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The role of inhaled and swallowed aeroallergens in treatment outcomes of adult patients with eosinophilic esophagitis (EoE) is unclear. We hypothesized that the pollen season contributes to the failure of the 6-food elimination diet (SFED) in EoE. We compared outcomes of patients with EoE who underwent SFED during vs outside of the pollen season. Consecutive adult patients with EoE who underwent SFED and skin prick test (SPT) for birch and grass pollen were included. Individual pollen sensitization and pollen count data were analyzed to define whether each patient had been assessed during or outside of the pollen season after SFED. All patients had active EoE (>=15 eosinophils/high-power field) before SFED and adhered to the diet under the supervision of a dietitian. Fifty-eight patients were included, 62.0% had positive SPT for birch and/or grass, whereas 37.9% had negative SPT. Overall, SFED response was 56.9% (95% confidence interval, 44.1%-68.8%). When stratifying response according to whether the assessment had been performed during or outside of the pollen season, patients sensitized to pollens showed significantly lower response to SFED during compared with outside of the pollen season (21.4% vs 77.3%; P = 0.003). In addition, during the pollen season, patients with pollen sensitization had significantly lower response to SFED compared with those without sensitization (21.4% vs 77.8%; P = 0.01). Pollens may have a role in sustaining esophageal eosinophilia in sensitized adults with EoE despite avoidance of trigger foods. The SPT for pollens may identify patients less likely to respond to the diet during the pollen season.

Background: Guidelines on Irritable Bowel Syndrome (IBS) are usually developed by specialists, with a possible translational gap in primary care. Aims: To evaluate the knowledge of IBS of Italian General Practitioners (GPs) and the difference compared to doctors in Training for General Practice (ITGPs). Methods: A questionnaire was completed by 170 GPs and 64 ITGPs. Results: The Rome Criteria and Bristol Scale are more familiar to ITGPs than GPs. The most frequently used diagnostic symptoms are abdominal pain, bowel movement frequency and bloating. GPs and ITGPs think that bloating and abdominal discomfort should be introduced into the definition of IBS. Intestinal motility disorders and psychological factors are considered to be the most probable cause of IBS. GPs report more frequently than ITGPs that the patient's request and difficulties in managing the disorder are reasons for a gastroenterological referral. Conclusions: There is still a gap between the indications provided by the experts and clinical practice, and this seems greater on the part of GPs than ITGPs. Abdominal pain and bowel frequency changes are considered the main symptoms for diagnosing IBS, but most GPs and ITGPs would like to include bloating among the diagnostic criteria. It would be highly desirable to develop commonly shared guidelines between gastroenterologists and GPs.

The most recent iteration of the classifications for functional esophageal disorders, Rome IV, proposed relevant modifications of the previous definitions for Rome III. They specifically considered increased esophageal acid exposure as the marker of gastroesophageal reflux disease (GERD), including the remaining part of non-erosive reflux disease patients with normal acid in the group with functional alterations, considering both reflux hypersensitivity and functional heartburn. However, recent pathophysiological and therapeutic data suggest the need for a return to including reflux hypersensitivity in the GERD spectrum. Indeed, physiologic alterations in esophageal mucosal integrity and chemical clearance, the presence of microscopic esophagitis, and strict symptom-reflux association support the concept that reflux hypersensitivity pertains to GERD. Surgical anti-reflux therapy has resulted in positive outcomes, even in the long term, in patients with reflux hypersensitivity and not in those with functional heartburn. Moreover, clinical trials using neuromodulators have been scarce and provided conflicting results. As a result, the real progress of the Rome IV classifications is in dispute. This article aims to summarize the most recent knowledge of non-erosive reflux disease and reflux hypersensitivity to discuss the utility of Rome IV criteria in the identification and management of functional esophageal disorders.

