Mentore Ribolsi

Dilated Intercellular Spaces of Esophageal Epithelium in Nonerosive Reflux Disease Patients with Physiological Esophageal Acid Exposure

OBJECTIVES:It has been demonstrated that dilation of intercellular spaces of esophageal epithelium is a marker of tissue injury in GERD patients with a pathological esophageal acid exposure time. To evaluate the relationship among ultrastructural changes, acid esophageal exposure, and GERD symptoms, intercellular space diameters have been assessed in nonerosive reflux disease (NERD) patients with/without abnormal acid exposure time.METHODS:Following a pharmacological wash-out, 20 NERD patients underwent upper endoscopy, esophageal manometry, and 24-h pH monitoring. Biopsies were taken at 5 cm above the lower esophageal sphincter and intercellular space diameters were measured on transmission electron microscopy photomicrographs. Seven asymptomatic controls underwent the same protocol.RESULTS:Acid exposure time was in the normal range in all controls and in 11 patients (NERD pH-negative); it was abnormal in 9 patients (NERD pH-positive). Mean intercellular space diameter in NERD pH-negative and in NERD pH-positive patients was three times greater than in controls (1.45 and 1.49 μm vs 0.45, p < 0.001). Mean values of maximum intercellular spaces in all NERD patients were greater, two-fold or more, than those in controls (p < 0.001). No difference in mean and maximal space diameters was observed between NERD pH-positive and pH-negative patients.CONCLUSIONS:Dilation of intercellular spaces is a feature of NERD patients, irrespective of esophageal acid exposure, and can be considered an objective, structural marker of GERD symptoms. Impaired esophageal mucosal resistance, even to small amounts of acid refluxate, plays a key role in the pathophysiology of NERD.

Presence of gas in the refluxate enhances reflux perception in non-erosive patients with physiological acid exposure of the oesophagus

Objective: The mechanisms underlying symptoms in gastro-oesophageal reflux disease, particularly in non-erosive reflux disease (NERD), remain to be fully elucidated. Weakly acidic reflux and the presence of gas in the refluxate could be relevant in the pathogenesis of symptoms. Methods: To assess the relationship between symptoms and weakly acidic, acid and mixed (liquid–gas) reflux, 24 h oesophageal pH–impedance monitoring was performed in 32 NERD and in 20 oesophagitis patients. In 12 NERD patients the study was repeated following 4 weeks treatment with a proton pump inhibitor (PPI). Impedance–pH data were compared with those of 10 asymptomatic controls. Heartburn and acid regurgitation were considered in the analysis of symptoms. Results: 15 NERD patients showed a physiological acid exposure time (pH-negative). Weakly acidic reflux was significantly less frequent in patients (25% (2%), mean (SE)) than in controls (54% (4%), p<0.01). Gas was present in 45–55% of reflux events in patient groups and controls, and decreased following PPI treatment. In NERD pH-negative patients, weakly acidic reflux accounted for 32% (10%) (vs 22% (6%) in NERD pH-positive and 12% (8%) in oesophagitis patients) and mixed reflux for more than two-thirds of all symptom-related refluxes. Multivariate logistic analysis showed that in NERD pH-negative patients, the risk of reflux perception was significantly higher when gas was present in the refluxate (odds ratio, 3.2; 95% CI, 1.2 to 10; p<0.01). Conclusions: The large majority of symptoms, in all patients, are related to acid reflux. In NERD patients, the presence of gas in the refluxate significantly enhances the probability of reflux perception. These patients are also more sensitive to less acidic reflux than oesophagitis patients.

