bwge2017

Authors
C. BROERS (1), B. VAN HOUTTE (2), P. VERMEERSCH (3), N. PEERSMAN (3), J. TACK (2), A. PAUWELS (2) / [1] KU Leuven, Leuven, Belgium, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, [2] KU Leuven, leuven, Belgium, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, [3] UZ Leuven, Leuven, Belgium, Laboratoriumgeneeskunde
Introduction Proton pump inhibitors (PPIs) are effective in healing oesophagitis, however 30% of non-erosive gastro-oesophageal reflux disease (NORD) patients remain symptomatic while taking PPIs. In these patients, oesophageal hypersensitivity is considered an important pathophysiological mechanism. Serotonin (5-HT) is predominantly found in the central nervous system and in the gastro-intestinal (GI) tract. 5-HT plays a major role in the regulation of GI secretion, motility and sensitivity, and has been associated with emotion regulation. Acute tryptophan depletion (ATD) temporarily reduces the availability of tryptophan (TRP), thereby decreasing central and peripheral 5-HT synthesis. From previous studies, ATD is known to affect GI physiology and enhance visceral pain perception in the colon.
Aim
To study the effect of ATD on oesophageal sensitivity in healthy volunteers (HV).
Methods Oesophageal multimodal sensitivity was assessed after intragastric infusion of an amino-acid mixture (AA-mix) containing 15 AAs with TRP (control condition) or without TRP (ATD condition). After an incubation period of 5 hours, a probe with a balloon was positioned in the distal oesophagus. Thermal (recirculating a heated saline solution through the balloon), mechanical (increasing balloon volume), electrical (2 stimulation electrodes) and chemical sensitivity (modified Bernstein) were tested. Stimulus intensities were evaluated for first perception, pain perception threshold (PPT) and pain toleration threshold (PTT). At 3 time points blood samples were collected for biochemical analysis. General mood was assessed by the Positive and Negative Affect Schedule (PANAS) and the State-Trait Anxiety Inventory (STAI) questionnaires. Results were analyzed using paired t-tests and two-way ANOVA repeated measures and corrected for multiple testing (Bonferroni correction). A p-value of <0.05 was considered significant.
Results We compared control condition with ATD in 11 HV (4m/7f, mean age 24y [range 21y-33y]. ATD significantly reduced plasma levels of TRP, 5 and 7 hours after administration of the AA-mix (5h: 139.0 µmol/L [97.1-175.1] vs. 6.1 µmol/L [3.3-21.1], 7h: 65.6 µmol/L [53.0-133.1] vs. 6.1 µmol/L [4.8-12.2], p<0.0001). ATD significantly decreased the PPT during chemical stimulation (p=0.03) with a pronounced effect size (Cohen’s d+=0.75) (Table 1). However, ATD had no significant influence on sensitivity to the other stimulation modalities. There was no significant difference in PANAS and STAI-State scores before, during and after the stimulations for the 2 conditions. Table 1: Results of oesophageal multimodal stimulation for control condition and acute tryptophan depletion (ATD). Results are presented as median [25th –75th percentile]. n=11, unless indicated otherwise since only HV reaching the sensitivity thresholds were taken into account for analysis. Temperature stimulation (°C) PPT control: 42.66°C [40.56-46.71] vs. PPT ATD: 43.71°C [41.22-46.65], p=0.53 PTT control: 46.43°C [45.00-49.04] vs. PTT ATD: 46.32°C [44.42-51.88], p=0.56 Mechanical stimulation (ml) PPT control: 17.70ml [16.00-19.40] vs. PPT ATD: 16.65ml [11.70-21.50], p=0.23 PTT control (n=9): 22.10ml [20.35-24.35] vs. PTT ATD (n=9): 25.00ml [17.90-30.80], p=0.17 Electrical stimualtion(mA) 1st perception control: 6.33mA [4.17-6.83] vs. 1st perception ATD: 6.00mA [4.33-13.33], p=0.17 PPT control: 11.83mA [8.50-14.33] vs. PPT ATD: 10.00mA [8.00-19.83], p=0.41 Chemical stimulation (ml) 1st perception control: 10.00ml [7.00-18.00] vs.1st perception ATD: 8.00ml [6.00-11.00], p=0.27 PPT control: 25.00ml [14.00-29.00] vs. PPT ATD: 14.00ml [13.00-24.00], p=0.03 PTT control: 34.00ml [24.00-42.00] vs. PTT ATD: 26.00ml [16.00-36.00], p=0.23
Conclusions To our knowledge, this is the first study to address the effect of ATD on oesophageal multimodal sensitivity in health. ATD significantly decreased pain perception threshold during chemical stimulation, without affecting sensitivity to mechanical, thermal or electrical stimulation. The findings may have implications for the understanding and treatment of refractory GORD or functional heartburn.

Authors

A. PAUWELS (1), V. BOECXSTAENS (1), C. BROERS (1), J. IVEN (1), D. ZHAO (1), T. VANUYTSEL (1), J. TACK (1) / [1] Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium, clinical and experimental medicine

Introduction
A significant proportion of patients with gastro-esophageal reflux disease (GERD) remains symptomatic while on proton pump inhibitor (PPI) therapy. PPIs significantly reduce the proportion of acid reflux, however they have no effect on non-acid reflux which can provoke symptoms in GERD patients. Baclofen, a γ-aminobutyric acid agonist, is able to decrease both acid and non-acid reflux. To date, studies with baclofen focused on mechanistic aspects in patients with proven ongoing weakly acidic reflux, but the symptomatic outcome of patients with refractory GERD symptoms has not received much attention.

