Non-erosive Reflux Disease Patients Research Articles

Acid reflux episodes sensitize the esophagus to perception of weakly acidic and mixed reflux in non‐erosive reflux disease patients

Non-erosive reflux disease (NERD) patients are more sensitive than erosive esophagitis patients to weakly acidic reflux and to the presence of gas in the refluxate. Intra-esophageal acid perfusion sensitizes esophageal receptors to mechanical and chemical stimuli. To establish whether acid sensitization plays a role in the perception of weakly acidic and mixed reflux episodes, 29 NERD patients, responders and 14 non-responders to proton pump inhibitors (PPIs), underwent pH-impedance monitoring. Non-responders repeated the study while on PPIs. To assess the effect of acid exposure on symptom perception, the time period with pH below 4 was measured in 15- and 30-minute time-windows preceding the onset of each reflux episode. Considering weakly acidic and mixed refluxes, both in responder and non-responder patients (off PPIs), the symptomatic refluxes were preceded by a significantly higher cumulative acid exposure than the asymptomatic refluxes. In all patients, following acid reflux, the percentage of symptomatic weakly acidic reflux episodes was significantly higher than that of asymptomatic refluxes. Non-responder patients, off-treatment, were characterized by a lower proportion of weakly acidic reflux and mixed reflux episodes. In the non-responder patients on PPI, only mixed and weakly symptomatic reflux episodes were preceded by a higher cumulative acid exposure. In NERD patients, spontaneous acid reflux enhances subsequent reflux perception, regardless of acidity or liquid/mixed composition of episodes; in non-responder patients on PPIs, only the perception of mixed and weakly acidic reflux episodes seems to be mediated by a preceding acid exposure.

In vivo Evaluation of Micro Alterations in Patients with Erosive Esophagitis and Non-erosive Reflux Disease (NERD) Using Probe-based Confocal Endomicroscopy (pCLE)

Purpose: In the U.S., up to 60% of patients suffer with GERD. Unfortunately, the “gold standard” for the diagnosis of gastroesophageal reflux disease (GERD) is still lacking, and the sensitivity of 24-hour pH monitoring for diagnosing NERD is unsatisfactory. Recent technological advances make the evaluation of the integrity of esophageal mucosa possible. Previous studies using confocal endoscope have demonstrated esophageal mucosal breaks and interpappilary loops (IPCLs) in patients with gastroesophageal reflux disease. pCLE is a newly developed endoscopic technique that allows the observation of living cells, tissue as well as vascular networks of the mucosal layer in the gastrointestinal tract during ongoing endoscopy. The highly magnified images (1 micron resolution) of the gastrointestinal tract mucosa can permit real-time histological analysis of the site during endoscopy. Therefore, pCLE can provide precise assessment of the esophageal squamous epithelial cells and IPCLs without the need of biopsy. We investigated the use of pCLE for in vivo evaluation of the micro alterations of the esophagus not observed by standard endoscopy in patients with NERD. Methods: A total of 19 patients with long standing reflux undergoing standard high definition upper endoscopy to evaluate for esophagitis. Eleven patients were diagnosed with NERD by the absence of endoscopic mucosal breaks. At the time of endoscopy 2.5 cc of 10% fluorescein was injected. The confocal probe was placed and optical biopsies obtained within 2 cm above the gastroesophageal junction (GEJ). Histologic specimens were also randomly obtained within 2 cm of GEJ. Transmission Electron Microscopy was performed in seven patients. The endomicroscopy images were interpreted by two experienced endoscopists. Results: See Table 1- Demographics, Table 2-Endomicroscopic Findings.Table. DemographicsConclusion: This is the first pilot study examining the utility of probe based confocal endomicrosocpy in the setting of NERD. The intercellular spaces and IPCL size were found to be largest in esophagitis group. They are also larger in NERD patients in comparison to the normal patients. pCLE could potentially provide an in vivo diagnosis via “optical biopsy.” It may be useful for evaluating microalterations of the esophagus in real time and assist the diagnosis of NERD. It could also be used as a marker to demonstrate therapeutic response for tissue healing in NERD patient and define the abnormalities at the microscopic level during endoscopy in pH negative and proton pump inhibitor unresponsive patients. Further prospective study with a larger cohort is warranted.Table: Table. Endomicroscopic Findings

