Diagnosis of supra‐esophageal gastric reflux: correlation of oropharyngeal pH with esophageal impedance monitoring for gastro‐esophageal reflux

Background Oropharyngeal (OP) pH monitoring has been developed as a new way to diagnose supra‐esophageal gastric reflux (SEGR), but has not been well validated. Our aim was to determine the correlation between OP pH and gastro‐esophageal reflux (GER) events detected by multichannel intraluminal impedance‐pH (MII‐pH). Methods Fifteen patients (11 males, median age 10.8 years) with suspected GER were prospectively evaluated with ambulatory 24‐h OP pH monitoring (positioned at the level of the uvula) and concomitant esophageal MII‐pH monitoring. Potential OP events were identified by the conventional pH threshold of <4 and by the following alternative criteria: (i) relative pH drop >10% from 15‐min baseline and (ii) absolute pH drop below thresholds of <5.5, 5.0, and 4.5. The 2‐min window preceding each OP event was analyzed for correlation with an episode of GER detected by MII‐pH. Key Results A total of 926 GER events were detected by MII‐pH. Application of alternative pH criteria increased the identification of potential OP pH events; however, a higher proportion of OP events had no temporal correlation with GER (45–81%), compared with the conventional definition of pH < 4 (40%). A total of 306 full‐column acid reflux episodes were detected by MII‐pH, of which 10 (3.3%) were also identified by OP pH monitoring. Conclusions & Inferences Use of extended pH criteria increased the detection of potential SEGR events, but the majority of decreases in OP pH were not temporally correlated with GER. Oropharyngeal pH monitoring without concurrent esophageal measurements may overestimate the presence of SEGR in children.     

Automated impedance‐manometry analysis detects esophageal motor dysfunction in patients who have non‐obstructive dysphagia with normal manometry

Background Automated integrated analysis of impedance and pressure signals has been reported to identify patients at risk of developing dysphagia post fundoplication. This study aimed to investigate this analysis in the evaluation of patients with non‐obstructive dysphagia (NOD) and normal manometry (NOD/NM). Methods Combined impedance‐manometry was performed in 42 patients (27F : 15M; 56.2 ± 5.1 years) and compared with that of 24 healthy subjects (8F : 16M; 48.2 ± 2.9 years). Both liquid and viscous boluses were tested. MATLAB‐based algorithms defined the median intrabolus pressure (IBP), IBP slope, peak pressure (PP), and timing of bolus flow relative to peak pressure (TNadImp‐PP). An index of pressure and flow (PFI) in the distal esophagus was derived from these variables. Key Results Diagnoses based on conventional manometric assessment: diffuse spasm (n = 5), non‐specific motor disorders (n = 19), and normal (n = 11). Patients with achalasia (n = 7) were excluded from automated impedance‐manometry (AIM) analysis. Only 2/11 (18%) patients with NOD/NM had evidence of flow abnormality on conventional impedance analysis. Several variables derived by integrated impedance‐pressure analysis were significantly different in patients as compared with healthy: higher PNadImp (P < 0.01), IBP (P < 0.01) and IBP slope (P < 0.05), and shorter TNadImp_PP (P = 0.01). The PFI of NOD/NM patients was significantly higher than that in healthy (liquid: 6.7 vs 1.2, P = 0.02; viscous: 27.1 vs 5.7, P < 0.001) and 9/11 NOD/NM patients had abnormal PFI. Overall, the addition of AIM analysis provided diagnoses and/or a plausible explanation in 95% (40/42) of patients who presented with NOD. Conclusions & Inferences Compared with conventional pressure‐impedance assessment, integrated analysis is more sensitive in detecting subtle abnormalities in esophageal function in patients with NOD and normal manometry.     

