Non-erosive Reflux Disease Patients Research Articles

Diagnostic Utility of Impedance-pH Monitoring in Refractory Non-erosive Reflux Disease.

Background/AimsApproximately one-third of non-erosive reflux disease (NERD) patients are refractory to proton pump inhibitors (PPI) and face a therapeutic challenge. Therefore, it is important to differentiate between pathological and non-pathological reflux utilizing multichannel intraluminal impedance-pH (MII-pH) to analyze symptom-reflux association and diagnose true NERD versus hyper-sensitive esophagus (HE) and functional heartburn (FH). Herein, we evaluated the diagnostic yield of MII-pH in refractory NERD and sub-classified it based on quantity and quality of acid/non-acid reflux and reflux-symptom association.MethodsSixty symptomatic NERD patients on twice daily PPI for > 2 months were prospectively evaluated by MII-pH. Distal and proximal refluxes, bolus exposure time (BET), esophageal acid exposure time, symptom index (SI) and symptom association probability (SAP) were measured.ResultsThirty-two (53%) patients had BET > 1.4% (MII-pH positive-true NERD), while 28 (47%) had BET < 1.4% (MII-pH negative NERD) where SI and SAP were negative in 15/60 (25%; categorized as FH) and SI or SAP were positive in 13/60 (22%; identified as HE). Thirty-eight (63%) patients reported significant SI or SAP parameters where > 80% of symptoms were associated with non-acid reflux. The number of distal refluxes in true NERD versus FH or HE were significantly different, but not between FH and HE.ConclusionsApproximately 60% of refractory PPI NERD patients had positive reflux-symptom association, primarily due to non-acid reflux. Nearly half of NERD patients on PPI had normal MII-pH monitoring, sub-divided further into FH and HE equally.

Randomized controlled trial comparing the efficacy of mosapride plus omeprazole combination therapy to omeprazole monotherapy in gastroesophageal reflux disease.

We investigated whether the prokinetic activity of mosapride, a 5-hydroxytryptamine 4 receptor agonist, in combination with proton pump inhibitor (PPI) would ameliorate symptoms of gastroesophageal reflux disease (GERD) in Japanese patients. Patients who experienced reflux symptoms more than twice weekly were eligible for this study. In all, 60 patients were randomized to receive mosapride 5 mg thrice daily combined with omeprazole 10 mg once daily (GO group), or omeprazole alone (O group) for 4 weeks. The patients completed the frequency scale for the symptoms of GERD (FSSG) at the beginning and the end of the study. The primary outcome compared changes in the FSSG reflux-related symptom (RS) score between treatment groups during the study period. The FSSG RS scores significantly decreased both in the GO group and the O group, with no differences in improvement between the groups (-5.86 for the GO group vs -4.89 for the O group, P = 0.49). In non-erosive reflux disease (NERD) patients the improvement was significantly lower than that in erosive GERD patients (-4.00 vs -7.67, P = 0.02). However, the addition of mosapride was effective in subgroup analyses of specific symptoms, such as burping. Combining mosapride with PPI provided no additional amelioration of reflux symptoms compared to PPI alone. Both regimens provided less relief from reflux symptoms in NERD than in erosive GERD patients. The addition of mosapride ameliorated reflux in patients with symptoms like burping.

Nonmedical therapeutic strategies for nonerosive reflux disease.

There has been a marked decline over the last several years in drug development for gastroesophageal reflux disease and specifically for nonerosive reflux disease (NERD), despite there being many areas of unmet need. In contrast, we have seen a proliferation, during the same period of time, in development of novel, nonmedical therapeutic strategies for NERD using cutting-edge technology. Presently, compliance and lifestyle modifications are readily available noninvasive therapeutic interventions for NERD. Other nonmedical therapies include, the Stretta procedure, transoral incisionless fundoplication, and the magnetic sphincter augmentation device (LINX). Antireflux surgery, in experienced hands, has been repeatedly shown to be efficacious in resolving NERD-related symptoms. Psychological therapeutic interventions and alternative medicine techniques, such as acupuncture, continue to show promise, especially in NERD patients who failed antireflux treatment.

Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito.

