Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus.

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors.

The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.

Weak acids induce PGE2 production in human oesophageal cells: novel mechanisms underlying GERD symptoms.

The role of weak acids with pH values in the range of 4-7 has been implicated in the symptoms of gastroesophageal reflux disease (GERD). Prostaglandin E2 (PGE2) is associated with heartburn symptom in GERD patients; however, the precise productive mechanisms remain unclear. In this study, we revealed that exposure to weak acids increases PGE2 production with a peak at pH 4-5, slightly in human normal oesophageal cells (Het-1A), and robustly in oesophageal squamous carcinoma cells (KYSE-270). Release of PGE2 from the oesophageal mucosa was augmented by weak acid treatment in rat. Chenodeoxycholic acid (CDCA), a bile acid, upregulated cyclooxygenase-2 (COX-2) expression in Het-1A and KYSE-270 and induced PGE2 production in KYSE-270 cells. Weak acid-induced PGE2 production was significantly inhibited by cytosolic phospholipase A2 (cPLA2), ERK, and transient receptor potential cation channel subfamily V member 4 (TRPV4), a pH-sensing ion channel, inhibitors. Hangeshashinto, a potent inhibitor of COX-2, strongly decreased weak acid- and CDCA-induced PGE2 levels in KYSE-270. These results indicated that weak acids induce PGE2 production via TRPV4/ERK/cPLA2 in oesophageal epithelial cells, suggesting a role in GERD symptoms like heartburn. Interventions targeting pH values up to 5 may be necessary for the treatment of GERD.

Duration of adhesion of swallowed alginates to distal oesophageal mucosa: implications for topical therapy of oesophageal diseases.

BACKGROUND: We have previously shown, ex vivo, that alginate solutions can have a topical protective effect on oesophageal mucosal biopsies exposed to simulated gastric juice. Oesophageal mucosal impedance can measure the duration of mucosal adherence of ionic solutions since the impedance drops when the solution is present, and rises to baseline as the solution clears. AIM: To investigate the in vivo duration of adhesion of swallowed alginate solution to distal oesophageal mucosa. METHODS: We studied 20 healthy volunteers and 10 patients with heartburn. A pH-impedance catheter was inserted, and baseline distal channel oesophageal impedance measured. Healthy volunteers received 10 mL of either sodium alginate (Gaviscon Advance), Gaviscon placebo (no alginate) or viscous slurry (saline mixed with sucralose), given in a randomised, single-blinded order over three visits. Patients received either sodium alginate or placebo on two visits. Initial impedance drop was measured, then 1-minute mean impedance was measured each minute until ≥75% recovery to baseline. RESULTS: In healthy volunteers, sodium alginate adhered to the oesophageal mucosa for longer than placebo or viscous slurry (10.4 [8.7] minutes vs 1.1 [1.6] vs 3.6 [4.0], P < 0.01). In patients, sodium alginate adhered to the oesophageal mucosa for longer than placebo (9.0 (5.4) vs 3.7 (4.1), P < 0.01). CONCLUSIONS: Sodium alginate solution adhered to the oesophageal mucosa for significantly longer than placebo or viscous slurry. This demonstrates that alginates could confer a protective benefit due to mucoadhesion and can be a basis for further development of topical protectants and for topical drug delivery in oesophageal disease.

Mucosal integrity and sensitivity to acid in the proximal esophagus in patients with gastroesophageal reflux disease.

