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1.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1007/s00535-012-0689-6
PMCID: PMC3654188  PMID: 23076541
Baseline impedance; Acid reflux; Intercellular spaces; Tight junction
2.  Esophageal cell proliferation in gastroesophageal reflux disease: Clinical-morphological data before and after pantoprazole 
AIM: To evaluate esophageal mucosal defense mechanisms at an epithelial level to establish if pantoprazole treatment can induce ultrastructural healing and improvement in the proliferation activity of the esophageal epithelium in gastroesophageal reflux disease (GERD).
METHODS: This was a single-blinded study for pH-monitoring, and histological, ultrastructural and MIB1 immunostaining evaluation. Fifty eight patients with GERD were enrolled and underwent 24 h pH-monitoring and endoscopy. Patients were treated for 12 and 24 mo with pantoprazole. Esophageal specimens were taken for histological and ultrastructural evaluation, before and after the treatment.
RESULTS: With transmission electron microscopy, all patients with GERD showed ultrastructural signs of damage with dilation of intercellular spaces (DIS). After 3 mo of therapy the mean DIS values showed a significant reduction and the mean MIB1-LI values of GERD showed an increase in cell proliferation. A further 3 mo of therapy significantly increased cell proliferation only in the erosive esophagitis (ERD) group.
CONCLUSION: Three months of pantoprazole therapy induced ultrastructural healing of mucosal damage in 89% and 93% of ERD and non-erosion patients, respectively. Moreover, long-term pantoprazole treatment may be helpful in increasing the capability for esophageal cell proliferation in GERD, particularly in ERD patients.
doi:10.3748/wjg.15.936
PMCID: PMC2653394  PMID: 19248192
Gastroesophageal reflux disease; Esophagitis; Cell proliferation; Electron microscopy; Pantoprazole
3.  How many cases of laryngopharyngeal reflux suspected by laryngoscopy are gastroesophageal reflux disease-related? 
AIM: To investigate the prevalence of gastroesophageal reflux disease (GERD) in patients with a laryngoscopic diagnosis of laryngopharyngeal reflux (LPR).
METHODS: 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).
RESULTS: 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/m2. 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).
CONCLUSION: 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.
doi:10.3748/wjg.v18.i32.4363
PMCID: PMC3436052  PMID: 22969200
Laryngopharyngeal reflux; Gastroesophageal reflux; Multichannel impedance and pH monitoring; Extra-esophageal reflux syndromes; Chronic laryngitis
4.  Relevance of Ultrastructural Alterations of Intercellular Junction Morphology in Inflamed Human Esophagus 
Background/Aims
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.5056/jnm.2013.19.3.324
PMCID: PMC3714410  PMID: 23875099
Extracellular space; Gastroesophageal reflux; Microscopy, Electron, Transmission; Tight junctions
5.  Nrf2 deficiency impairs the barrier function of mouse esophageal epithelium 
Gut  2013;63(5):711-719.
Objective
As a major cellular defense mechanism, the Nrf2/Keap1 pathway regulates expression of genes involved in detoxification and stress response. Our previous study revealed activation of the Nrf2/Keap1 pathway at the maturation phase during mouse esophageal development, suggesting a potential function in epithelial defense. Here we hypothesize that Nrf2 is involved in the barrier function of esophageal epithelium, and plays a protective role against gastroesophageal reflux disease (GERD).
Design
Human esophageal biopsy samples, mouse surgical models and Nrf2-/- mice were used to assess the role of the Nrf2/Keap1 pathway in esophageal mucosal barrier function. Trans-epithelial electrical resistance (TEER) was measured with mini-Ussing chambers. Hematoxylin and eosin (HE) staining and transmission electron microscopy were used to examine cell morphology, while gene microarray, immunohistochemistry, Western blotting and ChIP analysis were used to assess the expression of pathway genes.
Results
Nrf2 was expressed in normal esophageal epithelium and activated in GERD of both humans and mice. Nrf2 deficiency and gastroesophageal reflux in mice, either alone or in combination, reduced TEER and increased intercellular space diameter in esophageal epithelium. Nrf2 target genes and gene sets associated with oxidoreductase activity, mitochondrial biogenesis and energy production were down-regulated in the esophageal epithelium of Nrf2-/- mice. Consistent with the antioxidative function of Nrf2, a DNA oxidative damage marker (8OHdG) dramatically increased in esophageal epithelial cells of Nrf2-/- mice compared with those of wild-type mice. Interestingly, ATP biogenesis, Cox IV (a mitochondrial protein) and Claudin-4 (Cldn4) expression were down-regulated in the esophageal epithelium of Nrf2-/- mice, suggesting that energy-dependent tight junction integrity was subject to Nrf2 regulation. ChIP analysis confirmed the binding of Nrf2 to Cldn4 promoter.
Conclusion
Nrf2 deficiency impairs esophageal barrier function through disrupting energy-dependent tight junction. Elucidating the role of this pathway in GERD has potential implications for the pathogenesis and therapy of the disease.
doi:10.1136/gutjnl-2012-303731
PMCID: PMC3883925  PMID: 23676441
Nrf2; esophagus; TEER; GERD
6.  Gastroesophageal reflux disease and pulmonary function: A potential role of the dead space extension 
Summary
Background
To evaluate the differences in the existence and size of dead space in patients with and without Gastroesophageal Reflux Disease (GERD and non-GERD) expressed through the size of intrapulmonary shunt (QS/QT).
