Pim W. Weijenborg

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.

Normal values for solid-state esophageal high-resolution manometry in a European population; an overview of all current metrics

Esophageal high‐resolution manometry (HRM) allows accurate evaluation of esophageal motility. Normal values for HRM were established in the United States and several new parameters were introduced since. We aimed to provide a complete set of normal values for HRM obtained in a European population, including all current metrics used to describe the function of the upper esophageal sphincter (UES), the esophageal body, and the esophagogastric junction (EGJ).

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.

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.

Accuracy of hiatal hernia detection with esophageal high-resolution manometry.

The diagnosis of a sliding hiatal hernia is classically made with endoscopy or barium esophagogram. Spatial separation of the lower esophageal sphincter (LES) and diaphragm, the hallmark of hiatal hernia, can also be observed on high‐resolution manometry (HRM), but the diagnostic accuracy of this finding has not yet been investigated. To determine the diagnostic value of HRM in the detection of hiatal hernia.

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 sensitivity and mucosal integrity in patients with functional heartburn

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.

880 Acid Suppression Restores Impaired Esophageal Mucosal Integrity in Patients With Esophageal Eosinophilia

Introduction: Gastroesophageal reflux and allergies are both thought to play a role in the pathophysiology of eosinophilic esophagitis (EoE). It has been suggested that acid-induced esophageal mucosal damage promotes transepithelial allergen flux. Anecdotal evidence suggests that patients with typical signs and symptoms of EoE benefit from acid-suppressive therapy. The aim of our study was to evaluate esophageal mucosal integrity in patients with significant esophageal eosinophilia (SEE) and to study the effects of acid-suppressive therapy with PPI on symptoms, endoscopic signs, mucosal integrity, dilation of epithelial intercellular spaces (DIS), and peak eosinophilia and mastocytosis. Methods: We included 11 untreated adults with SEE (.15 eosinophils/hpf) and predominant symptoms of dysphagia and/or food impaction and typical endoscopic signs of EoE, and 11 controls. All study subjects underwent endoscopy at baseline; in SEE patients endoscopy was repeated after 8 weeks of esomeprazole 40 mg BID. Esophageal mucosal integrity was measured in vivo during endoscopy with a through-the-scope electrical tissue impedance spectroscopy probe (ETIS) at 5 cm proximal of the LES. At the same location, we obtained 2 biopsies for electron microscopic analysis of DIS and 4 biopsies for mucosal integrity experiments in Ussing chambers. In the Ussing chambers, we measured transepithelial electrical resistance (TER) and transmucosal flux of fluorescently-labelled molecules sized 0.3 and 40 kDa (size of food allergens) during 1 hour. In SEE patients, we additionally scored symptoms and endoscopic signs of EoE. Furthermore, eosinophilia and mastocytosis were scored in biopsies taken at the proximal, midand distal esophagus of SEE patients at each endoscopy. Results: Both structural (DIS) and in vivo and in vitro functional measurements (ETIS, TER, and molecule flux) of mucosal integrity showed significant impairment in SEE patients compared to HC (table 1). After acid-suppressive therapy, mucosal integrity was significantly improved in patients with SEE, but still did not reach the levels seen in controls. Esophageal peak eosinophilia andmastocytosis as well as dysphagia and endoscopic signs of EoE also decreased after acid-suppressive therapy. Conclusion: Patients with SEE have an impaired esophageal mucosal integrity, which is partially restored after acid-suppressive therapy. The observed reduction of transmucosal flux of molecules with a similar size as food allergens after acidsuppressive therapy supports the hypothesis that acid-induced mucosal damage facilitates transepithelial food allergen flux, which results in esophageal eosinophilia. Study parameters in HC and SEE patients

Impact of spatial resolution on results of esophageal high-resolution manometry

The Chicago classification for esophageal motility disorders was designed for a 36‐channel manometry system with sensors spaced at 1 cm. However, many motility laboratories outside the USA use catheters with a lower resolution in the segments outside the esophagogastric junction. Our aim was to investigate the effect of spatial resolution on the Chicago metrics and diagnosis.