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Introduction: Heartburn is a frequent symptom occurring in daily clinical practice and is mainly associated with gastroesophageal reflux disease (GERD). However, it can be stimulated by various factors and diseases other than GERD can present with heartburn. Therefore, physicians must be very careful in distinguishing GERD from non-GERD conditions in their patients, particularly when heartburn is refractory to anti-reflux medications., Areas Covered: The aim of this narrative review was to analyze the medical literature regarding the prevalence of heartburn and the various clinical disorders which can be present with this symptom. The type of medications usually adopted for treating heartburn and their grade of safety have been reviewed using an extensive computerized (Medline/PubMed) search with particular focus on the last 20 years., Expert Opinion: Many drugs can be used for relieving heartburn in patients with GERD, although PPIs are the pharmacological agents with the greatest efficacy. However, it must be highlighted that many non-GERD conditions may present clinically with this symptom whose intensity does not differ between GERD and functional esophageal disorders, which represent about 50% of all patients with suspected GERD. It is very important to identify these functional conditions because their treatment differs completely from that of GERD.

Background: On-therapy impedance-pH monitoring is recommended in patients with documented GERD and PPI-refractory heartburn in order to establish whether the unremitting symptom is reflux-related or not., Aims: To define on-PPI cut-offs of impedance-pH metrics allowing proper interpretation of on-therapy impedance-pH monitoring., Methods: Blinded expert review of impedance-pH tracings performed during double-dosage PPI, prospectively collected from 150 GERD patients with PPI-refractory heartburn and 45 GERD patients with PPI-responsive heartburn but persisting extra-esophageal symptoms. Acid exposure time (AET), number of total refluxes (TRs), post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI) were assessed. On-PPI cut-offs were defined and evaluated with ROC analysis and the area under curve (AUC)., Results: All the four impedance-pH metrics significantly differed between PPI-refractory and PPI-responsive heartburn cases. At ROC analysis, AUC was 0.73 for AET, 0.75 for TRs, 0.81 for PSPW index, and 0.71 for MNBI; best cut-offs were ≥1.7% for AET, ≥45 for TRs, ≤36% for PSPW index, and ≤ 1847 Ω for MNBI; AUC of such cut-offs was 0.66, 0.71, 0.73, and 0.68, respectively. Analysis of PSPW index and MNBI added to assessment of AET and TRs significantly increased the yield of on-therapy impedance-pH monitoring in the PPI-refractory cohort (97% vs. 83%, p < 0.0001). Notably, suboptimal acid suppression as shown by AET ≥1.7% was detected in 43% of 150 PPI-refractory cases., Conclusions: We have defined on-PPI cut-offs of impedance-pH metrics by which comprehensive assessment of impedance-pH tracings, including analysis of PSPW index and MNBI can efficiently characterize PPI-refractory GERD and support treatment escalation., (© 2023 John Wiley & Sons Ltd.)

The clinical diagnosis of gastro-esophageal reflux disease (GERD) is based on the presence of typical esophageal troublesome symptoms. In clinical practice, heartburn relief following a proton pump inhibitor (PPI) trial or endoscopy can confirm a diagnosis of GERD. In cases of diagnostic uncertainty or before anti-reflux interventions, combined impedance-pH monitoring (MII-pH) provides a comprehensive assessment of both physical and chemical properties of the refluxate, allowing to achieve a conclusive diagnosis of GERD. Recently, the Lyon Consensus proposed the use of mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave index (PSPW-I) as novel MII-pH metrics to support the diagnosis of GERD. The calculation of MNBI and PSPW-I currently needs to be performed manually, but artificial intelligence systems for the automated analysis of MII-pH tracings are being developed. Several studies demonstrated the increased diagnostic yield MNBI and PSPW-I for the categorization of patients with GERD at both on- and off-PPI MII-pH monitoring. Accordingly, we performed a narrative review on the clinical use and diagnostic yield of MNBI and PSPW-I when the diagnosis of GERD is uncertain. Based on currently available evidence, we strongly support the evaluation of PSPW-I and MNBI as part of the standard assessment of MII-pH tracings for the evaluation of GERD, especially in patients with endoscopy-negative heartburn., (© 2022. The Author(s).)