Ulcerative colitis is a chronic relapsing disease usually treated with mesalamine. The need of steroid therapy at diagnosis is generally considered as a poor prognostic factor. The aim of our study was to assess whether patients treated with corticosteroids at diagnosis have more clinical relapses, disease progression, or an increased risk of colectomy during a 5-year follow-up. We retrospectively evaluated patients who had received diagnosis of ulcerative colitis with a 5-year follow-up. Relapse was defined as a worsening of symptoms requiring an increase in medical treatment. Progression of disease was defined as a proximal extension of mucosal involvement, comparing the colonoscopy performed 5 years after diagnosis with the first one. The need of corticosteroid treatment at diagnosis was correlated to number of relapses, disease progression, and colectomy rate. We included 230 patients, 116 of them (50%) treated with steroids at diagnosis. Multivariate analysis demonstrated that there is a strong correlation between corticosteroid use and number of relapses (p

Several studies have indicated an overlap between gastroesophageal reflux disease (GERD) and various functional gastrointestinal disorders (FGIDs). The overlapping conditions reported have mainly been functional dyspepsia (FD) and irritable bowel syndrome (IBS). The available literature is frequently based on symptomatic questionnaires or endoscopic procedures to diagnose GERD. Rarely, among patients with heartburn, pathophysiological evaluations have been considered to differentiate those with proven GERD from those without. Moreover, both GERD and IBS or FD showed enormous heterogeneity in terms of the criteria and diagnostic procedures used. The GERD-IBS overlap ranges from 3-79% in questionnaire-based studies and from 10-74% when GERD has been diagnosed endoscopically. The prevalence of functional dyspepsia (after normal upper endoscopy) is 12-15% and an overlap with GERD has been reported frequently. Only a few studies have considered a potential overlap between functional heartburn (FH) and IBS using a 24-h pH-metry or impedance-pH evaluation. Similar data has been reported for an overlap between FH and FD. Recently, a revision of the Rome criteria for esophageal FGIDs identified both FH and hypersensitive esophagus (HE) as potential functional esophageal disorders. This might increase the potential overlap between different FGIDs, with FH and HE rather than with GERD. The aim of the present review article was to appraise and discuss the current evidence supporting the possible concomitance of GERD with IBS and FD in the same patients and to evaluate how various GERD treatments could impact on the quality of life of these patients.

The functional gastrointestinal disorders (FGIDs) are common conditions with an overall prevalence burden estimated at approximately one-third of the population. These represent a heterogeneous group of conditions which may include both abnormal symptom perception and functional causes and seems to share similar trigger factors as food, lifestyle and psychological factor. GERD develops when the reflux of gastric contents into the esophagus leads to troublesome symptoms, with or without mucosal involvement. Functional heartburn (FH) represents a subcategory of patients who refers with heartburn but without abnormal esophageal acid exposure, abnormal number of reflux events or any temporal correlation between symptoms and reflux events, on the same hands these patients do not report any symptom relief during antisecretory treatment with proton pump inhibitors. To date, several studies have reported a certain degree of overlap between GERD and FGIDs that it is only partially explained solely by chance. This review evaluated the overlap between GERD but especially FH and different FGIDs as: functional non-cardiac chest pain, irritable bowel syndrome, functional dyspepsia, gastric belching and supragastric belching and pharyngeal globus. A large number of mechanisms have been proposed to elucidate the connection between these numerous conditions. When pathophysiologic tests to subgroup GERD have been performed, FH seems overlap more frequently than GERD with FGIDs. From a therapeutic point of view visceral hypersensitivity, that characterize these functional disorders might be modulated by antidepressant therapy even if there are limited evidences. More studies and especially randomized controlled trials should consider these agents for future agenda researches.

A wide variety of pieces of evidence has suggested that obesity is associated with a significant increase in the risk for gastroesophageal reflux disease (GERD) symptoms and its complications. The aim of this study was to evaluate the effect of weight loss on reflux symptoms in overweight/obese patients with proven GERD. We enrolled overweight/obese patients with typical GERD symptoms and erosive esophagitis. At baseline, patients underwent detailed reflux symptoms evaluation and anthropometric assessment, and were divided into two treatment groups: group A received proton pump inhibitor (PPI) and a personalized hypocaloric diet and aerobic exercise; and group B received PPI and a 'standard of care diet'. The dietetic treatment was considered effective if at least 10% of weight loss was achieved within 6 months. All patients were evaluated in terms of anthropometric data, GERD symptoms, and PPI use. In group A, mean body mass index (BMI) decreased from 30.3 ± 4.1 to 25.7 ± 3.1 (P0.05), and mean weight decreased from 82.1 ± 16.9 kg to 69.9 ± 14.4 kg (P0.05). In group B, there was no change in BMI and weight. Symptom perception decreased (P0.05) in both groups during PPI therapy, but a higher improvement was recorded in group A. In group A, PPI therapy was completely discontinued in 27/50 of the patients, and halved in 16/50. Only 7/50 continued the same PPI dosage. In group B, 22/51 halved the therapy and 29/51 maintained full dosage of therapy, but none was able to discontinue PPI due to a symptom recurrence. Overall, weight loss of at least 10% is recommended in all patients with GERD in order to boost the effect of PPI on reflux symptom relief and to reduce chronic medication use.