BackgroundThe incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT.MethodsTwo hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups.ResultsThere were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain.ConclusionsRKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals).Trial registration(UMIN000005880)

More severe upper gastrointestinal symptoms associated with non-erosive reflux disease than with erosive gastroesophageal reflux disease during maintenance proton pump inhibitor therapy.

During maintenance proton pump inhibitor (PPI) therapy, patients with gastroesophageal reflux disease (GERD) sometimes complain of upper gastrointestinal symptoms. To evaluate upper gastrointestinal symptoms in patients on maintenance PPI therapy for erosive GERD or non-erosive reflux disease (NERD) without endoscopic mucosal breaks by using a new questionnaire. At Gunma University Hospital over a 12-month period during 2011-2012, we enrolled 30 consecutive patients with erosive GERD and 46 patients with NERD. All patients had been on maintenance PPI therapy for more than 1year. We used the modified frequency scale for the symptoms of GERD (mFSSG) questionnaire to assess upper gastrointestinal symptoms. We also asked patients about their satisfaction with maintenance therapy and whether they wished to change their current PPI. The NERD patients had significantly higher symptom scores than the erosive GERD patients. There was no difference in the treatment satisfaction rate between patients with erosive GERD and NERD, but more patients with NERD wanted to change their PPI therapy. There was no difference in the mFSSG score between NERD patients who wished to change their current PPI therapy and those who were satisfied with it. During maintenance PPI therapy, upper gastrointestinal symptoms were more severe in NERD patients than in patients with erosive GERD. NERD patients often wished to change their PPI therapy, but this was not dependent on the severity of their upper GI symptoms.

Tu1797 The Adoptive Transfer of Anxiety and Gut Dysfunction From IBS Patients to Axenic Mice Through Microbiota Transplantation

Studies of the effect of esophageal sensory stimulation on brain functional connectivity using magnetic resonance imaging (fc-MRI) requires insertion of perfusion or balloon catheters. The contribution of the presence of these catheters themselves on observed brain connectivity changes has not been systematically studied. Aim: To determine the effect of the presence of a catheter within the esophagus on a priori selected regional brain connectivity in healthy and patient volunteers. Methods: In 14 controls (7 female, age 27±4 years) and 12 nonerosive reflux disease (NERD) patients (6 female, age 46±5 years), fc-MRI data of amygdala connectivity to the rest of the brain were gathered during two 9-minute scans, one scan without transnasal esophageal intubation and one scan with esophageal intubation. Functional connectivity was quantified by the correlation coefficient (CC) between average fcMRI time series (seeds) in two spherical volumes centered in each of the right and left amygdala and time series of all fc-MRI volume elements (voxels) across the entire brain. The amygdala seeds were centered at the locations identified by the MNI atlas. Group analysis was performed using unpaired t-tests (with cluster size Monte Carlo simulation to correct for multiple comparison) of correlation coefficients to test amygdala-cortical connectivity differences across NERD patients and healthy subjects. Results: Amygdala connectivity was characterized by strong connections to the right and left superior temporal gyrus. The presence of esophageal catheter in the healthy controls resulted in significant differences in both left and right amygdala connectivity to the left superior temporal gyrus (Figure 1, p<0.001, corrected). No significant catheter effect was observed in the NERD patients. Presence of the catheter also effected the between group comparisons showing significant differences in amygdala connectivity. In the resting state without the catheter present, significant differences in both right and left amygdala connectivity to the right superior temporal gyrus were seen between the two groups (p<0,001, corrected). In the presence of catheter, significant differences were limited to the right amygdala connectivity to the right superior temporal gyrus (p<0,001, corrected). Conclusions: Pharyngo-esophageal stimulation by the presence of a catheter alters the functional connectivity of the amygdala in healthy controls. This response is absent in NERD patients which may represent a state of pre-existing maximum neural activity and associated BOLD signal alterations (ceiling effect). Furthermore, the presence of an esophageal catheter can affect the findings of comparative analyses between groups. This possibility needs to be taken into account when interpreting resting and non-resting state connectivity data involving esophageal stimulation.