Effect of endoscopic augmentation of the lower oesophageal sphincter (Gatekeeper reflux repair system) on intraoesophageal dynamic characteristics of acid reflux

Background and aims: Improvements in symptoms following endoscopic procedures for gastro-oesophageal reflux disease (GORD) are seldom supported by normalisation of acid exposure time at the distal oesophagus. However, the distribution of gastric acid within the proximal oesophagus is a main determinant of symptom generation in GORD patients. In this study, our aim was to assess the effect of endoscopic insertion of hydrogel expandable prostheses into the oesophageal submucosa on spatiotemporal characteristics of gastro-oesophageal reflux. Methods: Oesophageal manometry and multichannel ambulatory 24 hour pH monitoring were carried out in nine patients before and six months after the endoscopic procedure. Dynamic characteristics of gastro-oesophageal reflux in patients were also compared with those in 13 asymptomatic controls. Results: Acid exposure time (AET) at the distal oesophagus decreased from 11.7% (95% confidence interval 6.1–21.8) at baseline to 7.7% (3.7–11.6) at follow up (NS). Of the nine patients, distal AET normalised in three. AET at the middle (7.6% (2.9–12.3)) and proximal (2.4% (0.1–4.8)) oesophagus decreased significantly in all patients (2.4% (0.3–4.5), p <0.01; 1.2% (0.2–2.2), p<0.05 respectively). Proximal extent of acid events significantly decreased in all patients at follow up (37.3% v 9.5%), reaching values observed in asymptomatic controls. Median GORD health related quality of life scores significantly improved from 35.5 at baseline to 9.4. Conclusions: Despite the lack of a significant improvement in traditional pH variables, endoscopic implant of hydrogel prostheses above the lower oesophageal sphincter significantly decreases proximal spread of acid reflux into oesophageal body. This effect would explain the improvement in symptoms in patients six months after therapy.

Weak peristalsis with large breaks is associated with higher acid exposure and delayed reflux clearance in the supine position in GERD patients.

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

Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease

Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.

Characteristics of the Esophageal Low-Pressure Zone in Healthy Volunteers and Patients With Esophageal Symptoms: Assessment by High-Resolution Manometry

BACKGROUND:Esophageal motility studies in humans have documented a low-pressure zone (LPZ) in the area of transition from striated to smooth muscle. While preliminary studies indicate that a bolus might be retained in this area, the clinical relevance of the LPZ remains unclear.AIM:To investigate a possible relationship between esophageal symptoms and the size of the esophageal LPZ.METHODS:We reviewed high-resolution manometry (HRM) data from patients with esophageal symptoms (dysphagia, chest pain, and heartburn/regurgitation) and asymptomatic volunteers. The proximal border of the LPZ was defined as the point where the amplitude of the proximal contraction wave declined below 30 mmHg, and the distal border as the point where the distal contraction wave first increased above 30 mmHg.RESULTS:The average (± standard error of mean [SEM]) length of the LPZ in 44 asymptomatic individuals was 5.4 ± 0.6 cm and did not differ (P= 0.222) from the LPZ in 64 patients with dysphagia (6.8 ± 0.4 cm), 34 patients with chest pain (6.4 ± 0.6 cm), and 42 patients with gastroesophageal reflux disease (GERD) symptoms (7.0 ± 0.6 cm). These results did not change when the length of the LPZ was corrected for total esophageal length. The time width of the LPZ in asymptomatic individuals (1.6 ± 0.2 s) was shorter than in patients with dysphagia and GERD symptoms (dysphagia 2.4 ± 0.2 s, GERD symptoms 2.8 ± 0.3 s).CONCLUSION:A time delay between the proximal and distal esophageal contraction waves might be a meaningful variable in GERD and dysphagia.

Reflux pattern and role of impedance-pH variables in predicting PPI response in patients with suspected GERD-related chronic cough.

Gastro‐oesophageal reflux disease (GERD) may contribute to the onset of chronic cough (CC); however, the multichannel intraluminal impedance‐pH (MII‐pH) monitoring is often within the normal range and the response to proton pump inhibitors (PPIs) unsatisfactory. The measure of impedance baseline (IB) increases the sensitivity of MII‐pH in patients with typical symptoms.

