Functional Heartburn Patients Research Articles

Identification of novel immune cell signature in gastroesophageal reflux disease: altered mucosal mast cells and dendritic cell profile.

Heartburn pathogenesis in GERD remains incompletely understood. We aimed to identify differences in the immune cell signature and sensory mucosal markers between reflux phenotypes and healthy asymptomatic subjects. Thirty-seven patients with heartburn symptoms were phenotyped endoscopically and with objective reflux studies into erosive reflux disease (ERD) (N=10), nonerosive reflux disease (NERD) (N=9), functional heartburn (FH) (N=9), and Barrett's esophagus (BO) (N=9). Bulk mRNA-sequencing(RNA-seq) was conducted on RNA extracted from endoscopic biopsies, and immune cell deconvolution analysis was performed using CIBERSORT. RNA-seq findings were validated by immunofluorescent staining for CD1a, nerve growth factor (NGF), and mast cell tryptase in corresponding patient biopsies. Transcriptomic analysis detected higher mast cell abundance in BO, ERD, and NERD compared to healthy controls (p<0.05), with decreased dendritic cell infiltration in BO, ERD, and NERD patients compared to healthy controls and FH patients. CD1a-positive dendritic cell infiltration was significantly higher in the healthy esophageal mucosa at protein level compared to BO (p=0.0005), ERD (p=0.0004), and FH patients (p=0.0096). Moreover, NGF co-expression on mast cells in GERD patients was significantly higher than in healthy controls (p=0.0094). The mucosa in patients with GERD had a significant increase in NGF expression on mast cells, suggesting an upregulation of signalling for neuronal sprouting in GERD. Moreover, decreased dendritic cell abundance in GERD esophageal mucosa may play a role in reduced oral tolerance and development of subsequent immune responses which may participate in esophageal sensitivity.

Esophageal chemical clearance and mucosa integrity values in refractory gastroesophageal reflux disease patients with different esophageal dynamics

Objectives Esophageal post-reflux swallow-induced peristaltic wave index (PSPWI) and mean nocturnal baseline impedance (MNBI), novel impedance-based markers of reflux burden, are associated with esophageal dynamics. We aim to investigate the characteristics of PSPWI and MNBI in Chinese refractory gastroesophageal reflux disease (RGERD) patients with different esophageal dynamic changes. Materials and methods 201 RGERD and 76 functional heartburn patients, undergone off-PPI endoscopy, esophageal manometry and impedance-pH monitoring, were included. Comparisons of conventional and novel impedance-pH metrics were made among different esophageal dynamics groups. Receiver operating-characteristic analyses were utilized to evaluate the diagnostic efficacy of PSPWI and MNBI in differentiating abnormal esophageal dynamics. Correlations were used to investigate their associated factors. Results PSPWI and MNBI of RGERD with esophagogastric junction (EGJ) injury and esophageal dysmotility were lower than EGJ injury alone or normal dynamics (p < 0.05 for both comparisons). PSPWI with esophageal peristalsis abnormality was lower than EGJ injury (p = 0.049), while MNBI showed no statistical difference. PSPWI, MNBI and their combination have auxiliary diagnostic values for esophageal peristalsis [area under the curves (AUCs): 0.683, 0.656, 0.708)] while only their combination for EGJ injury (AUC: 0.610). And they positively correlated with esophageal motility while negatively correlated with ineffective swallows and acid reflux events. Conclusions PSPWI and MNBI, indicating impairment of esophageal chemical clearance and mucosa integrity, were lower in RGERD patients with multiple esophageal dynamic injuries than single injuries or normal dynamics. Moreover, they provided useful contributing information for potential dynamic injuries if manometry has already been found normal or marginal.

