Riser’s reflux – an eye‐opening experience

Background Patients with gastro‐oesophageal reflux disease (GORD) commonly report waking up in the morning with a sour or bitter taste in their mouth. The aim of the study was to compare the prevalence and frequency of acid reflux events prior to and immediately after awakening from sleep in the morning between GORD patients and normal subjects. Methods Thirty‐nine patients with heartburn at least three times a week and abnormal pH test and nine healthy controls were included. All subjects were evaluated by demographic and GORD Symptom Checklist questionnaires. Subjects underwent pH testing concomitantly with actigraphy. A novel technology that simultaneously integrates raw actigraphy and pH monitoring data was utilized to determine the presence, frequency, and characteristics of acid reflux events prior to (up to 1 h) and immediately after (10 and 20 min) awakening from sleep in the morning. Key Results Nineteen (48.7%) of the GORD patients had an acid reflux event within the first 20 min after awakening from sleep in the morning as compared to only seven (17.9%) during the hour prior to awakening. Within the first 10 and 20 min after awakening, patients had a total of 32 and 60 acid reflux events, respectively, as compared to 14 during the 1 h prior to awakening (P < 0.05). None of the healthy control patients demonstrated any reflux events during these three studied periods (P < 0.001). Conclusions & Inferences Riser’s reflux is very common among GORD patients and possibly may explain reports of early‐morning GORD symptoms.     

Assessment of 24-h oesophageal pH monitoring should be divided to awake and asleep rather than upright and supine time periods.

Oesophageal acid exposure analysis is divided to upright and supine, based on the assumption that the supine-awake period is similar to the supine-asleep period. To determine if the principal acid-reflux characteristics of supine-awake are closer to supine-asleep or upright period. Patients with heartburn underwent an upper endoscopy and pH testing. The patients were instructed to carefully document their upright, supine-awake and supine-asleep periods. A total of 64 patients were enrolled into this study (M/F 35/29; mean age 52.4 +/- 13.3). The mean percentage total time pH <4, frequency of acid-reflux events (per h) and number of sensed reflux events was not different between upright and the supine-awake period (P = ns). In contrast, the mean percentage total time pH <4, frequency of acid-reflux events and number of sensed reflux events was significantly higher in both upright and supine-awake periods vs supine-asleep (4.3 +/- 6.9, 1.86 +/- 2.7 and 0.01 +/- 0.05, P < 0.0001, respectively). The principal characteristics of the acid-reflux events in the supine-awake period are closer to the upright period than to the supine-asleep period.     

The added value of quantitative analysis of on-therapy impedance-pH parameters in distinguishing refractory non-erosive reflux disease from functional heartburn

Background By analysis of symptom‐reflux association, endoscopy‐negative refractory heartburn can be related to acid/non‐acid refluxes with impedance‐pH monitoring. Unfortunately, patients frequently do not report symptoms during the test. We aimed to assess the contribution of quantitative analysis of impedance‐pH parameters added to symptom‐reflux association in evaluating patients with endoscopy‐negative heartburn refractory to high‐dose proton pump inhibitor therapy. Methods The symptom association probability (SAP), the symptom index (SI), the esophageal acid exposure time and the number of distal and proximal refluxes were assessed at on‐therapy impedance‐pH monitoring. Relationships with hiatal hernia and manometric findings were also evaluated. Key Results Eighty patients were prospectively studied. Refractory heartburn was more frequently related to reflux by a positive SAP/SI and/or abnormal impedance‐pH parameters (52/80 cases) (65%) than by a positive SAP/SI only (38/80 cases) (47%) (P = 0.038). In patients with refractory non‐erosive reflux disease (NERD) defined by a positive SAP/SI and/or abnormal impedance‐pH parameters, the prevalence of hiatal hernia was significantly higher (56%vs 21%, P = 0.007) and the mean lower esophageal sphincter tone was significantly lower (18.7 vs 25.8 mmHg, P = 0.005) than in those (35%) with reflux‐unrelated, i.e., functional heartburn (FH). On the contrary, no significant difference was observed subdividing patients according to a positive SAP/SI only. Conclusions & Inferences Quantitative analysis of impedance‐pH parameters added to symptom‐reflux association allows a subdivision of refractory‐heartburn patients into refractory NERD and FH which is substantiated by pathophysiological findings and which restricts the diagnosis of FH to one third of cases.     

Impedance monitoring shows that posture and a meal influence gastro‐oesophageal reflux composition and frequency1

Abstract Impedance monitoring determines reflux composition as liquid and/or gas, and we assess with impedance the effect of posture and a meal on reflux composition. Twenty‐nine gastro‐oesophageal reflux disease (GORD) patients and 10 normal volunteers underwent simultaneous impedance, manometry and pH for three 40‐min periods, each 20‐min upright, 10‐min left side and 10‐min right side. One period was fasting, and two postprandial. We found that reflux event composition on the right side was liquid‐only near exclusively (93%). In contrast, 85% of reflux on the left side and 74% upright was gas‐only or liquid and gas (P < 0.001). More gas‐only reflux occurred fasting (80%) than postprandial (P < 0.01). Reflux composition was similar in the study groups and two postprandial periods (P > 0.25). After confirming gas reflux suppression on the right side, a pilot study assessed gastric anatomy as a cause. Five achalasia patients had fluid injected into the stomach at endoscopy, and the EG junction was submerged below liquid‐only on the right side. We conclude that reflux is nearly always liquid‐only on the right side where the EG junction may be below fluid. Reflux fasting is usually gas‐only. Different posture and fasting times may (i) explain variations in acid exposure during pH monitoring and (ii) promote or prevent GORD symptoms.     

