first presentation for patients with alarm symptoms referable to the upper gastrointestinal tract. It has also been proposed that all patients with chronic GERD should have a "once-in-a-lifetime" endoscopy; in the absence of Barrett's esophagus or other complications, no follow-up is required unless the patient's symptoms change significantly. A surveillance program with multiple biopsies should be instituted if there is evidence of Barrett's esophagus. Endoscopic evaluation should document the presence and extent of esophageal erosions using the L.A. or MUSE classification systems; complications should also be documented and may be recorded using the MUSE classification. Non-erosive changes such as erythema may be ignored on the basis of present evidence, and there are no clear data to support the use of endoscopic biopsies for the diagnosis of GERD.
PMCID: PMC2579014  PMID: 10780570
23.  Gastroesophageal reflux disease: Important considerations for the older patients 
Gastroesophageal reflux disease (GERD) is the most common upper gastrointestinal disorder seen in the elderly. The worldwide incidence of GERD is increasing as the incidence of Helicobacter pylori is decreasing. Although elderly patients with GERD have fewer symptoms, their disease is more often severe. They have more esophageal and extraesophageal complications that may be potentially life threatening. Esophageal complications include erosive esophagitis, esophageal stricture, Barrett’s esophagus and adenocarcinoma of the esophagus. Extraesophageal complications include atypical chest pain that can simulate angina pectoris; ear, nose, and throat manifestations such as globus sensation, laryngitis, and dental problems; pulmonary problems such as chronic cough, asthma, and pulmonary aspiration. A more aggressive approach may be warranted in the elderly patient, because of the higher incidence of severe complications. Although the evaluation and management of GERD are generally the same in elderly patients as for all adults, there are specific issues of causation, evaluation and treatment that must be considered when dealing with the elderly.
PMCID: PMC3010469  PMID: 21191512
Gastroesophageal reflux disease; Older patient; Elderly
24.  Investigation of relationships among gastroesophageal reflux disease subtypes using narrow band imaging magnifying endoscopy 
AIM: To investigate the relationships among subtypes of gastroesophageal reflux disease (GERD) using narrow band imaging (NBI) magnifying endoscopy.
METHODS: A reflux disease questionnaire was used to screen 120 patients representing the three subtypes of GERD (n = 40 for each subtypes): nonerosive reflux disease (NERD), reflux esophagitis (RE) and Barrett’s esophagus (BE). NBI magnifying endoscopic procedure was performed on the patients as well as on 40 healthy controls. The demographic and clinical characteristics, and NBI magnifying endoscopic features, were recorded and compared among the groups. Targeted biopsy and histopathological examination were conducted if there were any abnormalities. SPSS 18.0 software was used for all statistical analysis.
RESULTS: Compared with healthy controls, a significantly higher proportion of GERD patients had increased number of intrapapillary capillary loops (IPCLs) (78.3% vs 20%, P < 0.05), presence of microerosions (41.7% vs 0%, P < 0.05), and a non-round pit pattern below the squamocolumnar junction (88.3% vs 30%, P < 0.05). The maximum (228 ± 4.8 vs 144 ± 4.7, P < 0.05), minimum (171 ± 3.8 vs 103 ± 4.4, P < 0.05), and average (199 ± 3.9 vs 119 ± 3.9, P < 0.05) numbers of IPCLs/field were also significantly greater in GERD patients. However, comparison among groups of the three subtypes showed no significant differences or any linear trend, except that microerosions were present in 60% of the RE patients, but in only 35% and 30% of the NERD and BE patients, respectively (P < 0.05).
CONCLUSION: Patients with GERD, irrespective of subtype, have similar micro changes in the distal esophagus. The three forms of the disease are probably independent of each other.
PMCID: PMC3857464  PMID: 24363532
Gastroesophageal reflux; Gastroesophageal reflux disease; Intrapapillary capillary loops; Magnifying endoscopy; Narrow band imaging
25.  An update on the use of pantoprazole as a treatment for gastroesophageal reflux disease 
Gastroesophageal reflux disease (GERD) is a chronic, recurrent disease that affects nearly 19 million people in the US. The mainstay of therapy for GERD is acid suppression. Proton pump inhibitors (PPIs) are the most effective medication for both initial treatment and maintenance therapy of GERD. Pantoprazole, a first-generation PPI, was approved by the FDA in 2000 for the treatment of erosive esophagitis associated with GERD. It has been used in more than 100 different countries worldwide. It is one of the few PPIs available in multiple forms: a delayed-release oral capsule, oral suspension, and intravenous. Pantoprazole been shown to improve acid reflux-related symptoms, heal esophagitis, and improve health-related quality of life more effectively than histamine-2 receptor antagonists. Evaluated in over 100 clinical trials, pantoprazole has an excellent safety profile, is as efficacious as other PPIs, and has a low incidence of drug interactions. It has also been shown to be safe and effective in special patient populations, such as the elderly and those with renal or moderate liver disease.
PMCID: PMC3108659  PMID: 21694841
pantoprazole; GERD; esophagitis

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