Acid reflux episodes that extend to the proximal esophagus are more likely to be perceived. This suggests that the proximal esophagus is more sensitive to acid than the distal esophagus, which could be caused by impaired mucosal integrity in the proximal esophagus. Our aim was to explore sensitivity to acid and mucosal integrity in different segments of the esophagus. We used a prospective observational study, including 12 patients with gastroesophageal reflux disease (GERD). After stopping acid secretion-inhibiting medication, two procedures were performed: an acid perfusion test and an upper endoscopy with electrical tissue impedance spectroscopy and esophageal biopsies. Proximal and distal sensitivity to acid and tissue impedance were measured in vivo, and mucosal permeability and epithelial intercellular spaces at different esophageal levels were measured in vitro. Mean lag time to heartburn perception was much shorter after proximal acid perfusion (0.8 min) than after distal acid perfusion (3.9 min) (P = 0.02). Median in vivo tissue impedance was significantly lower in the distal esophagus (4,563 Ω·m) compared with the proximal esophagus (8,170 Ω·m) (P = 0.002). Transepithelial permeability, as measured by the median fluorescein flux was significantly higher in the distal (2,051 nmol·cm(-2)·h(-1)) than in the proximal segment (368 nmol·cm(-2)·h(-1)) (P = 0.033). Intercellular space ratio and maximum heartburn intensity were not significantly different between the proximal and distal esophagus. In GERD patients off acid secretion-inhibiting medication, acid exposure in the proximal segment of the esophagus provokes symptoms earlier than acid exposure in the distal esophagus, whereas mucosal integrity is impaired more in the distal esophagus. These findings indicate that the enhanced sensitivity to proximal reflux episodes is not explained by increased mucosal permeability.

Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn.

BACKGROUND: Patients with functional heartburn (FH) experience troublesome heartburn that is not related to gastroesophageal reflux. The etiology of the heartburn sensation in FH patients is unknown. In patients with reflux disease, esophageal hypersensitivity seems associated with impaired mucosal integrity. We aimed to determine esophageal sensitivity and mucosal integrity in FH and non-erosive reflux disease (NERD) patients. METHODS: In this prospective experimental study, we performed an acid perfusion test and upper endoscopy with biopsies in 12 patients with NERD and nine patients with FH. Mucosal integrity was measured during endoscopy using electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance and transepithelial permeability. KEY RESULTS: Lag time to heartburn perception was significantly longer in FH patients (median 12 min) than in NERD patients (median 3 min). Once perceived, intensity of heartburn was scored equal with median visual analog scale 6.5 and 7.1 respectively. Esophageal mucosal integrity was also comparable between FH and NERD patients, both in vivo extracellular impedance and ex vivo transepithelial resistance and permeability were similar. CONCLUSIONS & INFERENCES: Patients with FH did not show acid hypersensitivity as seen in patients with NERD. However, once perceived, intensity of heartburn is similar. Esophageal mucosal integrity is similar between NERD and FH patients, and is therefore unlikely to be the underlying cause of the observed difference in esophageal acid perception.

Esophageal Epithelial-Derived IL-33 Is Upregulated in Patients with Heartburn.

BACKGROUND: Interleukin-33 (IL-33) is a tissue-derived cytokine that is constitutively expressed in epithelial cells of tissues exposed to the environment and plays a role in sensing damage caused by inflammatory diseases. IL-33 acts as both a traditional cytokine and as a chromatin-associated nuclear factor in both innate and adaptive immunity. We recently showed that IL-33 in esophageal mucosa is upregulated in reflux esophagitis. However, IL-33 expression in patients with heartburn without mucosal injury and its relationship with intercellular space (ICS) have never been examined. We therefore examined the expression of cytokines and ICS in patients with heartburn. METHODS: The expression of IL-33 in the middle and distal esophageal mucosa of patients with heartburn without mucosal break and control samples was examined using real-time RT-PCR and immunofluorescence. The mRNA expression of IL-6, IL-8, MCP-1, and RANTES, and ICS was also analyzed. RESULTS: IL-33 expression and the mean ICS were significantly increased in the mucosa of patients with heartburn compared to that of the control. IL-33 and ICS were not different between the patients who were taking a PPI and those who were not. The upregulated IL-33 expression in the heartburn group was located in the nuclei of the basal cell layer. Although IL-6, IL-8, MCP-1 and RANTES levels were not different between control and patients with heartburn samples, IL-33 mRNA levels were still significantly correlated with IL-6, IL-8, or MCP-1 mRNA levels. CONCLUSION: Nuclear IL-33 is upregulated in patients with heartburn. Upregulated IL-33 in heartburn patients is related to the symptoms.

Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis.

Increased esophageal sensitivity and impaired mucosal integrity have both been described in patients with gastroesophageal reflux disease, but the relationship between hypersensitivity and mucosal integrity is unclear. The aim of the present study was to investigate acid sensitivity in patients with erosive and nonerosive reflux disease and control subjects to determine the relation with functional esophageal mucosal integrity changes as well as to investigate cellular mechanisms of impaired mucosal integrity in these patients. In this prospective experimental study, 12 patients with nonerosive reflux disease, 12 patients with esophagitis grade A or B, and 11 healthy control subjects underwent an acid perfusion test and upper endoscopy. Mucosal integrity was measured during endoscopy by electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance, transepithelial permeability and gene expression of tight junction proteins and filaggrin. Patients with nonerosive reflux disease and esophagitis were more sensitive to acid perfusion compared with control subjects, having a shorter time to perception of heartburn and higher perceived intensity of heartburn. In reflux patients, enhanced acid sensitivity was associated with impairment of in vivo and vitro esophageal mucosal integrity. Mucosal integrity was significantly impaired in patients with esophagitis, displaying higher transepithelial permeability and lower extracellular impedance. Although no significant differences in the expression of tight junction proteins were found in biopsies among patient groups, mucosal integrity parameters in reflux patients correlated negatively with the expression of filaggrin. In conclusion, sensitivity to acid is enhanced in patients with gastroesophageal reflux disease, irrespective of the presence of erosions, and is associated with impaired esophageal mucosal integrity. Mucosal integrity of the esophagus is associated with the expression of filaggrin.

Prostaglandin E(2) mediates acid-induced heartburn in healthy volunteers.

Prostaglandin E(2) (PGE(2)) plays a major role in pain processing and hypersensitivity. This study investigated whether PGE(2) levels are increased in the esophageal mucosa after acid infusion and whether increases in PGE(2) are associated with heartburn. Furthermore, expression of the PGE(2) receptor EP1 was investigated in human esophageal mucosa. Fourteen healthy male volunteers were randomized to 30-min lower esophageal acid (1% HCl) or saline perfusion. Before and after acid perfusion, endoscopic biopsies were taken from the distal esophagus. PGE(2) concentration (pg/mg protein) and EP1 mRNA and protein in biopsy samples were measured by ELISA, RT-PCR, and Western blotting. Symptom status of heartburn was evaluated with a validated categorical rating scale with a higher values corresponding to increasing intensity. PGE(2) levels in the esophageal mucosa significantly increased after acid infusion (before vs. after acid infusion: 23.2 ± 8.6 vs. 68.6 ± 18.3, P < 0.05), but not after saline infusion (before vs. after saline infusion: 9.3 ± 2.5 vs. 9.0 ± 3.2, NS). Time to first sensation (min) after acid infusion was less than after saline (saline vs. acid infusion: 22.1 ± 4.1 vs. 5.4 ± 1.5, P < 0.05). Intensity of heartburn in the acid-infusion group was also significantly greater compared with saline (saline vs. acid infusion: 54.3 ± 13.1 vs. 178.5 ± 22.8, P < 0.01). Changes in PGE(2) levels in the esophagus correlated with symptom intensity score (r = 0.80, P = 0.029). EP1 mRNA and protein expression were observed in the normal human esophageal mucosa. Esophageal PGE(2) expression is associated with mucosal acid exposure and heartburn.

Functional chest pain responds to biofeedback treatment but functional heartburn does not: what is the difference?

