Relationship Between Gastric Accommodation, TLESRs and Reflux in HV and in GERD With or Without Overlapping Dyspepsia
Relationship Between Gastric Accommodation, TLESRs and Reflux in HV and in GERD With or Without Overlapping Dyspepsia
Our group recently studied the relationship between intra-gastric pressure (IGP) and reflux
 events after a meal, both in gastro-esophageal reflux disease (GERD) and in healthy
 volunteers (HV). Ingestion of a meal was accompanied by a drop in IGP, probably representing
 gastric accommodation (GA). However, the magnitude of this IGP drop varied, and was inversely
 correlated with the number of transient lower esophageal sphincter relaxations (TLESRs) and
 the number of reflux events, both in patients and in HV: a smaller meal-induced drop in IGP
 was associated with a higher rate of reflux events, and vice versa. These findings suggest
 that impaired GA is a trigger for reflux. Furthermore, impaired GA is a well-established
 mechanism underlying symptom generation in functional dyspepsia (FD). Hence, the
 investigators hypothesize that impaired GA is an important pathophysiological feature
 explaining the overlap between GERD and FD. To evaluate this hypothesis, the investigators
 will study the relationship between GA, TLESRs and reflux events in HV and in a group of GERD
 patients which will be categorized as pure GERD or GERD/FD overlap.
1. INTRODUCTION Gastro-esophageal reflux (GER), the retrograde flow of gastric contents in
 the esophagus, is a physiologic phenomenon. However, when GER causes symptoms
 (heartburn/regurgitation) or lesions (esophagitis/Barrett's esophagus), it is referred
 to as gastro-esophageal reflux disease (GERD). GERD is a highly prevalent condition,
 occurring in up to 20% of the Western population. Gastric acid has been considered the
 main pathological factor in GERD and the development of proton pump inhibitors (PPIs),
 reducing gastric acid secretion, was a major break-through in GERD treatment. However, a
 large number of GERD patients remain symptomatic in spite of PPI therapy. Combined
 pH-impedance recordings identified ongoing weakly acidic reflux as the major factor
 underlying these refractory GERD symptoms. One therapeutic option to eliminate also
 weakly-acidic reflux is anti-reflux surgery, but this is not devoid of side-effects and
 has a higher risk of unfavorable outcome in refractory GERD. Hence, intense research was
 devoted to drugs inhibiting all types of reflux by controlling transient lower
 esophageal sphincter relaxations (TLESRs), the main mechanism underlying reflux. TLESRs
 are relaxations of the lower esophageal sphincter (LES) that are not triggered by
 swallowing and allow reflux of ingested air and gas during belching. They occur mainly
 postprandially and are triggered by gastric distension, which activates mechanoreceptors
 in the proximal stomach and a vago-vagal pathway resulting in release of nitric oxide at
 the LES. Although TLESR frequency is similar in GERD and healthy volunteers (HV), the
 selectivity of TLESRs to gas reflux is lost in patients and liquid reflux is more likely
 to occur.

 Pharmacological approaches to inhibit TLESRs, more specifically gamma-aminobutyric
 acid-B (GABA-B) receptor agonism and metabotropic glutamate receptor type 5 (mGLUR5)
 antagonism, were evaluated in larger-scale clinical trials. Short-term
 proof-of-principle studies showed the ability of these agents to increase postprandial
 LES pressure, inhibit TLESRs and decrease the number of reflux events. Clinical trials
 mainly evaluated the use of these drugs as add-on therapy in refractory GERD, but all
 trials failed to show substantial improvement in control of persisting reflux symptoms,
 with both agents over placebo. Two main problems were identified: 1) these drugs
 inhibited neurotransmission in the vago-vagal reflex pathways controlling TLESRs.
 However, it seems that parallel pathways using multiple neurotransmitters exists, as
 inhibition of TLESRs and reflux events with both agents was in the range of 30-50%; 2)
 it was suggested that these trials failed to distinguish between ongoing GERD symptoms
 and functional dyspepsia (FD) symptoms, and that only the former were likely to respond
 to reflux inhibition.

 FD is one of the most common gastrointestinal (GI) disorders and is defined by the Rome
 III criteria as the presence of chronic dyspeptic symptoms in the absence of underlying
 structural or metabolic disease that readily explains the symptoms. Based on these
 symptoms, the Rome III consensus proposed the subdivision of functional dyspepsia into
 postprandial distress syndrome (PDS), characterized by postprandial fullness and early
 satiation, and epigastric pain syndrome (EPS), characterized by epigastric pain or
 burning. Several studies have established a major overlap between GERD and FD, and
 against this background overlap of both symptom complexes is not surprising.

 2. RATIONALE AND OBJECTIVES Our group recently studied the relationship between
 intra-gastric pressure (IGP) and reflux events after a meal, both in GERD and in HV.
 Ingestion of a meal was accompanied by a drop in IGP, probably representing gastric
 accommodation (GA). However, the magnitude of this IGP drop varied, and was inversely
 correlated with the number of TLESRs and the number of reflux events, both in patients
 and in HV: a smaller meal-induced drop in IGP was associated with a higher rate of
 reflux events, and vice versa. These findings suggest that impaired GA is a trigger for
 reflux. Furthermore, impaired GA is a well-established mechanism underlying symptom
 generation in FD. Hence, the investigators hypothesize that impaired GA is an important
 pathophysiological feature explaining the overlap between GERD and FD. To evaluate this
 hypothesis, the investigators will study the relationship between GA, TLESRs and reflux
 events in HV and in a group of GERD patients which will be categorized as pure GERD or
 GERD/FD overlap.

