Philip Woodland

In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease

Objective Patients with non-erosive reflux disease (NERD) have impaired oesophageal mucosal integrity (dilated intercellular spaces). Oesophageal mucosal integrity reflects the balance between repeated reflux damage and mucosal recovery. The relationship between mucosal integrity and acid sensitivity is unclear. Oesophageal impedance may be used for in vivo mucosal integrity measurement. We studied acid-induced changes in oesophageal mucosal integrity and acid perception in patients with heartburn. Design 50 patients with heartburn whithout oesophagitis underwent impedance monitoring before, during and after 10 min oesophageal perfusion with neutral (pH6.5) and acid solutions (pH1). Symptoms and impedance were recorded during perfusion. Impedance recovery was assessed for 2 h post-perfusion in ambulatory conditions followed by 24-h impedance-pH study. Results Reflux monitoring discriminated 20 NERD and 30 functional heartburn (FH) patients. Neutral perfusion caused impedance fall that recovered within 10 min. Acid perfusion caused impedance fall with slow recovery: 6.5 Ω/min (IQR 3.3-12.0 Ω/min). Patients with slow recovery (<25th percentile) had lower baseline impedance (1273 Ω ±208 Ω vs. 3220 Ω ±275 Ω ±, p < 0.01) and more frequent acid sensitivity (10/12 vs. 4/12, p = 0.04) than those with fast (>75th percentile) recovery. Patients with NERD had lower baseline impedance (1669 ± 182 Ω vs. 2384 ± 211 Ω, p = 0.02) and slower impedance recovery (6.0 ± 0.9 Ω/min vs. 10.7 ± 1.6 Ω/min, p = 0.03) than patients with FH. Conclusion Impaired mucosal integrity might be the consequence of repeated reflux episodes with slow recovery. Mucosal integrity, recovery capacity and symptom perception are linked. Low basal impedance and slow recovery after acid challenge are associated with increased acid sensitivity.

Assessment and Protection of Esophageal Mucosal Integrity in Patients With Heartburn Without Esophagitis

OBJECTIVES:Intact esophageal mucosal integrity is essential to prevent symptoms during gastroesophageal reflux events. Approximately 70% of patients with heartburn have macroscopically normal esophageal mucosa. In patients with heartburn, persistent functional impairment of esophageal mucosal barrier integrity may underlie remaining symptoms. Topical protection of a functionally vulnerable mucosa may be an attractive therapeutic strategy. We aimed to evaluate esophageal mucosal functional integrity in patients with heartburn without esophagitis, and test the feasibility of an alginate-based topical mucosal protection.METHODS:Three distal esophageal biopsies were obtained from 22 patients with heartburn symptoms, and 22 control subjects. In mini-Ussing chambers, the change in transepithelial electrical resistance (TER) of biopsies when exposed to neutral, weakly acidic, and acidic solutions was measured. The experiment was repeated in a further 10 patients after pretreatment of biopsies with sodium alginate, viscous control, or liquid control “protectant” solutions.RESULTS:Biopsy exposure to neutral solution caused no change in TER. Exposure to weakly acidic and acidic solutions caused a greater reduction in TER in patients than in controls (weakly acid −7.2% (95% confidence interval (CI) −9.9 to −4.5) vs. 3.2% (−2.2 to 8.6), P<0.05; acidic −22.8% (−31.4 to 14.1) vs. −9.4% (−17.2 to −1.6), P<0.01). Topical pretreatment with alginate but not with control solutions prevented the acid-induced decrease in TER (−1% (−5.9 to 3.9) vs. −13.5 (−24.1 to −3.0) vs. −13.2 (−21.7 to −4.8), P<0.05).CONCLUSIONS:Esophageal mucosa in patients with heartburn without esophagitis shows distinct vulnerability to acid and weakly acidic exposures. Experiments in vitro suggest that such vulnerable mucosa may be protected by application of an alginate-containing topical solution.

The refluxate: The impact of its magnitude, composition and distribution

The pathogenesis of gastrointestinal reflux disease is multifactoral. Integral to the disease process is the refluxate itself. The characteristics and composition of the refluxate are dependent on several physiological variables. The refluxate may contain varying concentrations of acid, pepsin, gas, or contents of duodenal reflux (such as bile acid and pancreatic enzymes). Characteristics such as volume and proximal extent of the refluxate, and the chemical content of this refluxate can strongly influence the risk of symptom perception. Strong acid (pH<4) and duodeno-gastro-oesophageal reflux are also implicated in the development of mucosal damage in the form of oesophagitis, Barretts metaplasia and oesophageal adenocarcinoma. The manifestation of disease, however, is not entirely reliant on the refluxate, which must be considered in the context of the genetic, environmental and psychological susceptibility of the individual.

Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa.

Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus were taken, and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03], however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus (P < 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus, but proximal mucosal afferent nerves are in a more superficial location. The enhanced sensitivity to reflux-evoked symptoms of the proximal esophagus most likely has an anatomical basis.

Esophageal mucosal integrity in nonerosive reflux disease.

Gastroesophageal reflux disease, especially when refractory to standard therapy, remains a significant clinical problem. Although symptom pathogenesis in erosive reflux disease is relatively easy to understand, it is less clear how exposure of the macroscopically normal mucosa in nonerosive reflux disease (NERD) is able to cause heartburn. Over recent years it has become apparent that there may be microscopic and functional defects in the esophageal epithelial barrier in NERD, a so-called impairment of esophageal mucosal integrity. This can be expressed in morphologic or in functional terms. Morphologically the epithelium in NERD displays dilated intercellular spaces, which may represent a failed epithelial barrier, probably due to disruption of cell apical junctional complexes. Functionally, the mucosa in NERD displays more permeability to ions and small molecules than that of control subjects. Both morphologic and functional changes can be induced by exposure to refluxate-like solutions in vitro and in vivo. This article summarizes the evidence for impairment of esophageal mucosal integrity, and discusses its possible role in disease pathogenesis.

Increased Prandial Air Swallowing and Postprandial Gas-Liquid Reflux Among Patients Refractory to Proton Pump Inhibitor Therapy

BACKGROUND & AIMS Many patients with gastroesophageal reflux disease (GERD) have persistent reflux despite treatment with proton pump inhibitors (PPIs). Mixed gas-liquid reflux events are more likely to be perceived as symptomatic. We used esophageal impedance monitoring to investigate whether esophageal gas is processed differently among patients with GERD who do and do not respond to PPI therapy. METHODS We performed a prospective study of 44 patients with typical reflux symptoms with high levels of esophageal acid exposure during a 24-hour period; 18 patients were fully responsive, and 26 did not respond to PPI therapy. Twenty-four-hour pH impedance recordings were analyzed for fasting and prandial air swallows and reflux characteristics, including the presence of gas in the refluxate. RESULTS PPI-refractory patients had a higher number (83.1 ± 12.7 vs 47.8 ± 7.3, P < .05) and rate (10.5 ± 1.4 vs 5.9 ± 0.8/10 minutes, P < .05) of prandial air swallows than patients who responded to PPI therapy; they also had a higher number (25.5 ± 4.0 vs 16.8 ± 3.3, P < .05) and proportion (70% ± 0.03% vs 54% ± 0.06%, P < .05) of postprandial, mixed gas-liquid reflux. Symptoms of PPI-refractory patients were more often preceded by mixed gas-liquid reflux events than those of PPI responders. Fasting air swallowing and other reflux characteristics did not differ between patients who did and did not respond to PPIs. CONCLUSIONS Some patients with GERD who do not respond to PPI therapy swallow more air at mealtime than those who respond to PPIs and also have more reflux episodes that contain gas. These factors, combined with mucosal sensitization by previous exposure to acid, could affect perception of symptoms. These patients, who can be identified on standard 24-hour pH impedance monitoring, might be given behavioral therapy to reduce mealtime air swallowing.

Supragastric Belching: Prevalence and Association With Gastroesophageal Reflux Disease and Esophageal Hypomotility

Background/Aims Supragastric belching (SGB) is a phenomenon during which air is sucked into the esophagus and then rapidly expelled through the mouth. Patients often complain of severely impaired quality of life. Our objective was to establish the prevalence of excessive SGB within a high-volume gastrointestinal physiology unit, and evaluate its association with symptoms, esophageal motility and gastresophageal reflux disease. Methods We established normal values for SGB by analyzing 24-hour pH-impedance in 40 healthy asymptomatic volunteers. We searched 2950 consecutive patient reports from our upper GI Physiology Unit (from 2010–2013) for SGB. Symptoms were recorded by a standardized questionnaire evaluating for reflux, dysphagia, and dyspepsia symptoms. We reviewed the predominant symptoms, 24-hour pH-impedance and high-resolution esophageal manometry results. Results Excessive SGB was defined as > 13 per 24 hours. We identified 100 patients with excessive SGB. Ninety-five percent of these patients suffered from typical reflux symptoms, 86% reported excessive belching, and 65% reported dysphagia. Forty-one percent of patients with excessive SGB had pathological acid reflux. Compared to the patients with normal acid exposure these patients trended towards a higher number of SGB episodes. Forty-four percent of patients had esophageal hypomotility. Patients with hypomotility had a significantly higher frequency of SGB compared to those with normal motility (118.3 ± 106.1 vs 80.6 ± 75.7, P = 0.020). Conclusions Increased belching is rarely a symptom in isolation. Pathological acid exposure and hypomotility are associated with more SGB frequency. Whether SGB is a disordered response to other esophageal symptoms or their cause is unclear.