Esophageal manometry findings in patients with refractory symptoms of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder. High-resolution esophageal manometry (HREM) and 24-h pH study help to properly evaluate GERD patients. The aim of the present study was to classify patients with refractory GERD symptoms into various groups based on endoscopic and physiological testing.The present study is a retrospective analysis of patients referred for HREM and 24-h pH recording between 2019 and 2021. We included all adult patients (age > 18 years) who were referred for evaluation of refractory GERD symptoms. Upper gastrointestinal endoscopy findings, HREM, and 24-h pH findings were noted. Patients were divided into erosive reflux disease (ERD), non-erosive reflux disease (NERD), reflux hypersensitivity (RH), and functional heartburn (FH) based on test results. Demographic details and HREM parameters were compared in the four groups. Statistics used are one-way analysis of variance (ANOVA) and Chi-squared tests. A p-value of <0.05 was considered statistically significant.A total of 144 patients were included-NERD (56, 38.9%), ERD (42, 29.2%), RH (28, 19.5%), and FH (18, 12.5%). Age (p 0.74), andsex distribution (p 0.47), and symptom profile (p 0.12) were similar. The presence of type 2/3 esophagogastric junction (EGJ) morphology was commoner in ERD and NERD (p <0.001). Moreover, the esophagogastric junction contractile integral (EGJ-CI) and basal inspiratory pressures were significantly lower in these two groups (p<0.05). EGJ-CI was low in 32 cases of ERD (76.2%), 41 cases with NERD (73.2%), 7 cases with RH (25%), and 3 cases with FH (16.7%), respectively (p-value < 0.00001).FH and RH account for 32% of cases with refractory GERD symptoms. Impaired EGJ function was more common in ERD and NERD patients compared to FH and RH patients.

Recent insights on functional heartburn and reflux hypersensitivity.

Rome IV experts have proposed that gastroesophageal reflux disease (GERD) should be diagnosed only in patients with abnormal esophageal acid exposure, and that reflux hypersensitivity (RH) and functional heartburn (FH) both should be considered functional conditions separate from GERD. Although past and recent evidence support that FH can be completely distinguished from GERD, the concept that RH is not GERD is highly questionable. This review attempts to provide current data on these issues. Many recent investigations have provided new data on the different pathophysiological features characterizing RH and FH. Major differences have emerged from analyses of impedance-pH monitoring studies using the novel impedance metrics of baseline impedance (an index of mucosal integrity) and the rate of postreflux swallow-induced peristaltic waves (a reflection of the integrity of esophageal chemical clearance). The better ability to interpret impedance-pH tracings together with earlier data on the different prevalence of microscopic esophagitis in RH and FH patients, and recent studies documenting poor therapeutic efficacy of pain modulators and good results of antireflux surgery for RH support recategorization of RH within the GERD world. Further research is needed to correctly phenotype patients who have heartburn without mucosal breaks, and to guide their effective management.

Esophageal Nocturnal Baseline Impedance and Post-reflux Swallow-induced Peristaltic Wave Index in Identifying Proton Pump Inhibitor-refractory Non-erosive Reflux Disease.

Background/AimsEsophageal mean nocturnal baseline impedance (MNBI) levels and post-reflux swallow-induced peristaltic wave (PSPW) index could increase the diagnostic value of 24-hour multichannel intraluminal impedance and pH monitoring in patients with gastroesophageal reflux disease. This study aims to compare the MNBI and PSPW index in patients with no evidence of erosive reflux disease.MethodsImpedance-pH monitoring tracings from 70 patients, 50 with non-erosive reflux disease (NERD) and 20 with functional heartburn (FH), were reviewed. According to proton pump inhibitors (PPI) treatment response, NERD patients were divided into NERD/PPI responders and NERD/PPI nonresponders. MNBI, PSPW index, and intercellular spaces were measured and compared among each group.ResultsMNBI values and PSPW index were lower in NERD patients than in FH (P < 0.01 and P < 0.05, respectively). MNBI positively correlated with PSPW index (r = 0.525, P < 0.001). NERD/PPI responders had lower MNBI values and PSPW index compared to NERD/PPI nonresponders (both P < 0.01). MNBI and PSPW index distinguished NERD from FH patients with an area under the curve of 0.914 and 0.677, respectively. Wider intercellular space could be identified in patients with NERD (P < 0.01).ConclusionMNBI and PSPW index may differentiate NERD from FH patients and relate to PPI treatment efficacy in patients with NERD.