BACKGROUND: Patients with functional esophageal disorders represent a challenging treatment group. The purpose of this study was to evaluate the role of biofeedback in the treatment of patients with functional esophageal disorders. METHODS: In this prospective study, patients with typical/atypical symptoms of gastroesophageal reflux disease underwent upper endoscopy and 24-h pH monitoring. All patients filled out gastroesophageal Reflux Disease Symptom, Hospital Anxiety and Depression, and Symptom Stress Rating questionnaires. Patients with functional heartburn and those with functional chest pain were offered biofeedback treatment. A global assessment questionnaire was filled out at the end of treatment and then 2.8 (range 1-4) years later. RESULTS: From January 2006 to December 2009, 22 patients with functional esophageal diseases were included in the study. Thirteen had functional heartburn and nine had functional chest pain. Six patients from each group received biofeedback treatment. After treatment for 1-4 years, patients with functional chest pain showed significant improvements in symptoms compared with those who were not treated. Patients with functional heartburn showed no improvement. Patients with functional chest pain had a longer time of esophageal acid exposure than those with functional heartburn. CONCLUSION: Patients with functional chest pain have different central and intraesophageal factors associated with symptom generation in comparison with patients with functional heartburn. Biofeedback is a useful tool in the treatment of patients with functional chest pain, but not for those with functional heartburn.

Dietary nitrate may have a role in development of gastro-esophageal reflux disease.

BACKGROUND: Gastro-esophageal reflux disease (GERD) has become very common in the past three decades. The reason for this, as well as its exact pathophysiologic mechanisms are yet unknown. In this ecologic study we assessed the relation between water nitrate content and prevalence of GERD in Tehran, Iran. METHODS: We determined the prevalence of acid regurgitation, heartburn or any of them occurring on a frequent (at least weekly) or infrequent basis in areas with different water nitrate. The areas for nitrate were defined as below: <50 mg nitrate/L, 50-74 mg/L, 75-100 mg/L, and >100 mg/L. Frequency of each symptom was assessed in each area and compared. Adjustment for age, sex, education, NSAID-consumption, BMI, smoking, history of GERD in first degree relatives and spouse was done in a multivariate model. RESULTS: People living in areas with water nitrate content more than 100mg/L had a higher chance of suffering from frequent AR than those living in areas with water nitrate less than 100mg/L (25.5% vs. 12.0%, OR: 2.53, 95% CI: 1.36-4.73, P=0.006). After adjustment for the named factors, the relationship remained significant (OR: 3.65, 95% CI: 1.32-10.09). The relation for frequent heartburn or infrequent symptoms was not significant. CONCLUSION: In this ecologic study, we found a relation between experiencing frequent AR and drinking or cooking with water containing more than 100mg nitrate/L. Considering our current knowledge, if we put dietary nitrate into the puzzle of increased prevalence and/or pathophysiology of GERD, it can theoretically answer several questions. Hence we propose a nitrate-hypothesis for GERD pathogenesis.

The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease.

INTRODUCTION: Functional heartburn is defined by Rome III criteria as an endoscopy-negative condition with normal oesophageal acid exposure time, negative symptom association to acid reflux and unsatisfactory response to proton pump inhibitors. These criteria underestimated the role of non-acid reflux. AIM: To assess the contribution of impedance-pH with symptom association probability (SAP) analysis in identifying endoscopy-negative patients with reflux disease and separating them from functional heartburn. METHODS: Consecutive endoscopy-negative patients treated with proton pump inhibitors (n=219) undergoing impedance-pH monitoring off-therapy were analysed. Distal acid exposure time, reflux episodes, SAP and symptomatic response to proton pump inhibitors were measured. RESULTS: Based on impedance-pH/SAP, 67 (31%) patients were pH+/SAP+, 6 (2%) pH+/SAP-, 83 (38%) hypersensitive oesophagus and 63 (29%) functional heartburn. According to pH-metry alone/response to proton pump inhibitors, 62 (28%) were pH+/SAP+, 11 (5%) pH+/SAP-, 61 (28%) hypersensitive oesophagus and 85 (39%) functional heartburn. In the normal-acid exposure population the contribution of impedance-pH/SAP compared to pH-metry alone/response to proton pump inhibitors in identifying patients with reflux disease and functional heartburn resulted to be 10%. In patients with abnormal-acid exposure, the contribution of impedance-pH/SAP increased by 3%. CONCLUSION: Comparing impedance-pH testing with pH-metry alone plus the response to proton pump inhibitor therapy demonstrated that the latter ones cause underestimation of reflux disease patients and overestimation of functional heartburn patients.