Transient lower oesophageal sphincter relaxations play an insignificant role in gastro-oesophageal reflux to the proximal oesophagus.

Gastro-oesophageal reflux to the proximal oesophagus may cause atypical symptoms of gastro-oesophageal reflux disease (GORD). The motor abnormalities underlying reflux into the proximal oesophagus are still unclear. The aim of this study was to analyse the oesophageal motility during reflux into the proximal oesophagus in a group of healthy subjects and in patients with atypical symptoms of GORD. We concentrated particularly on lower oesophageal sphincter (LOS) activity and transient lower oesophageal sphincter relaxations (TLOSRs). Ten patients (7M, 3F, age 25-51 years) with mild oesophagitis (Savary-Miller grade I-II) and 10 healthy subjects (6M, 4F, age 23-54 years) underwent a 24-h dual pH-metric and manometric recording, using an electronic portable device. This recorded distal and proximal oesophageal pH values, oesophageal body and LOS motility. GORD patients had more distal and proximal reflux (DR and PR) compared with healthy controls (DR P < 0.001; PR P < 0.05). TLOSRs were the most frequent event during reflux into the distal oesophagus, whereas TLOSR frequency was much lower during reflux to the proximal oesophagus in GORD patients and in healthy controls (P < 0.05 and P < 0.01 vs. distal reflux, respectively). A significant relationship between TLOSRs and distal refluxes was present but no relationship with proximal reflux was detected. We conclude that TLOSRs are much less frequent during reflux to the proximal oesophagus than distal oesophageal reflux in patients with mild GORD suffering from atypical manifestations. The mechanism of acid reflux to the proximal oesophagus is unclear.     

Poor effectiveness of proton pump inhibitors in non‐erosive reflux disease: the truth in the end!

Despite acid secretion being normal in the majority of patients with gastro‐esophageal reflux disease (GERD) or Barrett’s esophagus, acid inhibition represents the mainstay of treatment for both these conditions, with the aim of reducing the aggressive nature of the refluxate toward the esophageal mucosa. Proton pump inhibitors (PPIs) represent, therefore, the first choice medical treatment for GERD, in that they are able to provide an 80–85% healing rate for esophageal lesions, a 56–76% symptom relief and also reduce the incidence of complications, such as strictures as well as dysplasia and adenocarcinoma in Barrett’s esophagus. According to a widely quoted systematic review, compared to patients with erosive esophagitis, patients with non‐erosive reflux disease (i.e., NERD) display a reduced symptom relief with PPIs, with about 20% reduction of therapeutic gain. In this issue of NeuroGastroenterology & Motility, Weijenborg et al. address for the first time the PPI efficacy in subpopulations of patients with NERD. The study shows clearly that, when the diagnosis is accurately made by including a functional test, NERD patients respond to PPI therapy in a similar way to those with erosive disease. Although not as frequent as previously suggested, however, PPI‐refractory heartburn does exist. Some 20% (range: 15–27%) of correctly diagnosed and appropriately treated patients do not respond to PPI treatment at standard doses. Although the pathophysiology underlying PPI failure in GERD is complex and likely multifactorial, acid (be it the sole component of refluxate or not) still remains a major causative factor. A better and more predictable form of acid suppression should therefore be pursued.     

Increased TRPV1 gene expression in esophageal mucosa of patients with non‐erosive and erosive reflux disease

Background Transient receptor potential channel vanilloid subfamily member‐1 (TRPV1) may play a role in esophageal perception. TRPV1 mRNA and protein expression were examined in the esophageal mucosa of non‐erosive reflux disease (NERD) and erosive esophagitis (EE) patients and correlated to esophageal acid exposure. Methods Seventeen NERD patients, eight EE patients and 10 healthy subjects underwent endoscopy after a 3‐week washout from proton pump inhibitors or H2 antagonists. Biopsies, obtained from the distal esophagus, were used for conventional histology, for Western blot analysis and/or quantitative real‐time polymerase chain reaction (qPCR). Overall 13 NERD patients, four EE patients and five controls underwent ambulatory pH‐testing. Key Results TRPV1 expression was increased in all NERD and EE patients, as measured by Western blot analysis (0.65 ± 0.07 and 0.8 ± 0.05 VS 0.34 ± 0.04 in controls; P < 0.01) and by qPCR (1.98 ± 0.21 and 2.52 ± 0.46 VS 1.00 ± 0.06; P < 0.01). Neutrophilic infiltration, in the mucosa, was detected only in EE patients. Conclusions & Inferences Non‐erosive reflux disease and EE patients presented increased TRPV1 receptors mRNA and protein, although no correlation with acid exposure was demonstrated. Increased TRPV1 in the esophageal mucosa may contribute to symptoms both in NERD and EE patients and possibly account for peripheral mechanisms responsible for esophageal hypersensitivity in NERD patients.     

