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.

Effects of antidepressants in patients with functional esophageal disorders or gastroesophageal reflux disease: a systematic review.

BACKGROUND & AIMS: Patients with functional esophageal disorders present with symptoms of chest pain, heartburn, dysphagia, or globus in the absence of any structural abnormality. Visceral hypersensitivity is a feature of these functional disorders, and might be modulated by antidepressant therapy. We evaluated evidence for the efficacy of antidepressant therapy for symptoms associated with esophageal visceral hypersensitivity in patients with functional esophageal disorders or gastroesophageal reflux disease (GERD). METHODS: We performed a systematic search of the Cochrane Comprehensive Trial Register, MEDLINE, and EMBASE (through February 2014). We analyzed relevant randomized, placebo-controlled trials reporting the effect of antidepressant therapy on experimentally induced esophageal sensation or intensity, or frequency of heartburn, chest pain, dysphagia, or globus. RESULTS: The search strategy identified 378 articles; 15 described randomized controlled trials that were eligible for inclusion. In addition, 1 conference abstract and 2 case reports were included, providing the best available evidence on specific symptoms. Esophageal pain thresholds increased by 7% to 37% after antidepressant therapy. Antidepressant therapy reduced functional chest pain over a range from 18% to 67% and reduced heartburn in patients with GERD over a range of 23% to 61%. One study included patients with globus and none of the studies included patients with functional heartburn or functional dysphagia. CONCLUSIONS: Based on a systematic review, antidepressants modulate esophageal sensation and reduce functional chest pain. There is limited evidence that antidepressants benefit a subgroup of patients with GERD. More controlled trials are needed to investigate the effects of antidepressants on functional esophageal disorders.

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.

Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis.

BACKGROUND & AIMS: Histologic analysis is used to distinguish patients with proton pump inhibitor-responsive eosinophilia (PPI-REE) from those with eosinophilic esophagitis (EoE). It is not clear whether these entities have different etiologies. Exposure to acid reflux can impair the integrity of the esophageal mucosal. We proposed that patients with EoE and PPI-REE might have reflux-induced esophageal mucosal damage that promotes transepithelial flux of allergens. We therefore assessed the integrity of the esophageal mucosal in these patients at baseline and after PPI. METHODS: We performed a prospective study of 16 patients with suspected EoE and 11 controls. Patients had dysphagia, endoscopic signs of EoE, and esophageal eosinophilia (>15 eosinophils/high-power field [eos/hpf]). All subjects underwent endoscopy at baseline; endoscopy was performed again on patients after 8 weeks of treatment with high-dose esomeprazole. After PPI treatment, patients were diagnosed with EoE (>10 eos/hpf; n = 8) or PPI-REE (≤10 eos/hpf; n = 8). We evaluated the structure (intercellular spaces) and function (electrical tissue impedance, transepithelial electrical resistance, transepithelial molecule flux) of the esophageal mucosal barrier. RESULTS: Compared with controls, electrical tissue impedance and transepithelial electrical resistance were reduced in patients with EoE (P < .001 and P < .001, respectively) and PPI-REE (P = .01 and P = .06, respectively), enabling transepithelial small-molecule flux. PPI therapy partially restored these changes in integrity and inflammation in patients with PPI-REE, but not in those with EoE. CONCLUSIONS: The integrity of the esophageal mucosa is impaired in patients with EoE and PPI-REE, allowing transepithelial transport of small molecules. PPI therapy partially restores mucosal integrity in patients with PPI-REE, but not in those with EoE. Acid reflux might contribute to transepithelial allergen flux in patients with PPI-REE. Trialregister.nl number: NTR3480.

Water-perfused esophageal high-resolution manometry: normal values and validation.

