Normal Esophageal Acid Exposure Research Articles

The effectiveness and safety of the anti gastroesophageal reflux system in the treatment of gastroesophageal reflux disease: a single center study of 23 cases

Objective: To evaluate the safety and efficacy of domestically produced magnetic sphincter augmentation (MSA) for gastroesophageal reflux disease. Method: This study is a prospective cohort study. Patients with typical heartburn and reflux symptoms (at least partial response to proton pump inhibitors), abnormal esophageal acid exposure and normal esophageal peristalsis were included, prospectively in the Department of Gastroesophageal Surgery, Rocket Force Characteristic Medical Center from June 2019 to September 2022. Patients with hiatal hernia >2 cm and severe esophagitis were excluded. The MSA was wrapped around the distal esophagus after esophageal hiatus repair by laparoscopy. A postoperative questionnaire survey was conducted to assess the relief of symptom, complications, the discontinuation rate of proton pump inhibitor, and surgical satisfaction. Gastroscopy, high-resolution esophageal pressure measurement, and pH value impedance monitoring were also reviewed. The pre- and postoperative rates were compared using the McNeinar χ2 test. Result: Currently, 23 patients with gastroesophageal reflux disease were enrolled and underwent MSA surgery. There were 20 males and 3 females, aged (M (IQR)) 48 (14) years (range: 25 to 64 years). All cases were successfully implanted with MSA. Subjective indicators were followed for 17 (18) months (range: 14 to 53 months), while objective indicators were followed for 17 (1) months (range: 12 to 23 months). The postoperative gastrointestinal and extraesophageal symptom scores showed a significant decrease compared to preoperative levels as follows: the degree of subjective relief of overall digestive symptoms was 90 (20)% (range:0~100%), the degree of subjective relief of overall respiratory symptoms was 100(10)% (range: 10%~100%), the overall satisfaction rate was 83% (19/23), the proton pump inhibitor discontinuation rate was 70% (16/23). The proportion of esophagitis has decreased from 44% (10/23) to 9% (2/23) (κ=0.169, P=0.039), The Hill grade of gastroesophageal valve morphology improved from 1 case of grade Ⅰ, 5 cases of grade Ⅱ, 10 cases of grade Ⅲ, and 7 cases of grade Ⅲ preoperative to 22, 1, 0, and 0 cases postoperative. The proportion of lower esophageal sphincter pressure below normal has decreased from 70% (16/23) to 35% (8/23) (κ=0.170, P=0.012). There were 21 patients who restored normal esophageal acid exposure. Eleven patients had mild long-term dysphagia, but it didn't affect their daily life. No postoperative device migration, erosion, or secondary surgical removal occurred. Conclusions: Laparoscopic implantation of the MSA device was safe and well tolerated. It can effectively control the symptoms of gastroesophageal reflux disease, reduce medication, restore normal cardia morphology and function, and esophageal acid exposure. The main postoperative complication was dysphagia, but it was relatively mild.

Safety and efficacy of an implantable device for management of gastroesophageal reflux in lung transplant recipients.

BackgroundMagnetic sphincter augmentation (MSA) is a promising minimally invasive surgical technique for management of gastroesophageal reflux disease (GERD); however, device implantation after transplantation has not been studied and may be concerning in these immunosuppressed patients. We explored the safety of the LINX Reflux Management System (MSA device) for management of GERD following lung transplantation (LTx).MethodsLung transplant recipients who underwent LINX implantation at our institution between 2017 and 2019 were followed prospectively in the Reflux Following Lung Transplantation and Associated Treatment Registry. Ambulatory pH testing and acid-suppressing medication use were compared before and after LINX implantation. One-year outcomes and change in pulmonary function were compared between matched LINX and fundoplication groups.ResultsOf 17 patients who underwent post-lung transplant LINX implantation, 8 (47.1%) agreed to undergo post-LINX pH testing. Three/eight (37.5%) patients achieved normal esophageal acid exposure time; 14 (82.4%) remained on acid-suppressing medication at one-year under the direction of their transplant teams. One-year patient survival and change in pulmonary function were similar between groups. LINX patients experienced more early side effects.ConclusionsUse of the LINX MSA device in a cohort of lung transplant recipients at our institution was associated with similar short-term safety compared to traditional fundoplication, however assessment of efficacy was limited. Further investigation is needed to characterize the long-term efficacy of LINX implantation after LTx.