Impedance baseline and reflux perception in responder and non-responder non-erosive reflux disease patients

Abstract Background. It was recently shown that GERD patients have lower impedance baseline (IB) values than healthy controls and, that the esophageal acid exposure time (AET) correlates with IB levels. Goals. To explore the sensitivity of IB measurements in NERD patients, responders and non-responders to PPIs, when compared with pH-impedance (MII-pH) variables, and to evaluate whether this variable could represent a marker of GERD symptoms. Reproducibility and inter-observer agreement of IB measurement were also assessed. Study. MII-pH tracings from 44 NERD responders and 22 non-responders were analysed. Ten healthy volunteers underwent the same protocol. IB values were measured at the distal and proximal esophagus. IB was also analysed in a subgroup of patients and in controls with two methods and by two blinded operators. Results. Mean IB values at the distal esophagus were significantly lower in NERD patients than in controls. IB values did not differ between responders and non-responders. Of the 8 responders with negative AET and symptom association probability (SAP), 3 (37.5%) showed IB values lower than controls. IB values in responders with positive and negative SAP were similar (1832 (1596–2068) Ω vs 1667 (1361–1973) Ω, p: n.s.). No differences were found between the IB values measured with the two methods and the inter-observer agreement was good. Conclusions. IB is a promising and easy to calculate MII-pH variable and appears to increase the sensitivity of MII-pH monitoring. IB values cannot predict PPI response and are not associated with reflux perception in NERD patients.

Increased frequency and enhanced perception of reflux in non-erosive reflux disease patients non-responders to proton pump inhibitors.

BACKGROUND The unsatisfactory response to medical treatment in non-erosive patients is becoming a real challenge for gastroenterologists. Non-responder patients, evaluated under treatment, present symptoms which are related to non-acidic, mixed and proximal reflux episodes. METHODS To elucidate the reflux pattern and mechanisms related to persistence of symptoms despite treatment, oesophageal pH-impedance was performed in 55 non-erosive responder and 24 non-responder patients, studied off therapy. Ten responder and 10 non-responder patients underwent a repeated study during proton pump inhibitor treatment. RESULTS Non-responders were characterised by a higher overall number and larger proportion of symptomatic reflux episodes. Non-responders were also characterised by an enhanced sensitivity to acidic, mixed and proximal refluxes. Weakly acidic reflux accounted for 29% of symptomatic refluxes in non-responders and 34% in responders. Proportions of acidic and weakly acidic reflux episodes were comparable both in responders and non-responders when analysed off and on treatment. CONCLUSIONS An increased overall number of reflux episodes and enhanced sensitivity to reflux are strongly associated with treatment failure. Treatment strategies aimed at decreasing transient lower oesophageal sphincter relaxations, pain modulators or anti-reflux surgery should be considered in non-responders in whom a significant relationship between symptoms and reflux has been confirmed.

Effect of oesophagitis on proximal extent of gastro‐oesophageal reflux

Abstract  Proximal oesophageal acid reflux is increased in gastro‐oesophageal reflux disease (GORD) patients with oesophageal and extra‐oesophageal symptoms, the latter particularly in presence of oesophagitis. This study was aimed to assess the proximal extent of reflux, both acid and weakly acidic, in GORD patients with and without oesophagitis and to characterize, using an animal model of GORD, the relationship between acute oesophagitis and proximal extent of reflux. Proximal extent of reflux was evaluated during 24‐h pH‐impedance monitoring in 17 oesophagitis, 27 non‐erosive reflux disease (NERD) patients and 10 asymptomatic controls. In five adult cats, reflux events were simulated by intra‐oesophageal retrograde injection of a radiopaque solution. Proximal extent of simulated reflux was fluoroscopically assessed before and after inducing acute oesophagitis. The percentage of proximal reflux was 11% in controls, 22% in NERD and 38% in oesophagitis patients (P < 0.05 vs NERD). Weakly acidic reflux showed higher proximal extent in oesophagitis than in NERD patients but it was less proximally propagated than acid reflux. In cats, proximal reflux was significantly increased during acute oesophagitis. Oesophagitis patients show higher proximal extent of reflux, acid and weakly acidic, when compared with NERD patients and controls. In the experimental model, acute oesophagitis favours proximal migration of simulated reflux.