Prevalence of behavioral disorders in patients with vonoprazan-refractory reflux symptoms.

Behavioral disorders, such as supragastric belching (SGB) and rumination syndrome (RS), which may be treated by cognitive behavioral therapy, are common in patients with reflux symptoms refractory to proton pump inhibitors (PPI). Vonoprazan (VPZ) has been used as a new type of acid inhibitor in Japan since 2015. We herein investigated the prevalence of behavioral disorders in patients with VPZ-refractory reflux symptoms and attempted to identify predictive factors. We retrospectively analyzed esophagogastroduodenograms, high-resolution manometry, and 24-h multiluminal impedance pH-metry (MIIpH) in patients with VPZ-refractory reflux symptoms (heartburn or regurgitation) receiving 20mg VPZ who underwent these tests at our hospital between January 2015 and April 2020. Patients were divided as follows: non-erosive reflux disease with pathological esophageal acid exposure (NERD), functional heartburn (FH), reflux hypersensitivity (RH), excessive (> 13 per day) SGB, and possible RS based on MIIpH parameters. Among 49 patients, 6 (12.2%) had SGB, 4 (8.2%) possible RS, 29 (59.2%) FH, 9 (18.4%) RH, and 1 (2%) NERD. Possible RS patients had more postprandial non-acid reflux events than FH patients (p < 0.05). The multivariate logistic regression analysis did not identify any predictive factors with statistical significance. More than 20% patients with VPZ-refractory reflux symptoms had behavioral disorders. The use of HRM and MIIpH may be clinically relevant for a better diagnosis and more specific treatment.

High-resolution Manometry Findings During Solid Swallows Correlate With Delayed Reflux Clearance and Acid Exposure Time in Non-erosive Reflux Disease Patients.

Background/AimsThe role of esophageal motility in determining gastroesophageal reflux disease (GERD) severity has not been completely evaluated. A few studies have investigated high-resolution manometry (HRM) patterns during solid swallows. The present study evaluates the HRM patterns of non-erosive reflux disease (NERD) patients during both liquid and solid swallows and their correlation with the severity of GERD.MethodsIn 23 NERD patients and 15 healthy volunteers (HVs) HRM was performed during a standard solid meal in a seated position, followed by 24-hour impedance-pH monitoring.ResultsOf the 31 patients, 10 showed a pathological acid exposure time (AET; NERD patients), 13 a normal pH profile with positive symptom association probability (SAP; reflux hypersensitivity patients), and 8 normal AET and SAP (functional heartburn patients). Mean distal contractile integral and distal latency values, in all patient groups and HVs, were significantly higher during solid swallows. In the group of 10 NERD patients, the number of large breaks of the esophageal peristalsis was 16 out of 100 liquid swallows (16%) and 31 out of 171 solid swallows (18%). Fourteen out of 100 liquid swallows (14%) and 25 out of 171 solid swallows (15%) resulted ineffective. Mean reflux clearing time at multichannel intraluminal impedance-pH was 17.6 ± 3.7 seconds. NERD patients presented, during solid swallows, a significantly higher proportion of large peristaltic breaks and of ineffective swallows than reflux hypersensitivity and functional heartburn patients.ConclusionHRM during solid swallows reveals motor abnormalities, undetected during liquid swallows, which might be involved in delaying reflux and acid clearance in patients with GERD.

Prevalence and clinical characteristics of refractoriness to optimal proton pump inhibitor therapy in non-erosive reflux disease.