Gastroesophageal reflux disease (GERD) is a common disorder of the upper gastrointestinal tract which is typically characterized by heartburn and acid regurgitation. These symptoms are widespread in the community and range from 2.5% to more than 25%. Economic analyses showed an increase in direct and indirect costs related to the diagnosis, treatment and surveillance of GERD and its complications. The aim of this review is to provide current information regarding the natural history of GERD, taking into account the evolution of its definition and the worldwide gradual change of its epidemiology. Present knowledge shows that there are two main forms of GERD, that is erosive reflux disease (ERD) and non-erosive reflux disease (NERD) and the latter comprises the majority of patients (up to 70%). The major complication of GERD is the development of Barrett esophagus, which is considered as a pre-cancerous lesion. Although data from medical literature on the natural history of this disease are limited and mainly retrospective, they seem to indicate that both NERD and mild esophagitis tend to remain as such with time and the progression from NERD to ERD, from mild to severe ERD and from ERD to Barrett's esophagus may occur in a small proportion of patients, ranging from 0 to 30%, 10 to 22% and 1 to 13% of cases, respectively. It is necessary to stress that these data are strongly influenced by the use of powerful antisecretory drugs (PPIs). Further studies are needed to better elucidate this matter and overcome the present limitations represented by the lack of large prospective longitudinal investigations, absence of homogeneous definitions of the various forms of GERD, influence of different treatments, clear exclusion of patients with functional disorders of the esophagus.

Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographical signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender, vs healthy controls, or hepatitis B virus infected patients. In patients with "HCV-associated mixed cryoglobulinemia" (MC+HCV), a higher prevalence of autoimmune thyroid disorders was shown not only compared to controls, but also compared to HCV patients without cryoglobulinemia. Patients with MC+HCV or with HCV chronic infection, show an higher prevalence of papillary thyroid cancer than in controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC+HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine than patients without thyroiditis. Probably, HCV thyroid infection acts by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes, that secrete interferon-gamma and tumor necrosis factor-alpha. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, that may lead into the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function and nodules are recommanded in HCV patients.

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

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%; 1145Ω) than in 41 HRE (25%; 1741Ω) and in 68 NERD (29%; 2374Ω) patients, and in all three GERD subgroups compared to 41 FH cases (67%; 3488Ω) (P

Introduction: Gastro-esophageal reflux disease (GERD) is a highly prevalent, chronic, relapsing disorder, whose knowledge has increased in last years thanks to the advent of new sophisticated techniques, such as 24-h impedance-pH monitoring and high-resolution manometry, for the study of esophageal functions. Areas covered: This review provides an overview of our advancements in understanding the complex pathophysiology, improving the diagnosis and defining the modern pharmacological therapeutic approach to GERD. Expert opinion: The growing clinical application of impedance-pH testing has allowed us to know the diversity of patients with non-erosive reflux disease (NERD), who nowadays represent about 70% of the whole population with reflux symptoms. We have realized that NERD has to be considered as an umbrella term covering various subgroups with different pathophysiologies. The development of new impedance metrics, in particular mean nocturnal baseline impedance, seems to be promising in the improvement of the diagnostic process of this disease. There are no particularly innovative features in the pharmacological therapy of GERD, unless the interest toward drugsis able to increase the defense properties of esophageal mucosa and/or its protection. These compounds can be of help in combination with proton pump inhibitors in NERD patients with partial response to antisecretory drugs alone.