Obesity Does Not Affect Treatment Outcomes With Proton Pump Inhibitors

Obesity is associated with increased risk of gastroesophageal reflux disease (GERD). To evaluate the effect of obesity on symptom resolution in patients with nonerosive reflux disease (NERD) and healing rates in patients with erosive esophagitis (EE). Two post hoc analyses were performed. Analyses included pooled data from randomized, double-blind, multicenter studies of proton pump inhibitors (PPIs) in GERD patients. Analysis 1 included 704 patients with NERD receiving esomeprazole 20 mg, esomeprazole 40 mg, or placebo. Analysis 2 included 11,027 patients with EE receiving esomeprazole 40 mg, omeprazole 20 mg, or lansoprazole 30 mg. For NERD patients, no significant association between baseline heartburn severity and body mass index (BMI) was observed. In EE patients, overweight (BMI 25 to <35 kg/m) and obese (BMI ≥35 kg/m) patients had significantly higher rates of Los Angeles (LA) grade C or D EE than patients with BMI <25 kg/m (P<0.0001). Percentages of PPI-treated patients who achieved heartburn resolution or EE healing within a given LA grade were similar across BMI categories. Heartburn resolution was significantly associated with treatment (esomeprazole vs. placebo), increasing age, and for men versus women (all P≤0.0284). EE healing was significantly associated with PPI treatment (esomeprazole and lansoprazole vs. omeprazole), increasing age, race, presence of a hiatal hernia, and lower LA grade at baseline (all P≤0.0183). In patients with GERD, high BMI was associated with more severe EE at baseline. However, during PPI treatment, BMI is not a significant independent predictor of heartburn resolution or EE healing.

The efficacy, safety and cost‐effectiveness of hydrotalcite versus esomeprazole in on‐demand therapy of NERD: A multicenter, randomized, open‐label study in China

The aim of the study was to investigate whether hydrotalcite was comparable to esomeprazole, a proton pump inhibitor, in on-demand therapy for non-erosive reflux disease (NERD). This was a multicenter, randomized, open-label clinical trial with initial and on-demand therapy. Patients who had complete symptom relief in the initial therapy were randomized to either hydrotalcite or esomeprazole in the on-demand therapy. The percentage of patients who quit on-demand therapy in the two groups and the cost-effectiveness of the treatment were evaluated as primary end points. The rate of symptom relief and the improvement of symptom score for initial therapy and the weekly average symptom score and weekly average number of days on treatment for on-demand therapy were evaluated as secondary end points. In total, 398 patients were recruited in the initial therapy group, among whom 253 were included in on-demand therapy, with 127 patients in the hydrotalcite group and the remaining 126 in the esomeprazole group. 14 (11.0%) patients in the hydrotalcite group and six (4.8%) in the esomeprazole group quit the on-demand therapy due to unsatisfactory symptom control (P = 0.065). Cost-effectiveness calculated as the ratio of the cost of hydrotalcite to that of esomeprazole (per person/day) was 35.3% in the on-demand therapy. Similar number of patients achieved symptom relief in both groups. Hydrotalcite is a good option of on-demand therapy for NERD patients due to its cost-effectiveness and speed of action.

Response to Ottonello et al.: Non-erosive reflux disease patients are more complex than the sole endoscopy tells us

Response to Ottonello et al.: Non-erosive reflux disease patients are more complex than the sole endoscopy tells us

Non-erosive reflux disease patients are more complex than the sole endoscopy tells us

Non-erosive reflux disease patients are more complex than the sole endoscopy tells us

Association of Sleep Dysfunction and Emotional Status With Gastroesophageal Reflux Disease in Korea