Tu1088 Distal and Proximal Esophageal Impedance Basal Values in Patients With Non-Erosive Reflux Disease and Functional Heartburn

Background and aim: Several studies have shown that proximal extent of reflux episodes plays an important role in gastro-esophageal reflux symptom perception. The relative hypersensitivity of the proximal esophagus is most evident in patients with non-erosive reflux disease (NERD). Recent studies demonstrated that low distal basal impedance values may reflect impaired mucosal integrity and increased acid sensitivity. The aim was to compare distal and proximal basal impedance values in patients with NERD and functional heartburn (FH). Methods: According to impedance and pH (MII-pH) monitoring off-therapy, we selected patients with NERD (i.e. pathological acid exposure time, AET) and FH (i.e. normal AET and reflux number; negative symptom association). FH patients did not show any symptom relief after acid suppression therapy. For each patient, we evaluated basal impedance values at the distal (3 cm) and proximal (17 cm) channel, during the overnight rest, at three different times: 1, 2, 3 am. Results: Male/female ratio was 23/23 in NERD and 13/33 in FH patients. Mean age was 52.3±13.2 in NERD and 49.2±11.3 in FH. Mean AET was higher in NERD (6.1%±3.8%) than in FH (0.6%±0.7%) (p<0.05). NERD group recorded higher total reflux number (67.8±18.2) than FH group (23.7±9.4) (p<0.05). Basal impedance values were significantly (p<0.05) lower in NERD than in FH, both at the distal (1294.3±529.9 Ohm vs 3502.1±809.2 Ohm) and proximal (3480.7 ±1322.6 Ohm vs 4344.9±976.2 Ohm) channels. Distal basal values were significantly lower than proximal basal values, both in NERD and FH group (p<0.05). Moreover, in NERD group, 24/46 patients (52.2%) had an abnormal number of proximal refluxes. These NERD patients with pathological proximal refluxes did not show lower basal impedance values than NERD patients with normal number of proximal refluxes even if distal (1226.7±453 vs 1243.1±497.1; P=0.5239) or proximal channels (2670.8±1163.4 vs 2849.2±1434.2; p=0.5046) were compared. Summary and conclusion: Patients with NERD showed lower basal impedance values both at the distal and proximal esophagus. Consistently with the concept that low basal impedance may reflect impaired mucosal integrity, our results might be helpful to better investigate the pathophysiological role of proximal refluxes.

Tu1089 Evaluation of Sleep Disruptions by Means of Impedance-pH Monitoring in Patients With NERD

Background and aim: Several studies have shown that proximal extent of reflux episodes plays an important role in gastro-esophageal reflux symptom perception. The relative hypersensitivity of the proximal esophagus is most evident in patients with non-erosive reflux disease (NERD). Recent studies demonstrated that low distal basal impedance values may reflect impaired mucosal integrity and increased acid sensitivity. The aim was to compare distal and proximal basal impedance values in patients with NERD and functional heartburn (FH). Methods: According to impedance and pH (MII-pH) monitoring off-therapy, we selected patients with NERD (i.e. pathological acid exposure time, AET) and FH (i.e. normal AET and reflux number; negative symptom association). FH patients did not show any symptom relief after acid suppression therapy. For each patient, we evaluated basal impedance values at the distal (3 cm) and proximal (17 cm) channel, during the overnight rest, at three different times: 1, 2, 3 am. Results: Male/female ratio was 23/23 in NERD and 13/33 in FH patients. Mean age was 52.3±13.2 in NERD and 49.2±11.3 in FH. Mean AET was higher in NERD (6.1%±3.8%) than in FH (0.6%±0.7%) (p<0.05). NERD group recorded higher total reflux number (67.8±18.2) than FH group (23.7±9.4) (p<0.05). Basal impedance values were significantly (p<0.05) lower in NERD than in FH, both at the distal (1294.3±529.9 Ohm vs 3502.1±809.2 Ohm) and proximal (3480.7 ±1322.6 Ohm vs 4344.9±976.2 Ohm) channels. Distal basal values were significantly lower than proximal basal values, both in NERD and FH group (p<0.05). Moreover, in NERD group, 24/46 patients (52.2%) had an abnormal number of proximal refluxes. These NERD patients with pathological proximal refluxes did not show lower basal impedance values than NERD patients with normal number of proximal refluxes even if distal (1226.7±453 vs 1243.1±497.1; P=0.5239) or proximal channels (2670.8±1163.4 vs 2849.2±1434.2; p=0.5046) were compared. Summary and conclusion: Patients with NERD showed lower basal impedance values both at the distal and proximal esophagus. Consistently with the concept that low basal impedance may reflect impaired mucosal integrity, our results might be helpful to better investigate the pathophysiological role of proximal refluxes.