Introduction: Bariatric surgery is increasingly performed. Since there are numerous surgical techniques, the effects of these on the esophageal function are still poorly understood. We aimed at assessing the effect of different techniques on esophagogastric junction (EGJ), esophageal peristalsis and reflux exposure using high-resolution manometry (HRM), and impedance-pH monitoring (MII-pH). Methods: All obese patients underwent symptomatic questionnaires, endoscopy, HRM, and MII-pH before and 1year after surgery. Esophageal function and EGJ were classified according to Chicago Classification V. 3.0. Intragastric pressure (IGP) and gastroesophageal pressure gradient (GEPG) were assessed. Total acid exposure time (AET %), total number of refluxes, and symptom association probability (SAP) were assessed. A group of healthy volunteers (HVs) served as control. Results: One hundred and twelve obese subjects and 15 HVs (normal weight) were studied. Thirteen underwent endoscopic balloon placement (BIB), 12 gastric banding (GB), 26 sleeve gastrectomy (SG), 18 Roux-en-Y gastric bypass (RYGB), 15 mini-gastric bypass (MGB), 16 biliointestinal bypass (BIBP), and 12 biliopancreatic diversion (BPD). IGP and GEPG significantly decreased after RYGP, BPD, and BPBP, whereas they significantly increased after GB and SG. Post-operative greater AET (p < 0.05) and increased total number of reflux (p < 0.001) were present after GB and SG. RYGB and MGB showed a significant decrease in AET (p < 0.05) and total number of reflux (p < 0.001). Conclusions: HRM verified that different bariatric techniques produced different modification of IGP and GEPG, leading to different reflux exposure. Only GB and SG can negatively impact on esophageal function and reflux exposure.

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&nbsp

Patients with esophageal symptoms potentially associated with gastroesophageal reflux disease such as heartburn, regurgitation, chest pain, or cough represent one of the most frequent reasons for referral to gastroenterological evaluation. The utility of esophageal reflux monitoring in clinical practice is: (1) to accurately define reflux burden, (2) to segregate patients according to reflux monitoring results as true GERD, reflux hypersensitivity and functional heartburn, and (3) to establish a treatment plan. With this in mind, in the last decade, investigations and technical advances, with the introduction of impedance-pH monitoring and wireless pH capsule, have enhanced our understanding and management of GERD. The following recommendations were discussed and approved after a comprehensive review of the medical literature pertaining to reflux testing techniques and their recent application. This review created under the auspices of the Società Italiana di Gastroenterologia ed Endoscopia Digestiva (SIGE), Società Italiana di Neuro-Gastro-Enterologia e Motilità (SINGEM) and Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) is intended to help clinicians in applying reflux studies in the most fruitful manner within the context of their patients with esophageal symptoms.

Background: Esophageal hypercontractility can manifest with and without esophagogastric junction (EGJ) outflow obstruction. We investigated clinical presentations and motility patterns in patients with esophageal hypercontractile disorders. Methods: Esophageal HRM studies fulfilling Chicago Classification 3.0 criteria for jackhammer esophagus (distal contractile integral, DCI >8000mmHg.cm.s in≥20% swallows) with (n=30) and without (n=83) EGJ obstruction (integrated relaxation pressure, IRP>15mmHg) were retrospectively reviewed from five centers (4 in Europe, 1 in US). Single swallows (SS) and multiple rapid swallows (MRS) were analyzed using HRM software tools (IRP, DCI, distal latency, DL); MRS: SS DCI ratio >1 defined contraction reserve. Comparison groups were achalasia type 3 (n=72, positive control for abnormal inhibition and EGJ obstruction) and healthy controls (n=18). Symptoms, HRM metrics, and MRS contraction reserve were analyzed within jackhammer subgroups and comparison groups. Key Results: The esophageal smooth muscle was excessively stimulated at baseline in jackhammer subgroups, with lack of augmentation following MRS identified more often compared with controls (P=.003) and type 3 achalasia (P=.07). Consistently abnormal inhibition was identified in type 3 achalasia (47%), and to a lower extent in jackhammer with obstruction (37%, P=.33), jackhammer esophagus (28%, P=.01), and controls (11%, P&nbsp