Background/AimsSleep disturbances and emotional dysfunction are commonly associated with gastroeophageal reflux disease (GERD). The aims of this study were to evaluate GERD symptoms and disturbance in erosive reflux disease (ERD) and nonerosive reflux disease (NERD) patients, and to compare sleep dysfunction, depressive mood, anxiety and quality of life (QOL) among the control, ERD and NERD patients in Korea.MethodsThe Korean subjects were enrolled between 2010 and 2012, classified into 3 groups; the control group with no symptom and normal endoscopic findings, the ERD group with erosive esophagitis and the NERD group with more than one episode of heartburn or acid regurgitation per week, positive response to proton pump inhibitor, and normal endoscopic findings. Questionnaire included GERD symptoms, GERD impact scale (GIS) and daytime pathological sleepiness (Epworth sleepiness scale), sleep dysfunction (Pittsburgh sleep quality index, PSQI), depression and anxiety (Hospital anxiety and depression scale, HADS) and QOL (WHO quality of life scale abbreviated version, WHOQOL-BREF).ResultsA total of 217 subjects were enrolled as follows; control (n = 70), ERD (n = 70) and NERD (n = 77). Impact of symptom of GIS score was higher in the NERD (9.2 ± 0.4) than in the ERD (6.5 ± 0.3) group (P < 0.001). Sleep dysfunctions were more frequent in GERD than the control group (PSQI score [P = 0.021]). Anxiety subscale of HAD score was higher in NERD (7.0 ± 0.5, P = 0.002) and ERD (6.2 ± 0.7, P = 0.004) groups than control (4.3 ± 0.7) group. WHOQOL-BREF scores in NERD (54.9 ± 2.3) and ERD (57.8 ± 2.4) groups were significantly lower than those in the control group (63.8 ± 2.4) (P = 0.002; P = 0.014, respectively). ConclusionsThe patients with NERD than ERD suffered more from the symptoms and disturbance in Korea. Sleep dysfunction and anxiety mood were higher and QOL was decreased in GERD, especially in NERD, suggesting that those factors might affect the severity of NERD.

Visceral Hypersensitivity in Non-erosive Reflux Disease: Neurogenic Overwhelming in Esophagus?

The mechanism underlying the pathogenesis of heartburn and chest pain in gastro-esophageal reflux disease (GERD) has not been clearly established. An important advance in understanding how heartburn is experienced has been accomplished with the reporting of dilated intracellular spaces (DIS) in the esophageal mucosa of patients with erosive GERD and non-erosive reflux disease (NERD) [1]. Although the presence of DIS provides a theoretical pathway for direct entry of hydrogen ions into the mucosa [2], its relationship to esophageal barrier function is still controversial since there are no direct measurements of esophageal acid permeability in vivo to support its contribution to barrier function. Another important breakthrough is the detection of transient receptor potential vanilloid subfamily member-1 receptors (TRPV1) in the esophageal mucosa [3], which may potentially contribute to visceral hypersensitivity as one of the important mechanisms in patients with NERD [4]. This notion is supported by the observation that perception of heartburn and esophageal sensitization can be induced by TRPV1 activation after the exposure to capsaicin and related TRPV1 activators such as heat and acid [5]. TRPV1 activation has also been hypothesized to induce neurogenic inflammation by the release of substance P and calcitonin-gene-related peptide (CGRP) in primary afferent neurons [6]. These neuropeptides mediate nociception and neurogenic inflammation via neurokinin 1 receptor (NK1R) for substance P and receptor activity-modifying protein 1 (RAMP1) for CGRP [7–9]. Therefore, the upregulation of TRPV1 expression in the esophageal mucosa is likely explanation for the phenomenon of visceral sensitization in NERD. Moreover, an induction of proteinase-activated receptor-2 (PAR-2) expression was reported in the esophageal mucosa of GERD patients, which correlated well with mucosal inflammatory changes and elevated tissue interleukin (IL)-8 concentrations, providing a possible mechanism for proinflammatory changes in GERD [10]. Furthermore, PAR-2 also mediates nociception via the release of substance P [11]. Finally, although anion-sensing ion channels (ASICs) have been implicated in the chemosensitivity in primary afferent fibers [12], its clinical implication is yet unclear in GERD and is thought to be more likely referred to the mechanosensitivity of the esophagus. In this issue of Digestive Diseases and Sciences [13], Yoshida et al. test the hypothesis regarding the role of nociceptors and neuropeptides in the pathogenesis of visceral hypersensitivity of NERD by examining the expression of acid-sensitive nociceptors including TRPV1, ASIC3, PAR-2, and neuropeptides such as substance P and CGRP with their cognate receptors NK1R and RAMP1 in the esophageal mucosa of NERD patients as compared with age-matched healthy controls. Not surprisingly, increased mRNA expression for TRPV1 and PAR-2 was present in the esophageal mucosa of NERD patients accompanied by a similar increase in substance P protein level and mRNA of its receptor NK1R. They also reported the presence of substance P-positive and CGRP-positive nerves in lamina propria of the esophageal mucosa of their patients by immunohistochemistry. They reported a positive correlation between substance P protein level and acid reflux score. Their data suggest that visceral hypersensitivity in NERD patients appears to be related to nociception and neurogenic inflammation, which supports their hypothesis C.-L. Chen (&) Department of Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan e-mail: harry.clchen@msa.hinet.net