Current management of proton pump inhibitor-refractory gastroesophageal reflux disease

Here we review current concepts in diagnosis and treatment of proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (PPIGERD) which includes an insufficient response to daily PPI 8-week therapy in combination with pathological gastroesophageal reflux. Patients with PPI-GERD frequently suffer from non-acidic and asymptomatic gastroesophageal reflux. In developed countries, PPI-GERD accounts for 30-40% of all patients receiving PPIs. Diagnosis of PPIGERD is performed by means of clinical anamnesis, esophagogastroscopy and impedance-pH monitoring. PPI-GERD needs to be differentiated with functional heartburn, reflux hypersensitivity and nonerosive reflux disease. Functional heartburn is characterised by reference time with a esophageal pH < 4 and the absence of a link between reflux episodes and GERD symptoms. Reflux hypersensitivity is diagnosed with normal esophageal acid exposure and association of reflux episodes with symptoms of GERD. Nonerosive reflux disease can be diagnosed solely by evaluating pathological acid exposure (pH < 4 for > 6% of the time). Treatment of PPI-GERD includes diet and lifestyle modification to reduce weight in obese patients, optimization of PPI use, and administration of alginate, prokinetics, baclofen and other drugs. Surgical treatment is also widely used and provide good results.

Products of Mature Adipocytes in Visceral Fat of Obese Patients Impair Esophageal Epithelial Barrier Formation and Function

ObjectiveVisceral obesity is associated with GERD and its complications of reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma. A traditional explanation for these associations is that visceral fat causes pathological acid reflux by increasing intra‐abdominal pressure. However, for unknown reasons, the esophagus of obese patients who have normal esophageal acid exposure can exhibit evidence of impaired epithelial barrier function including dilated intercellular spaces (DIS) and reduced transepithelial resistance (TER). In this study, we explored our hypothesis that the visceral fat of obese individuals secretes substances that impair esophageal barrier function, thus predisposing to injury by GERD.MethodsWe obtained subcutaneous (SQ) and visceral (VIS) fat from 1 non‐obese (BMI 18) and 2 obese (BMIs 51& 42) patients having foregut surgery; VIS included both mesenteric fat and gastroesophageal junction (GEJ) fat pad. Fat contains both mature adipocytes (MAs) and adipocyte derived stem cells (ADSCs), which were isolated from adipocyte tissues by collagenase digestion and differential centrifugation; immunofluorescence (CD90+, CD44+, CD31−, CD45−) was used to confirm ADSC isolation. Telomerase‐immortalized normal, human esophageal squamous cells (NES‐B10T) were seeded into transwells and grown to confluence for 3 days. On day 4, the cells were raised to an air‐liquid interface (ALI) to allow for differentiation, stratification, and formation of an esophageal epithelial barrier. ALI cultures were exposed to conditioned media (CM) from MAs or ADSCs, or to control NES medium beginning at day 4. TER was measured (in Ω·cm2) on days 4, 6, and 8 using the EVOM2 Epithelial Volt/Ohm Meter (World Precision Instruments, Sarasota, FL). On day 10, ALI cultures were stained with H&E and imaged.ResultsCM from ADSCs of SQ and VIS fat from an obese patient did not reduce the TER of NES ALI cultures at any time point; CM from MAs of SQ fat from all 3 patients also did not reduce TER. In contrast, CM from MAs of VIS fat from both obese patients significantly reduced TER on day 6 compared with control medium; TER also remained lower than control on day 8 (Table 1). CM from MAs of VIS fat from the non‐obese patient did not reduce TER of NES ALI cultures at any time point (Table 1). H&E staining demonstrated DIS only in those ALI cultures grown with the CM from MAs of VIS fat from the obese patients.ConclusionsSubstances produced by MAs, but not by ADSCs, in the VIS fat of obese patients impair esophageal epithelial barrier integrity and cause morphologic changes of DIS. No such effects were found for substances produced by MAs in the SQ fat of any patient, or from those produced by MAs in VIS fat of the non‐obese patient. Moreover, VIS fat in the mesentery and at the GEJ exert similar functional and morphologic effects on esophageal barrier formation. We are conducting further investigations to identify the mechanisms underlying the impairment of esophageal barrier formation caused by visceral adiposity, specifically for the GEJ fat pad that surrounds the distal esophagus.Support or Funding InformationBaylor Scott & White Research Institute Transepithelial Resistance (Ω·cm2 ±SEM) of NES on Day 6 and Day 8 of ALI Culture Exposed to Conditioned Media from Mature Adipocytes from Subcutaneous (SQ), Mesenteric, and GEJ Adipocyte Tissues BMI Control Day 6 SQ Day 6 Mesenteric Day 6 GEJ Day 6 Control Day 8 SQ Day 8 Mesenteric Day 8 GEJ Day 8 18 241±2.1 242±2.0 234±2.0 235±2.5 245±3.8 256±2.2 243±4.2 248±7.2 51 212±2.0 204±3.5 194±3.0 * 192±0.5 ** 235±8.5 233±1.0 209±6.5 207±8.0 42 264±3.6 263±5.5 236±2.3 ** 239±3.3 ** 251±2.4 296±45 249±0.9 237±2.6 * *p≤0.05; **p≤0.01 compared with control

Esophageal dysmotility and other preoperative factors associated with acid suppressive therapy after fundoplication

