Lower Esophageal Sphincter Function Research Articles

M1861 Effect of AZD3355, a Novel GABA B Agonist, On Reflux and Lower Esophageal Sphincter Function in Patients with GERD with Symptoms Despite Proton Pump Inhibitor Treatment

M1861 Effect of AZD3355, a Novel GABA B Agonist, On Reflux and Lower Esophageal Sphincter Function in Patients with GERD with Symptoms Despite Proton Pump Inhibitor Treatment

775 Influence of the Cannabinoid Type 1 Receptor Antagonist Rimonabant On Esophageal Function in Man

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

778 Cytokeratin Assisted Laser Scanning Cytometry (LSC) Permits Fully Automated Detection of Aneuploidy in Fixed Barrett's Biopsies

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

776 Novel Fluorescence-Labeled Peptide for Targeting Intra-Epithelial Neoplasia in Barrett's Esophagus

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

492 Influence of Itopride On Esophageal Function in Man

Introduction: Defective barrier function of the lower esophageal sphincter (LES), caused by a hypotonic sphincter or transient lower esophageal sphincter relaxations (TLESRs), is a major factor in the pathogenesis of gastroesophageal reflux disease (GERD). Itopride is a new prokinetic agent which combines antidopaminergic and acetylcholinesterase inhibitory actions. Previous studies suggested that itopride improves heartburn in functional dyspepsia patients, and decreases esophageal acid exposure in GERD. It is unclear whether this effect is due to motor effects of itopride on the LES. Aims: To study the effects of itopride on fasting and postprandial LES function in healthy subjects. Materials and methods: twelve fasted healthy volunteers (5 males; 32.6±2.0 years) underwent three esophageal sleeve manometry studies after 3 days premedication with itopride 50 mg, itopride 100 mg or placebo t.i.d. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals, and gastrointestinal symptoms were scored on 100 mm visual analogue scales (VAS) at 10minute intervals. Results: Both doses of itopride significantly decreased intragastric pressures compared to placebo (respectively 16.0±1.3 and 17.3±1.5 vs. 20.4±1.7mmHg, both p<0.05). Compared to placebo, the 50 mg dose of itopride was associated with a lower LES pressure before the meal (17.3±3.0 vs. 11.8±1.6 mmHg, p<0.05), but postprandial LES pressures did not differ from placebo for any time points for both doses of itopride. Swallow-induced relaxations and the amplitude or duration of peristaltic contractions were not altered by both doses of itopride, at all time points. The 50 mg dose of itopride inhibited TLESRS compared to placebo (TLESRs total 1.7±0.7 vs. 3.3±0.5, p=0.03; preprandially 0.4±0.3 vs.1.3±0.3, p=0.04; postprandially 1.3±0.4 vs. 2.0±0.4, p=0.16). The 100 mg dose did not significantly alter the rate of TLESRs before or after the meal. Conclusions: Itopride 50 mg inhibits TLESRswithout significantly affecting esophageal peristaltic function or LES pressure. Both doses of itopride decrease intragastric pressures. Identifying the nature and location of the receptors involved in this effect of itopride requires additional studies. Our observations support further studies with itopride in GERD.

W1856 Augmenting Lower Esophageal Sphincter Function and Anatomy with a Novel Intraluminal Therapy

W1856 Augmenting Lower Esophageal Sphincter Function and Anatomy with a Novel Intraluminal Therapy

Brainstem sites controlling the lower esophageal sphincter and crural diaphragm in the ferret: A neuroanatomical study

The lower esophageal sphincter (LES) and the crural diaphragm (CD) surrounding the esophagogastric junction are key components of the gastroesophageal reflex mechanism, which engages the vago-vagal brainstem circuitry. Although both components work in conjunction to prevent gastroesophageal reflux, little is known about the brain area(s) where this integration takes place. The aims of this study were to: (1) trace the brainstem circuitry associated with the CD and the LES, and (2) determine possible sites of convergence. Experiments were done in adult male ferrets. Under isoflurane anesthesia, recombinant strains of the transneuronal pseudorabies virus (PRV-151 or PRV-Bablu) or the monosynaptic retrograde tracer cholera toxin beta-subunit (CTb) were injected into either the CD or the LES. Following a survival period of 5–7 days, animals were euthanized, perfused and their brains removed for dual-labeling immunofluorescence processing. In animals injected with recombinants of PRV into the CD and the LES, distinct labeling was found in various brainstem nuclei including: area postrema, DMV, nucleus tractus solitarius (NTS), medial reticular formation (MRF) and nucleus ambiguous (NA). Double-labeled cells were only evident in the DMV, NTS and MRF. Injections of CTb into the CD or the LES resulted in retrograde labeling only in the DMV. These findings demonstrate the presence of a direct projection from the DMV to the CD. They further suggest that the neuronal connections responsible for CD or LES function are contained in circuitries that, though largely independent, may converge at the level of DMV, NTS and MRF.