664 Newly Developed Bioelectrical Admittance Measurement Distinguishes Patients With Non-Erosive Reflux Disease From Those With Functional Heartburn

Background & Aims: Almost 70% of patients complaining of heartburn have no macroscopic evidence of esophageal mucosal damage, and are termed as having either non-erosive reflux disease (NERD) or functional heartburn (FH). Microscopic esophagitis (ME) is common in patients with NERD, and the succeeding changes of dilation of intercellular spaces (DIS) has been regarded as the potential main mechanism of symptom generation. It has been reported that edema and inflammation as well as DIS in the tissue are related to the decreasing electrical impedance. The aim of this study was to validate our newly developed bioelectrical admittance method (BAM) as a measure of admittance (numerically equal to the reciprocal of the impedance) of esophageal wall and investigate the differences in bioelectrical admittance between NERD and FH patients. Methods: The BAM was performed at the distal esophagus during upper endoscopy in consecutive 25 patients with heartburn. In each patient, three specimens were taken from the same lesion where the BAM was performed. The histological alterations and gene expression levels of mediators of inflammation and tight junction proteins such as claudin1, claudin4, ZO-1 and occludin were evaluated, and DIS was also evaluated by an electron microscope. The correlation between bioelectrical admittance and tissue resistance measured by an Ussing chamber was investigated for 5 subjects. All patients were prescribed double doses of proton pump inhibitor (PPI) for 2 weeks, and after that patients were divided into 2 groups: good response to PPI (Group A) and poor response to PPI (Group B). Results: There were17 patients in the Group A and 18 patients in the Group B. Symptom severity of heartburn was not significantly different between the two groups. The histopathological findings showed that the prevalence of ME was significantly higher (p<0.05) in the Group A (65%) than in the Group B (10%). DIS also showed similar rates of prevalence. There were differences in expression levels of tight junction proteins between the two groups. Furthermore, patients in the Group A were characterized by the increase in the mRNA expression level of TNFα. There was a significant negative correlation between bioelectrical admittance and tissue resistance evaluated by an Ussing chamber (p<0.05). Patients in the Group A displayed significant higher bioelectrical admittance than those in the Group B (p<0.05), and a significant association between the severity of lowgrade inflammation and the extent of increased bioelectrical admittance of esophageal wall (r=0.45, p<0.05). Conclusions: The BAM is a new method to evaluate esophageal mucosal integrity during upper endoscopy. The low-grade inflammation on esophageal mucosa and electrical conductivity are good clinical markers for the assessment of the responsiveness to PPI in patients with heartburn.

Tu1794 Differences in Amygdala Functional Connectivity Between Erosive (ERD) and Non-Erosive Reflux Disease (NERD) Patients During Esophageal Acid Exposure

Tu1794 Differences in Amygdala Functional Connectivity Between Erosive (ERD) and Non-Erosive Reflux Disease (NERD) Patients During Esophageal Acid Exposure

Sa1093 Clinical Characteristics of Elderly Patients With PPI-Refractory NERD From the G-PRIDE Study Who Responded to Rikkunshito