Background and aims: Acid suppressive therapy (AST) is frequently used after fundoplication. Prior studies show that most patients requiring AST after fundoplication have normal esophageal acid exposure and therefore do not need AST. Our aim was to determine the indications for AST use following fundoplication and the associated factors.Methods: Retrospective analysis of patients who underwent fundoplication at our institution between 2006 and 2013 with pre and postoperative esophageal physiologic studies was performed. Demographic data, symptoms, and findings on high resolution manometry, esophageal pH monitoring and upper endoscopy were collected.Results: Three hundred and thirty-nine patients were included with a median follow up time of 12.8[2.6, 47.7] months. Mean age was 59.6 ± 13.3 years and 71.4% were women. Of those, 39.5% went on AST following fundoplication with a median time to AST use of 15.7[2.8, 36.1] months. The most common reason for AST use was heartburn. Only 29% of patients had objective evidence of acid reflux. Preoperative factors associated with AST use following fundoplication were male gender (HR1.6, p = 0.019), esophageal dysmotility (HR1.7, p = 0.004), proton pump inhibitor use (HR2.3, p < 0.001) and prior history of fundoplication (HR1.8, p = 0.006). In those with paraesophageal hernia repair with Collis gastroplasty (N = 182), esophageal dysmotility (HR1.7, p = 0.047) and NSAID use (HR1.9, p = 0.023) were associated with AST use postoperatively.Discussion: AST use is common after fundoplication. Male gender, preoperative esophageal dysmotility, proton pump inhibitor use and redo fundoplication were associated with AST use following fundoplication. In those undergoing combined Collis gastroplasty, preoperative NSAID use and esophageal dysmotility predicted AST use.

The outcome of fundoplication in patients with GERD based on abnormal impedance testing.

The role of impedance testing in selecting patients for antireflux surgery is poorly understood. The aim of this study was to compare the outcomes of patients that underwent antireflux surgery for GERD based on an abnormal pH/abnormal impedance test versus a normal pH/abnormal impedance test. Records of patients who had an abnormal off-medication impedance test (≥ 48 total reflux events) who underwent antireflux surgery were reviewed and divided into two groups: normal [pH-] or abnormal [pH+] esophageal acid exposure (DeMeester score > 14.7). Symptom resolution was compared: scale 1 (no resolution) to 5 (complete resolution). Eighty-two patients met criteria: 44 [pH+] and 38 [pH-]. There were no differences in the demographics or indications for surgery. The frequencies of heartburn and regurgitation symptoms were significantly reduced by fundoplication in both groups. Complete resolution of heartburn was more common in the [pH+] group (90%) compared to the [pH-] group (67%) [p = 0.02]. Resolution of regurgitation was similar in both groups (90% in the [pH+] group vs 79% in the [pH-] group, p = 0.20). The mean dysphagia frequency score decreased for the [pH+] group, but increased in the [pH-] group. New-onset dysphagia was more common in [pH-] patients (23%) compared to [pH+] patients (5%), (p = 0.02). Continued use of PPI medications was significantly more likely in [pH-] group (42%) compared to the [pH+] group (21%). There was no difference in surgical satisfaction rates between groups. Patients with abnormal impedance and increased esophageal acid exposure had significantly better symptom resolution, less dysphagia, and less frequent PPI use with antireflux surgery versus those with normal pH. These findings urge caution in the use of abnormal impedance values with normal esophageal acid exposure for the selection of patients for an antireflux operation.

Objective Evidence of Reflux Control After Magnetic Sphincter Augmentation: One Year Results From a Post Approval Study.

To report 1-year results from a 5-year mandated study. In 2012, the United States Food and Drug Administration approved magnetic sphincter augmentation (MSA) with the LINX Reflux Management System (Torax Medical, Shoreview, MN), a novel device for the surgical treatment of gastroesophageal reflux disease (GERD). Continued assessment of safety and effectiveness has been monitored in a Post Approval Study. Multicenter, prospective study of patients with pathologic acid reflux confirmed by esophageal pH testing undergoing MSA. Predefined clinical outcomes were assessed at the annual visit including a validated, disease-specific questionnaire, esophagogastricduodenoscopy and esophageal pH monitoring, and use of proton pump inhibitors. A total of 200 patients (102 males, 98 females) with a mean age of 48.5 years (range 19.7-71.6) were treated with MSA between March 2013 and August 2015. At 1 year, the mean total acid exposure time decreased from 10.0% at baseline to 3.6%, and 74.4% of patients had normal esophageal acid exposure time (% time pH<4 ≤5.3%). GERD Health-Related Quality of Life scores improved from a median score of 26.0 at baseline to 4.0 at 1 year, with 84% of patients meeting the predefined success criteria of at least a 50% reduction in total GERD Health-Related Quality of Life score compared with baseline. The device removal rate at 1 year was 2.5%. One erosion and no serious adverse events were reported. Safety and effectiveness of magnetic sphincter augmentation has been demonstrated outside of an investigational setting to further confirm MSA as treatment for GERD.

Management options for patients with GERD and persistent symptoms on proton pump inhibitors: recommendations from an expert panel.