Material/Methods
The study enrolled 86 subjects – 43 patients referred for endoscopy because of symptoms of GERD (heartburn, acid regurgitation, dysfagia) and 43 healthy subjects with similar anthropometric characteristics without GERD symptoms. Based on endoscopy findings, patients were classified into the erosive reflux disease (ERD) group and non-erosive reflux disease (NERD) group. Spirometry values, single-breath diffusing capacity of the lung for carbon monoxide (DLCO) and intrapulmonary shunt (venous shunt – QS/QT) determined by the oxygen method were measured in all participants.
Results
Statistically significant differences between GERD and non-GERD groups in FVC (p=0.034), FEV1 (p=0.002), FEV1/FVC (p=0.001), and PEF (p=0.001) were observed. There were no statistically significant differences in FEF 25% (p=0.859), FEF 50% (p=0.850), and FEF 75% (p=0.058). Values of DLCO (p=0.006) and DLCO/VA (p=0.001) were significantly lower and QS/QT was significantly higher (p=0.001) in the GERD group than in the non-GERD group. However, in both groups the average values of DLCO and DLCO/VA expressed as a percentage of predictive values were within normal range, while the value of QS/QT in the GERD group showed pathological (6.0%) mean value (normal value ≤5.0%). There were no significant differences in respiratory function test results between patients with ERD and NERD.
Conclusions
Our results suggest that microaspiration of stomach contents may cause surfactant damage, development of microatelectasis, and dead space expansion with consequent increase of intrapulmonary (venous) shunt.
doi:10.12659/MSM.882731
PMCID: PMC3560634  PMID: 22534705
GERD; intrapulmonary shunt; lung extraesophageal manifestations
7.  Incidence of gastroesophageal reflux disease in Uygur and Han Chinese adults in Urumqi 
AIM: To investigate the incidence of gastroesophageal reflux disease (GERD) and its related risk factors in Uygur and Han Chinese adult in Urumqi, China.
METHODS: A population-based cross-sectional survey was undertaken in a total of 972 Uygur (684 male and 288 female) aged from 24 to 61 and 1023 Han Chinese (752 male and 271 female) aged from 23 to 63 years. All participants were recruited from the residents who visited hospital for health examination from November 2011 to May 2012. Each participant signed an informed consent and completed a GERD questionnaire (Gerd Q) and a lifestyle-food frequency questionnaire survey. Participants whose Gerd Q score was ≥ 8 and met one of the following requirements would be enrolled into this research: (1) being diagnosed with erosive esophagitis (EE) or Barrett’s esophagus (BE) by endoscopy; (2) negative manifestation under endoscopy (non-erosive reflux disease, NERD) with abnormal acid reflux revealed by 24-h esophageal pH monitoring; and (3) suffering from typical heartburn and regurgitation with positive result of proton pump inhibitor test.
RESULTS: According to Gerd Q scoring criteria, 340 cases of Uygur and 286 cases of Han Chinese were defined as GERD. GERD incidence in Uygur was significantly higher than in Han Chinese (35% vs 28%, χ2 = 11.09, P < 0.005), Gerd Q score in Uygur was higher than in Han Chinese (7.85 ± 3.1 vs 7.15 ± 2.9, P < 0.005), and Gerd Q total score in Uygur male was higher than in female (8.15 ± 2.8 vs 6.85 ± 2.5, P < 0.005). According to normalized methods, 304 (31%) cases of Uygur were diagnosed with GERD, including 89 cases of EE, 185 cases of NERD and 30 cases of BE; 256 (25%) cases of Han Chinese were diagnosed with GERD, including 90 cases of EE, 140 cases of NERD and 26 cases of BE. GERD incidence in Uygur was significantly higher than in Han Chinese (31% vs 25%, χ2 = 9.34, P < 0.005) while the incidences were higher in males of both groups than in females (26% vs 5% in Uygur, χ2 = 35.95, P < 0.005, and 19.8% vs 5.2% in Han, χ2 = 5.48, P < 0.025). GERD incidence in Uygur male was higher than in Han Chinese male (26% vs 19.8%, χ2 = 16.51, P < 0.005), and incidence of NERD in Uygur was higher than in Han Chinese (χ2 = 10.06, P < 0.005). Occupation (r = 0.623), gender (r = 0.839), smoking (r = 0.322), strong tea (r = 0.658), alcohol drinking (r = 0.696), meat-based diet (mainly meat) (r = 0.676) and body mass index (BMI) (r = 0.567) were linearly correlated with GERD in Uygur (r = 0.833, P = 0.000); while gender (r = 0.957), age (r = 0.016), occupation (r = 0.482), strong tea (r = 1.124), alcohol drinking (r = 0.558), meat diet (r = 0.591) and BMI (r = 0.246) were linearly correlated with GERD in Han Chinese (r = 0.786, P = 0.01). There was no significant difference between Gerd Q scoring and three normalized methods for the diagnosis of GERD.