The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms.

Heartburn is the most common and characteristic symptom of gastroesophageal reflux disease. It ultimately results from contact of refluxed gastric acid with nociceptors within the esophageal mucosa and transmission of this peripheral signal to the central nervous system for cognition. Healthy esophageal epithelium provides an effective barrier between refluxed gastric acid and esophageal nociceptors; but this barrier is vulnerable to attack and damage, particularly by acidic gastric contents. How gastric acid is countered by defensive elements within the esophageal mucosa is a major focus of this discussion. When the defense is successful, the subject is asymptomatic and when unsuccessful, the subject experiences heartburn. Those with heartburn commonly fall into one of three endoscopic types: nonerosive reflux disease, erosive esophagitis and Barrett's esophagus. Although what determines endoscopic type remains unknown; it is proposed herein that inflammation plays a key, modulating role.

Recurrent symptoms after fundoplication with a negative pH study--recurrent reflux or functional heartburn?

INTRODUCTION: A small cohort of patients present after antireflux surgery complaining of recurrent heartburn. Over two thirds of these patients will have a negative 24-h pH study. The aim of our study is to determine whether these patients have an associated functional disorder or abnormal cytokine activity and to examine the reproducibility of pH testing. METHODS: A prospective analysis was carried out on a cohort of patients who had undergone a fundoplication and postoperative pH testing for recurrent heartburn: group A--patients with recurrent heartburn and a negative 24-h pH study and group B (control group)--patients with recurrent heartburn and a positive pH study. Questionnaires, a blood sample, and repeat pH testing were completed. RESULTS: Sixty-nine patients were identified. Group A's depression score (8.6 +/- 4.1) was significantly higher than group B's (5.9 +/- 4.2; P = 0.03). Cytokine levels were similar in both groups. Forty-seven of 49 (96%) patients who underwent repeat pH testing had a negative study. Symptom-reflux correlation was highly significant (P < 0.001). CONCLUSION: Some patients with recurrent heartburn and a negative pH study have associated functional or psychiatric comorbidities such as depression. Reproducibility of 24-h pH testing in these patients is excellent.

Acid-related oesophageal sensitivity, not dysmotility, differentiates subgroups of patients with non-erosive reflux disease.

BACKGROUND: Patients with non-erosive reflux disease can experience reflux symptoms with similar frequency and severity as those with erosive reflux disease. Oesophageal motility and acid sensitivity are thought to influence symptom occurrence. AIM: To compare the effect of infused hydrochloric acid on oesophageal physiology in patients with non-erosive reflux disease and erosive reflux disease. METHODS: Twelve healthy controls and 39 patients with reflux disease [14 erosive reflux disease, 11 non-erosive reflux disease with normal (functional heartburn) and 14 non-erosive reflux disease with excess acid exposure] had hydrochloric acid and saline infused into distal and then proximal oesophagus. Oesophageal contraction amplitude, lower oesophageal sphincter pressure and pain intensity were documented at baseline and during each infusion. RESULTS: Patients with non-erosive reflux disease had higher pain sensitivity to acid than those with erosive reflux disease and controls. Proximal acid infusion caused greater pain than distal in patients with non-erosive reflux disease. Acid and saline sensitivity were more pronounced in patients with functional heartburn. Lower oesophageal sphincter pressure and oesophageal contraction amplitudes were lower in the erosive reflux disease and non-erosive reflux disease groups, but did not change during infusions. CONCLUSIONS: Patients with non-erosive reflux disease and, to a lesser extent, patients with erosive reflux disease, are sensitive to acid in the oesophagus, being more sensitive to proximal acid. Hypersensitivity is most marked in functional heartburn patients. This acid sensitivity is not associated with motility change.