PTU-163 Proximal Oesophageal Functional Mucosal Integrity during Distal Oesophageal Acidification in Patients with Nerd and FH

IntroductionAlthough macroscopically normal, the oesophageal mucosa in patients with non-erosive reflux disease (NERD) displays epithelial dilated intercellular spaces (DIS). Such loss of barrier integrity is thought to be important in...

Su2107 Resting State Functional Connectivity of Thalamus With the Cingulate and Insula Are Different in Nonerosive Reflux Disease (NERD) Patients Compared to Healthy Subjects

Su2107 Resting State Functional Connectivity of Thalamus With the Cingulate and Insula Are Different in Nonerosive Reflux Disease (NERD) Patients Compared to Healthy Subjects

Histology of symptomatic gastroesophageal reflux disease: Is it predictive of response to proton pump inhibitors?

To examine the differences in esophageal histopathology between non-erosive reflux disease (NERD) and reflux esophagitis (RE), and to investigate whether baseline esophageal histopathology can predict the therapeutic response to proton pump inhibitors (PPIs). The subjects comprised 94 patients with NERD (n = 71) or mild RE (n = 23). Tissue was biopsied from 5 cm above the squamo-columnar junction (SCJ), and the degree or presence of nine histopathological markers was assessed. The patients were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. If complete heartburn relief was not achieved, RPZ was increased to 10 mg twice daily for another 2 weeks, and then to 20 mg twice daily for another 2 weeks if heartburn remained. Features of esophageal histopathology 5 cm above the SCJ differed between NERD and RE patients. The esophageal histopathology in patients unresponsive to RPZ was characterized by Protein Gene Product (PGP) 9.5 negativity in those with NERD, and intraepithelial bleeding in those with RE. In addition, the combination of dilated intercellular spaces (DIS) (+)/PGP 9.5 (-) was indicative of strong resistance to PPI therapy in NERD patients. The therapeutic efficacy of PPI can be predicted from the features of biopsied esophageal tissue. Factors predictive of resistance to treatment with PPI are negativity for PGP 9.5 in NERD patients and intraepithelial bleeding in RE patients.

Answers to “The esophageal acid exposure still plays a major role in patients with NERD” by Dr. Savarino

Dear editor, We are very pleased and appreciate to Dr. Savarino’s great interest in our paper published on Journal of Gastroenterology [1]. We studied the comments carefully and answered as follows: Concerning about the sub-grouping of non-erosive reflux disease (NERD) patients, we did take into account of the esophageal acid exposure time (AET) data. In our article, we showed the scatter plot of AET and baseline impedance regarding all subjects, and we came up with the conclusion that baseline impedance is negatively correlated with AET. On the other hand, reflux episodes have normal reference values for each type of reflux event, which can be easily used to group NERD patients [2], while AET only focuses on acid reflux severity and is less powerful to differentiate other types of reflux. Based on our data, different reflux episodes may also represent different severities of acid exposure (or AET). Furthermore, to specify how episodes represent acid exposure, we find that in our NERD subgroups, mean AET increases across the spectrum of mild to severe acid reflux episodes (weakly alkaline reflux group: 0.5 %; weakly acidic reflux group: 3 %; mixed reflux group: 7 %; and acid reflux group: 16 %). Additionally, the percentage of patients with positive AET in each subgroup also increases across the spectrum. Besides, in our NERD patients, acid reflux episodes show a positive correlation with AET (r = 0.63, p 0.001). Taken together, we believe the way that using reflux episodes to divide NERD subgroups is able to differentiate the extent of acid, weakly acid and weakly alkaline compared with just considering AET. As described on the paper, most of the enrolled GERD were first-visit patients. For those patients who had received PPI therapy, we required one week off the medication. We assume that high number of patients with abnormal weakly acidic reflux events might be the feature of NERD population. Finally, transmission electron microscopy (TEM) is still considered as the golden standard for DIS diagnosis now. We have had read some publications on this issue and are very glad to learn that updated research as a support for the light microscopy (LM) measurement method.