Water-perfused high-resolution manometry (HRM) catheters with 36 unidirectional pressure channels have recently been developed, but normal values are not yet available. Furthermore, the technique has not been validated and compared with solid-state HRM. We therefore aimed to develop normal values for water-perfused HRM and to assess the level of agreement between water-perfused HRM and solid-state HRM. We included 50 healthy volunteers (mean age 35 yr, range 21-64 yr; 15 women, 35 men). Water-perfused HRM and solid-state HRM were performed in a randomized order. Normal values were calculated as 5th and 95th percentile ranges, and agreement between the two systems was assessed with intraclass correlation coefficient (ICC) statistics. The 5th-95th percentile range was 3.0-6.6 cm/s for contractile front velocity (CFV), 141.6-3,674 mmHg·s·cm for distal contractile integral (DCI), 6.2-8.7 s for distal contraction latency (DL), and 1.0-18.8 mmHg for integrated relaxation pressure (IRP 4s). Mean (SD) and ICC for water-perfused HRM and solid-state HRM were 4.4 (1.1) vs. 3.9 (0.9) cm/s, ICC: 0.49 for CFV; 1,189 (1,023) vs. 1,092 (1,019) mmHg·s·cm, ICC: 0.90 for DCI; 7.4 (0.8) vs. 6.9 (0.9) s, ICC: 0.50 for DL; and 8.1 (4.8) vs. 7.9 (5.1), ICC: 0.39 for IRP 4s. The normal values for this water-perfused HRM system are only slightly different from previously published values with solid-state HRM, and moderate to good agreement was observed between the two systems, with only small differences in outcome measures.

How reflux causes symptoms: reflux perception in gastroesophageal reflux disease.

In gastroesophageal reflux disease (GERD) symptoms arise due to reflux of gastric content into the oesophagus. However, the relation between magnitude and onset of reflux and symptom generation in GERD patients is far from simple; gastroesophageal reflux occurs several times a day in everyone and the majority of reflux episodes remains asymptomatic. This review aims to address the question how reflux causes symptoms, focussing on factors leading to enhanced reflux perception. We will highlight esophageal sensitivity variance between subtypes of GERD, which is influenced by peripheral sensitization of primary afferents, central sensitization of spinal dorsal horn neurons, impaired mucosal barrier function and genetic factors. We will also discuss the contribution of specific refluxate characteristics to reflux perception, including acidity, and the role of bile, pepsin and gas and proximal extent. Further understanding of reflux perception might improve GERD treatment, especially in current partial responders to therapy.

Esophageal acid exposure decreases intraluminal baseline impedance levels.

OBJECTIVES: Intraluminal baseline impedance levels are determined by the conductivity of the esophageal wall and can be decreased in gastroesophageal reflux disease (GERD) patients. The aim of this study was to investigate the baseline impedance in GERD patients, on and off proton pump inhibitor (PPI), and in healthy controls. METHODS: Ambulatory 24-h pH-impedance monitoring was performed in (i) 24 GERD patients with and 24 without pathological esophageal acid exposure as well as in 10 healthy controls and in (ii) 20 patients with refractory GERD symptoms despite PPI, once on PPI and once off PPI. Baseline impedance levels in the most distal and the most proximal impedance channels were assessed. RESULTS: Median (interquartile range) distal baseline impedance in patients with physiological (2,090 (1,537-2,547) Ω) and pathological (781 (612-1,137) Ω) acid exposure was lower than in controls (2,827 (2,127-3,270) Ω, P<0.05 and P<0.001). A negative correlation between 24-h acid exposure time and baseline impedance was observed (r=-0.7, P<0.001). In patients measured off and on PPI, median distal baseline impedance off PPI was significantly lower than on PPI (886 (716-1,354) vs. 1,372 (961-1,955) Ω, P<0.05) and distal baseline impedance in these groups was significantly lower than in healthy controls (P<0.05 and P<0.001). Proximal baseline impedance did not differ significantly between the patients off PPI and on PPI (1,793 (1,384-2,489) vs. 1,893 (1,610-2,561) Ω); however, baseline impedance values in both measurements were significantly lower than in healthy controls (3,648 (2,815-3,932) Ω, both P<0.001). CONCLUSIONS: These findings suggest that baseline impedance is related to esophageal acid exposure and could be a marker of reflux-induced changes to the esophageal mucosa.