CONCLUSION: GERD is highly prevalent in adult in Urumqi, especially in Uygur. Male, civil servant, smoking, strong tea, alcohol drinking, meat diet and BMI are risk factors correlated to GERD.
doi:10.3748/wjg.v18.i48.7333
PMCID: PMC3544039  PMID: 23326142
Gastroesophageal reflux disease; Incidence; Uygur; Han; Risk factors; Urumqi
8.  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.
doi:10.3748/wjg.v17.i39.4429
PMCID: PMC3218158  PMID: 22110270
Gastroesophageal reflux disease; Clinical parameters; Stretta procedure; Radiofrequency
9.  Quality of Life in GERD and Barrett’s Esophagus is Related to Gender and Manifestation of Disease 
Introduction
Gastroesophageal reflux disease (GERD) is a common condition that impacts patients’ health-related quality of life (HRQoL). The HRQoL of Barrett’s esophagus (BE) has been less well studied. Furthermore, it is unknown to what extent BE patients suffer from psychological distress as a result of carrying a diagnosis of a premalignant condition. We sought to compare BE and GERD (stratified by erosive (ERD) and non-erosive reflux disease (NERD)) with regards to HRQoL and psychological impact.
Methods
In this single-center study of subjects presenting for elective upper endoscopy, consecutive patients with BE and GERD were enrolled. Participants completed questionnaires assessing generic HRQoL (Medical Outcomes Study Short Form-36: SF-36), disease-specific HRQoL (Gastrointestinal Quality of Life Index: GIQLI), a measure of psychological distress (the Revised Hopkins Symptom Checklist: SCL-90R) and a patient-centered assessment of impact of disease severity (the GERD health-related quality of life measure: GERD HRQL).
Results
Patients with BE had the lowest symptom severity compared to those with NERD or ERD (GERD HRQL: 13.7 vs. 18 and 15.9 respectively, p<0.01). Those with BE also had better disease-specific quality of life compared to NERD or ERD patients (GIQLI: 137.2 vs. 124.3 and 131.0 respectively, p<0.001). After adjusting for potential confounding variables including symptom severity and gender, BE patients continued to demonstrate better disease-specific HRQoL, scoring 12.2 points higher on the GIQLI than NERD patients (95% CI 5.1 – 19.3) and 16.3 points higher than ERD patients (95% CI 5.4 – 27.3), as well as better generic HRQoL, scoring 4.8 points higher on the SF-36 physical component summary than NERD patients (95% CI 0.8 – 8.8) and 7.1 points higher than ERD patients (95% CI 1.2–13.1). There were no significant differences between groups in psychological distress, as demonstrated by the SCL-90R global severity index, though BE patients scored lower on the somatization domain compared to NERD and ERD patients. When stratified by gender, females with NERD and BE had worse disease-specific HRQoL than males.
Conclusions
Patients with BE have better generic and disease-specific HRQoL when compared to patients with NERD and ERD. This difference is only partially attributable to lower symptom severity amongst BE patients. Psychological distress did not differ significantly amongst groups. Female gender was associated with worsened HRQoL regardless of GERD disease manifestation. Though more precise instruments may aid in detecting any HRQoL decrements in BE patients due to perceived cancer risk or fear of developing or dying from cancer, we were unable to demonstrate an additional decrement in HRQoL due to cancer risk in subjects with BE.
doi:10.1038/ajg.2009.504
PMCID: PMC3073722  PMID: 19755967
Barrett esophagus; Gastroesophageal reflux; Erosive esophagitis; Non-erosive esophagitis; Quality of Life; Gender
10.  Halimeter ppb Levels as the Predictor of Erosive Gastroesophageal Reflux Disease 
Gut and Liver  2010;4(3):320-325.
Background/Aims
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.5009/gnl.2010.4.3.320
PMCID: PMC2956342  PMID: 20981207
Volatile sulfur compound; H2S; Halitosis; Gastroesophageal reflux disease; Nonerosive gastroesophageal reflux disease; Hiatal hernia; Body mass index
11.  Study of Respiratory Disorders in Endoscopically Negative and Positive Gastroesophageal Reflux Disease 
Background/Aim:
The relation between respiratory disorders and reflux symptoms has been debated since the beginning of the last century and the interest in this question has increased during the last few decades. This study aims to investigate the relation between specified respiratory disorders and reflux symptoms and examine the correlations between respiratory disorders and endoscopic findings in patients with gastroesophageal reflux disease.
Patients and Methods:
This study included 515 patients evaluated for gastroesophageal reflux disease (GERD) by patient self-report symptom questionnaire; modified four grade Likert scale and endoscopic assessment using endoscopic Los Angeles Classification. All participants were asked about various respiratory symptoms experienced during the past six months and exposed to measuring body mass index (BMI), medical history, pulmonary physical examination, chest X-ray, respiratory function tests and available sleep studies.