The aim of this study was to assess expert gastroenterologists' opinion on treatment for distinct gastroesophageal reflux disease (GERD) profiles characterized by proton pump inhibitor (PPI) unresponsive symptoms. Fourteen esophagologists applied the RAND/UCLA Appropriateness Method to hypothetical scenarios with previously demonstrated GERD (positive pH-metry or endoscopy) and persistent symptoms despite double-dose PPI therapy undergoing pH-impedance monitoring on therapy. A priori thresholds included: esophageal acid exposure (EAE) time >6.0%; symptom-reflux association: symptom index >50% and symptom association probability >95%; >80 reflux events; large hiatal hernia: >3 cm. Primary outcomes were appropriateness of four invasive procedures (laparoscopic fundoplication, magnetic sphincter augmentation, transoral incisionless fundoplication, radiofrequency energy delivery) and preference for pharmacologic/behavioral therapy. Laparoscopic fundoplication was deemed appropriate for elevated EAE, and moderately appropriate for positive symptom-reflux association for regurgitation and a large hiatal hernia with normal EAE. Magnetic sphincter augmentation was deemed moderately appropriate for elevated EAE without a large hiatal hernia. Transoral incisionless fundoplication and radiofrequency energy delivery were not judged appropriate in any scenario. Preference for non-invasive options was as follows: H2RA for elevated EAE, transient lower esophageal sphincter relaxation inhibitors for elevated reflux episodes, and neuromodulation/behavioral therapy for positive symptom-reflux association. For treatment of PPI unresponsive symptoms in proven GERD, expert esophagologists recommend invasive therapy only in the presence of abnormal reflux burden, with or without hiatal hernia, or regurgitation with positive symptom-reflux association and a large hiatus hernia. Non-invasive pharmacologic or behavioral therapies are preferred for all other scenarios.

Ineffective esophageal motility: clinical, manometric, and outcome characteristics in patients with and without abnormal esophageal acid exposure.

The etiology and clinical impact of ineffective esophageal motility (IEM) remain poorly understood. Unless gastroesophageal acid reflux (GERD) is identified, symptomatic patients with IEM are challenging to treat. We sought to determine whether any clinical or functional characteristics could distinguish those patients with IEM and either normal or abnormal esophageal acid exposure.In this retrospective cohort study, we identified 46 consecutive patients presenting with heartburn, and other GER symptoms who underwent clinical, endoscopic, and functional evaluation that included high-resolution manometry (HRM) and ambulatory pH monitoring. IEM was defined using the Chicago Classification criteria (v.3) as ≥50% ineffective swallows (DCI ≤ 450 mmHg.s.cm). Esophageal acid exposure by ambulatory pH monitoring was considered abnormal when total time with esophageal pH < 4 exceeded 4.2%.Of the 46 IEM patients identified, 19 (mean age: 42 years, 37% female), had normal esophageal acid exposure and 27 patients, mean age 54 years, 33% female, evidence of pathologic acid reflux. There was a 12 years age difference between the groups, with those with normal acid exposure being significantly younger (P < 0.01); the mean body mass index (BMI) was 22.6 ± 0.6 in the normal group and 25.4 ± 0.7 in the abnormal group (P < 0.001); otherwise the groups were endoscopically and histologically similar. Symptoms were not discriminatory and heartburn and regurgitation were the most prevalent in both groups. HRM did not discriminate symptomatic patients with IEM and either normal or abnormal esophageal acid exposure. Proton pump inhibition (PPI) therapy was significantly more effective (74% vs. 10%) in patients with pathologic acid reflux (P < 0.001). As pH exposure becomes abnormal in the context of IEM, there is dominance for supine reflux.IEM appears to be an early, primary event, eventually associated with pathologic acid exposure, particularly supine. Higher BMI is also associated with abnormal esophageal acid exposure in such patients. GER symptoms are not discriminatory in patients with IEM with and without underlying pathologic acid reflux. Clinical response to PPI in such patients depends on the presence of esophageal pathologic acid exposure. Those with IEM and normal acid exposure remain symptomatic and mostly resistant to therapy.

Foregut symptoms, somatoform tendencies, and the selection of patients for antireflux surgery.