The real size of the gastro-oesophageal reflux disease (GERD) population not responding to proton pump inhibitor (PPI) therapy has still not been fully elucidated. Causes of PPI refractoriness include incorrect diagnosis and lack of adherence to therapy, in terms of incorrect dosage and timing. To evaluate the prevalence of refractoriness to optimal PPI therapy and the contribution of non-erosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn, to PPI refractoriness. The association of functional GI symptoms in non-responders was evaluated. Frequency and severity of GERD symptoms (heartburn, regurgitation, chest pain), dysphagia, belching, epigastric pain, postprandial distress, irritable bowel syndrome (IBS), globus, and ear nose and throat (ENT) symptoms were evaluated in patients previously classified as non-responders. Patients with at least one of the oesophageal symptoms with a frequency ≥3 /week were treated with esomeprazole 40mg once daily for 8weeks and then re-evaluated. Non-responders (patients with oesophageal symptoms ≥3 times per week) underwent 24hour multichannel intraluminal impedance-pH monitoring. Of 573 consecutive patients, 92 with oesophageal symptoms and classified as PPI-refractory underwent the esomeprazole trial; 60 did not respond. IBS, epigastric pain, and post-prandial distress episodes were associated with a poor response on multivariate analysis. NERD, reflux hypersensitivity, and functional heartburn patients constituted 32%, 42%, and 26%, respectively of the PPI-refractory group. True refractoriness in patients with GERD symptoms attending a secondary care setting is lower than previously reported. Following a careful history and optimal PPI dosing, the rate of refractoriness was 20%. True NERD constitutes only a third of the PPI-refractory group.

Reclassifying Functional Heartburn Using Impedance pH in Refractory GERD Patients

Introduction: Background: Functional heartburn as a term has changed in meaning over the years. The most recent definition was introduced based upon Rome IV criteria, as typical heartburn symptoms in the presence of normal upper endoscopy findings (including normal biopsies), normal esophageal pH testing, and a negative association between symptoms and reflux events. Functional heartburn is very common, affecting women more than men. The majority of GERD patients respond to 4-8 weeks of proton-pump inhibitors therapy but up to 40% will demonstrate partial or complete lack of response. This defines the refractory group. 24 hr-impedance pH is the current gold standard for diagnosing all GERD types including acid and non-acid reflux. Symptom index is used as an adjunctive diagnostic tool to link symptoms to specific reflex events. Aim: The aim of the study is to review and reclassify functional heartburn patients using impedance pH.2767 Figure 1 No Caption available.Methods: Retrospective chart review of patient who continued to have GERD symptoms despite being on antisecretory therapy. We reviewed impedance pH studies for adult patients (>18 years old) between 2012-2018. Only patients with refractory symptoms were included. Data including esophageal acid exposure, number of reflux episodes (acids and non-acid), symptoms index and upper endoscopy findings (including esophageal biopsies) were collected. The data was reviewed and classified based on reflux events and symptom index. Cut off for abnormal of reflux episodes was 48, counting both acid and nonacid episodes. All patients were studied while on PPI therapy, once or twice a day. Results:Results 166 patients were included, 68% were females, mean age was 51±19 years, and 62% were on once daily PPI dosing.73% had positive symptom index (see figure). Conclusion: Patients with persistent GERD symptoms on PPI therapy represent a heterogenous group. Exclusively using pH esophageal monitoring, such as in the current functional heartburn classification, risks missing patients who's persistent symptoms are due to non-acid reflux.

Relationship Between Salivary Pepsin Concentration and Esophageal Mucosal Integrity in Patients With Gastroesophageal Reflux Disease.