Results:
A total number of 515 patients were categorized according to endoscopic findings into two groups; (group1) subjects with normal endoscopic studies (NERD) 118 (22.9%) patients and (group2) subjects with abnormal endoscopic studies (ERD) 397 (77.1%). The proportion of females was significantly higher in ERD group (80.1%) as compared with NERD group (62.7%) (P<0.02). Duration of reflux symptoms found to be significantly prolonged in ERD group (P<0.03). The cases of ERD group were more likely to be overweight (BMI > 25) P<0.02. History of pulmonary symptoms preceding GERD symptoms was found in 15% of patients. There were 294 patients (57.1%) with different pulmonary manifestations. These manifestations were significantly higher among female group (P<0.01) and among obese, above 40 years old (P<0.001, 0.05 respectively). Among all patients with respiratory manifestations the commonest disorders diagnosed were chronic pharyngitis (50.3%), chronic bronchitis (15.8%), bronchial asthma (12.6%) and recurrent pneumonia (3.3%). Obstructive sleep apnea and recurrent hemoptysis were present in 2.7% and 1.5% of the studied patients respectively. There were three cases of chronic lung abscess. There was a significant difference between ERD and NERD groups in their relations to respiratory disorders (P<0.001). There were statistically significant differences in FEV1, FVC and FEV1/FVC (P<0.02, P<0.05 and P<0.05) respectively in ERD group as compared with NERD group.
Conclusion:
The study confirms the strong link between gastroesophageal reflux symptoms and various respiratory disorders. Endoscopy of the upper digestive tract remains an important exam in the evaluation of GERD. Respiratory symptoms are more prevalent among erosive esophagitis patients with a positive correlation with degree of severity. There is direct relationship between the severity of airways obstruction as detected by FEV1 and FEV1/FVC and GER symptoms.
doi:10.4103/1319-3767.61233
PMCID: PMC3016511  PMID: 20339176
Gastroesophageal reflux disease; NERD; respiratory symptoms
12.  Controversies in the treatment of gastroesophageal reflux and achalasia 
The immense success of laparoscopic surgery as an effective treatment of gastroesophageal reflux disease (GERD) and achalasia has established minimal invasive surgery as the gold standard for these two conditions with lower morbidity and mortality, shorter hospital stay, faster convalescence, and less postoperative pain. One controversy in the treatment of GERD evolves around laparoscopic antireflux surgery (LARS) as the preferred treatment for Barrett’s esophagus and the procedure’s potential to reduce the risk of adenocarcinoma of the esophagus. GERD has also been associated with respiratory symptoms, asthma and laryngeal injury, and a second controversy prompts discussions about whether total or partial fundoplication is the more appropriate treatment for GERD. A new and promising alternative in the treatment of GERD is endoluminal therapy. Three types of this new treatment option will be discussed: radiofrequency energy delivered to the lower esophageal sphincter, the creation of a mechanical barrier at the gastroesophageal junction, and the direct endoscopic tightening of the lower esophageal sphincter.
Laparoscopic surgery is discussed not only as a very effective treatment for GERD but also as permanent cure for achalasia. This review analyzes the three most important treatment options for achalasia: medications, pneumatic dilatation, and surgical therapy. Medications as the only true non-invasive option in the treatment of achalasia are not as effective as LARS because of their short half-life and variable absorption due to the poor esophageal emptying. The second treatment option, pneumatic dilatation, involves the stretching of the lower esophagus and is still considered the most effective non-surgical treatment for achalasia. Finally, surgical therapy for achalasia and the two major controversies concerning this laparoscopic treatment are discussed. The first involves the extent to which the myotomy is extended onto the stomach, and the second concerns the necessity and type of antireflux procedure to prevent GERD after myotomy.
LARS and laparoscopic Heller myotomy are the agreed upon as the gold standards for surgical treatment of GERD and achalasia, respectively. In the hands of an experienced laparoscopic surgeon both are safe and effective treatments for patients with excellent subjective and objective long-term results with at least 90% patient satisfaction.
doi:10.3748/wjg.v12.i20.3155
PMCID: PMC4087956  PMID: 16718833
Gastroesophageal reflux disease; Nissen; Toupet; Fundoplication; Achalasia; Heller myotomy
13.  Lifestyle factors affecting gastroesophageal reflux disease symptoms: a cross-sectional study of healthy 19864 adults using FSSG scores 
BMC Medicine  2012;10:45.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1741-7015-10-45
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)
14.  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
15.  Atrial fibrillation in patients with gastroesophageal reflux disease: A comprehensive review 
AIM: To analyze the potential relationship between gastroesophageal reflux disease (GERD) and the development of atrial fibrillation (AF).
METHODS: Using the key words “atrial fibrillation and gastroesophageal reflux”, “atrial fibrillation and esophagitis, peptic”, “atrial fibrillation and hernia, hiatal” the PubMed, EMBASE, Cochrane Library, OVIDSP, WILEY databases were screened for relevant publications on GERD and AF in adults between January 1972-December 2013. Studies written in languages other than English or French, studies not performed in humans, reviews, case reports, abstracts, conference presentations, letters to the editor, editorials, comments and opinions were not taken into consideration. Articles treating the subject of radiofrequency ablation of AF and the consecutive development of GERD were also excluded.