Laparoscopic anti-reflux surgery to treat proton pump inhibitor-resistant non-erosive reflux disease

We performed surgery for proton pump inhibitor-resistant non-erosive reflux disease patients whose symptom index, confirmed by combined multichannel intraluminal impedance–pH monitoring, was positive. Laparoscopic Nissen fundoplication was performed in five patients and laparoscopic Toupet fundoplication in 3 patients. In 6 of 8 patients, non-acid or minor acid reflux caused the symptoms. Satisfaction percentages assessed 1 year postoperatively were 12.5 % (excellent) and 87.5 % (good).The number of total reflux events decreased to 28.5 ± 14.4 % postoperatively. The symptom index decreased from 63.8 to 20.8 %. It is controversial whether the surgery reduces weakly acidic reflux to the same degree as acid reflux. Previous reports discuss the effect of laparoscopic Nissen fundoplication on acid and weakly acidic reflux; however, the results of these studies are contradictory. In our cases, laparoscopic Toupet fundoplication as well as Nissen fundoplication improved symptoms, and reduced acid and non-acid reflux similarly. These findings strongly support the importance of surgical intervention in proton pump inhibitor-resistant non-erosive reflux disease patients.

Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain

Objective. Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhibitors (PPIs). Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 (TRPV1) antagonists. Aim.To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients. Material and methods. Enrolled patients had NERD and a partial PPI response (moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks' PPI therapy). Fourteen patients (21–69 years, 9 women) were block-randomized into this placebo-controlled, double-blinded, crossover study examining efficacy of a single dose (95 mg) of AZD1386. On treatment days, each participant's esophagus was stimulated with heat, distension, and electrical current at teaching hospitals in Denmark and Sweden. Heat and pressure pain served as somatic control stimuli. Per protocol results were analyzed. Results. Of 14 randomized patients, 12 were treated with AZD1386. In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [–3%, 95% confidence interval (CI), –22;20%], distension (–11%, 95% CI, –28;10%), or electrical current (6%, 95% CI, –10;25%). Mean cutaneous heat tolerance increased by 4.9°C (95% CI, 3.7;6.2°C). AZD1386 increased the maximum body temperature by a mean of 0.59°C (95% CI, 0.40–0.79°C), normalizing within 4 h. Conclusions.AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response, whereas it increased cutaneous heat tolerance. TRPV1 does not play a major role in heat-, mechanically and electrically evoked esophageal pain in these patients. ClinicalTrials.gov identifier: D9127C00002.

Acid Sensitization of Esophageal Mucosal Afferents

Sensitization of esophageal chemoreceptors, either directly by intermittent acid exposure or indirectly through esophagitis-associated inflammatory mediators, is likely to be the mechanism underlying the perception of heartburn. To compare basal esophageal sensitivity with electrical stimulation and acid, and to compare the degree of acid-induced sensitization in controls and in patient groups across the entire spectrum of gastroesophageal reflux disease: erosive oesophagitis (EO), nonerosive reflux disease (NERD), and functional heartburn (FH). Esophageal sensory and pain thresholds to electrical stimulation were measured before, 30, and 60 minutes after an intraesophageal infusion of saline or HCl. Patients received a 30-minute infusion of 0.15 M HCl and controls were randomized to receive either HCl (n = 11) or saline (n = 10). After electrical sensory threshold testing, participants received another 30-minute infusion of HCl to determine whether sensitivity to acid is increased by prior acid exposure All patient groups had higher basal sensory thresholds than healthy controls (controls, 13 ± 1.4 mA; FH, 20 ± 5.1 mA; NERD, 21 ± 5.1 mA; EO, 23 ± 5.4 mA; P < 0.05). Acute esophageal acid exposure reduced sensory thresholds to electrical stimulation in FH and NERD patients (P < 0.05). The level of acid sensitivity during the first HCl infusion was comparable between all patient groups and controls. The secondary infusion caused increased discomfort in all participants (P < 0.01). This acid-induced sensitization to HCl was significantly elevated in the patient groups ( P < 0.05). (1) Esophageal acid infusion sensitizes it to subsequent electrical and chemical stimulation. (2) The acid-related sensitization is greater in gastroesophageal reflux disease than in controls and may influence in part symptom perception in this population. (3) Acid-related sensitization within the gastroesophageal reflux disease population is not dependant on mucosal inflammation.