Background: A hierarchical approach for gastro-oesophageal reflux disease (GERD) diagnosis by impedance-pH monitoring was proposed by the Lyon Consensus, based on acid exposure time (AET) and supportive impedance metrics., Aims: To establish the clinical value of Lyon Consensus criteria in the work-up of patients with proton pump inhibitory (PPI)-refractory heartburn., Methods: Expert review of off-therapy impedance-pH tracings from unproven GERD patients with PPI-refractory heartburn prospectively evaluated at referral centers. Impedance metrics, namely total reflux episodes, postreflux swallow-induced peristaltic wave index, and mean nocturnal baseline impedance, were assessed. Expert review of on-therapy preoperative impedance-pH tracings from a separate cohort of surgically treated erosive/nonerosive GERD cases., Results: Off-therapy, normal, inconclusive, and abnormal AET was found in 59%, 17%, and 23% of 317 cases. Supportive evidence of GERD was provided by abnormal impedance metrics in up to 22% and 62% of cases in the normal and inconclusive AET groups, respectively. Adding the cases with inconclusive AET and abnormal impedance metrics to the abnormal AET group, a significant increase in GERD evidence was observed (from 23% to 37% of cases, p < 0.0002). At the on-therapy presurgical evaluation, abnormal/inconclusive AET and supraphysiological values of impedance metrics showed ongoing reflux in 21% and 90% of 96 cases, respectively (p < 0.00001); a relationship between on-therapy ongoing reflux and PPI-refractory heartburn was confirmed by the favorable surgical outcome at 3-year follow-up, 88% of cases being in persistent off-PPI heartburn remission., Conclusions: Impedance-pH monitoring, off- and on-therapy, is of high clinical value in the work-up of patients with PPI-refractory heartburn., (© 2022 John Wiley & Sons Ltd.)

Background and Aims: Acid exposure time (AET) and reflux episode thresholds from the Lyon Consensus may not apply for pH impedance studies performed while on proton pump inhibitor (PPI) therapy. We aimed to determine metrics from "on PPI" pH impedance studies predicting need for escalation of therapy., Methods: De-identified pH impedance studies performed while on twice-daily PPI (Diversatek, Boulder, CO) in healthy volunteers (n = 66, median age 37.5 years, 43.9% female), and patients with proven gastroesophageal reflux disease (GERD) (European heartburn-predominant cohort: n = 43, median age 57.0 years, 55.8% female; North American regurgitation-predominant cohort: n = 42, median age 41.6 years, 42.9% female) were analyzed. Median values and interquartile ranges for pH impedance metrics in healthy volunteers were compared with proven GERD patients with and without 50% symptom improvement on validated measures. Receiver operating characteristic (ROC) analyses identified optimal thresholds predicting symptom response., Results: Both conventional and novel reflux metrics were similar between PPI responders and nonresponders (P ≥ .1 for each) despite differences from healthy volunteers. Combinations of metrics associated with conclusively abnormal reflux burden (AET >4%, >80 reflux episodes) were seen in 32.6% and 40.5% of heartburn and regurgitation-predominant patients, respectively, 57.1% and 82.4% of whom reported nonresponse; and 85% with these metrics improved with invasive GERD management. On ROC analysis, AET threshold of 0.5% modestly predicted nonresponse (sensitivity, 0.62; specificity, 0.51; P = .22), and 40 reflux episodes had better performance characteristics (sensitivity, 0.80; specificity, 0.51; P = .002); 79% with these metrics improved with invasive GERD management., Conclusion: Combinations of abnormal "on PPI" pH impedance metrics are associated with PPI nonresponse in proven GERD patients, and can be targeted for treatment escalation, including surgery, particularly in regurgitation-predominant GERD., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Mean nocturnal baseline impedance (MNBI) and postreflux swallow-induced peristaltic wave (PSPW) index are novel impedance-based markers of reflux, but the effect of bile reflux on these metrics is unknown. The aim of this study was to evaluate bile reflux, MNBI, and PSPW index in patients with endoscopy-negative GERD partially responsive to PPI therapy., Methods: All patients underwent off-PPI endoscopy, esophageal manometry, multichannel intraluminal impedance pH (MII-pH), and bile reflux monitoring. Abnormal esophageal acid exposure time (AET) was required for inclusion. Symptom intensity (using 10-cm visual analog scales), and conventional and novel MII-pH metrics were compared between patients with and without abnormal bile reflux., Key Results: We evaluated 42 NERD patients (29 males, mean age: 53.4 ± 13. years), mean AET 6.1 ± 2%, of which 21 had abnormal bile reflux (Group A, 10.2 ± 4.9%), and 21 had normal bile reflux (Group B, 0.4 ± 0.1%, P < .05 compared with Group A). Heartburn reporting on PPI was higher in Group A (7.2 ± 2.1 vs 5.8 ± 0.9; P = .002), but AET, number of reflux events (acidic and weakly acidic), did not differ between the two groups. However, both PSPW index and MNBI were lower in Group A (P < .001). A strong inverse linear correlation was found between bile reflux and both MNBI (Pearson's test; R = -0.714; P < .001) and PSPW index (R = -0.722; P < .001)., Conclusions and Inferences: Compared to acid reflux alone, the presence of bile in an acidic esophageal environment is associated with more severe heartburn, lesser relief from PPI therapy, higher impairment of esophageal mucosal integrity and less effective chemical clearance., (© 2020 John Wiley & Sons Ltd.)