RESULTS: Two thousand one hundred sixty-one titles were found of which 8 articles met the inclusion criteria. The presence of AF in patients with GERD was reported to be between 0.62%-14%, higher compared to those without GERD. Epidemiological data provided by these observational studies showed that patients with GERD, especially those with more severe GERD-related symptoms, had an increased risk of developing AF compared with those without GERD, but a causal relationship between GERD and AF could not be established based on these studies. The mechanisms of AF as a consequence of GERD remain largely unknown, with inflammation and vagal stimulation playing a possible role in the development of these disorders. Treatment with proton pomp inhibitors may improve symptoms related to AF and facilitate conversion to sinus rhythm.
CONCLUSION: Although links between AF and GERD exist, large randomized clinical studies are required for a better understanding of the relationship between these two entities.
doi:10.3748/wjg.v20.i28.9592
PMCID: PMC4110594  PMID: 25071357
Gastroesophageal reflux disease; Esophagitis; Atrial fibrillation; Pathophysiology; Proton pump inhibitors
16.  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.
Background
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.
Aim
The aim of this study was to determine which lifestyle factors may be associated with GERD in Japan.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10620-011-1679-x
PMCID: PMC3179841  PMID: 21487772
Gastroesophageal reflux disease (GERD); Japanese; Lifestyle; Gender
17.  Role of E-cadherin in the Pathogenesis of Gastroesophageal Reflux Disease 
OBJECTIVES
An early event in the pathogenesis of gastroesophageal reflux disease (GERD) is an acid-induced increase in junctional (paracellular) permeability in esophageal epithelium (EE). The molecular events that account for this change are unknown. E-cadherin is a junctional protein important in barrier function in EE. Therefore, defects in barrier function in EE were sought in GERD as well as whether their presence correlated with abnormalities in e-cadherin.
METHODS
Endoscopic biopsies of EE from GERD (n = 20; male 10; female 10; mean age 50 ± 10 years) and subjects with a healthy esophagus (controls; n = 23; male 11; female 12; mean age 51 ± 11 years) were evaluated in mini-Ussing chambers and by western blot and immunochemistry; and serum analyzed by enzyme-linked immunosorbent assay (ELISA). A role for e-cadherin was also assessed using a unique conditional knockout of e-cadherin in adult mouse esophagus.
RESULTS
EE from GERD patients had lower electrical resistance and higher fluorescein flux than EE from controls; and the findings in GERD associated with cleavage of e-cadherin. Cleavage of e-cadherin in GERD was documented in EE by the presence of a 35-kDa, C-terminal fragment of the molecule on western blot and by an increase in soluble N-terminal fragments of the molecule in serum. Activation of the membrane metalloproteinase, A Disintegrin And Metalloproteinase (ADAM-10), was identified as a likely cause for cleavage of e-cadherin by western blot and immunostaining and a role for e-cadherin in the increased junctional permeability in EE from GERD supported by showing increased permeability after deletion of e-cadherin in mouse EE.
CONCLUSIONS
The EE in GERD has increased junctional permeability and this is in association with proteolytic cleavage of e-cadherin. As loss of e-cadherin can, alone, account for the increase in junctional permeability, cleavage of e-cadherin likely represents a critical molecular event in the pathogenesis of GERD, and identification of cleaved fragments may, if confirmed in larger studies, be valuable as a biomarker of GERD.
doi:10.1038/ajg.2011.102
PMCID: PMC3568513  PMID: 21448147
18.  Transoral Mucosal Excision Sutured Gastroplasty 
Surgical Innovation  2014;21(5):456-463.
Introduction. An outpatient transoral endoscopic procedure for gastroesophageal reflux disease (GERD) and obesity would be appealing if safe, effective, and durable. We present the first in human experience with a new system. Methods. Eight patients with GERD (3) and obesity (5) were selected according to a preapproved study protocol. All GERD patients had preprocedure manometry and pH monitoring to document GERD as well as quality of life and symptom questionnaires. Obese patients (body mass index >35) underwent a psychological evaluation and tests for comorbidities. Under general anesthesia, a procedure was performed at the gastroesophageal junction including mucosal excision, suturing of the excision beds for apposition, and suture knotting. Results. One patient with micrognathia could not undergo the required preprocedural passage of a 60 F dilator and was excluded. The first 2 GERD patients had incomplete procedures due to instrument malfunction. The subsequent 5 subjects had a successfully completed procedure. Four patients were treated for obesity and had an average excess weight loss of 30.3% at 2-year follow-up. Of these patients, one had an 8-mm outlet at the end of the procedure recognized on video review—a correctable error—and another vomited multiple times postoperatively and loosened the gastroplasty sutures. The treated GERD patient had resolution of reflux-related symptoms and is off all antisecretory medications at 2-year follow-up. Her DeMeester score was 8.9 at 24 months. Conclusion. The initial human clinical experience showed promising results for effective and safe GERD and obesity therapy.
doi:10.1177/1553350613508228
PMCID: PMC4230565  PMID: 24623807
esophageal surgery; flexible endoscopy; gastric surgery; NOTES; interventional endoscopy
19.  GERD assessment including pH metry predicts a high response rate to PPI standard therapy 
BMC Gastroenterology  2013;13:12.