A large variety of foregut symptoms can occur in patients with gastroesophageal reflux disease (GERD), which can overlap with other disorders such as somatoform disorders and dyspepsia. Due to unclear diagnostic situations, these patients are often not adequately treated. The aim of this study was the evaluation of patients with foregut symptoms, referred for possible antireflux surgery, regarding their relationship with GERD and somatization tendencies based on control data from an unselected population. Symptom evaluation and somatization screening were initiated both in volunteers and in patients with foregut symptoms and GERD. Unselected volunteers from a village population were also evaluated by symptom analysis and for somatisation tendency. In addition, patients with foregut symptoms were diagnosed for GERD, and symptom analysis and psychodiagnostic evaluation were performed. There is no major significant difference in the symptom-spectrum in patients with foregut symptoms, whether they have a proven pathologic acid exposure from GERD or not. The probability for the risk of somatization was 5.6% in the unselected population of nonpatient volunteers (n = 267). In patients with foregut symptoms (n = 750), the probability for the presence of somatoform tendencies was approximately 20%, independent whether these patients had a documented GERD or a normal esophageal acid exposure, implicating further diagnostic work-up for the selection of patients for antireflux surgery. There is a remarkable symptom load and variety in patients with GERD, in patients with foregut symptoms, and in an unselected population of volunteers. There is no difference in the risk for somatization between patients with foregut symptoms and those with documented GERD. Therapeutic decision making especially prior to antireflux surgery requires an awareness of mental and emotional challenges.

Complexity and diversity of gastroesophageal reflux disease phenotypes.

Gastroesophageal reflux disease (GERD) is defined as a condition which develops when the reflux of gastric contents causes troublesome symptoms, impairs quality of life, or leads to mucosal damage or complications. There are two main phenotypic presentations of GERD, the erosive (ERD) and non-erosive reflux disease (NERD), with the latter one representing up to 70% of GERD spectrum. Moreover, patients with GERD can be clinically subdivided into two distinct syndromes: patients with esophageal and extraesophageal symptoms. The diagnosis of NERD should be supported by the evidence that symptoms are due to reflux episodes on the basis of an excess of acid into the esophagus or a positive correlation between symptoms and acid and/or weakly acidic reflux episodes as evidenced by 24-hour impedance-pH monitoring. Patients with normal esophageal acid exposure and no correlation between heartburn and any kind of chemical reflux are considered affected by functional heartburn and do not pertain to the realm of NERD. They do not usually respond to PPI therapy as further empirical criterion and are included in the large group of functional digestive disorders with the expression of altered generation or perception of symptoms at the esophageal level and can often overlap with functional dyspepsia and irritable bowel syndrome.

Prevalence and characteristics of acid gastro-oesophageal reflux disease in Jackhammer oesophagus

BackgroundAn association between acid gastro-oesophageal reflux disease (GERD) and Jackhammer oesophagus has been suggested. AimTo assess the prevalence and characteristics of acid-GERD in Jackhammer oesophagus and the efficacy of proton pump inhibitors. MethodsData and outcomes of patients with Jackhammer oesophagus were assessed. Two groups were compared: (i) GERD, defined by endoscopic oesophagitis or by an increase in acid exposure time or by an acid-hypersensitive oesophagus and (ii) non-GERD defined by normal oesophageal acid exposure without acid-hypersensitive oesophagus. ResultsAmong the 1994 high-resolution manometries performed, 44 Jackhammer oesophagus (2.2%) were included (sex ratio M/F: 19/25; median age: 66 [61–75] years). Nineteen patients (43.2%) had GERD, 16 (36.4%) had no GERD and 9 patients (20.4%) were undetermined. Dysphagia was the predominant symptom (37/43 (86%)). After a median follow-up of 25.3 months [9.6–31.4], dysphagia was improved in 22/36 (61.1%) patients. Dysphagia improvement as well as other symptoms improvement was not associated with GERD status or proton-pump inhibitors use. ConclusionThe prevalence of GERD is high among patients with Jackhammer oesophagus. The rates of symptom improvement in Jackhammer oesophagus were high regardless of the use of proton-pump inhibitors treatment or of the presence of GERD.

Esophageal hypermotility: cause or effect?

Nutcracker esophagus (NE), Jackhammer esophagus (JHE), distal esophageal spasm (DES), and hypertensive lower esophageal sphincter (HTLES) are defined by esophageal manometric findings. Some patients with these esophageal motility disorders also have abnormal gastroesophageal reflux. It is unclear to what extent these patients' symptoms are caused by the motility disorder, the acid reflux, or both. The aim of this study was to determine the effectiveness of laparoscopic Nissen fundoplication (LNF) on esophageal motility disorders, gastroesophageal reflux, and patient symptoms. Between 2007 and 2013, we performed high-resolution esophageal manometry on 3400 patients, and 221 patients were found to have a spastic esophageal motility disorder. The medical records of these patients were reviewed to determine the manometric abnormality, presence of gastroesophageal symptoms, and amount of esophageal acid exposure. In those patients that underwent LNF, we compared pre- and postoperative esophageal motility, gastroesophageal symptom severity, and esophageal acid exposure. Of the 221 patients with spastic motility disorders, 77 had NE, 2 had JHE, 30 had DES, and 112 had HTLES. The most frequently reported primary and secondary symptoms among all patients were: heartburn and/or regurgitation, 69.2%; respiratory, 39.8%; dysphagia, 35.7%; and chest pain, 22.6%. Of the 221 patients, 192 underwent 24-hour pH monitoring, and 103 demonstrated abnormal distal esophageal acid exposure. Abnormal 24-hour pH monitoring was detected in 62% of patients with heartburn and regurgitation, 49% of patients with respiratory symptoms, 36.8 % of patients with dysphagia, and 32.6% of patients with chest pain. Sixty-six of the 103 patients with abnormal 24-hour pH monitoring underwent LNF. Thirty-eight (13NE, 2JHE, 6 DES, and 17 HTLES) of these 66 patients had a minimum of 6-month postoperative follow-up that included clinical evaluation, esophageal manometry, and 24-hour pH monitoring. Postoperatively, all 38 patients had normal distal esophageal acid exposure. Of these 38 patients, symptoms resolved in 28 and improved in 10. Of six patients (one with NE, two JHE, and three with HTLES) that underwent postoperative esophageal manometry, five exhibited normal motility. Typical reflux symptoms are common among patients with esophageal hypermotility disorders. Abnormal 24-hour pH monitoring is present in the majority of patients with who report typical reflux symptoms and almost half of patients who report respiratory symptoms. Conversely, the majority of patients who report dysphagia or chest pain have normal distal esophageal acid exposure. Based on a small number of patients in this study, it also appears that motility disorders often improve after LNF. LNF is associated with resolution or improvement in reflux related symptoms and esophageal motility parameters in patients exhibiting abnormal esophageal acid exposure. This suggests that patient symptoms are due to abnormal acid exposure and not the motility disorder.