Risk factors for proton pump inhibitor refractoriness in Chinese patients with non-erosive reflux disease

To analyze risk factors for refractoriness to proton pump inhibitors (PPIs) in patients with non-erosive reflux disease (NERD). A total of 256 NERD patients treated with the PPI esomeprazole were enrolled. They were classified into symptom-free and residual symptoms groups according to Quality of Life in Reflux and Dyspepsia (QolRad) scale. All subjects completed questionnaires on psychological status (self-rating anxiety scale; self-rating depression scale) and quality of life scale (Short Form 36). Multivariate analysis was used to determine the predictive factors for PPI responses. According to QolRad, 97 patients were confirmed to have residual reflux symptoms, and the remaining 159 patients were considered symptom free. There were no significant differences between the two groups in lifestyle factors (smoking and alcohol consumption), age, Helicobacter pylori infection, and hiatal hernia. There were significant differences between the two groups in relation to sex, psychological distress including anxiety and depression, body mass index (BMI), and irritable bowel syndrome (IBS) (P < 0.05). Logistic regression analysis found that BMI < 23, comorbid IBS, anxiety, and depression were major risk factors for PPI resistance. Symptomatic patients had a lower quality of life compared with symptom-free patients. Some NERD patients are refractory to PPIs and have lower quality of life. Residual symptoms are associated with psychological distress, intestinal disorders, and low BMI.

Gastroesophageal reflux disease: Update on inflammation and symptom perception

Although gastroesophageal reflux disease (GERD) is a common disorder in Western countries, with a significant impact on quality of life and healthcare costs, the mechanisms involved in the pathogenesis of symptoms remain to be fully elucidated. GERD symptoms and complications may result from a multifactorial mechanism, in which acid and acid-pepsin are the important noxious factors involved. Prolonged contact of the esophageal mucosa with the refluxed content, probably caused by a defective anti-reflux barrier and luminal clearance mechanisms, would appear to be responsible for macroscopically detectable injury to the esophageal squamous epithelium. Receptors on acid-sensitive nerve endings may play a role in nociception and esophageal sensitivity, as suggested in animal models of chronic acid exposure. Meanwhile, specific cytokine and chemokine profiles would appear to underlie the various esophageal phenotypes of GERD, explaining, in part, the genesis of esophagitis in a subset of patients. Despite these findings, which show a significant production of inflammatory mediators and neurotransmitters in the pathogenesis of GERD, the relationship between the hypersensitivity and esophageal inflammation is not clear. Moreover, the large majority of GERD patients (up to 70%) do not develop esophageal erosions, a variant of the condition called non-erosive reflux disease. This summary aims to explore the inflammatory pathway involved in GERD pathogenesis, to better understand the possible distinction between erosive and non-erosive reflux disease patients and to provide new therapeutic approaches.

Investigation of relationships among gastroesophageal reflux disease subtypes using narrow band imaging magnifying endoscopy

To investigate the relationships among subtypes of gastroesophageal reflux disease (GERD) using narrow band imaging (NBI) magnifying endoscopy. 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. 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). 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.

Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease

Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.

How to differentiate non‐erosive reflux disease from functional heartburn

Heartburn is a common symptom in gastroesophageal reflux disease. Endoscopic examination can differentiate between reflux esophagitis and non-erosive reflux disease (NERD), but not between NERD and functional heartburn. With the development of new techniques, more NERD patients could be identified among those previously diagnosed with functional heartburn. Most patients with NERD, however, could be identified based on their clinical characteristics and response to proton pump inhibitors and/or integrated anti-gastroesophageal reflux therapy.