Background/AimsIncreased salivary pepsin could indicate an increase in gastro-esophageal reflux, however, previous studies failed to demonstrate a correlation between salivary pepsin concentrations and 24-hour esophageal acid exposure. This study aims to detect the salivary pepsin and to evaluate the relationship between salivary pepsin concentrations and intercellular spaces (IS) in different gastroesophageal reflux disease phenotypes in patients.MethodsA total of 45 patients and 11 healthy volunteers were included in this study. All subjects underwent upper gastrointestinal endoscopy, 24-hour ambulatory multichannel impedance-pH (MII-pH) monitoring, and salivary sampling at 3-time points during the 24-hour MII-pH monitoring. IS were measured by transmission electron microscopy, and salivary pepsin concentrations were determined by enzyme-linked immunosorbent assay.ResultsThe IS measurements were greater in the esophagitis (EE), non-erosive reflux disease (NERD), and hypersensitive esophagus (HO) groups than in the functional heartburn (FH) and healthy volunteer groups, and significant differences were indicated. Patients with NERD and HO had higher average pepsin concentrations compared with FH patients. A weak correlation was determined between IS and salivary pepsin among patients with NERD (r = 0.669, P = 0.035).ConclusionsWe confirmed the presence of a higher level of salivary pepsin in patients with NERD than in patients with FH. Salivary pepsin concentrations correlated with severity of mucosal integrity impairment in the NERD group. We suggest that in patients with NERD, low levels of salivary pepsin can help identify patients with FH, in addition the higher the pepsin concentration, the more likely the severity of dilated IS.

The Rome IV versus Rome III criteria for heartburn diagnosis: A comparative study.

The phenotypes of heartburn patients are heterogeneous. The objective of this study was to investigate the proportion of heartburn phenotypes in a Chinese population and to compare the Rome IV and III criteria for heartburn diagnosis. A retrospective study was performed among heartburn patients referred for upper endoscopy and esophageal function tests in a tertiary hospital. Their symptoms fulfilled Rome IV and III criteria. A total of 233 patients were included. Fifty-nine patients (25%) were diagnosed with esophagitis, 96 (41%) with non-erosive reflux disease (NERD) and 78 (34%) with functional heartburn (FH) based on Rome III criteria. Approximately 70% of the Rome III NERD patients were changed based on Rome IV criteria, with 36 patients (15%) diagnosed with reflux hypersensitivity (RH) and 32 patients (14%) who didn't fulfill the criteria considered unclassified. The FH and RH patients showed higher esophagogastric junction-contractile integral (EGJ-CI) and less hiatal hernia than did Rome IV NERD patients. The unclassified had more hiatal hernias than the FH and RH (p < 0.05). The EGJ-CI was similar between Rome III NERD and FH cases. The Rome IV criteria were stricter for heartburn diagnosis and superior in distinguishing NERD from functional disorders on motility patterns than Rome III.

Esophageal chemical clearance and baseline impedance values in patients with chronic autoimmune atrophic gastritis and gastro-esophageal reflux disease

BackgroundThe factors influencing new markers of gastro-esophageal reflux disease detected by impedance-pH monitoring – mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index – need to be evaluated. AimTo compare endoscopy-negative heartburn with chronic autoimmune atrophic gastritis (CAAG). Materials and methods24 patients with CAAG, 25 with non-erosive reflux disease (NERD) and 25 with functional heartburn (FH) were included. In all patients the main impedance-pH monitoring parameters were calculated. ResultsCAAG and NERD patients had a number of reflux events (non-acid ones being more common among the former group) which was higher than that found in FH (p<0.001). MNBI decreased progressively in FH (>3000Ohm), CAAG (>2000Ohm) and NERD (<1000Ohm) patients (p=0.0046). The PSPW index was similar between CAAG and NERD patients but significantly lower in comparison to FH (p<0.0001). ConclusionPatients with CAAG have evidence of non-acid reflux based on the high number of reflux events and confirmed by low values of MNBI and PSPW index. MNBI is a strong marker of acid/non-acid reflux-induced mucosal damage, whereas the PSPW index can reliably discriminate patients with reflux from those with FH, independently of the acidity of refluxate.

An analysis of 342 patients with refractory gastroesophageal reflux disease symptoms using questionnaires, high-resolution manometry, and impedance-pH monitoring.