Evaluation of Proton Pump Inhibitor-Resistant Nonerosive Reflux Disease by Esophageal Manometry and 24-Hour Esophageal Impedance and pH Monitoring

Background: Patients with proton pump inhibitor (PPI)-resistant nonerosive reflux disease (NERD) include subgroups that have markedly different pathophysiology. This study aimed to clarify the pathophysiology of NERD by esophageal manometry with 24-hour esophageal impedance and pH monitoring. Methods: Eighteen consecutive outpatients referred to our expert center for functional gastrointestinal motility with suspected PPI-resistant NERD were enrolled. Manometry was performed to detect esophageal motility disorders. Subsequently, 24-hour esophageal impedance and pH monitoring was done while patients were on PPI therapy. Results: Manometry revealed 1 case of achalasia, 1 case of nutcracker esophagus and 3 cases of diffuse esophageal spasm. Three patients had ineffective esophageal motility, with impedance and pH monitoring being performed in 2 of them. Esophageal acid exposure (%time pH <4) was normal in both, but the symptom index (SI) was positive for nonacidic reflux in 1 patient. One of the 10 patients with normal esophageal motility had abnormal esophageal acid exposure. The SI was positive for weakly acidic and nonacidic reflux in 3 of the remaining 9 patients with normal esophageal acid exposure. Five of the other 6 patients seemed to have functional heartburn. Conclusion: A substantial percentage (28%) of patients with suspected PPI-resistant NERD had primary esophageal motility disorders. Both nonacidic reflux and weakly acidic reflux are important contributors to the symptoms of patients with PPI-resistant NERD. Esophageal manometry is required to exclude motility disorders, while 24-hour esophageal impedance and pH monitoring is invaluable for assessing symptom-reflux associations and the indications for fundoplication in patients with suspected PPI-resistant NERD.

Lower pH values of weakly acidic refluxes as determinants of heartburn perception in gastroesophageal reflux disease patients with normal esophageal acid exposure.

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.

Tu1101 Basal Cell Hyperplasia and Dilation of Intercellular Spaces Are the Main Histologic Features Associated to the Endoscopic/Impedance-pH Diagnosis of GERD and Its Related Mucosal Integrity Impairment

Background: During pathological assessment of esophageal biopsies several histological features characterizing the diagnosis of microscopic esophagitis [basal cell hyperplasia (BCH), papillary enlongation (PE), dilated intercellular spaces (DIS) and epithelial neutrofilic/eosinophilic infiltration (Neu/Eos)] can be assessed. Limited data are available about the single contribution of these histological abnormalities on the diagnosis of GERD and its related mucosal integrity in well-defined patients with reflux disease. Aim: To determine whether these histological features contribute differently to the diagnosis GERD and to the impairment of mucosal integrity as expressed by baseline impedance (BI) levels. Methods:One hundred and four consecutive patients with typical reflux symptoms underwent upper endoscopy and multiple biopsies were taken at Z-line and 2 cm above it, in order to assess the presence and severity of BCH, PE, DIS and Neu/Eos [0 (absent), 1 (mild), and 2 (marked)]. Within 3 days from endoscopy, patients underwent impedance-pH testing off-therapy. During manual analysis of the impedance-pH tracings, we measured the esophageal acid expsosure time (AET) over the 24 hours and the total (acid + non-acid) number of impedance-detected reflux episodes. We evaluated BI values at 3 and 5cm above the LES, during the overnight rest, for at least 30 minutes after excluding swallows and reflux induced changes. Twenty healthy volunteers (HVs; 11F/9M; mean age 44) who underwent the same procedures were also enrolled as controls. Results:We included 85 patients with an endoscopic/impedancepH diagnosis of GERD (45F/40M; mean age 46) who had esophageal mucosal breaks at upper endoscopy or an abnormal esophageal acid exposure or a normal esophageal acid exposure but a positive reflux-symptom association at impedance-pH testing. Among these patients, BI values at both 3 and 5 cm above the LES positively correlated with the esophageal AET (r2=0.2033, P<0.001 and r2=0.1859, P<0.001, respectively) and the number of impedance-detected reflux episodes (r2=0.1373, P<0.001 and r2=0,1526, P<0.001, respectively). Moreover, as shown in the Table, BCH and DIS were the lesions more significantly correlated with the endoscopic/impedance-pH diagnosis of GERD. No significant correlation was observed between BI values and impedance-pH parameters or histological lesions in HVs (p=ns). Conclusions: BCH and DIS contribute more than PE and Eos/Neu to the endoscopic/ impedance-pH diagnosis of GERD. Moreover, the same lesions seem to play a greater role than PE and Eos/Neu in determining mucosal integrity impairment as expressed by BI values in GERD patients. Overall, BCH and DIS can be considered the histological markers requiring more carefully evaluation during pathologic assessment in order to help the diagnosis of GERD. Correlation of BI levels with ME histologic features