The neurophysiology of the esophagus.

This paper reports on the neurophysiology of the esophagus, including on the uneven distribution of innervation in the esophagus, reflected by the increased sensitivity and perception of gastroesophageal reflux disease (GERD) events in the proximal rather than distal esophagus; the role of the enteric nervous system (ENS) in swallowing; the role of the physiological stress‐responsive systems, including the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis in mediating esophageal pain; the advances in understanding pain mechanisms and brain structure provided by technological imaging advances; investigations into the efficacy of the descending‐pain control system, including diffuse noxious inhibitory control (DNIC); the role of abnormal nervous signaling in afferent pathways in the pathogenesis of Barretts esophagus (BE); and the contribution of the esophageal mucosa to reflux symptoms.

Oesophageal mucosal barrier: a key factor in the pathophysiology of non-erosive reflux disease (NERD) and a potential target for treatment

The stratified squamous epithelium of the oesophageal mucosa usually forms a tight protective barrier against noxious components of gastro-oesophageal reflux (such as acid and bile acids), a necessary function since the distal oesophageal mucosa is exposed to physiological reflux events, even in health. If there is a disruption to the effectiveness of this epithelial barrier (a so-called impairment of the mucosal integrity), its protective function is likely to be compromised, resulting in reflux-induced symptoms. Non-erosive reflux disease (NERD) is the phenotype of gastro-oesophageal reflux disease most frequently encountered in clinical practice, and may be more difficult to treat than erosive reflux disease.1 Contrary to endoscopic appearances, the oesophageal mucosa in patients with NERD is not completely normal and integrity of the mucosal barrier is impaired. This has been demonstrated by morphological and functional studies. In NERD, the basal layer of oesophageal mucosal epithelium demonstrates dilated intercellular spaces (DIS).2 This histological abnormality is not specific for NERD but is related to mucosal exposure to intraluminal acid since it resolves with successful proton pump inhibitors (PPI) therapy.3 Functional studies confirm impairment of oesophageal mucosal integrity in NERD. These studies have been performed both in vitro, in biopsies of NERD patients, and in vivo, by measuring oesophageal baseline impedance. Measurements of trans-epithelial electrical resistance (TEER) (a measure of paracellular permeability to ions), either in tissue sections or in biopsies, are used to interrogate the oesophageal mucosal barrier function. When the mucosa is exposed to solutions containing acid and bile acids, the TEER falls and the magnitude of such reduction correlates with permeability to small molecules (such …

Management of gastro-oesophageal reflux disease symptoms that do not respond to proton pump inhibitors.

Purpose of review Treatment-refractory gastro-oesophageal reflux disease (GERD) remains a significant problem in the gastroenterology clinic. In recent years, several studies have investigated the assessment and treatment of refractory GERD. Recent findings Patients presenting with ‘refractory GERD’ in fact represent a quite heterogeneous group consisting of those with ongoing reflux-related symptoms and those with reflux-unrelated problems such as functional heartburn, dyspepsia or even eosinophilic oesophagitis. The greatest symptom indicators of persistent true reflux are retrosternal burning and acid taste in the mouth alone. Combined pH-impedance studies allow detection of reflux regardless of pH, and weakly acidic reflux has been suggested as a mechanism of residual symptoms in some patients. The use of reflux–symptom association calculations may help to determine the symptom causation, but refinement and outcome studies are needed. New treatments of refractory GERD have been disappointing. Surgery remains an option in very carefully selected patients, but again better outcome studies are required. Summary Careful history and investigation is required in the assessment of the proton pump inhibitor (PPI)-refractory patient. Care to exclude alternative diagnoses is needed, and to phenotype those with reflux-related symptoms. Optimization of PPI therapy may help, as may surgery in selected patients.