The effect of antireflux treatment on patients with gastroesophageal reflux disease undergoing a mental arithmetic stressor

Background Acute stress exacerbates heartburn in gastroesophageal reflux disease (GERD) patients by enhancing the perceptual responses to intraesophageal acid. The aim of the study was to determine if antireflux treatment can still alter stimulus response functions to acid in patients undergoing acute stress as compared with placebo. Methods Symptomatic GERD patients with erosive esophagitis (EE) or an abnormal pH test were included. Patients underwent stimulus response functions to intraesophageal acid perfusion using the mental arithmetic stressor test. Thereafter, patients were randomized (2 : 1 ratio) to either esomeprazole 40 mg once daily or placebo for 8 weeks. On the last day of treatment, subjects underwent stimulus response functions to intraesophageal acid perfusion using a similar stressor as baseline. Key Results A total of 31 patients were randomized into the treatment arm (mean age 48.6 ± 2.8, M/F 21/10) and 16 into the placebo arm (mean age 52.3 ± 4.3, M/F 12/4). In the esomeprazole group, there was a significant increase in lag time to symptom perception (P = 0.02) and decreased in intensity rating (P = 0.01) as well as acid perfusion sensitivity score (P = 0.01). There was no significant difference in any of the stimulus response functions to acid in the placebo group between baseline and treatment. Interpersonal sensitivity was the only independent clinical predictor factor for response to antireflux treatment. Conclusions & Inferences Long‐term antireflux treatment with a proton pump inhibitor is effective in reducing esophageal perception responses to acid during acute stress.     

Concomitant irritable bowel syndrome is associated with failure of step‐down on‐demand proton pump inhibitor treatment in patients with gastro‐esophageal reflux disease

Background The predictors for treatment failure of on‐demand proton pump inhibitor (PPI) therapy in gastro‐esophageal reflux disease (GERD) patients are unclear. We studied the efficacy and predictors for treatment failure of step‐down on‐demand PPI therapy in patients with non‐erosive reflux disease (NERD) and those with low grade erosive esophagitis. Methods Consecutive symptomatic GERD patients who had positive esophageal pH studies and complete symptom resolution with initial treatment of esomeprazole were given step‐down on‐demand esomeprazole for 26 weeks. Patients with esophagitis of Los Angeles (LA) grade C or above and recent use of PPI were excluded. Treatment failure was defined as an inadequate relief of reflux symptoms using global symptom assessment. Potential predictors of treatment failure were determined using multivariate analysis. Key Results One hundred and sixty three NERD and 102 esophagitis patients were studied. The 26‐week probability of treatment failure was 36.2% (95% CI: 23.9–46.5%) in NERD group and 20.1% (95% CI: 10.9–28.3%) in esophagitis group, respectively (P = 0.021). Irritable bowel syndrome (adjusted HR: 2.1, 95% CI: 1.5–3.8, P = 0.01), in addition to daily reflux symptom (adjusted hazard ratio: 2.7, 95% CI: 1.9–4.2, P = 0.001) and concomitant dyspepsia (adjusted hazard ratio: 1.7, 95% CI: 1.1–2.8, P = 0.04), were independent predictors for treatment failure. Conclusions & Inferences Compared to patients with esophagitis, NERD patients have higher failure rate of on‐demand PPI therapy. Concomitant irritable bowel syndrome, in addition to daily reflux symptom and dyspepsia, is associated with the failure of on‐demand PPI in these patients.     

The effect of once daily omeprazole and succinic acid (VECAM) vs once daily omeprazole on 24-h intragastric pH

Background Parietal cell H⁺/K⁺ATPase activation is essential for optimal proton pump inhibitor (PPI) activity. Succinic acid (SA) was shown to induce gastric acid secretion. VECAM is a combination of omeprazole (OMP) and SA. To compare the effect of once daily bedtime dosing of VECAM 40 and VECAM 20 without food vs OMP 20 mg administered before breakfast on gastric acidity. Methods Open label, randomized, crossover study enrolling 36 healthy subjects comparing the study treatments at steady state for 24 h intragastric pH monitoring. Key Results The median percent time intragastric pH > 4 demonstrated that VECAM 40 was superior to VECAM 20 (65.7%vs 49.1%P < 0.0001) and OMP 20 mg (65.7%vs 47.6%P = 0.005) during 24 h. VECAM 40 was superior to VECAM 20 (52.8%vs 38.8%P = 0.0079) and OMP 20 mg (52.8%vs 27.2%P < 0.0001), and VECAM 20 was superior to OMP 20 mg (38.8 vs 27.2 P = 0.0069) during the nighttime. VECAM 20 and OMP 20 mg were comparable during 24 h. Conclusions & Inferences VECAM 40 and VECAM 20 were significantly better in maintaining intragastric pH > 4 during the nighttime than OMP 20 mg. Succinic acid eliminates the need for a subsequent meal for intragastric pH control by VECAM.     

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.