Symptoms of refractory gastroesophageal reflux disease (GERD) are commonly encountered in clinical practice. The aim of this study was to analyze the data obtained from questionnaires, high-resolution manometry (HRM), and ambulatory impedance-pH monitoring in patients with persisting GERD symptoms and to explore the possible underlying causes for this clinical presentation. After completing the questionnaires, the selected patients underwent endoscopy, HRM, and ambulatory impedance-pH monitoring. Based on the results of these investigations, we divided the patients into 4 groups: reflux esophagitis (RE), hypersensitive esophagus (HE), functional heartburn (FH), and nonerosive gastroesophageal reflux disease (NERD). The data from 342 patients were analyzed. One hundred twenty-nine (37.72%) patients experienced refractory GERD symptoms related to acid reflux. The scores on some scales in the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire differed significantly among groups (all P < 0.05). Liquid reflux occurred more frequently in patients with GERD (RE and NERD), while gas reflux was more common in non-GERD patients (FH and HE; all P < 0.05). The RE and NERD groups showed more percent bolus exposure time (BET) when upright (all P < 0.05). Acid exposure time (AET) in the RE and NERD groups was longer than that in the HE and FH groups (all P < 0.05). Fewer than half of the patient symptoms were related to acid reflux. The GSRS questionnaire may be an optimal indicator for patients with refractory GERD symptoms. BET and AET are useful indices to distinguish GERD from other diseases. Gas reflux is probably related to persisting symptoms in FH and HE patients.

Functional Heartburn Overlaps With Irritable Bowel Syndrome More Often than GERD.

We aimed to evaluate the prevalence of irritable bowel syndrome (IBS) in patients with typical reflux symptoms as distinguished into gastroesophageal reflux disease (GERD), hypersensitive esophagus (HE), and functional heartburn (FH) by means of endoscopy and multichannel intraluminal impedance (MII)-pH monitoring. The secondary aim was to detect pathophysiological and clinical differences between different sub-groups of patients with heartburn. Patients underwent a structured interview based on questionnaires for GERD, IBS, anxiety, and depression. Off-therapy upper-gastrointestinal (GI) endoscopy and 24 h MII-pH monitoring were performed in all cases. In patients with IBS, fecal calprotectin was measured and colonoscopy was scheduled for values >100 mg/kg to exclude organic disease. Multivariate logistic regression analysis was performed to identify independent risk factors for FH. Of the 697 consecutive heartburn patients who entered the study, 454 (65%) had reflux-related heartburn (GERD+HE), whereas 243 (35%) had FH. IBS was found in 147/454 (33%) GERD/HE but in 187/243 (77%) FH patients (P<0.001). At multivariate analysis, IBS and anxiety were independent risk factors for FH in comparison with reflux-related heartburn (GERD+HE). IBS overlaps more frequently with FH than with GERD and HE, suggesting common pathways and treatment. HE showed intermediate characteristic between GERD and FH.

About the Diagnosis and Management of Functional Heartburn: Heartburn and Oesophageal Motility Disorders.

To the Editor: We read with interest the clinical and systematic review on diagnosis and management of functional heartburn by Christine Hachem and Nicholas J. Shaheen (1). Authors have done a remarkable job that help readers to enter patients in correct categories of disease, despite the confusing nature of the topic. In a pathophysiological point of view they highlighted how patients with functional heartburn do not have acid-mediated symptoms, differentiating them from those with oesophageal hypersensitivity because of the absence of correlation between reflux events and symptoms. They evoked different mechanism as heightened sensitivity of mechano-receptors and chemoreceptors or alteration of central visceral afferent sensitization. Authors also reported that there is no consensus on the diagnostic criteria for pH-impedance testing in functional heartburn patients and that the value of oesophageal motility testing is similarly unclear, suggesting that the interpretation of these studies is limited. We believe that this is a very interesting point of discussion and, about that, we would add some comments suggested by the lesson learned with bariatric surgery. Some restrictive bariatric procedures such as adjustable gastric banding represent unintentionally an experimental model because of the modification induced in oesophageal motility makes these patients at higher risk for developing oesophageal motility disorders. These abnormalities are frequently related to heartburn and are often reversible after desufflation of the banding but they may be also permanent (2). Sometimes they are similar to those reported for acalasia but can also be minimal and non-specific. Consequently, the oesophago-gastric junction plays as a very sensitive anatomical region and, in a similar manner, we are encouraged to think that FH could be mostly related to a disfunction of the oesophago-gastric junction rather than a psychological disorder. Nevertheless, with actual functional tests, we are not capable of interpreting minimal motility disorders, because of their low sensitivity. Moreover, considering that obese patients are at higher risk for gastroesophageal reflux disease (refs 3, 4) and given the lack of evidence on the impact of lifestyle, body mass index, eating behaviour, and weight loss on FH, it seems a priority to investigate these aspects as possible factors acting in the manifestation of symptoms. On this point of view a large population-based study seems appropriate, with the aims to detect the real incidence of such variables and its correlation with FH, which we believe underestimated. If these factors may be able to cause dysfunction of oesophago-gastric junction is an interesting question to answer.

Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn.

Patients with functional heartburn (FH) experience troublesome heartburn that is not related to gastroesophageal reflux. The etiology of the heartburn sensation in FH patients is unknown. In patients with reflux disease, esophageal hypersensitivity seems associated with impaired mucosal integrity. We aimed to determine esophageal sensitivity and mucosal integrity in FH and non-erosive reflux disease (NERD) patients. In this prospective experimental study, we performed an acid perfusion test and upper endoscopy with biopsies in 12 patients with NERD and nine patients with FH. Mucosal integrity was measured during endoscopy using electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance and transepithelial permeability. Lag time to heartburn perception was significantly longer in FH patients (median 12 min) than in NERD patients (median 3 min). Once perceived, intensity of heartburn was scored equal with median visual analog scale 6.5 and 7.1 respectively. Esophageal mucosal integrity was also comparable between FH and NERD patients, both in vivo extracellular impedance and ex vivo transepithelial resistance and permeability were similar. Patients with FH did not show acid hypersensitivity as seen in patients with NERD. However, once perceived, intensity of heartburn is similar. Esophageal mucosal integrity is similar between NERD and FH patients, and is therefore unlikely to be the underlying cause of the observed difference in esophageal acid perception.

A More In-depth Evaluation of Impedance-pH Could Assist in Distinguishing Reflux-related From Reflux-unrelated Heartburn.

TO THE EDITOR: We read with interest the study by Penagini et al,1 who investigated 50 refractory patients with a diagnosis of functional heartburn (FH) according to Rome III criteria in the first 24 hours of wireless pH monitoring. They described that 15/50 patients had a pathological acid exposure time (AET) after the first day of monitoring, which changed their diagnosis from FH to non-erosive reflux disease (NERD). The authors concluded that more prolonged pH-recording period was able to increase NERD diagnosis in patients wrongly classified as FH patients. We congratulate the authors with their study that underlined one of the main limitation of the 24-hour tests such as impedance pH monitoring, that is the day-to-day variability. However, we would like to stress that with the recent novelties regarding the potential application of 24-hours impedance-pH monitoring, this limitation could be overcome without the need of additional tests, but with a more in depth analysis of impedance tracings. Indeed, impedance-pH has different advantages compared to pH-metry only. First, impedance-pH can recognize patients in whom symptoms are related to non-acid reflux events.2,3 In keeping, providing data on all type of reflux and their association with symptoms, impedance-pH has shown the ability to rule out reflux as the main cause of esophageal symptoms and to refine the current definition of functional heartburn.3 Nevertheless, the limitation related to the day-to-day variability in AET and symptom perception still persists, although reduced, and so far the test may be inaccurate.4 To confirm, in 2 different studies a lack of correlation between the 24-hour monitoring and response to proton pump inhibitor therapy has been observed.5,6 However, recently, novel impedance parameters, manually calculated, evaluating esophageal chemical clearance, the post-re-flux swallow-induced peristaltic wave (PSPW) index, and mucosal integrity, the baseline impedance, have been proposed.7–9 The PSPW index is suitable for valuation off as well as on proton pump inhibitor therapy: lower values have been found in erosive than in NERD, in both significantly lower than in FH.7 Baseline impedance values were found strictly associated with epithelial structural abnormalities and are inversely correlated with AET.10 These impedance features provided promising results in distinguishing patients with reflux disease from those without and seem to be not affected by day-to-day variability and further limitations associated to AET or symptoms perception. In line with these findings, we suggest that a more in-depth evaluation of multichannel intraluminal impedance-pH could assist in distinguishing reflux-related from reflux-unrelated heart-burn. However, further outcome studies are mandatory to confirm their relevance in gastroesophageal reflux disease management.