Tu1102 A New Method for Constant Mucosal Contact and Reliable Measurement of Esophageal Mucosal Impedance

Background: During pathological assessment of esophageal biopsies several histological features characterizing the diagnosis of microscopic esophagitis [basal cell hyperplasia (BCH), papillary enlongation (PE), dilated intercellular spaces (DIS) and epithelial neutrofilic/eosinophilic infiltration (Neu/Eos)] can be assessed. Limited data are available about the single contribution of these histological abnormalities on the diagnosis of GERD and its related mucosal integrity in well-defined patients with reflux disease. Aim: To determine whether these histological features contribute differently to the diagnosis GERD and to the impairment of mucosal integrity as expressed by baseline impedance (BI) levels. Methods:One hundred and four consecutive patients with typical reflux symptoms underwent upper endoscopy and multiple biopsies were taken at Z-line and 2 cm above it, in order to assess the presence and severity of BCH, PE, DIS and Neu/Eos [0 (absent), 1 (mild), and 2 (marked)]. Within 3 days from endoscopy, patients underwent impedance-pH testing off-therapy. During manual analysis of the impedance-pH tracings, we measured the esophageal acid expsosure time (AET) over the 24 hours and the total (acid + non-acid) number of impedance-detected reflux episodes. We evaluated BI values at 3 and 5cm above the LES, during the overnight rest, for at least 30 minutes after excluding swallows and reflux induced changes. Twenty healthy volunteers (HVs; 11F/9M; mean age 44) who underwent the same procedures were also enrolled as controls. Results:We included 85 patients with an endoscopic/impedancepH diagnosis of GERD (45F/40M; mean age 46) who had esophageal mucosal breaks at upper endoscopy or an abnormal esophageal acid exposure or a normal esophageal acid exposure but a positive reflux-symptom association at impedance-pH testing. Among these patients, BI values at both 3 and 5 cm above the LES positively correlated with the esophageal AET (r2=0.2033, P<0.001 and r2=0.1859, P<0.001, respectively) and the number of impedance-detected reflux episodes (r2=0.1373, P<0.001 and r2=0,1526, P<0.001, respectively). Moreover, as shown in the Table, BCH and DIS were the lesions more significantly correlated with the endoscopic/impedance-pH diagnosis of GERD. No significant correlation was observed between BI values and impedance-pH parameters or histological lesions in HVs (p=ns). Conclusions: BCH and DIS contribute more than PE and Eos/Neu to the endoscopic/ impedance-pH diagnosis of GERD. Moreover, the same lesions seem to play a greater role than PE and Eos/Neu in determining mucosal integrity impairment as expressed by BI values in GERD patients. Overall, BCH and DIS can be considered the histological markers requiring more carefully evaluation during pathologic assessment in order to help the diagnosis of GERD. Correlation of BI levels with ME histologic features

Tu1104 Objective Identification of Common Daily Activities by Their Manometric Signatures Using Ambulatory Pressure Recording