Objective: Heartburn is the most specific symptom of reflux disease and is highly responsive to proton pump inhibitor (PPI) therapy. Some patients do not respond to PPIs, but mechanisms of refractoriness have not yet been fully elucidated. Impedance-pH monitoring, allowing comprehensive on-therapy assessment of reflux, represents a valuable test to investigate PPI refractoriness., Methods: Prospective multicenter study comparing endoscopy-negative patients with PPI-refractory and PPI-responsive heartburn. Reflux disease was demonstrated by off-PPI impedance-pH monitoring and mechanisms of refractoriness were studied with on-PPI impedance-pH monitoring. Assessment of impedance-pH tracings comprised conventional parameters, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI)., Results: Sixty-four patients entered the study, 32 with PPI-refractory and 32 with PPI-responsive heartburn. On PPI, median percentage gastric and esophageal acid exposure time and number of acid refluxes did not differ between the two groups; conversely, number of total and weakly acidic refluxes and percentage bolus exposure were significantly higher while PSPW index and MNBI were significantly lower in PPI-refractory cases. At multivariate logistic regression analysis, PSPW index was the sole independent risk factor for PPI refractoriness (OR 1.082, 95% CI 1.022-1.146, P = 0.007). Comparing off- and on-PPI parameters, median PSPW index did not change in PPI-refractory patients (24% vs. 26%, P = 0.327) but increased significantly in PPI-responsive cases (29% vs. 46%, P < 0.001)., Conclusions: Lack of improvement of impaired chemical clearance is a major determinant of PPI refractoriness. Timely post-reflux salivary swallowing represents a key defensive mechanism and a potential target for future treatment modalities in PPI-refractory reflux-related heartburn.

Background: Acid exposure time (AET) is considered the most useful parameter to predict response of reflux-related heartburn to medical or surgical treatment. However, recent studies showed high rates of heartburn response to proton pump inhibitor (PPI) therapy in patients with normal AET. We aimed to compare the efficacy of postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) with AET in linking PPI-responsive heartburn to reflux., Methods: Off-therapy impedance-pH tracings from 425 patients, 317 with PPI-responsive and 108 with PPI-refractory heartburn were blindly re-analyzed. Demographic and endoscopic characteristics, conventional impedance-pH variables, PSPW index, and MNBI were assessed with multivariate logistic regression to identify factors independently associated with PPI responsiveness. Prediction models were developed to assess the strength of reflux linkage with factors independently associated with PPI responsiveness by calculating the area under the curve (AUC) at receiver-operating-characteristic (ROC) analysis., Key Results: At multivariate logistic regression analysis, AET, MNBI, and PSPW index were the only factors independently associated with PPI responsiveness, abnormal values found in 60%, 76%, and 92% of PPI-responsive cases (P<.017). At ROC analysis, PSPW index (AUC:.794, P=.002) and MNBI (AUC: 0.742, P=.003), both separately and combined (AUC: 0.811, P<.001) linked reflux with PPI-responsiveness better than AET (AUC: 0.687)., Conclusions & Inferences: AET, PSPW index, and MNBI are independently associated with PPI-responsive heartburn. PSPW index and MNBI can link PPI-responsive heartburn to reflux better than AET and should become part of the standard analysis of impedance-pH tracings., (© 2017 John Wiley & Sons Ltd.)