3D‐high resolution manometry of the esophagogastric junction

Background The esophagogastric junction (EGJ) is a complex structure that challenges accurate manometric recording. This study aimed to define EGJ pressure morphology relative to the squamocolumnar junction (SCJ) during respiration with 3D‐high resolution manometry (3D‐HRM). Methods A 7.5‐cm long 3D‐HRM array with 96 independent solid‐state pressure sensors (axial spacing 0.75 cm, radial spacing 45°) was used to record EGJ pressure in 15 normal subjects. Concurrent videofluoroscopy was used to localize the SCJ marked with an endoclip. Ex vivo experiments were done on the effect of bending the probe to match that seen fluoroscopically. Key Results 3D‐high resolution manometry EGJ pressure recordings were dominated by an asymmetric pressure peak superimposed on the lower esophageal sphincter (LES) attributable to the crural diaphragm (CD). Median peak CD pressure at expiration and inspiration (51 and 119 mmHg, respectively) was much greater in 3D‐HRM than evident in HRM with circumferential pressure averaging. Esophagogastric junction length, defined as the zone of circumferential pressure exceeding that of adjacent esophagus or stomach was also substantially shorter (2.4 cm) than evident in conventional HRM. No consistent circumferential EGJ pressure was evident distal to the SCJ in 3D‐HRM recordings and ex vivo experiments suggested that the intra‐gastric pressure peak seen contralateral to the CD related to bending the assembly rather than the sphincter per se. Conclusions & Inferences 3D‐high resolution manometry demonstrated a profoundly asymmetric and vigorous CD component to EGJ pressure superimposed on the LES. Esophagogastric junction length was shorter than evident with conventional HRM and the distal margin of the EGJ sphincteric zone closely correlated with the SCJ.     

Platelet‐activating factor and distinct chemokines are elevated in mucosal biopsies of erosive compared with non‐erosive reflux disease patients and controls

Background A distinction between symptomatic non‐erosive reflux disease (NERD) and erosive esophagitis (EE) patients is supported by the presence of inflammatory response in the mucosa of EE patients, leading to a damage of mucosal integrity. To explore the underlying mechanism of this difference, we assessed inflammatory mediators in mucosal biopsies from EE and NERD patients and compared them with controls. Methods Nineteen NERD patients, 15 EE patients, and 16 healthy subjects underwent endoscopy after a 3‐week washout from PPI or H₂ antagonists. Biopsies obtained from the distal esophagus were examined by quantitative real‐time polymerase chain reaction (qPCR) and multiplex enzyme‐linked immunosorbent assay for selected chemokines and lyso‐PAF acetyltransferase (LysoPAF‐AT), the enzyme responsible for production of platelet‐activating factor (PAF). Key Results Expression of LysoPAF‐AT and multiple chemokines was significantly increased in mucosal biopsies derived from EE patients, when compared with NERD patients and healthy controls. Upregulated chemokines included interleukin 8, eotaxin‐1, ‐2, and ‐3, macrophage inflammatory protein‐1α (MIP‐1α), and monocyte chemoattractant protein‐1 (MCP‐1). LysoPAF‐AT and the chemokine profile in NERD patients were comparable with healthy controls. Conclusions & Inferences Levels of selected cytokines and Lyso‐PAF AT were significantly higher in the esophageal mucosa of EE patients compared with NERD and control patients. This difference may explain the distinct inflammatory response occurring in EE patients’ mucosa. In contrast, as no significant differences existed between the levels of all mediators in NERD and control subjects, an inflammatory response does not appear to play a major role in the pathogenesis of the abnormalities found in NERD patients.     

Treatment of gastro‐esophageal reflux disease: the new kids to block

Refractory gastro‐esophageal reflux disease (GERD), defined as persistent symptoms despite proton pump inhibitor (PPI) therapy, is an increasingly prevalent condition and is becoming a major challenge for the clinician. Since non‐acidic reflux may be associated with symptoms persisting during PPI treatment, the lower esophageal sphincter (LES), the most important barrier protecting against reflux, has become an important target for the treatment of (refractory) GERD. Preclinical research has identified several receptors that are involved in the control of transient lower esophageal sphincter relaxations (TLESRs), the predominant mechanism of both acid and non‐acidic reflux events, and several drugs have now been tested in humans. The GABA_B agonist baclofen has demonstrated to effectively reduce the rate of TLESRs and the amount of reflux in both GERD patients and healthy volunteers. Nevertheless, the occurrence of central side effects limits its clinical use for the treatment of GERD. Several analogues are being developed to overcome this limitation and have shown promising results. Additionally, metabotropic glutamate receptor 5 (mGluR5) receptor antagonists have shown to reduce both acid and non‐acidic reflux in GERD patients and several molecules are currently being evaluated. Although CB₁ antagonists have been shown to reduce TLESRs, they are also associated with central side effects, limiting their clinical applicability. Despite the identification of several potentially interesting drugs, the main challenge for the future remains the reduction of central side effects. Moreover, future studies will need to demonstrate the efficacy of these treatments in patients with refractory GERD.