Oesophageal function in tracheoesophageal fistula speakers after laryngectomy

Patients who have undergone tracheoesophageal puncture for surgical voice restoration often use unnaturally high oesophageal air pressures during speech. This study examined the effect of high oesophageal air pressure on oesophageal body motility, lower oesophageal sphincter function and dyspeptic symptoms. Cross-sectional study using several investigative tests of oesophageal function. Sixteen patients who used tracheoesophageal fistula speech underwent several investigations, including: oesophageal manometry, videofluoroscopy, barium swallow, and tracheal pressure measurements during speech. The patients were also asked to complete a dyspepsia questionnaire. We demonstrated that more than 50 per cent of these patients had subjective or objective disordered oesophageal function. Videofluoroscopy and manometry identified oesophageal dysmotility in the same patients. Oesophageal function appears to be altered by tracheoesophageal fistula speech. However, our study showed that there is no contraindication to proceeding with tracheoesophageal fistula voicing even in patients with a history of oesophageal dysfunction.

Refractory GERD: Reaching for the high-hanging fruit*

COMPARED TO OTHER GASTROINTESTINAL (GI) SYMPTOM COMPLEXES, the medical management of gastroesophageal reflux disease (GERD) appears fairly straightforward. Whereas there are few pharmacotherapeutic options for many other GI symptoms for which patients may seek medical advice, the majority of patients with troublesome GERD symptoms can be rendered asymptomatic with a once-daily dose of a proton pump inhibitor (PPI) within 4 to 8 weeks of starting therapy. Thus, many may consider GERD an easily treated problem that can be vanquished with the mere stroke of a pen. Yet as a gastroenterologist, I find my patients with GERD to be some of the most difficult to treat. The patients I see are the relatively small group who do not obtain relief with that PPI prescription. Unfortunately, there are currently few therapeutic options that are effective in alleviating GERD symptoms that persist despite PPI use. While I often recommend that patients take their PPI twice daily instead of once, or switch to another PPI, this decision is based on limited data from uncontrolled open-label trials with significant methodologic flaws.1,2 Stepping down PPI therapy from double-dose to standard doses is successful for most patients.3 There are no other proven therapies, and I am left with limited therapeutic options for patients with refractory GERD. These patients are the proverbial high-hanging fruit that are the most difficult to reach. However, these fruit can grow the largest, rewarding those who develop tools to snare them. It is important to gain a better understanding of GERD pathophysiology to devise better strategies for helping these patients to obtain relief. GERD has been traditionally thought of as the reflux of acidic gastric contents into the esophagus, resulting in symptoms and/or esophageal injury. The gold standard diagnostic criteria for GERD involves 24-hour esophageal pH monitoring, requiring an intra esophageal pH of less than 4 for more than 4% of the time over a 24-hour period. It is generally believed that if there is no gastric acid production, there can be no reflux symptoms. However, reflux symptoms often persist. Studies confirm that the majority of patients with GERD-like symptoms, despite high-intensity (double-dose or greater) PPI therapy, have a very low prevalence of reflux by the gold standard definition.4 So what are the mechanisms responsible for ongoing symptoms? Because PPIs have been so effective in relieving GERD symptoms, the basic mechanism that enables gastroesophageal reflux has been mostly ignored. I am referring here to the presence of both anatomic factors, such as the presence of a hiatus hernia, and physiologic factors, specifically the function of the lower esophageal sphincter (LES). It is possible that non-acid gastric contents that access the esophagus through a faulty LES may cause symptoms. Another possibility may be that GERD-like symptoms are independent of gastroesophageal reflux, and are merely interpreted as GERD. A new clinical tool may help both investigation and management. With multichannel impedance manometry (MIM), an impedance catheter is passed transnasally into the esophagus. It detects the presence of gas and fluid in the esophagus, and the direction of travel (i.e., towards the stomach with a swallow, towards the mouth with gastroesophageal reflux). With MIM and pH monitoring, reflux episodes can be counted and separated into acidic and non-acidic events. If further combined with a patient symptoms diary, a clinician can determine the relationship of GERD-like symptoms to reflux events. Using MIM, researchers have shown that patients with GERD who are treated with PPIs do not have fewer reflux events, but the refluxate composition changes from primarily acidic to primarily non-acidic.5 Baclofen, which decreases LES relaxation frequency, decreases reflux events and symptom burden.6 Unfortunately, due to its side-effect profile, baclofen will likely not be widely used for refractory GERD symptoms. However, there may be other medications that improve LES function and have similar effects. It is also possible that surgical interventions may be useful for patients with refractory GERD symptoms who have ongoing non-acidic reflux.7 Hopefully, the development of MIM will foster further research into the pathophysiology of refractory GERD, allowing pharmaceutical developers to better identify potential therapeutic targets, and giving clinicians the tools necessary to pluck the juiciest fruit right from the highest reaches of the trees. Meanwhile, pharmacists should strive to identify patients with symptoms refractory to PPI therapy, who may be candidates for a PPI reduction or discontinuation. ■