Background/Aim: One of the features of gastroesophageal reflux disease (GERD) in Japan is that its frequency and severity tend to increase in elderly women. In addition, elderly patients (≥65 years) with non-erosive reflux disease (NERD) present with typical symptoms more frequently than do non-elderly patients with NERD. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and enhances gastric emptying and improves gastric accommodation. Our previous prospective randomized multicenter placebo-controlled study, the G-GRIDE study, showed that RKT combined with a standard-dose of rabeprazole (RPZ) therapy significantly improved the acid-related dysmotility (ARD) symptoms in elderly patients with PPI-refractory NERD. The aim of this study was to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. Methods: Two hundred forty-two patients with PPI-refractory NERD were enrolled from August 2011 to July 2012 at 71 hospitals in Japan. Patients were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) plus rikkunshito (7.5 g/t.i.d.) (RKT group) or RPZ plus placebo (PL group) therapy. Of the 242 patients, 95 were elderly patients (≥65 years) with ARD (RKT group: n=52, PL group: n=43). We analyzed the changes using the 12 subscale score of the frequency scale for the symptoms of GERD (FSSG) at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. Results: No significant differences were seen between the 2 groups in terms of subject background. The FSSG score (mean±SD; at 0, 4, and 8 weeks) in both the RKT [16.0±7.0; 9.9±8.4; 7.0±6.4] and PL [15.1±6.4; 10.9±6.7, 11.1±8.5] groups significantly decreased after the treatment. However, the degree of improvement of total and ARD scores of FSSG after 8 weeks of treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach after meals, and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. Conclusion: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. RKT was especially effective for resolving postprandial GERD symptoms (heavy feeling in stomach after meals, sick feeling after meals, and heartburn after meals).

A randomized prospective study comparing the efficacy of on-demand therapy versus continuous therapy for 6 months for long-term maintenance with omeprazole 20 mg in patients with gastroesophageal reflux disease in Japan

Aim. To assess the efficacy of continuous therapy (cont) and on-demand therapy (on-demand) as maintenance therapy for gastroesophageal reflux disease (GERD). Methods. Patients with upper GI endoscopy (EGD)-proven GERD who completed 8 weeks of initial therapy were randomized to cont (omeprazole 20 mg od) or on-demand (omeprazole 20 mg on-demand) group. Assessments by the Global Overall Symptom (GOS) scale at baseline (at the start of maintenance therapy) and at 8-week, 16–week, and 24-week visits were made and EGD was performed at 24 weeks. Symptom relief was defined as percentages of patients whose GOS score of 1 or 2. Results. Of the 117 enrolled patients, cont/on-demand was 59/58 and nonerosive reflux disease (NERD)/reflux esophagitis (RE) before the initial therapy was 35/82. Symptom relief in cont/on-demand were 57.6%/48.3% at baseline (n.s.), 66.7%/54.7% at 8 week (n.s.), 64.6%/54.7% at 16 weeks (n.s.), and 66.7%/74.0% at 24 weeks (n.s.). When subjects were divided into NERD and RE, symptom relief in cont/on-demand were 33.3%/41.2% at baseline (n.s.), 43.8%/64.3% at 8 weeks (n.s.), 50.0%/42.9% at 16 weeks (n.s.), and 50.0%/69.2% at 24 weeks (n.s.) in NERD, while those were 68.3%/51.2% at baseline (n.s.), 76.3%/51.3% at 8 weeks (p < 0.05), 70.6%/59.0% at 16 weeks (n.s.), and 72.7%/75.7% at 24 weeks (n.s.) in RE, respectively. At 24-week EGD, all patients in NERD remained as NERD but number of healed patients was significantly higher in cont (85.3%) than in on-demand (44.4%) (p < 0.01) in RE. Conclusions. Since NERD is defined by symptoms, as a result of the limited efficacy of continuous therapy, on-demand therapy would be sufficient as maintenance therapy in NERD patients. Regarding RE, continuous therapy would be recommended in terms of reduced symptoms and maintaining mucosal healing.

Effect of mosapride combined with esomeprazole in non-erosive reflux disease patients

Effect of mosapride combined with esomeprazole in non-erosive reflux disease patients

The Role of Gastroesophageal Reflux in Relation to Symptom Onset in Patients with Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease Accompanied by an Underlying Esophageal Motor Disorder

