David P. Hirsch

Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis.

BACKGROUND & AIMS Nitric oxide (NO) is well accepted as an inhibitory neurotransmitter in the gastrointestinal tract; however, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) in humans remains to be determined. Therefore, the effect of NG-monomethyl-L-arginine (L-NMMA), a specific NO synthase blocker, on gastric distention-induced TLESRs was investigated. METHODS Esophageal manometry was performed using a perfused sleeve assembly. The effect of L-NMMA was evaluated on water swallow-evoked primary peristalsis (n = 8; single-blind, placebo-controlled) and on the rate of TLESRs during gastric distention (n = 8; double-blind, placebo-controlled). RESULTS L-NMMA increased the amplitude of peristaltic pressure waves in the distal esophagus and increased peristaltic velocity in the proximal esophagus. In contrast, L-NMMA had no effect on basal lower esophageal sphincter pressure, nadir pressure, duration, and area under the curve of lower esophageal sphincter relaxation. L-NMMA significantly inhibited the increase in TLESRs during gastric distention. L-NMMA also increased the intraballoon pressure during distention. CONCLUSIONS NO is one of the neurotransmitters involved in the reflex arc mediating the triggering of TLESRs. NO is involved in the timing of human esophageal peristalsis and may exert a tonic inhibition on the proximal stomach.

Long term results of pneumatic dilation in achalasia followed for more than 5 years

OBJECTIVE:We aimed to evaluate the long term therapeutic outcome in achalasia patients treated with pneumatic dilation, specifically focusing on those patients treated more than 15 yr ago.METHODS:All patients treated in our center whose records were available for review were asked to fill out a questionnaire assessing their degree of dysphagia, retrosternal pain, regurgitation, weight loss, and coughing during the night. The number of dilations was collected from the clinical records. The results of the treatment were classified into four different classes (excellent, good, moderate, poor). For those patients who had died, the cause of death was ascertained from the medical records or from the general practitioner.RESULTS:The questionnaires were distributed to 249 patients, 32 of whom had died. Of the 125 patients who completed the questionnaire, 81 (45 male and 36 female) were treated more than 5 yr ago. The mean follow-up was 12 ± 1 yr. The therapeutic success rate was 50%, obtained after a median of four dilations (interquartile range = 3–6). Of this cohort, 25 patients (18 male and seven female, aged 35–84 yr) were treated more than 15 yr ago (mean follow-up = 20.5 ± 0.5 yr). The median number of dilations was four (interquartile range = 3–7), with a therapeutic success rate of 40%. Two patients experienced a perforation, and seven were referred for surgery. Six patients out of 32 (19%) died of esophageal cancer.CONCLUSIONS:The long term success rate of pneumatic dilation is rather low, resulting in permanent successful treatment of achalasia in only 40–50% of patients. Achalasia is a risk factor for esophageal cancer.

Efficacy of treatment for patients with achalasia depends on the distensibility of the esophagogastric junction.

BACKGROUND & AIMS Many patients with persistent dysphagia and regurgitation after therapy have low or no lower esophageal sphincter (LES) pressure. Distensibility of the esophagogastric junction (EGJ) largely determines esophageal emptying. We investigated whether assessment of the distensibility of the EGJ is a better and more integrated parameter than LES pressure for determining efficacy of treatment for patients with achalasia. METHODS We measured distensibility of the EGJ using an endoscopic functional luminal imaging probe (EndoFLIP) in 15 healthy volunteers (controls; 8 male; age, 40 ± 4.1 years) and 30 patients with achalasia (16 male; age, 51 ± 3.1 years). Patients were also assessed by esophageal manometry and a timed barium esophagogram. Symptom scores were assessed using the Eckardt score, with a score <4 indicating treatment success. The effect of initial and additional treatment on distensibility and symptoms was evaluated in 7 and 5 patients, respectively. RESULTS EGJ distensibility was significantly reduced in untreated patients with achalasia compared with controls (0.7 ± 0.9 vs 6.3 ± 0.7 mm(2)/mm Hg; P < .001). In patients with achalasia, EGJ distensibility correlated with esophageal emptying (r = -0.72; P < .01) and symptoms (r = 0.61; P < .01) and was significantly increased with treatment. EGJ distensibility was significantly higher in patients successfully treated (Eckardt score <3) compared with those with an Eckardt score >3 (1.6 ± 0.3 vs 4.4 ± 0.5 mm(2)/mm Hg; P = .001). Even when LES pressure was low, EGJ distensibility could be reduced, which was associated with impaired emptying and recurrent symptoms. CONCLUSIONS EGJ distensibility is impaired in patients with achalasia and, in contrast to LES pressure, is associated with esophageal emptying and clinical response. Assessment of EGJ distensibility by EndoFLIP is a better parameter than LES pressure for evaluating efficacy of treatment for achalasia.