Manometric study of the lower esophageal sphincter and esophagus in subtotal gastrectomy patients

There is controversy in the literature regarding the motor function behavior of the lower esophageal sphincter and esophagus following partial gastrectomy. We studied 26 patients with gastric adenocarcinoma of the distal corpus and/or antrum who underwent radical subtotal gastrectomy with Roux-en-Y reconstruction. There were 15 women (57.69%) and 11 men (42.31%) with a mean age of 57.2 years; 21 were White (80.8%) and five were of African descent (19.2%). Before the surgery and 3 months afterwards, every patient underwent manometric and endoscopic examinations. The lower esophageal sphincter showed reductions in mean respiratory pressure (19.41-15.59 mmHg, P= 0.02) and maximum expiratory pressure (8.13-5.54 mmHg, P= 0.02) without significant alteration in diaphragmatic crura pressure (32.92-30.64 mmHg, P= 0.37). An increase in peristaltic wave amplitude (91.43-124.86 mmHg, P < 0.01) and peristaltic wave conduction velocity (3.29 cm/s to 4.23 cm/s; P= 0.024) were detected in esophageal function. The presence of erosive esophagitis decreased from 10 (38.46%) patients to none (P= 0.002). We concluded that following surgery the lower esophageal sphincter function was impaired, through decreased pressure in the esophageal component without alteration in diaphragmatic crura pressure. On the other hand, there was significant increase in peristaltic wave amplitude and velocity, and improvement of the erosive esophagitis. The authors suggest that subtotal gastrectomy, with gastroesophageal junction preservation, and Roux-en-Y reconstruction should be the preferred operation for distal gastric cancer to minimize esophageal dysfunction and gastroesophageal reflux disease.

Practical Approaches to the Surgical Management of Achalasia

Achalasia is a primary motor disorder of the esophagus characterized by an abnormal hypertensive, nonrelaxing lower esophageal sphincter (LES) and nonfunctioning, aperistaltic esophageal body resulting in significant regurgitation and dysphagia. The primary goal of treatment is palliation of symptoms. At present, all treatment techniques are directed at relieving the functional obstruction at the level of the LES by disruption or paralysis of the esophageal muscle constituting the LES. Destruction of the LES function also places the patient at risk for pathologic gastroesophageal reflux disease. Therefore, the treatment of patients with achalasia must strike a balance between the relief of dysphagia and potential creation of pathologic gastroesophageal reflux. The advent of laparoscopic esophageal myotomy for the treatment of achalasia over the past decade has resulted in most patients with the disease being referred to surgeons for definitive treatment. At the time of consultation the patient may present with a myriad of symptoms, investigative results, and previous treatments. Based on our experience of over 300 patients treated with surgery at our institution between 1990 and 2007, this review will address the practical problems encountered in the surgical management of achalasia.