OBJECTIVES: Role of reflux and mechanisms of response to proton pump inhibitor (PPI) therapy in eosinophilic esophagitis (EoE) have not yet been fully elucidated. Comprehensive assessment by impedance-pH monitoring could clarify these issues. METHODS: Prospective multicenter study comparing EoE patients with healthy controls and gastroesophageal reflux disease cases. Patients with EoE were evaluated off- and on PPI; responsiveness was assessed by histology. Impedance-pH appraisal included chemical clearance, assessed with the postreflux swallow-induced peristaltic wave (PSPW) index, and mucosal integrity measured with mean nocturnal baseline impedance (MNBI). RESULTS: Sixty consecutive patients with EoE were compared with 60 age- and sex-matched healthy controls and 60 subjects with gastroesophageal reflux disease. The number of total refluxes was higher, while the PSPW index was lower in patients with EoE than in healthy controls. Off PPI, a lower MNBI gradient between the mid and distal esophagus distinguished 20 patients with PPI-refractory EoE from 40 patients with PPI-responsive EoE and was a predictor of PPI failure. On PPI, a lower PSPW index was the sole reflux parameter distinguishing PPI-refractory from PPI-responsive EoE; all reflux parameters improved in PPI-responsive patients, whereas the PSPW index was not modified in PPI-refractory cases and was independently associated with PPI-responsiveness. MNBI in the distal and mid esophagus improved much more in PPI-responsive than in PPI-refractory EoE. DISCUSSION: Reflux plays a role in the pathogenesis of EoE, more relevant in PPI-responsive cases. Low impedance gradient between the mid and distal esophagus may be useful to predict PPI refractoriness. PPIs mainly act by improving chemical clearance, i.e., by an antireflux action supporting long-term prescription in PPI-responsive EoE.

Background: Hiatal hernia is diagnosed by barium-swallow esophagogram or esophagogastroduodenoscopy, with possible suboptimal results. High-resolution manometry clearly identifies crural diaphragm and lower esophageal sphincter. Objectives: To assess the diagnostic accuracy of high-resolution manometry in detecting hiatal hernia compared to esophagogram and esophagogastroduodenoscopy, using as reference the surgical invivo measurement. Methods: Patients were studied with esophagogram, esophagogastroduodenoscopy, high-resolution manometry and invivo evaluation of the esophago-gastric junction. Esophago-gastric junction was classified as type I (no separation between crural diaphragm and lower esophageal sphincter); type II (≥1, ≤ 2 cm separation); type III (>2 cm). During invivo measurement, distance between the esophago-gastric junction and crural diaphragm proximal border was recorded. Results: Surgery identified 53 hiatal hernias in 100 patients. Forty-seven percent were classified as type I esophago-gastric junction, 35% type II and 18% type III. Referenced to invivo evaluation, high-resolution manometry showed superior diagnostic sensitivity and specificity (94.3% and 91.5%, respectively) to esophagogram and esophagogastroduodenoscopy, with 92.6% predictive value of a positive test and 93.5% predictive value of a negative test. The kappa value for high-resolution manometry and invivo evaluation was 0.85. High-resolution manometry showed optimal sensitivity and specificity in detecting types I, II and III esophago-gastric junction. Conclusions: High-resolution manometry enables an accurate diagnosis of hiatal hernia and a better classification than endoscopy and radiology, reaching optimal agreement with invivo assessment.

Jackhammer esophagus (JE) is a hypercontractile disorder, the pathogenesis of which is incompletely understood. Multiple rapid swallows (MRS) and rapid drink challenge (RDC) are complementary tests used during high-resolution manometry (HRM) that evaluate inhibitory and excitatory neuromuscular function and latent obstruction, respectively. Our aim was to evaluate esophageal pathophysiology using MRS and RDC in 83 JE patients (28 men; median age: 63 yr; IQR: 54–70 yr). Twenty-one healthy subjects (11 men; median age: 28 yr; range: 26–30 yr) were used as a control group. All patients underwent solid-state HRM with ten 5-ml single swallows (SS) and one to three 10-ml MRS; 34 patients also underwent RDC. Data are shown as median (interquartile range). Abnormal motor inhibition was noted during at least one MRS test in 48% of JE patients compared with 29% of controls ( P = 0.29). Mean distal contractile integral (DCI) after MRS was significantly lower than after SS [6,028 (3,678–9,267) mmHg·cm·s vs. 7,514 (6,238–9,197) mmHg·cm·s, P = 0.02], as was highest DCI ( P < 0.0001). Consequently, 66% of JE patients had no contraction reserve. At least one variable of obstruction during RDC (performed in 34 patients) was outside the normal range in 25 (74%) of JE patients. Both highest DCI after SS and pressure gradient across the esophagogastric junction (EGJ) during RDC were higher in patients with dysphagia versus those without ( P = 0.04 and 0.01, respectively). Our data suggest altered neural control in JE patients with heterogeneity in inhibitory function. Furthermore, some patients had latent EGJ obstruction during RDC, which correlated with the presence of dysphagia. NEW & NOTEWORTHY Presence of abnormal inhibition was observed during multiple rapid swallows (MRS) in some but not all patients with jackhammer esophagus (JE). Unlike healthy subjects, JE patients were more strongly stimulated after single swallows than after MRS. An obstructive pattern was frequently observed during rapid drink challenge (RDC) and was related to presence of dysphagia. MRS and RDC during high-resolution manometry are useful to show individual pathophysiological patterns in JE and may guide optimal therapeutic strategies.