The proximal stomach and postprandial symptoms in functional dyspeptics

OBJECTIVE:It remains unclear whether postprandial symptom profiles in patients with visceral hypersensitivity and in those with impaired fundic accommodation differ. Therefore, we evaluated the postprandial symptoms in functional dyspepsia (FD) patients classified according to proximal stomach function. In addition, the effect of gastric relaxation induced by sumatriptan on postprandial symptoms was studied in FD patients with impaired fundic accommodation.METHODS:Twenty-five healthy volunteers (HVs) and 44 FD patients filled out a disease-specific questionnaire (Nepean Dyspepsia Index) and underwent a gastric barostat study to evaluate visceral sensitivity, meal-induced fundic relaxation, and postprandial symptoms. Postprandial symptoms evoked by a drink test or reported during the barostat study were compared between FD patients subdivided according to the underlying pathophysiological mechanism. Finally, the effect of sumatriptan on postprandial symptoms evoked by a drink test was investigated in HVs and in FD patients with impaired fundic accommodation.RESULTS:There was no clear relationship between any of the 15 Nepean Dyspepsia Index symptoms and proximal stomach function. Postprandial symptoms evoked during the barostat study or after the drink tests were significantly higher in FD patients than in HVs; however, no clear differences in symptom profile could be demonstrated between the different subclasses of FD. Sumatriptan did not affect the maximal ingested volume or the postprandial symptoms in HVs or FD patients after a drink test.CONCLUSIONS:No clear relationship could be demonstrated between postprandial symptoms and proximal stomach function.

Involvement of cholecystokininA receptors in transient lower esophageal sphincter relaxations triggered by gastric distension.

Objective:Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastroesophageal reflux. In the present study we evaluated the effect of loxiglumide, a specific cholecystokininA (CCKA)-receptor antagonist, on the occurrence of TLESRs evoked by gastric distension.Methods:Eight healthy subjects underwent esophageal manometry using a 10-lumen sleeve assembly during placebo or loxiglumide (10 mg/kg/h) in a randomized double-blind order. Gastric distension was induced by inflation of 400 ml of air.Results:Basal lower esophageal pressure (LESP) and swallow-induced relaxation were not affected by loxiglumide. Loxiglumide significantly reduced the number of TLESRs, from 11.5 (5.8–18.3) to 6.0 (3.3–14.3) during the total recording period of 1 h, and from 5.5 (4.25–7.5) to 2.0 (0.5–6.8) during the first 15 min. The number of common cavities was significantly decreased by loxiglumide, from 8.0 (4.0–20.0) to 5.0 (2.0–7.8). TLESRs represented the main mechanism (60% during placebo, 74% during loxiglumide) underlying common cavities, followed by swallow-induced relaxation.Conclusions:Loxiglumide significantly reduces the number of TLESRs triggered by gastric distension without interfering with swallow-related relaxation of the lower esophageal sphincter, suggesting the involvement of CCKA receptors in the reflex pathway mediat-ing TLESRs.

Transient lower oesophageal sphincter relaxations--a pharmacological target for gastro-oesophageal reflux disease?

The oesophago‐gastric junction functions as an anti‐reflux barrier preventing increased exposure of the oesophageal mucosa to gastric contents. Failure of this anti‐reflux barrier results in gastro‐oesophageal reflux disease, and may lead to complications such as oesophagitis, Barrett’s oesophagus and eventually oesophageal carcinoma.

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period

Background The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. Objective To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). Methods Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. Results Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). Conclusion Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. clinical trial registration http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers

Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans.

High-resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event

Background  Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro‐esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high‐resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head‐to‐head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs.

Effect of prolonged gastric distention on lower esophageal sphincter function and gastroesophageal reflux

OBJECTIVES: Morbidly obese patients treated with an intragastric balloon report a transient increase in gastroesophageal reflux (GER) symptoms. In the present study, we evaluated the underlying mechanisms of GER and examined the effect of prolonged gastric distention on lower esophageal sphincter function. METHODS: Fasting and postprandial manometric studies were performed in obese subjects (n = 15) before, immediately after, and 10 and 20 wk after placement of a 500-ml water-filled balloon. RESULTS: Residual lower esophageal sphincter (LES) pressure after water swallows was not affected after balloon placement, excluding mechanical interaction with sleeve function. Postprandial LES pressure was significantly increased after 10 and 20 wk. GER was increased in the right recumbent position until 10 wk after balloon placement, mainly because of an increased percentage of transient lower esophageal sphincter relaxations (TLESRs) accompanied by GER. TLESRs were the main mechanisms underlying reflux both before and after balloon placement. The rate of TLESRs was increased significantly immediately after introduction of the balloon, returning to baseline values after 20 wk. After balloon placement, reflux episodes were evoked by gastric contractions that were not inhibited by meals. CONCLUSIONS: Chronic distention by an intragastric balloon increased reflux up to 10 wk after placement because of an increase in the percentage of TLESRs accompanied by a reflux episode. In addition, prolonged balloon distention increased the rate of TLESRs and created a postprandial state even 10 wk after balloon placement. After 20 wk these effects largely resolved, illustrating adaptation to this artificial situation.