Background
Inadequate response to proton pump inhibitor (PPI) therapy in patients with gastroesophageal reflux disease (GERD) is reported in up to 40%. Patients with non erosive reflux disease (NERD) have lower response rates compared to patients with erosive reflux disease (ERD); pH metry contributes to GERD diagnosis and is critical for proper diagnosis of NERD.
Aim of the study was to assess the need for doubling esomeprazole standard dose (40 mg) for 4 weeks in PPI naive patients with typical reflux symptoms and diagnosis of GERD based on endoscopy and 48 hours, wireless pH metry.
Methods
All patients underwent upper GI endoscopy. Symptoms were recorded with a structured questionnaire (RDQ) and acid exposure was determined by 48 hours, wireless pH monitoring (BRAVO). In case of abnormal acid exposure, patients received a short term treatment with esomeprazole 40 mg q.d. for 4 weeks. If symptoms persisted, patients underwent a second pH metry on PPI and the dose was increased to 40 mg b.i.d.
Results
31 consecutive patients with typical reflux symptoms underwent 48 hours pH monitoring. 22 patients (71%) had abnormal acid exposure, 9 patients had normal pH metry (29%). Of the 9 patients with normal pH metry, 2 were found with erosive esophagitis and 7 without endoscopic abnormalities.
24 patients with documented GERD received esomeprazole treatment. 21 patients achieved complete symptom resolution with 40 mg q.d. after 4 weeks (88%). Only 2 patients required doubling the dose of esomeprazole for complete symptom resolution, 1 patient remained with symptoms.
Conclusions
Patients with typical reflux symptoms and abnormal acid exposure have a high response rate to standard dose esomeprazole regardless of whether they have ERD or NERD.
doi:10.1186/1471-230X-13-12
PMCID: PMC3562521  PMID: 23324360
GERD; NERD; PPI; Esomeprazole; Treatment; ph metry; Diagnosis; Therapy
20.  Risk factors for gastroesophageal reflux disease, reflux esophagitis and non-erosive reflux disease among Chinese patients undergoing upper gastrointestinal endoscopic examination 
AIM: To analyze the spectrum and risk factors of gastroesophageal reflux disease (GERD) based on presenting symptoms and endoscopic findings.
METHODS: A cross-sectional survey in a cluster random sample was conducted from November 2004 to June 2005 using a validated Chinese version Reflux Disease Questionnaire (RDQ) and other items recording the demographic characteristics and potential risk factors for GERD. Subjects were defined as having GERD symptoms according to the RDQ score (> 12). All subjects were endoscopied and the definition and severity of erosive esophagitis were evaluated by Los Angeles classification. The statistical analysis was performed with SPSS13.0 programs.
RESULTS: Of 2231 recruited participants, 701 (31.40%) patients were diagnosed as having GERD while 464 (20.80%) patients had objective findings of reflux esophagitis (RE). Of those 464 patients, only 291 (13.00%) were reported as subjects with GERD symptoms. A total of 528 (23.70%) patients were found to have GERD symptoms, including 19.50% patients with grade A or B reflux esophagitis, 0.90% with grade C and 0.40% with grade D. On multivariate analysis, old age, male, moderate working burden, divorced/widowed and strong tea drinking remained as significant independent risk factors for erosive esophagitis. Meanwhile, routine usage of greasy food and constipation were considered as significant independent risk factors for non-erosive reflux disease (NERD).
CONCLUSION: GERD is one of the common GI diseases with a high occurrence rate in China and its main associated factors include sex, anthropometrical variables and sociopsychological characteristics.
doi:10.3748/wjg.v13.45.6009
PMCID: PMC4250882  PMID: 18023091
Gastroesophageal reflux disease; Reflux esophagitis; Non-erosive reflux disease; Prevalence; Risk factors; Endoscopy
21.  Impact of self-reported Gastroesophageal reflux disease in subjects from COPDGene cohort 
Respiratory Research  2014;15(1):62.
Background
The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.
Methods
Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.
Results
GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p < 0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p < 0.0001), and poorer quality of life (QOL) scores (St. George’s Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p < 0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.
Conclusions
In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.
doi:10.1186/1465-9921-15-62
PMCID: PMC4049804  PMID: 24894541
COPD; Gastroesophageal reflux; Comorbidity; Exacerbations; Quality-of-life; Chronic bronchitis
22.  Recent advances in oesophageal diseases 
Abstract
Dong Y, Qi B, Feng XY, Jiang CM. Meta-analysis of Barrett's esophagus in China. World J Gastroenterol 2013;19(46):8770-8779
The disease pattern of Barrett's esophagus (BE) in China is poorly characterised particularly in comparison with other developed countries. This meta-analysis of 3873 cases of BE collated from 69 clinical studies conducted in 25 provinces between 2000 and 2011 investigated the epidemiology and characteristics of BE in China compared to Western countries. The total endoscopic detection rate of BE was 1.0% (95%CI: 0.1%-1.8%) with an average patient age of 49.07 ± 5.09 years, lower than many Western countries.The authors postulate this may be attributed to environmental risk factor variation, distinct genetics and different medical practice including diagnostic criteria for BE and expertise in endoscopy. This study identified a 1.781 male predominancefor BE in China, consistent with Western reports. Short-segment BE accounted for 80.3% of cases with island type and cardiac type the most common endoscopic (44.8%) and histological (40.0%) manifestations respectively. Of the 1283 BE cases followed up for three to 36 months the incidence of esophageal cancer was 1.418 per 1000 person-years, lower than the incidence reported in Western countries.