Comparisons of the distribution of oesophageal acid exposure throughout the sleep period among the different gastro-oesophageal reflux disease groups.

BACKGROUND: Nocturnal gastro-oesophageal reflux diseases (GERD) can lead to oesophageal mucosal injury and extra-oesophageal complications. AIM: To compare distribution of oesophageal acid exposure during sleep time among patients with non-erosive reflux disease and abnormal pH test (NERD-positive), erosive oesophagitis (EO) and Barrett's oesophagus (BO). METHODS: Patients underwent endoscopy followed by 24-h oesophageal pH testing. Oesophageal acid exposure was assessed every 2 h of the sleep period (0-2, 2-4, 4-6 and 6-8 h). Each period of 2 h was evaluated for acid reflux parameters. All groups were matched by age, time from last meal and duration of sleep time. RESULTS: Thirty-eight patients were enrolled (NERD-positive, 16; EO, 1.4; and BO, 8). All GERD groups demonstrated higher oesophageal acid exposure in the first vs. second half of the sleep period as determined by percent time pH <4 (BO: 34.7 vs.11.6, EO: 13.5 vs. 6.9, NERD-positive: 8.8 vs. 2.5, all P < 0.01). In general, patients with BO had a significantly higher distribution of oesophageal acid exposure than those with NERD-positive and EO. CONCLUSIONS: Oesophageal acid exposure generally declines throughout the sleep period regardless of GERD group, but BO patients demonstrated the greatest decline during the sleep period.

The extent of oesophageal acid exposure overlap among the different gastro-oesophageal reflux disease groups.

BACKGROUND: Studies have demonstrated that patients with Barrett's oesophagus have the highest oesophageal acid exposure profile, followed by erosive oesophagitis and non-erosive reflux disease patients, but the exact extent of overlap remains unknown. AIM: To determine the extent of overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups. METHODS: A total of 121 patients with gastro-oesophageal reflux disease underwent an upper endoscopy and were classified as having Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-all (non-erosive reflux disease-positive and functional heartburn). Subsequently, patients underwent pH testing and overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups was determined. RESULTS: Of those enrolled, 24 had Barrett's oesophagus, 30 erosive oesophagitis and 28 were non-erosive reflux disease-positive. Mean oesophageal acid exposure time was 224.8 +/- 35, 134.3 +/- 21.9 and 141.3 +/- 19.8 min for Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-positive respectively. Per cent overlap for total, upright and supine time between non-erosive reflux disease-positive and erosive oesophagitis was 47.4%, 64.7% and 81.8%, between Barrett's oesophagus and erosive oesophagitis was 47.8%, 40.7% and 24%, and between Barrett's oesophagus and non-erosive reflux disease-positive was 31.6%, 37.5% and 20.8% respectively. CONCLUSIONS: Our study demonstrated a high oesophageal acid exposure overlap between patients with non-erosive reflux disease-positive and erosive oesophagitis, Barrett's oesophagus and erosive oesophagitis, as well as Barrett's oesophagus and non-erosive reflux disease-positive patients.

Patients with functional heartburn are more likely to report retrosternal discomfort during wireless pH monitoring.

BACKGROUND: Although the wireless Bravo pH system is effective, some patients experience retrosternal sensations possibly caused by esophageal sensitivity that may complicate clinical application. METHODS: Ambulatory pH of 40 consecutive patients with GERD who had erosive esophagitis or nonerosive reflux disease, were monitored for 2 days with the Bravo system. Results were stratified and compared on the basis of self-awareness of the intraesophageal capsule. RESULTS: Pathologic acid reflux was diagnosed in 20 patients and normal reflux was diagnosed in 20 patients. Seventeen patients (42.5%) reported retrosternal discomfort, and 12 of them (70.6%) had normal reflux. Patients with retrosternal discomfort were less likely to have moderate endoscopic esophagitis, i.e., Los Angeles classification grades B, C, and D endoscopic esophagitis (p = 0.006), and were less likely to have significantly elevated esophageal acid exposure (p = 0.0036) than those who did not perceive the discomfort. Reported discomfort was not associated with age, gender, or the presence of endoscopic esophagitis. CONCLUSIONS: The negative correlation between Bravo-capsule-induced retrosternal discomfort and esophageal-acid exposure indicates modified mechanical afferent nerve function after long-term acid stimulation. Capsule-induced retrosternal discomfort in the presence of normal acid exposure suggests functional heartburn.