Background: The 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., Aim: To compare endoscopy-negative heartburn with chronic autoimmune atrophic gastritis (CAAG)., Materials and Methods: 24 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., Results: CAAG 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)., Conclusion: Patients 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., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Hypersensitive esophagus (HE) is defined by endoscopy-negative heartburn with a normal acid exposure time but positive symptom association probability (SAP) and/or symptom index (SI) on impedance-pH monitoring, and proton pump inhibitor (PPI) responsiveness. Functional heartburn (FH) is distinguished by negative SAP/SI and PPI refractoriness. The clinical value of SAP and SI has been questioned. We aimed to investigate whether impairment of chemical clearance and of mucosal integrity, expressed by the postreflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI), characterize HE independently of SAP and SI., Methods: Impedance-pH tracings from PPI-responsive endoscopy-negative patients, 125 with nonerosive reflux disease and 108 with HE, distinguished by an abnormal and a normal acid exposure time, and from 70 patients with FH were retrospectively selected and blindly reviewed., Results: The mean PSPW index and MNBI were significantly lower in nonerosive reflux disease (30 %, 1378 Ω) than in HE (51 %; 2274 Ω) and in both of them as compared with FH (76 %; 3445 Ω) (P = 0.0001). Both the PSPW index (adjusted odds ratio 0.863, P = 0.001) and the MNBI (adjusted odds ratio 0.998, P = 0.001) were independent predictors of HE; with their combined assessment, the area under the curve on receiver operating characteristic analysis was 0.957. SAP and/or SI was positive in 67 of the 108 HE patients (62 %), whereas the PSPW index and/or MNBI was abnormal in 99 of the 108 HE patients (92 %; P < 0.0001)., Conclusions: HE is characterized by impairment of chemical clearance and mucosal integrity, which explains the increased reflux perception. When SAP and SI afford uncertain results, the PSPW index and MNBI should be analyzed.

Background: On-therapy impedance-pH monitoring in proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) yielded conflicting results. We aimed to assess the diagnostic value of postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) in PPI-refractory heartburn., Methods: On-therapy impedance-pH tracings from 189 consecutive patients with PPI-refractory heartburn were blindly reviewed. Patients were subdivided into refractory reflux esophagitis (RRE), healed reflux esophagitis (HRE), non-erosive reflux disease (NERD), and functional heartburn (FH) according to endoscopic and conventional impedance-pH findings. The diagnostic accuracy of PSPW index and MNBI in separating NERD from FH was assessed with receiver-operating-characteristic (ROC) analysis. Objectively documented persistent reflux remission at 3-year follow-up in 53 patients who underwent laparoscopic fundoplication served to evaluate PSPW index and MNBI as independent predictors of PPI-refractory GERD confirmed by positive surgical outcome., Key Results: Median PSPW index and MNBI values were significantly lower in 39 RRE (16%; 1145 Ω) than in 41 HRE (25%; 1741 Ω) and in 68 NERD (29%; 2374 Ω) patients, and in all three GERD subgroups compared to 41 FH cases (67%; 3488 Ω) (P<.008). At ROC analysis, comparing NERD to FH the area under the curve was 0.886 with PSPW index and 0.677 with MNBI (P=.005). PSPW index was an independent predictor of PPI-refractory GERD (odds ratio 0.6983, P=.012)., Conclusions & Inferences: At on-therapy impedance-pH monitoring, PSPW index and MNBI efficiently distinguish PPI-refractory NERD from FH. The PSPW index represents an independent predictor of PPI-refractory GERD., (© 2016 John Wiley & Sons Ltd.)

Objectives: 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., Methods: 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., Results: 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)., Conclusions: IBS overlaps more frequently with FH than with GERD and HE, suggesting common pathways and treatment. HE showed intermediate characteristic between GERD and FH.

Nonerosive reflux disease (NERD) is a common condition and the most frequent phenotype of gastroesophageal reflux disease (GERD). NERD is extremely heterogeneous and includes patients with negative endoscopy but abnormal esophageal acid exposure and/or positive reflux-symptom association analysis (hypersensitive esophagus). This segregation is only possible owing to the use of impedance-pH monitoring. Indeed, weakly acidic reflux represents one of the most common causes of refractory symptoms in patients evaluated off antisecretory therapy and, more importantly, during antisecretory drug treatment. Patients with heartburn who do not have any type of reflux underlying their symptoms (functional heartburn) must be excluded from the category of GERD. The drawbacks of impedance-pH are mainly due to the day-to-day variability of the test and the fact that the accuracy of the symptom-reflux correlation scores is often far from perfect. Some histopathological characteristics, such as dilated intercellular spaces, can be helpful in distinguishing patients with NERD through esophageal biopsies. Patients with NERD in whom acid is the main pathogenetic factor respond successfully to proton pump inhibitor therapy, while those with hypersensitive esophagus to weakly acidic reflux could be treated with reflux inhibitors or surgery, although further controlled studies are required., (© 2016 New York Academy of Sciences.)