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 Multiple rapid swallows (MRS) is a provocative test for assessment of contraction reserve, however reproducibility on repetitive MRS is incompletely understood. Our aim was to determine the optimal number of MRS sequences for consistent assessment of contraction reserve. Methods One hundred and fifty-nine consecutive patients (79 IEM and 80 normal motility) who underwent high-resolution manometers were enrolled. Ten single swallows (SS) and 10 MRS were performed. Gold standard for evaluation of the contraction reserve was the ratio between the mean DCI of 10 MRS and the mean DCI of 10 SS (MRS/SS DCI ratio). Rates of false negatives and false positives were calculated for increasing numbers of MRS sequences, using either mean DCI or the MRS with the highest DCI. Key results According to the gold standard, 50 IEM and 50 normal motility patients had contraction reserve. With progressively increasing numbers of MRS sequences, contraction reserve was detected using mean MRS DCI within three and four MRS sequences in IEM and normal motility respectively, whereas two and three MRS sequences were needed using the MRS sequence with the highest DCI. False positives were much higher with highest DCI method compared with mean DCI, (22% vs 9% respectively in IEM; 24% vs 9% in normal motility) when three MRS sequences were considered. Conclusions & inferences At least three MRS are needed to reliably assess contraction reserve. The mean DCI of the three MRS sequences is the best variable to utilize as evidence of contraction reserve.

Background and Aims. By means of 24 h impedance-pH monitoring, we aimed to evaluate the effect of two different meals with a bromatological balanced composition: one with a prevailing component of animal proteins and the other with vegetable proteins.Patients and Methods. We enrolled 165 patients with heartburn and negative endoscopy, who underwent impedance-pH monitoring off therapy. Patients were allocated to receive a Mediterranean diet with a total caloric intake of about 1694 kcal, divided into two meals: one with a prevailing component of animal proteins and the other with vegetable proteins. We evaluated the total reflux number, acid exposure time (AET), and symptom-reflux association with impedance-pH analysis. Moreover, during the first postprandial hour (at lunch and dinner), we evaluated the total reflux number, number of acid and weakly acidic refluxes, AET, and presence of symptoms.Results. The male/female ratio was 80/85. Mean age was 51.9 ± 12.1 years. Impedance-pH analysis showed that 55/165 patients had pathological AET or a number of refluxes (nonerosive reflux disease (NERD)), 49/165 had normal AET and a number of refluxes but positive symptom-reflux association (hypersensitive esophagus (HE)), and 61/165 had normal AET and a number of refluxes with negative symptom-reflux association (functional heartburn (FH)). The overall first postprandial hour analysis showed a higher total reflux number, acid reflux number, and AET after the animal protein meal than after the vegetable protein meal. Moreover, more symptoms were reported after the animal protein meal. Similar results have been observed in the three different subcategories of patients (NERD, HE, and FH).Conclusions. Vegetable proteins are associated with a lower number of refluxes, particularly acid refluxes, and with a reduced number of symptoms during the first postprandial hour. This is a pilot study and future investigations are warranted to confirm these results.

Heartburn is the most specific symptom of gastroesophageal reflux disease (GERD). In clinical practice, heartburn relief by a proton pump inhibitor (PPI) trial does suffice to confirm GERD. However, an objective diagnosis of GERD is required before anti-reflux endoscopic or surgical interventions, independently from PPI response. Thus, since normal findings at upper endoscopy are detected in the majority of patients with heartburn, reflux monitoring is often required. When traditional catheter-based or wireless pH tests are used, reflux episodes are conventionally identified by pH drops below 4.0 units. Combined impedance-pH monitoring has the advantage to provide a comprehensive assessment of both physical and chemical properties of refluxate and the distinction between acid and weakly acidic refluxes, both proven to cause heartburn. Unfortunately, the conventional impedance-pH parameters, namely acid exposure time and number of reflux events, are characterized by suboptimal diagnostic sensitivity, and the reliability of symptom–reflux association indexes remains questionable. Therefore, novel impedance parameters, namely the post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI), have recently been proposed in order to achieve a better diagnostic yield. In fact, they proved to be highly accurate in distinguishing reflux-related from reflux-unrelated heartburn, off- as well as on-PPI therapy. Currently, manual review of impedance-pH tracings is needed because of the modest accuracy of available software tools for automated analysis. PSPW index and MNBI are highly applicable and reproducible, and their calculation requires a few additional minutes during the manual review of impedance-pH tracings. So far, we believe that PSPW index and MNBI are ready for prime time and should become part of the standard analysis of impedance-pH tracings for GERD diagnosis in patients with endoscopy-negative heartburn.