Background: The symptom improvement rate is low with proton pump inhibitors (PPIs) in nonerosive reflux disease (NERD). The underlying pathogenic mechanism is complex. Esophageal motility disorders (EMDs) are thought to be a factor, but their prevalence, type, symptoms and the role played by gastroesophageal reflux (GER) in symptom onset have not been fully investigated. Aim: To investigate the role of GER in symptom onset in PPI-refractory NERD patients with EMDs. Methods: This study comprised 76 patients with PPI-refractory NERD. Manometry was performed during PPI treatment and patients were divided into an EMD group and normal motility (non-EMD) group. Then, multichannel intraluminal impedance-pH monitoring was performed and medical interviews were conducted. Results: Nineteen patients (25%) had an EMD. Data were compared between 17 patients, excluding 2 with achalasia and 57 non-EMD patients. No significant differences were observed between groups in 24-hour intraesophageal pH <4 holding time (HT), mean number of GER episodes or mean number of proximal reflux episodes. The reflux-related symptom index (≥50%) showed a relationship between reflux and symptoms in 70.5% of EMD patients and 75% of non-EMD patients. In the EMD group, the score for FSSG (Frequency Scale for the Symptoms of GERD) question (Q)10 was significantly correlated with the number of GER episodes (r = 0.58, p = 0.02) and the number of proximal reflux episodes (r = 0.63, p = 0.02). In addition, the score for Q9 tended to be correlated with the number of GER episodes (r = 0.44, p = 0.06). Conclusion: Our results suggest that some PPI-refractory NERD patients have EMDs, and that GER plays a role in symptom onset.

Not All Patients With Non-erosive Reflux Disease Share Psychological Distress as Main Mechanism of Disease

TO THE EDITOR: We read with interest the study by Nam et al, 1 who evaluated the association between irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD) and concluded that IBS is strongly linked to non-erosive reflux disease (NERD) and not with erosive esophagitis. The authors stated that the association between IBS and NERD is due to the fact that both disorders share psychological distress, such as somatization and anxiety. However, we believe that it is deceiving to refer all patients with NERD to a unique pathogenetic mechanism represented by psychological distress. This population with typical reflux symptoms represents about 70% of GERD patients and it is simplistic to diagnose them exclusively on the basis of negative endoscopy, as Nam et al 1 have done. We have shown that NERD patients are an heterogeneous group from a pathophysiological point of view. 2 The use of pH-impedance testing allows us to identify 3 distinct subpopulations of NERD 3-6 : the first with excess acid in esophagus, the second with normal acid, but an esophagus hypersensitive to acid or non-acid or both, the third without any kind of reflux underlying symptoms. This last subgroup is called functional heartburn (FH) and must be excluded from the realm of GERD, as already acknowledged by the experts of Rome III criteria for esophageal functional disorders. We have also demonstrated that FH is significantly associated with dyspeptic symptoms pertaining to the postprandial distress syndrome, 3 thus supporting also the fact that they are likely to be combined with IBS. 7 Therefore, the analysis of the Nam et al. did not take into any consideration the pathophysiological complexity of NERD and this reduces substantially the strength of their conclusions. Moreover, Nam et al assessed also patients with atypical symptoms supposed to be due to reflux (hoarseness, chronic cough), but there was no mention of the methods they used in correlating them to reflux disease. It is well known that the relationship of causality between reflux and extraesophageal symptoms is a controversial issue. 8,9

Association between the length of peristaltic break of esophageal body and the severity of the symptoms in patients with non-erosive reflux disease and negative pH monitoring

Objective To explore the correlation between the length of peristaltic break (LPB) and the severity of the symptoms in patients with non-erosive reflux disease (NERD) and negative pH monitoring.Methods A total of 35 patients with NERD and negative pH monitoring were enrolled,and at same time 10 healthy individuals were selected as controls.The LPB of esophageal body of both groups was measured by high resolution manometry (HRM).Meanwhile,the symptom of NERD patients with negative pH monitoring was scored.The LPB of esophageal body between the two groups was compared by t test.The correlation between the LPB and the severity of the symptoms in NERD patients with negative pH monitoring was analyzed by Pearson correlation analysis.Results The average LPB of esophageal body of NERD patients with negative pH monitoring was (3.3±0.9)cm,which was longer than that of healthy controls ((1.2 ± 0.4) cm),and the difference was statistically significant (t=9.17,P＜0.01).The symptom score of NERD patients with negative pH monitoring was 21.6± 7.8.There was a positive correlation between the LPB and NERD symptom score (r=0.894,P＜ 0.01).Conclusion The LPB of esophageal body is a kind of expression of esophageal motility dysfunction,which is correlated with the symptom of NERD. Key words: Hydrogen-ion concentration; Gastroesophageal reflux; Manometry; Peristalsis