Multichannel impedance pH monitoring has shown that weakly acidic refluxes are able to generate heartburn. However, data on the role of different pH values, ranging between 4 and 7, in the generation of them are lacking. The aim of this study was to evaluate whether different pH values of weakly acidic refluxes play a differential role in provoking reflux symptoms in endoscopy-negative patients with physiological esophageal acid exposure time and positive symptom index and symptom association probability for weakly acidic refluxes. One hundred and forty-three consecutive patients with gastroesophageal reflux disease, nonresponders to proton pump inhibitors (PPIs), were allowed a washout from PPIs before undergoing: upper endoscopy, esophageal manometry, and multichannel impedance pH monitoring. In patients with both symptom index and symptom association probability positive for weakly acidic reflux, each weakly acidic reflux was evaluated considering exact pH value, extension, physical characteristics, and correlation with heartburn. Forty-five patients with normal acid exposure time and positive symptom association probability for weakly acidic reflux were identified. The number of refluxes not heartburn related was higher than those heartburn related. In all distal and proximal liquid refluxes, as well as in distal mixed refluxes, the mean pH value of reflux events associated with heartburn was significantly lower than that not associated. This condition was not confirmed for proximal mixed refluxes. Overall, a low pH of weakly acidic reflux represents a determinant factor in provoking heartburn. This observation contributes to better understand the pathophysiology of symptoms generated by weakly acidic refluxes, paving the way toward the search for different therapeutic approaches to this peculiar condition of esophageal hypersensitivity., (© 2014 International Society for Diseases of the Esophagus.)

Background: Oesophageal clearance has been scarcely studied., Aims: Oesophageal clearance in endoscopy-negative heartburn was assessed to detect differences in bolus clearance time among patients sub-grouped according to impedance-pH findings., Methods: In 118 consecutive endoscopy-negative heartburn patients impedance-pH monitoring was performed off-therapy. Acid exposure time, number of refluxes, baseline impedance, post-reflux swallow-induced peristaltic wave index and both automated and manual bolus clearance time were calculated. Patients were sub-grouped into pH/impedance positive (abnormal acid exposure and/or number of refluxes) and pH/impedance negative (normal acid exposure and number of refluxes), the former further subdivided on the basis of abnormal/normal acid exposure time (pH+/-) and abnormal/normal number of refluxes (impedance+/-)., Results: Poor correlation (r=0.35) between automated and manual bolus clearance time was found. Manual bolus clearance time progressively decreased from pH+/impedance+ (42.6s), pH+/impedance- (27.1s), pH-/impedance+ (17.8s) to pH-/impedance- (10.8s). There was an inverse correlation between manual bolus clearance time and both baseline impedance and post-reflux swallow-induced peristaltic wave index, and a direct correlation between manual bolus clearance and acid exposure time. A manual bolus clearance time value of 14.8s had an accuracy of 93% to differentiate pH/impedance positive from pH/impedance negative patients., Conclusions: When manually measured, bolus clearance time reflects reflux severity, confirming the pathophysiological relevance of oesophageal clearance in reflux disease., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Esophageal impedance measurements have been proposed to indicate the status of the esophageal mucosa, and might be used to study the roles of the impaired mucosal integrity and increased acid sensitivity in patients with heartburn. We compared baseline impedance levels among patients with heartburn who did and did not respond to proton pump inhibitor (PPI) therapy, along with the pathophysiological characteristics of functional heartburn (FH)., Methods: In a case-control study, we collected data from January to December 2013 on patients with heartburn and normal findings from endoscopy who were not receiving PPI therapy and underwent impedance pH testing at hospitals in Italy. Patients with negative test results were placed on an 8-week course of PPI therapy (84 patients received esomeprazole and 36 patients received pantoprazole). Patients with more than 50% symptom improvement were classified as FH/PPI responders and patients with less than 50% symptom improvement were classified as FH/PPI nonresponders. Patients with hypersensitive esophagus and healthy volunteers served as controls. In all patients and controls, we measured acid exposure time, number of reflux events, baseline impedance, and swallow-induced peristaltic wave indices., Results: FH/PPI responders had higher acid exposure times, numbers of reflux events, and acid refluxes compared with FH/PPI nonresponders (P < .05). Patients with hypersensitive esophagus had mean acid exposure times and numbers of reflux events similar to those of FH/PPI responders. Baseline impedance levels were lower in FH/PPI responders and patients with hypersensitive esophagus, compared with FH/PPI nonresponders and healthy volunteers (P < .001). Swallow-induced peristaltic wave indices were similar between FH/PPI responders and patients with hypersensitive esophagus., Conclusions: Patients with FH who respond to PPI therapy have impedance pH features similar to those of patients with hypersensitive esophagus. Baseline impedance measurements might allow for identification of patients who respond to PPIs but would be classified as having FH based on conventional impedance-pH measurements., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Recently, it has been suggested that low esophageal basal impedance may reflect impaired mucosal integrity and increased acid sensitivity. We aimed to compare baseline impedance levels in patients with heartburn and pathophysiological characteristics related to functional heartburn (FH) divided into two groups on the basis of symptom relief after proton pump inhibitors (PPIs)., Methods: Patients with heartburn and negative endoscopy were treated with esomeprazole or pantoprazole 40 mg daily for 8 weeks. According to MII-pH (off therapy) analysis, patients with normal acid exposure time (AET), normal reflux number, and lack of association between symptoms and refluxes were selected; of whom 30 patients with a symptom relief higher than 50% after PPIs composed Group A, and 30 patients, matched for sex and age, without symptom relief composed Group B. A group of 20 healthy volunteers (HVs) was enrolled. For each patient and HV, we evaluated the baseline impedance levels at channel 3, during the overnight rest, at three different times., Key Results: Group A (vs Group B) showed an increase in the following parameters: mean AET (1.4 ± 0.8% vs 0.5 ± 0.6%), mean reflux number (30.4 ± 8.7 vs 24 ± 6.9), proximal reflux number (11.1 ± 5.2 vs 8.2 ± 3.6), acid reflux number (17.9 ± 6.1 vs 10.7 ± 6.9). Baseline impedance levels were lower in Group A than in Group B and in HVs (p < 0.001)., Conclusions & Inferences: Evaluating baseline impedance levels in patients with heartburn and normal AET could achieve a better understanding of pathophysiology in reflux disease patients, and could improve the distinction between FH and hypersensitive esophagus., (© 2014 John Wiley & Sons Ltd.)