Lee HS, Jeon SW. Barrett esophagus in Asia: same disease with different pattern. ClinEndosc 2014;47(1):15-22
Barrett's esophagus (BE) is a common, pre-cancerous condition characterised by intestinal metaplasia of squamous esophageal epithelium usually attributed to chronic gastric acid exposure. This review article explores important differences in the disease pattern of BE between Asian and the Western countries.
Overall the prevalence of BE is lower in Asia compared to the West with a greater proportion of short-segment type. The authors identify great variability in the endoscopic and pathologic diagnostic criteria for BE. Many of the studies in Asian countries did not use a standardised four-quadrant biopsy protocol which may have led to an underestimation of BE prevalence. The review highlights an increasing incidence of esophageal adenocarcinoma in the West but unclear disease trend in Asia with inter-country variability. Similarly in Asian and Western countries BE is associated with the presence of hiatus hernia, advancing age, male gender, alcohol consumption, smoking, abdominal obesity and longer duration of gastro-esophageal reflux disease. The authors postulate that Helicobacter pylori infection, more prevalent in Asia than the West, may have a protective effect on BE.
There is a need for larger, prospective studies to further clarify the disease pattern of BE in Asian countries. Clearly standardisation of the diagnostic process for BE is important to validate the differences in disease trends between Asian and Western countries.
Kiadaliri AA. Gender and social disparities in esophagus cancer incidence in Iran, 2003-2009: a time trend province-level study.Asian Pac J Cancer Prev 2014;15(2):623-7
Esophageal cancer (EC) is a major cause of morbidity and mortality particuarly in Iran where the incidence rate exceeds the global average. An understanding of the factors influencing the province-specific incidence of EC in Iran is important to inform disease-prevention strategies and address health inequalities. This ecological study used cancer registry data to investigate the relationship between gender and social class and the incidence of EC in Iran at province-level between 2003 and 2009. The age standardised incidence rates (ASIR) of EC were greatest in the Northern provinces of Iran, specifically Razavi Khorasan in males and Kordestan in females. Overall the EC incidence did not significantly differ according to gender.
Interestingly, during the study period the ASIR increased by 4.6% per year in females (p=0.08) and 6.5% per year in males (p=0.02). This may reflect increasing rates of establised risk factors for EC including obsesity and gastro-esophageal reflux disease alongside more vigilant recording of new cases. Social class was inversely associated with the ASIR of EC regardless of gender which may be attributed to class differences in risk factor distribution particularly smoking, diet and obesity. An appreciation for the limitations of an epidemiological study is important when interpreting results which should be further evaluated in future studies.
Islami F et al.Determinants of gastroesophageal reflux disease, including hookah smoking and opium use- A cross-sectional analysis of 50,000 individuals. PLoS One 2014;9(2):e89256
Gastroesophageal reflux disease (GERD) is a highly prevalent cause of gastrointestinal symptoms worldwide incurring great cost to the primary and secondary healthcare sectors. An improved understanding of the factors which influence GERD symptoms in low- to medium- income countries may inform public health initiatives. This study analysed prospective data from the Golestan cohort study, primarily established to investigate determinants of upper gastrointestinal cancers, toexplore the risk factors influencing GERD symptoms (regurgitation and/or heartburn) in 50,045 individuals aged 40-75 years in Golestan Province, Iran enrolled between 01/2004 and 06/2008.Of note, 39.12% of individuals denied ever experiencing GERD symptoms. A further 19.89% reported at least once weekly GERD symptoms with 11.83% experiencing daily symptoms. Severe symptoms, defined as disturbing daily work or sleep, were recorded by 11.33% of individuals.
Separately the occurrence of daily GERD symptoms and severe symptoms were inversely associated with male gender (OR 0.36, 95% CI 0.33-0.39 both), level of formal education (p=0.01 and p=0.001 respectively), wealth score (p<0.001 both) and regular nass chewing (OR 0.86, 95% CI 0.75-0.98 and OR 0.87, 95% CI 0.76-0.99 respectively)and were positively associated with body mass index (p<0.001 both), intensity of physical activity (p=0.04 both), cigarette pack years (p<0.001 both), alcohol consumption (OR 1.36, 95% CI 1.13-1.64 and OR 1.53, 95% CI 1.28-1.83 respectively) and opium use (OR 1.82, 95% CI 1.67-1.99 and OR 1.70, 95% CI 1.55-1.87 respectively).In addition hookah smoking had a borderline significant correlation with mild and moderate severity GERD symptoms in individuals who had never smoked cigarettes (OR 1.41, 95% CI 1.00-1.99 and OR 1.25, 95% CI 0.99-1.57 respectively).
Overall this large study contributes useful data to inform the prevention and management of GERD symptoms particularly regarding the use of hookah, opium and nass which was previously unclear.