Weak Peristalsis With Large Breaks Is Associated With Higher Acid Exposure and Delayed Reflux Clearance in the Supine Position in GERD Patients

Ineffective esophageal motility is frequently observed in gastroesophageal reflux disease (GERD) patients but its clinical relevance remains controversial. In healthy subjects and in patients with nonobstructive dysphagia, it has been demonstrated, by means of high-resolution manometry (HRM), that long breaks of esophageal peristalsis predict delayed bolus clearance. HRM and 24-h multichannel impedance-pH (MI-pH) monitoring were performed in 40 GERD patients with no evidence of hiatal hernia. Total bolus clearing time (BCT) in upright and supine position and acid exposure time (AET) were calculated. Of the 40 patients, 23 showed a pathological AET and 15 erosive reflux disease (ERD). Patients with a pathological number of large breaks were characterized by a significantly lower BCT value in the supine position and higher AET. In all, 10/15 ERD patients (67%) and 5/25 nonerosive reflux disease patients (20%) were characterized by an abnormal number of small or large breaks (P<0.05). ERD patients were characterized by significantly higher AET and BCT in the supine position. GERD patients with a pathological number of large breaks, assessed by HRM, are characterized by a significantly prolonged reflux clearance in the supine position and higher AET. ERD patients display a higher number of esophageal breaks that might explain the development of erosions.

Effect of nortriptyline on brain responses to painful esophageal acid infusion in patients with non‐erosive reflux disease

Non-erosive reflux disease (NERD) patients generally present with heartburn as the main symptom. Antidepressants might help to relieve heartburn by acting on the esophagus-brain axis. We aimed to assess the effect of nortriptyline on behavioral and brain responses to painful esophageal acid infusion in NERD patients evaluated with functional magnetic resonance imaging (fMRI). In a randomized double-blind crossover design, 20 NERD patients off proton pump inhibitors (36.1±9.3years, 75% women) were assigned to 21days of nortriptyline and placebo, in counterbalanced order, with a 21days washout period in between both treatment periods. Changes in acid-induced brain response on fMRI and heartburn perception were assessed and at the end of each treatment. Nortriptyline significantly reduced the acid-induced brain response in prefrontal cortex (median [IQR]: -1.9 [-4.5 to -0.1] vs -0.3 [-2.5 to 2.3]; p=0.050), caudate (-3.0 [-5.1 to -0.01] vs 0.48 [-1.9 to 3.1]; p=0.029), insula (-2.4 [-4.8 to -0.6] vs -0.2 [-1.5 to 1.5]; p=0.029), cingulate (-4.2 [-8.8 to -0.1] vs -0.6 [-1.8 to 3.0]; p=0.017), and hippocampus (-2.7 [-6.0 to 0.5] vs -0.04 [-2.3 to 1.9]; p=0.006) in comparison with placebo. However, there was no significant difference between nortriptyline and placebo in clinical outcomes and side effects. Nortriptyline decreased the brain response to esophageal acid infusion more markedly than placebo, but without clinical significance.

Role of Ultrastructural Alterations of Intercellular Junction and Tight-junction Proteins in Patients With Gastroesophageal Reflux Disease