Several studies indicate a significant degree of overlap between irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD). Likewise, both functional heartburn (FH) and IBS are functional digestive disorders that may occur in the same patients. However, data establishing a solid link between FH and IBS are lacking, mainly because the clinical definition of FH has undergone substantial changes over the years. The available literature on the overlap between GERD or FH and IBS highlights considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess heartburn and IBS. In particular, several epidemiological studies included patients with concomitant IBS and GERD without any attempt to distinguish FH (as defined by the Rome III criteria) from GERD via pathophysiological investigations. Independent of these critical issues, there is preliminary evidence supporting a significant degree of FH-IBS overlap. This underscores the need for studies based on updated diagnostic criteria and accurate pathophysiological classifications, particularly to distinguish FH from GERD. This distinction would represent an essential starting point to achieving a better understanding of pathophysiology in the subclasses of patients with GERD and FH and properly assessing the different degrees of overlap between IBS and the subcategories of heartburn.The present review article intends to appraise and critically discuss current evidence supporting a possible concomitance of GERD or FH with IBS in the same patients and to highlight the pathophysiological relationships between these disorders.

Background: Microscopic esophagitis (ME) is common in patients with non-erosive reflux disease (NERD), and dilation of intercellular spaces (DIS) has been regarded as the potential main mechanism of symptom generation. We aimed to compare these histological abnormalities in healthy volunteers (HVs) and patients with erosive esophagitis (EE), NERD, and functional heartburn (FH)., Methods: Consecutive patients with heartburn prospectively underwent upper endoscopy and impedance-pH off-therapy. Twenty EE patients and fifty-seven endoscopy-negative patients (NERD), subclassified as 22 with pH-POS (positive for abnormal acid exposure), 20 with hypersensitive esophagus (HE; normal acid/symptom association probability [SAP]+ or symptom index [SI]+), and 15 with FH (normal acid/SAP-/SI-/ proton pump inhibitor [PPI] test-), were enrolled. Twenty HVs were also included. In each patient/control, multiple specimens (n = 5) were taken from the distal esophagus and histological alterations were evaluated. ME was diagnosed when the global histological score was >0.35., Results: The prevalence of ME was higher (p < 0.0001) in EE (95 %), pH-POS (77 %), and HE (65 %) NERD patients than in FH patients (13 %) and HVs (15 %). Also, basal cell hyperplasia (p < 0.0023), DIS (p < 0.0001), and papillae elongation (p < 0.0002) showed similar rates of prevalence in the above populations (p < 0.0001). ME, including each histological lesion, had similar low frequencies in FH and HVs (p = 0.9990). Considering the histological abnormalities together, they permitted us to clearly differentiate EE and NERD from FH and HVs (p < 0.0001 and p < 0.0001, respectively)., Conclusions: The lack of ME in the esophageal distal biopsies of FH patients indicates a limited role of these histological abnormalities in symptom generation in them. ME can be considered as an accurate and reliable diagnostic marker for distinguishing FH patients from GERD patients and has the potential to be used to guide the correct therapy.