Barbera M et al. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut 2014;0:1–9. doi:10.1136/gutjnl-2013-306171
Current knowledge on human esophageal tissue homeostasis and injury repair is derived predominantly from murine models and hence may be inaccurate due to cellular and architectural differences. This study used 3D imaging in conjunction withstaining for cell lineage markers to investigate the cellular mechanisms involved in homeostasis of the normal human squamous esophagus in 10 participants undergoing esophagectomy for esophageal cancer. The self-renewal potential of cell subpopulations was also assessed using in vitro and in vivo assays.
A decreasing gradient of cell proliferation was observed from the inter-papillary basal layer to the tip of the papilla where there was no evidence of mitosis. The expression ofβ1-integrin, a putative stem cell marker, was consistent throughout the basal layer and therefore the entire basal layer can be considered undifferentiated. Quiescent β1-integrin/CD34-positive cells which failed to stain for CD45, S-100 or F4-80were identified at the tip of the papilla suggesting this is an extension of the basal layer. Contrary to previous data, this study found progenitor cells widely distributed in human esophageal tissue and included already differentiated epithelial cells. This insight into esophageal homeostasis may inform future studies exploring the pathological mechanisms underpinning homeostatic disruption in disease states such as Barrett's esophagus.
Papers were prepared by:
Drs Ishfaq Ahmad and Luke Materacki, Department of Medicine, Alexandra Hospital, Redditch, UK
PMCID: PMC4129572  PMID: 25120902
23.  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.
doi:10.3748/wjg.14.5712
PMCID: PMC2748207  PMID: 18837089
Reflux esophagitis; Non-erosive gastroesophageal reflux diseases; Electron microscopy; Questionnaire
24.  Association Between Gastroesophageal Reflux Disease After Pneumatic Balloon Dilatation and Clinical Course in Patients With Achalasia 
Background/Aims
The occurrence of gastroesophageal reflux disease (GERD) is known to be associated with lower post-treatment lower esophageal sphincter pressure in patients with achalasia. This study aimed to elucidate whether GERD after pneumatic balloon dilatation (PD) has a prognostic role and to investigate how the clinical course of GERD is.
Methods
A total of 79 consecutive patients who were first diagnosed with primary achalasia and underwent PD as an initial treatment were included in this retrospective study. Single PD was performed using a 3.0 cm balloon. The patients were divided into two groups: 1) who developed GERD after PD (GERD group) and 2) who did not develop GERD after PD (non-GERD group). GERD was defined as pathological acid exposure, reflux esophagitis or typical reflux symptoms.
Results
Twenty one patients (26.6%) developed GERD after PD during follow-up. There were no significant differences between the two groups in demographic or clinical factors including pre- and post-treatment manometric results. All patients in GERD group were well responsive to maintenance proton pump inhibitor therapy including on demand therapy or did not require maintenance. During a median follow-up of 17.8 months (interquartile range, 7.1–42.7 months), achalasia recurred in 15 patients (19.0%). However, the incidence of recurrence did not differ according to the occurrence of GERD after PD.
Conclusions
GERD often occurs after even a single PD for achalasia. However, GERD after PD is well responsive to PPI therapy. Our data suggest that GERD after PD during follow-up does not appear to have a prognostic role.
doi:10.5056/jnm.2014.20.2.212
PMCID: PMC4015191  PMID: 24840373
Esophageal achalasia; Gastroesophageal reflux; Pneumatic balloon dilatation; Prognosis
25.  Clinical epidemiology and natural history of gastroesophageal reflux disease. 
In the MUSE classification of gastroesophageal reflux disease (GERD), esophagitis is assessed by the presence of metaplasia, ulcer, stricture, or erosion, each being graded as absent, mild or severe. Daily reflux symptoms affect about 4 to 7 percent of the population; erosive esophagitis occurs in about 2 percent; the prevalence rate of Barrett's metaplasia is 0.4 percent; and esophageal adenocarcinoma leads to two deaths per million living population. In persons with GERD symptoms, about 20 percent are found to have erosive esophagitis, while ulcers or strictures are found in less than 5 percent of all patients with erosive esophagitis. No clear-cut temporal progression exists between successive grades of disease severity, as the most severe grade of GERD is reached at the onset of the disease. Mild forms of GERD tend to be more common in women than men, while severe GERD characterized by erosive esophagitis, esophageal ulcer, stricture or Barrett's metaplasia are far more common in men than women. All forms of GERD affect Caucasians more often than African Americans or Native Americans. The prevalence of GERD is high among developed countries in North America and Europe and relatively low in developing countries in Africa and Asia. During the past three decades, hospital discharges and mortality rates of gastric cancer, gastric ulcer and duodenal ulcer have declined, while those of esophageal adenocarcinoma and GERD have markedly risen. These opposing time trends suggest that corpus gastritis secondary to Helicobacter pylori infection protects against GERD. This hypothesis is consistent with the geographic and ethnic distributions of GERD. Case-control studies also indicate that cases with erosive esophagitis are less likely to harbor active or chronic corpus gastritis than controls without esophagitis.
PMCID: PMC2579001  PMID: 10780569

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