TO THE EDITOR: I read with great interest the study by Liu et al 1 regarding the significant correlation between presence of desmosomal junction alterations and the severity of gastroesophageal reflux disease (GERD). The authors reported that tight-junction proteins (TJP) such as claudin-1 and claudin-2 were abundant not only in asymptomatic controls but also in patients with gastroesophageal reflux disease and, a significant intercellular space (ICS) dilatation occurred only in upper stratified squamous epithelium of patients with moderate erosive esophagitis, while there was no difference in ICS dilatation of lower basal cuboidal epithelium among different groups of patients with GERD and controls. Furthermore, this study revealed that alterations in desmosomal junctions and their processes under transmission electron microscopy increased in parallel with the severity of GERD. Esohageal mucosal ICS were frequently seen with nonerosive reflux disease (NERD) and patients with esophagitis. 2 In addition, dilatation of intercellular spaces was an early marker of damage caused by gastroesophageal reflux, and treatment of proton pump inhibitor led to a complete recovery of dilated intercellular spaces in 97.4%. 3 Although the authors showed an important results of ultrastructural alterations of esophageal mucosa in patients with GERD, there were a few limitations most of which had been discussed in this paper. First, in contrast to this study, previous studies demonstrated that dilated ICS was associated with NERD and erosive GERD. For instance, Caviglia et al 4 reported that mean ICS diameter in NERD patients was 3 times greater than in controls. Moreover, Zhong et al 5 reported that reflux esophagitis (RE) patients showed wider ICS (1.29 μm [1.10-1.46 μm], n = 6) than NERD patients (1.10 μm [0.95-1.21 μm], n = 16) and controls (1.01 μm [0.94-1.17 μm], n = 12). Differences in the study population and definition of GERD severity may contribute to this discrepancy. In this study, authors defined mild RE in case of Los Angeles classification A (LA-A) esophagitis and moderate RE in case of LA-B esohagitis, but there were no patients with LA-C or LA-D eosphagitis. However, Zhong et al 5 classified LA-A/B into mild RE and LA-C/D into severe RE. I wonder whether the severe GERD patients including LA-C/D may have influence on the results or not, but there was no explanation regarding this matter in the discussion. Second, the authors showed that there were no differences in the presence of claudin-1 and claudin-2 expression among patients with GERD, NERD and controls. However, previous study revealed that claudin-1 expression in RE and NERD patients were significantly higher than in the control. Moreover, expression of occludin tended to be lower in the RE patients and the expression of claudin-3 tended to be higher in the RE and NERD patients, however, none of these were statistically significant. 3 These findings suggested the role of several other TJP including several types of claudins, occludins and junctional adhesion molecules, as authors have mentioned in the discussion. Despite these limitations of the present study, it provides us with the important information in the ultrastructural alterations of ICS and TJP in the inflamed esophageal mucosa. Further studies are needed to validate the results of the present study.

Commentary: biopsy to diagnose GERD - better, but not yet a stand-alone test

Empiric medical therapy with a proton pump inhibitor (PPI) is recommended in patients with typical heartburn. These patients are presumed to have gastro-oesophageal reflux disease (GERD). However, the sensitivity and specificity of the history and PPI response to diagnose GERD are mediocre.1, 2 As such, many with continued heartburn require a diagnostic work up that typically includes endoscopy and pH or impedance-pH studies, to differentiate refractory GERD3 from functional heartburn (FH). Routine biopsies of the distal oesophagus to diagnose GERD are not recommended by the recent ACG guidelines.4 Kandulski et al. report a well-designed, prospective study examining the potential for biopsy to distinguish non-erosive reflux disease (NERD) from FH in these refractory patients.5 Endoscopy and impedance-pH study were used as the gold standard tests for NERD and FH. Refractory heartburn (RH), NERD, FH and control groups were clearly defined. Confirmatory tests were carried out off PPI. The pathologist was blinded to other results. Statistical analyses were robust and included correction for multiple comparisons. A semi-quantitative score of 0–3 (absent to severe) for basal cell hyperplasia, papillary elongation and dilated intercellular spaces was given by the pathologist. These scores, individually and collectively, were significantly different between NERD and FH patients (Pm <0.05). A score of ≥5 had 85% sensitivity and 64% specificity to distinguish NERD from FH. The results of this study are encouraging, offering new insights into the potential for oesophageal biopsy to help with diagnosis in these difficult patients. However, the sensitivity and specificity needs substantial improvement and the scoring system requires validation before the results would allow us to recommend routine biopsy. Most importantly, an expert pathologist is needed, particularly to make an accurate assessment of dilated intracellular spaces. At this time, patients with RH still require pH or impedance-pH study after a normal endoscopy to confirm the diagnosis of NERD or FH. Declaration of personal and funding interests: None.