Aim: To evaluate the effect of a novel alginate-based compound, Faringel, in modifying reflux characteristics and controlling symptoms., Methods: In this prospective, open-label study, 40 patients reporting heartburn and regurgitation with proven reflux disease (i.e., positive impedance-pH test/evidence of erosive esophagitis at upper endoscopy) underwent 2 h impedance-pH testing after eating a refluxogenic meal. They were studied for 1 h under basal conditions and 1 h after taking 10 mL Faringel. In both sessions, measurements were obtained in right lateral and supine decubitus positions. Patients also completed a validated questionnaire consisting of a 2-item 5-point (0-4) Likert scale and a 10-cm visual analogue scale (VAS) in order to evaluate the efficacy of Faringel in symptom relief. Tolerability of the treatment was assessed using a 6-point Likert scale ranging from very good (1) to very poor (6)., Results: Faringel decreased significantly (P < 0.001), in both the right lateral and supine decubitus positions, esophageal acid exposure time [median 10 (25th-75th percentil 6-16) vs 5.8 (4-10) and 16 (11-19) vs 7.5 (5-11), respectively] and acid refluxes [5 (3-8) vs 1 (1-1) and 6 (4-8) vs 2 (1-2), respectively], but increased significantly (P < 0.01) the number of nonacid reflux events compared with baseline [2 (1-3) vs 3 (2-5) and 3 (2-4) vs 6 (3-8), respectively]. Percentage of proximal migration decreased in both decubitus positions (60% vs 32% and 64% vs 35%, respectively; P < 0.001). Faringel was significantly effective in controlling heartburn, based on both the Likert scale [3.1 (range 1-4) vs 0.9 (0-2); P < 0.001] and VAS score [7.1 (3-9.8) vs 2 (0.1-4.8); P < 0.001], but it had less success against regurgitation, based on both the Likert scale [2.6 (1-4) vs 2.2 (1-4); P = not significant (NS)] and VAS score [5.6 (2-9.6) vs 3.9 (1-8.8); P = NS]. Overall, the tolerability of Faringel was very good 5 (2-6), with only two patients reporting modest adverse events (i.e., nausea and bloating)., Conclusion: Our findings demonstrate that Faringel is well-tolerated and effective in reducing heartburn by modifying esophageal acid exposure time, number of acid refluxes and their proximal migration.

Background Multiple rapid swallowing ( MRS) during high-resolution manometry ( HRM) is increasingly utilized as provocative test to assess esophageal peristaltic reserve. The aim of this study was to evaluate the correlation between MRS response and impedance and pH ( MII-pH) parameters in endoscopy negative heartburn ( ENH) patients. Methods We enrolled consecutive ENH patients, who underwent HRM and MII-pH study, with a selected MII-pH profile: abnormal MII-pH (pH+/ MII+); normal MII-pH (pH−/ MII−). HRM was performed with 10 wet swallows ( WS) and one MRS. Mean distal contractile integral ( DCI) during WS and MRS were calculated. MII-pH parameters including acid exposure time ( AET), reflux events, baseline impedance levels ( BI) and the efficacy of chemical clearance evaluated with the postreflux swallow-induced peristaltic wave ( PSPW) index were measured. Key Results We analyzed 103 patients: 49 MII+/pH+ (27 male), and 54 MII−/pH− (19 male). Mean age was similar between the two groups. As expected, mean AET and number of refluxes were higher in pH+/ MII+ ( p < 0.05). HRM was normal in all selected patients. Mean DCI- WS was similar between two groups ( p = n.s.). Mean DCI- MRS- was higher in MII−/pH− vs MII+/pH+ ( p < 0.05). The increase in DCI- MRS was inversely correlated with AET (−0.699; p < 0.001) and directly correlated with BI values (0.631; p < 0.001) and PSPW index (0.626; p < 0.001). Conclusions & Inferences Following MRS, patients with abnormal impedance-pH test showed suboptimal contraction response as compared with those with normal impedance-pH test. Moreover, MRS response was inversely correlated with AET and directly correlated with BI values and PSPW index. [ABSTRACT FROM AUTHOR]