Relief of reflux symptoms after endoscopic gastroplication may be associated with reduced esophageal Acid sensitivity: a pilot study.

BACKGROUND AND STUDY AIMS: Although the new endoscopic techniques for the treatment of gastroesophageal reflux disease (GERD) lead to marked clinical benefit, the underlying mechanism of this is unknown. MATERIALS AND METHODS: In this prospective study, the effect of endoscopic gastroplication was investigated in six patients with GERD, who were assessed before and 4 weeks after treatment. The effect on reflux symptoms, quality of life, proton pump inhibitor (PPI) consumption, reflux esophagitis, acid exposure, esophageal motility, lower esophageal sphincter pressure (LESP), and gastric emptying was measured. Esophageal acid sensitivity before and after treatment was investigated using a standardized acid provocation test, and compared with that of six age- and sex-matched healthy controls. RESULTS: Significant clinical benefit and discontinuation of PPI consumption after gastroplication was seen. Among the objectively measured parameters, only acid exposure was significantly reduced and gastric emptying significantly delayed. However, acid exposure remained pathologically high. Esophageal acid sensitivity was significantly reduced. The induction of heartburn and/or pain was abolished in four patients after gastroplication. In two patients the intensity of heartburn/pain was significantly reduced by 40 % or 60 %, and the time to provoke heartburn/pain significantly prolonged by 40% or 100%. CONCLUSION: These preliminary data suggest that the decrease of esophageal sensitivity to acid after endoscopic gastroplication is part of the mechanism responsible for the reduction of reflux symptoms.

Efficacy of a pectin-based anti-reflux agent on acid reflux and recurrence of symptoms and oesophagitis in gastro-oesophageal reflux disease.

OBJECTIVE: Gastro-oesophageal reflux disease may be treated with a drug forming a floating neutral raft in the stomach. The pectin-based raft-forming anti-reflux agent Aflurax (Idoflux) was examined, first regarding reduction of oesophageal acid exposure, and next as to its efficacy as maintenance treatment in patients with healed oesophagitis. DESIGN: Double-blind, placebo-controlled randomized clinical trials. SETTING: Open access endoscopy unit. PARTICIPANTS: Fourteen patients with erosive oesophagitis had measurement of acid exposure. Eighty-eight patients with healed erosive/ulcerative oesophagitis and relief of heartburn after pre-treatment with omeprazole received maintenance treatment. INTERVENTIONS: Crossover 12-h oesophageal pH monitoring during Aflurax/placebo treatment. Maintenance treatment for up to 6 months with two tablets of Aflurax 1200 mg or placebo four times daily. MAIN OUTCOME MEASURES: Percentage time pH less than 4 in 6 plus 6 h (upright + supine). Time to recurrence of moderate or severe heartburn (life table analysis). RESULTS: The median (interquartile range) acid exposure times in the upright position were: 3.1% (1.6-13.0%) on Aflurax versus 6.7% (2.5-14.9%) on placebo (P = 0.10). In the supine position no difference was found (Aflurax 13.7%, placebo 13.2%). The time to recurrence of heartburn with Aflurax treatment was prolonged significantly; after 6 months the life table estimates were 48% of patients in remission on Aflurax versus 8% on placebo (P = 0.01). Following treatment, erosive oesophagitis was found in 17/34 on Aflurax versus 28/38 on placebo (P < 0.05). CONCLUSION: Aflurax significantly delays recurrence of moderate or severe heartburn and erosive oesophagitis, when used as maintenance treatment. The acid exposure was not significantly reduced with pH monitoring.