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.

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

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. Esophagogastric junction (EGJ) plays an important role in defense mechanisms against reflux. Defining EGJ vigor with high-resolution manometry (HRM) may be useful to predict an abnormal impedance-pH testing in reflux disease. This study aims to establish a correlation between EGJ-contractile integral (EGJ-CI) and different reflux parameters, detected during impedance-pH monitoring in GERD patients. Esophagogastric junction contractile integral is calculated at HRM enclosing the upper and lower margins of the EGJ in a DCI toolbox, during three consecutive respiratory cycles and referenced to gastric pressure. The value computed with the DCI tool in mmHg*s*cm is then divided by the duration of the three respiratory cycles (in seconds) yielding EGJ-CI units of mmHg*cm. The value below 13 is established in a series of normal volunteers as a defective EGJ-CI. Reflux parameters determined at impedance-pH monitoring are total number of reflux, total esophageal acid exposure time (AET), and symptom association. Our findings show that, when a defective EGJ-CI is present, a gradual and significant increase IN reflux can be present.

Background & Aims: Analyses of impedance parameters such as the post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI) have been proposed to increase the accuracy of diagnosis of reflux disease. We assessed whether these improve the diagnostic yield of impedance pH monitoring of reflux disease. Methods: We performed a prospective study of consecutive patients with proton pump inhibitor-responsive heartburn who underwent 24-hour impedance pH monitoring at hospitals in Italy from January 2011 through December 2013. Reviewers blindly analyzed off-therapy impedance pH tracings from 289 patients with proton pump inhibitor-responsive heartburn, 68 with erosive reflux disease and 221 with non-erosive reflux disease (NERD), along with 50 healthy individuals (controls). The PSPW index, the MNBI, the esophageal acid exposure time, the number of total refluxes, and the bolus exposure were calculated, as well as the symptom association probability (SAP) and the symptom index (SI). Results: In receiver operating characteristic analysis, the area under curve of the PSPW index (0.977; 95% confidence interval, 0.961-0.993) was significantly greater than that of the other impedance pH parameters in identifying patients with reflux disease (P < .001). The PSPW index and the MNBI identified patients with erosive reflux disease with the highest level of sensitivity (100% and 91%, respectively), as well as the 118 pH-positive (99% and 86%) and 103 pH-negative (77% and 56%) cases of NERD. The PSPW index and the MNBI identified pH-negative NERD with the highest level of sensitivity; values were 82% and 52% for the 65 SAP-positive and/or SI-positive cases and 68% and 63% for the 38 SAP-negative and SI-negative cases. Diagnoses of NERD were confirmed by pH-only criteria, including those that were positive on the basis of the SAP or SI, for 165 of 221 cases (75%) and by impedance pH criteria for 216 of 221 cases (98%) (P = .001). Conclusions: The PSPW index and the MNBI increase the diagnostic yield of impedance pH monitoring of patients with reflux disease. Analysis of impedance pH data by calculating the PSPW index and the MNBI can increase the accuracy of diagnosis of patients with reflux disease, compared with pH-only data.

Background High-resolution manometry (HRM) provides information on esophagogastric junction (EGJ) morphology, distinguishing three different subtypes. Data on the correlation between EGJ subtypes and impedance-pH detected reflux patterns are lacking. We aimed to correlate the EGJ subtypes with impedance-pH findings in patients with reflux symptoms. Methods Consecutive patients with suspected gastroesophageal reflux disease (GERD) were enrolled. All patients underwent HRM and impedance-pH testing off-therapy. EGJ was classified as: Type I, no separation between the lower esophageal sphincter (LES) and crural diaphragm (CD); Type II, minimal separation (>1 and