Multichannel impedance pH monitoring has shown that weakly acidic refluxes are able to generate heartburn. However, data on the role of different pH values, ranging between 4 and 7, in the generation of them are lacking. The aim of this study was to evaluate whether different pH values of weakly acidic refluxes play a differential role in provoking reflux symptoms in endoscopy-negative patients with physiological esophageal acid exposure time and positive symptom index and symptom association probability for weakly acidic refluxes. One hundred and forty-three consecutive patients with gastroesophageal reflux disease, nonresponders to proton pump inhibitors ( PPIs), were allowed a washout from PPIs before undergoing: upper endoscopy, esophageal manometry, and multichannel impedance pH monitoring. In patients with both symptom index and symptom association probability positive for weakly acidic reflux, each weakly acidic reflux was evaluated considering exact pH value, extension, physical characteristics, and correlation with heartburn. Forty-five patients with normal acid exposure time and positive symptom association probability for weakly acidic reflux were identified. The number of refluxes not heartburn related was higher than those heartburn related. In all distal and proximal liquid refluxes, as well as in distal mixed refluxes, the mean pH value of reflux events associated with heartburn was significantly lower than that not associated. This condition was not confirmed for proximal mixed refluxes. Overall, a low pH of weakly acidic reflux represents a determinant factor in provoking heartburn. This observation contributes to better understand the pathophysiology of symptoms generated by weakly acidic refluxes, paving the way toward the search for different therapeutic approaches to this peculiar condition of esophageal hypersensitivity. [ABSTRACT FROM AUTHOR]

Background 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. Methods 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. Key Results 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 5 mmHg cm yielded the optimal performance in identifying GERD at impedance-pH (sensitivity 89%-specificity 63%). Conclusions & Inferences 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. [ABSTRACT FROM AUTHOR]

Background A short-course of proton pump inhibitors ( PPIs) is often used to confirm gastroesophageal reflux disease ( GERD). However, some patients with PPI responsive heartburn do not seem to have evidence of GERD on impedance-pH monitoring (MII-pH). The aim of the study was to evaluate patients with reflux symptoms and a negative endoscopy, who well respond to PPIs with MII-pH. Methods We enrolled 312 patients with GERD symptoms and negative endoscopy: 144 reported well-controlled symptoms after 8-week PPIs and 155 were non-responders. Symptom relief was evaluated with GERD Impact Scale and visual analog scale score. All patients underwent MII-pH off-therapy. Thirteen patients were excluded from analysis. Patients were grouped as follows: non-erosive reflux disease ( NERD; increased acid exposure time, AET); hypersensitive esophagus ( HE; normal AET, positive symptom association, SI/ SAP); MII-pH-/ PPI+ (normal AET, negative SI/ SAP) in the responder group; MII-pH-/ PPI- in non-responders. Key Results MII-pH in PPI responders (symptom relief during PPI therapy > 75%) showed: 79/144 NERD (54.9%); 37/144 HE (25.7%); 28/144 MII-pH-/ PPI+ (19.4%). MII-pH-/ PPI+ patients reported the same symptom relief when compared with NERD and HE. In non-responder (symptom relief during PPI therapy < 50%) group, 27/155 patients were NERD (17.4%); 53/155 were HE (34.2%); 75/155 were MII-pH-/ PPI- (48.4%). NERD diagnosis was significantly higher in responder group (p < 0.01). Conclusions & Inferences In a substantial subgroup of patients responding to PPI with typical reflux symptoms, the diagnosis of GERD cannot be confirmed with pH-impedance monitoring. Proton pump inhibitor response and presence of typical symptoms are thus not reliable predictors of the diagnosis and antireflux surgery should always be preceded by reflux monitoring. [ABSTRACT FROM AUTHOR]