 3. GENERAL DESCRIPTION OF THE STUDY In 20 HV, a combined solid state high resolution
 esophageal impedance and manometry (HRiM) catheter will be placed into the stomach. The
 investigators will record 30 min before and 60 min after administration of a high
 carbohydrate and high fat meal (1000 kcal). Esophageal body contractility, LES pressure,
 TLESRs and reflux events will be identified and classified using established criteria.
 The number of TLESRs and the number of reflux events will be counted. In sensors 5 cm
 below the lower border of LES, the magnitude of the meal-induced drop in IGP (deltaIGP)
 will be measured. Upper gastrointestinal symptoms will be recorded throughout the
 studies. These measures will provide normal range reference data for further
 pathophysiological and mechanistic studies in GERD and FD.

 The same protocol will also be used to study 50 GERD patients who will be categorized as
 pure GERD or GERD/FD overlap (26). GA, quantified as deltaIGP, and the prevalence of
 impaired GA will be determined in both groups. The correlation between diagnostic
 category and size of GA will be evaluated, and the investigators will analyze the
 presence of a hiatal hernia (HH), esophageal peristalsis, fasting and postprandial LES
 pressure, occurrence of TLESRs, occurrence and characterization of reflux events and
 their possible correlation with GA. Based on previous studies in GERD, FD and health,
 the numbers should be sufficient to detect differences in IGP with a power of 80% at a
 significance level of 0.05.

 4. MATERIALS AND METHODS

 STUDY SUBJECTS This study will be performed in 20 HV, and in 25 GERD and 25 GERD/FD overlap
 patients. All subjects are aged between 18 and 65 years, and will receive and sign a copy of
 the informed consent, before initiation of the study. Discontinuation of all acid suppressive
 therapy for at least 7 days is mandatory in all patients.

 --> HEALTHY VOLUNTEERS

 Exclusion criteria:

 -  history of any upper gastrointestinal (GI) symptoms or GI surgery;

 -  psychological disorders;

 -  any drug history;

 -  use of medication altering GI motility;

 -  pregnant or nursing women.

 -  GERD PATIENTS

 Inclusion criteria:

 -  typical symptoms of reflux, such as heartburn and/or regurgitation;

 -  gastro-esophageal reflux assessed by 24-h pH-impedance monitoring or a positive symptom
 association or;

 -  esophagitis assessed by upper GI endoscopy with careful evaluation of the presence and
 extent of a hiatal hernia (HH).

 Exclusion criteria:

 -  psychological disorders;

 -  any drug history;

 -  use of medication affecting GI motility;

 -  pregnant or nursing women;

 -  history of GI surgery.

 -->DETECTION OF FD OVERLAP IN THE GERD POPULATION

 -  FD symptoms according to the Rome III criteria. The symptoms of FD include one or more
 of: bothersome postprandial fullness occurring after normal sized meals, early satiation
 that prevents finishing a regular meal, epigastric pain, and epigastric burning at least
 several times per week during the last 6 months.

 -  The investigators will stratify to have equal numbers of overlap and non-overlap
 patients.

 STUDY PROTOCOL Patients and volunteers will be fasted for at least 12 h before the manometry
 study. Furthermore, they will be asked to refrain from alcohol, tea and coffee at least 12 h
 before participation, and to refrain from smoking cigarettes at least 1 h before the start of
 the experiment.

 The HRiM catheter (Medical Measurement Systems, Enschede, The Netherlands) incorporating 36
 pressure sensors, spaced at 2 cm in the stomach and esophagus and at 1 cm in the LES and
 upper esophageal sphincter (UES), and 16 impedance channels throughout the esophagus, will be
 placed transnasally, after topical anesthesia. Manometry will be used to record pressures in
 the stomach, the esophagus, the LES and the UES. In this way, it is possible to detect and
 characterize TLESRs, and to measure GA. The impedance channels will be used to measure bolus
 movement, and thus to detect and characterize gastro-esophageal reflux.

 Patients and volunteers will be studied in a semi-recumbent fashion for a 5-10 min
 stabilization period after the placement of the catheter. Thereafter, subjects will be given
 10 wet swallows of 5 ml saline to study esophageal peristalsis. Recordings will be made for
 30 minutes after which all subjects will receive a high carbohydrate and high fat meal of
 1000 kcal (mashed potatoes, meatloaf, and apple sauce). After meal ingestion, subjects will
 be monitored for 5 h, after which the catheter will be removed.
Inclusion Criteria:

 -  GERD patients:

 -  typical symptoms of reflux, such as heartburn and/or regurgitation;

 -  gastro-esophageal reflux assessed by 24-h pH-impedance monitoring or a positive
 symptom association or;

 -  esophagitis assessed by upper GI endoscopy with careful evaluation of the
 presence and extent of a hiatal hernia (HH).

 -  GERD/FD overlap:

 -  FD symptoms according to the Rome III criteria. The symptoms of FD include one or
 more of: bothersome postprandial fullness occurring after normal sized meals,
 early satiation that prevents finishing a regular meal, epigastric pain, and
 epigastric burning at least several times per week during the last 6 months.

 Exclusion Criteria:

 -  Healthy volunteers:

 -  history of any upper gastrointestinal (GI) symptoms or GI surgery;

 -  psychological disorders;

 -  any drug history;

 -  use of medication altering GI motility;

 -  pregnant or nursing women.

 -  GERD patients:

 -  psychological disorders;

 -  any drug history;

 -  use of medication affecting GI motility;

 -  pregnant or nursing women;

 -  history of GI surgery.