Aim

The aim of this study was to assess the efficacy of baclofen 10mg t.i.d. vs placebo as add-on therapy in GERD patients with insufficient response to PPI therapy, in a randomized, parallel, double-blind, placebo-controlled study.

Methods
Patients with an incomplete control of typical GERD symptoms (heartburn/regurgitation) in spite of PPI therapy were randomized to baclofen or placebo for 4 weeks. Patients were taking PPIs (b.i.d) throughout the entire study. Prior to the study and at the end of the treatment, patients underwent a 24h impedance-pH monitoring and were asked to fill out the ReQuest questionnaire to assess symptoms of GERD. Reflux parameters post-treatment were compared to baseline using Wilcoxon signed rank test and were compared between baclofen and placebo using Mann-Whitney test. The differences in wellbeing and acid complaints ReQuest domains after treatment were compared using mixed models.

Results
60 patients were included (age 47.5y (range 19-73), BMI 24.99kg/m2, 41f/19m). One patient decided not to start with the medication and 5 patients did not complete the study due to side effects (headache, nausea, drowsiness); all of them were taking baclofen at that time. 26 patients were randomized in the baclofen arm, while 28 patients were randomized in the placebo arm. There was a decrease in total number of reflux episodes, the number of non-acid reflux episodes and the number of reflux episodes with a high proximal extent in the baclofen condition compared to baseline, while no differences were observed in the placebo condition (Table 1). There was a significant main effect of time on wellbeing in all patients (p=0.018), but we found no difference between both arms. Similar results were found for the scores for acid complaints, with a significant time effect (0.016), a borderline condition effect (p=0.048) but no interaction effect.

Conclusions
Although several reflux parameters decrease with baclofen treatment, there was no gain in symptom control or wellbeing from add-on baclofen therapy over placebo in patients with persisting typical GERD symptoms on PPI. These findings argue against add-on baclofen therapy based on symptom evaluation alone.

Authors

N. GOELEN (1), F. CARBONE (1), L. HOLVOET (2), A. VANDENBERGHE (3), J. ARTS (2), P. CAENEPEEL (2), H. PIESSEVAUX (4), J. TACK (1) / [1] KU Leuven, Leuven, Belgium, TARGID, [2] UZ Leuven, Leuven, Belgium, Gastroenterology, [3] Medical Research Consultant, Chaumont-Gistoux, Belgium, , [4] Cliniques Universitaires St Luc, Brussels, Belgium, Gastroenterology

Introduction
Functional gastrointestinal disorders (FGID) are a heterogeneous group of chronic conditions without a known organic etiology, although with a significant socio-economic impact. Despite the upgraded Rome IV criteria, several challenges remain to interfere with the appropriate assessment of FGI symptoms. Accurate interpretation and communication of the symptom pattern is imperative for a correct diagnosis. Hence, our group recently developed a Rome III criteria-based Waiting Room Questionnaire (WRQ) with pictograms as a visual aid to improve symptom identification.

Aim

The aim of this study is to validate the WRQ for symptom assessment and diagnosis of frequent FGID.

Methods
Ambulatory patients completed the WRQ which includes 40 questions with pictograms used to diagnose gastroesophageal reflux disease (GERD), functional dyspepsia (FD) subgroups PDS and EPS, irritable bowel syndrome (IBS) and chronic idiopathic nausea (CIN). Cohen’s kappa statistic was used to assess inter-rater concordance, defined as the fraction of cases where the predominant symptomatic profile identified by the clinician’s interview matched with the profile identified by the patient on the WRQ which was completed in absence of a clinician. Secondary endpoints were the clarity and relevance of the drawings and cognitive validity.

Results
In total, 138 ambulatory patients from 10 Belgian gastroenterology clinics presenting with FGID symptoms (75% female, 42 ± 1.3 years) filled out the WRQ while waiting for their consultation. After the consultation and based on their expert opinion, clinicians diagnosed 20 patients with predominant GERD, 45 PDS, 22 EPS, 37 IBS and 14 CIN. Pictograms entailed an added value for 77% of the patients and 87% of the patients understood all questions. Clinicians indicated that > 90% of the written answers were confirmed during their interview in 75% of the cases. Patients were highly reliable in 81% of the cases with regard to meal-related symptoms and in 83% with regard to bowel movements. Overall, concordance for the predominant symptomatic profile identified by the WRQ and by the clinician (inter-rater agreement) was ‘good’ (72.3%, κ = 0.65 ± 0.05). Concordance was the highest for CIN (93%) and EPS (86%), followed by IBS (76%), PDS (64%) and GERD (50%) (Figure 1). The concordance was 80% for the pooled FD population. Solely based on the answers in the WRQ 45% of GERD patients would have been misdiagnosed with PDS or EPS. PPI usage was a major confounder, probably through its effect on heartburn: 78% of the patients with a physician-based diagnosis of GERD not confirmed by the WRQ received PPI therapy. The prevalence of PPI therapy was also higher in the GERD patients (80%) compared to the other groups (32 - 64%, p = 0.02).

Conclusions
The new WRQ is a reliable, accurate and easy to handle tool that can provide diagnostic guidance in (non-)specialist settings and clinical research. Implementation in clinical practice would standardize and enhance the diagnostic approach for a vast population of FGID patients.