Esophagogastric junction contractility for clinical assessment in patients with GERD: a real added value?

The role of esophagogastric junction contractile integral (EGJ-CI) as assessed by high-resolution manometry (HRM) is unclear. We aimed to correlate the EGJ-CI with impedance-pH findings in gastro-esophageal reflux disease (GERD) patients. Consecutive patients with GERD symptoms were enrolled. All patients underwent upper endoscopy, HRM, and impedance-pH testing. The EGJ-CI was calculated using the distal contractile integral tool box during three consecutive respiratory cycles. The value was then divided by the duration of these cycles. A value below 13 was considered as a defective EGJ-CI. We also assessed EGJ morphology, esophageal acid exposure time (AET), number of reflux episodes (NRE), and symptom association analysis (SAA). A positive impedance-pH monitoring was considered in case of abnormal AET and/or NRE and/or positive SAA. Among 130 patients we enrolled, 91 had GERD (abnormal AET and/or elevated NRE and/or positive SAA) and 39 had functional heartburn (FH) (negative endoscopy, normal AET, normal NRE, and negative SAA). The GERD patients had a lower median value of EGJ-CI (11 [3.1-20.7] vs 22 [9.9-41], p<0.02) compared to FH patients. Patients with a defective EGJ-CI had, more frequently, a positive impedance-pH monitoring or esophageal mucosal lesions at endoscopy (p<0.05 and p<0.05, respectively) than patients with a normal EGJ-CI. An EGJ-CI cut-off value of 5mmHgcm yielded the optimal performance in identifying GERD at impedance-pH (sensitivity 89%-specificity 63%). A defective EGJ-CI at HRM is clearly associated with evidence of GERD at impedance-pH monitoring. Evaluating EGJ-CI may be useful to predict an abnormal impedance-pH testing.

Inconsistency in the Diagnosis of Functional Heartburn: Usefulness of Prolonged Wireless pH Monitoring in Patients With Proton Pump Inhibitor Refractory Gastroesophageal Reflux Disease.

Background/AimsThe diagnosis of functional heartburn is important for management, however it stands on fragile pH monitoring variables, ie, acid exposure time varies from day to day and symptoms are often few or absent. Aim of this study was to investigate consistency of the diagnosis of functional heartburn in subsequent days using prolonged wireless pH monitoring and its impact on patients’ outcome.MethodsFifty proton pump inhibitotor refractory patients (11 male, 48 years [range, 38–57 years]) with a diagnosis of functional heart-burn according to Rome III in the first 24 hours of wireless pH monitoring were reviewed. pH variables were analysed in the following 24-hour periods to determine if tracings were indicative of diagnosis of non-erosive reflux disease (either acid exposure time > 5% or normal acid exposure time and symptom index ≥ 50%). Outcome was assessed by review of hospital files and/or telephone interview.ResultsFifteen out of 50 patients had a pathological acid exposure time after the first day of monitoring (10 in the second day and 5 in subsequent days), which changed their diagnosis from functional heartburn to non-erosive reflux disease. Fifty-four percent of non-erosive reflux disease vs 11% of functional heartburn patients (P < 0.003) increased the dose of proton pump inhibitors or underwent fundoplication after the pH test. Outcome was positive in 77% of non-erosive reflux disease vs 43% of functional heartburn patients (P < 0.05).ConclusionsOne-third of patients classified as functional heartburn at 24-hour pH-monitoring can be re-classified as non-erosive reflux disease after a more prolonged pH recording period. This observation has a positive impact on patients’ management.

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.