Background: During pathological assessment of esophageal biopsies several histological features characterizing the diagnosis of microscopic esophagitis [basal cell hyperplasia (BCH), papillary enlongation (PE), dilated intercellular spaces (DIS) and epithelial neutrofilic/eosinophilic infiltration (Neu/Eos)] can be assessed. Limited data are available about the single contribution of these histological abnormalities on the diagnosis of GERD and its related mucosal integrity in well-defined patients with reflux disease. Aim: To determine whether these histological features contribute differently to the diagnosis GERD and to the impairment of mucosal integrity as expressed by baseline impedance (BI) levels. Methods:One hundred and four consecutive patients with typical reflux symptoms underwent upper endoscopy and multiple biopsies were taken at Z-line and 2 cm above it, in order to assess the presence and severity of BCH, PE, DIS and Neu/Eos [0 (absent), 1 (mild), and 2 (marked)]. Within 3 days from endoscopy, patients underwent impedance-pH testing off-therapy. During manual analysis of the impedance-pH tracings, we measured the esophageal acid expsosure time (AET) over the 24 hours and the total (acid + non-acid) number of impedance-detected reflux episodes. We evaluated BI values at 3 and 5cm above the LES, during the overnight rest, for at least 30 minutes after excluding swallows and reflux induced changes. Twenty healthy volunteers (HVs; 11F/9M; mean age 44) who underwent the same procedures were also enrolled as controls. Results:We included 85 patients with an endoscopic/impedancepH diagnosis of GERD (45F/40M; mean age 46) who had esophageal mucosal breaks at upper endoscopy or an abnormal esophageal acid exposure or a normal esophageal acid exposure but a positive reflux-symptom association at impedance-pH testing. Among these patients, BI values at both 3 and 5 cm above the LES positively correlated with the esophageal AET (r2=0.2033, P<0.001 and r2=0.1859, P<0.001, respectively) and the number of impedance-detected reflux episodes (r2=0.1373, P<0.001 and r2=0,1526, P<0.001, respectively). Moreover, as shown in the Table, BCH and DIS were the lesions more significantly correlated with the endoscopic/impedance-pH diagnosis of GERD. No significant correlation was observed between BI values and impedance-pH parameters or histological lesions in HVs (p=ns). Conclusions: BCH and DIS contribute more than PE and Eos/Neu to the endoscopic/ impedance-pH diagnosis of GERD. Moreover, the same lesions seem to play a greater role than PE and Eos/Neu in determining mucosal integrity impairment as expressed by BI values in GERD patients. Overall, BCH and DIS can be considered the histological markers requiring more carefully evaluation during pathologic assessment in order to help the diagnosis of GERD. Correlation of BI levels with ME histologic features

Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis

The pathophysiological mechanisms underlying proton pump inhibitor-refractory reflux oesophagitis has been scarcely studied. To assess impedance-pH parameters relevant to the pathogenesis of refractory reflux oesophagitis. Cases referred for heartburn/regurgitation refractory to high-dosage proton pump inhibitors between January 2008 and December 2012 were reviewed and subdivided into refractory oesophagitis (29 patients, 72% males, median age 50 years), healed oesophagitis (18 patients, 67% males, median age 54 years), and non-erosive reflux disease (49 patients, 53% males, median age 42 years). On-therapy impedance-pH tracings were blindly re-analysed by one observer to assess gastric and oesophageal acid exposure time and chemical clearance as expressed by the post-reflux swallow-induced peristaltic wave index. The median gastric and oesophageal acid exposure time did not differ among the three groups (35%, 34%, 41% and 1.2%, 0.7%, 0.8%, respectively; P>0.05 for all comparisons). A normal oesophageal acid exposure time was found in two thirds of patients with refractory oesophagitis. The post-reflux swallow-induced peristaltic wave index was significantly lower in refractory oesophagitis (16%) than in healed oesophagitis (30%) and non-erosive reflux disease (29%) (P=0.003). Refractory reflux oesophagitis is characterized by impairment of chemical clearance. Adequate acid suppression is found in the majority of patients who would likely not benefit from further proton pump inhibitor dose escalation.

Functional heartburn

Patients with heartburn and normal upper gastrointestinal endoscopy, normal oesophageal acid exposure, no symptom-reflux association and who fail to respond to a proton-pump inhibitor are classified as having functional heartburn (FH). This study aimed (i) to characterize the symptoms and functional abnormalities of patients with FH and (ii) to describe their clinical outcome. Among all patients referred for 24 h multichannel intraluminal impedance-pH (MII-pH), patients with FH were identified. The clinical characteristics and high-resolution oesophageal pressure topography recordings of FH patients were analyzed at the time of the 24-h MII-pH test. A symptom-related and health-related quality-of-life questionnaire was then sent to FH patients to assess the long-term outcome. Forty patients fulfilled the criteria for FH, representing 8.5% of the referred population. Twenty-two months after initial testing, 66% of patients still suffered from heartburn. The rate of mixed reflux (liquid/gas) was higher in patients with persisting heartburn at the final evaluation (63 vs. 50%, P=0.04). Sixty-six per cent of patients had one or more manometric abnormalities. Acid clearance time in MII-pH was significantly higher in patients with weak peristalsis than patients with normal peristalsis (60 ± 45 vs. 31 ± 19 s, P=0.03). A high rate of mixed reflux and/or a manometric abnormality were associated with a higher risk of persistent heartburn. FH is a chronic disorder with persisting symptoms in two-thirds of patients. An increased rate of mixed reflux and/or the presence of manometric abnormalities are associated with a higher risk of persisting symptoms and may help to identify the population with unmet therapeutic needs.