Sildenafil relieves symptoms and normalizes motility in patients with oesophageal spasm: a report of two cases

Oesophageal spasm presents with dysphagia and chest pain. Current treatments are limited by poor efficacy and side effects. Studies in health and oesophageal dysmotility show that sildenafil reduces peristaltic pressure and velocity; however the clinical efficacy and tolerability in symptomatic oesophageal spasm remains uncertain. We provided open-label sildenafil treatment to two patients with severe, treatment resistant symptoms associated with oesophageal spasm. The effects of sildenafil on oesophageal function and symptoms were documented by high resolution manometry (HRM). Patients were followed up to assess the efficacy of maintenance treatment with sildenafil b.i.d. HRM revealed focal and diffuse spasm in the smooth muscle oesophagus that were associated with symptoms in both cases, especially on swallowing solids. Lower oesophageal sphincter function was normal. A therapeutic trial of 25-50 mg sildenafil suppressed oesophageal contraction almost completely for water swallows; however effective, coordinated peristalsis returned with reduced frequency of spasm for solid swallows. Dysphagia and chest pain resolved during the therapeutic trial and efficacy was maintained on maintenance treatment with 25-50 mg sildenafil b.i.d. without troublesome side effects. This report shows that sildenafil can improve oesophageal function and relieve dysphagia and chest pain in patients with oesophageal spasm in whom other treatments have failed.

The Effect of an Effortful Swallow on the Normal Adult Esophagus

The effect of an effortful swallow on the healthy adult esophagus was investigated using concurrent oral and esophageal manometry (water perfusion system) on ten normal adults (5 males and 5 females, 20-35 years old) while swallowing 5-ml boluses of water. The effects of gender, swallow condition (effortful versus noneffortful swallows), and sensor site within the oral cavity, esophageal body, and lower esophageal sphincter (LES) were examined relative to amplitude, duration, and velocity of esophageal body contractions, LES residual pressure, and LES relaxation duration. The results of this study provide novel evidence that an effortful oropharyngeal swallow has an effect on the esophageal phase of swallowing. Specifically, effortful swallowing resulted in significantly increased peristaltic amplitudes within the distal smooth muscle region of the esophagus, without affecting the more proximal regions containing striated muscle fibers. The findings pertaining to the LES are inconclusive and require further exploration using methods that permit more reliable measurements of LES function. The results of this study hold tremendous clinical potential for esophageal disorders that result in abnormally low peristaltic pressures in the distal esophageal body, such as achalasia, scleroderma, and ineffective esophageal motility. However, additional studies are necessary to both replicate and extend the present findings, preferably using a solid-state manometric system in conjunction with bolus flow testing on both normal and disordered populations, to fully characterize the effects of an effortful swallow on the esophagus.

Obesity Is Associated With Increased Transient Lower Esophageal Sphincter Relaxation

Obesity has been associated with gastroesophageal reflux disease (GERD) and its complication, but the mechanism is unclear. We evaluated the association between obesity and function of lower esophageal sphincter (LOS) in subjects without GERD. We prospectively recruited consecutive obese (BMI >30) patients referred for weight reduction procedure and age- and sex-matched overweight (BMI 25-30) and normal weight (BMI > or =20 and <25) subjects. Exclusion criteria included esophagitis, reflux symptoms, use of proton pump inhibitor, hiatus hernia >2 cm, and diabetes mellitus with microvascular complication. All participants underwent combined 2-hour postprandial esophageal manometry and pH monitoring after a standard test meal followed by 24-hour ambulatory pH monitoring. Eighty-four subjects (obese, 28; overweight, 28; normal weight, 28) were studied. All 3 groups had comparable mean LOS pressure, LOS length, and peristaltic function. During the postprandial period, both obese and overweight groups had substantial increase in 2-hour rate of transient lower esophageal sphincter relaxation (TLOSR) (normal weight: 2.1 +/- 1.2 vs overweight: 3.8 +/- 1.6 vs obese: 7.3 +/- 2.0, P < .001), proportion of TLOSR with acid reflux (normal weight: 17.6% +/- 22.0% vs overweight 51.8% +/- 22.5% vs obese: 63.5% +/- 21.7%, P < .001), and gastroesophageal pressure gradient (GOPG) (normal weight: 4.5 +/- 1.2 mm Hg vs overweight: 7.1 +/- 1.4 mm Hg vs obese: 10.0 +/- 1.5 mm Hg, P < .001). Using multiple regression model, BMI (r(2): 0.70, B: 0.28, 95% CI: 0.24-0.33, P < .001) and waist circumference (r(2): 0.65, unstandardized regression coefficient [B]: 0.10, 95% CI: 0.08-0.11, P < .001) were significantly correlated with TLOSR. Obesity is associated with increased TLOSR and acid reflux during the postprandial period in subjects without GERD. Abnormal postprandial LOS function may be an early event in the pathogenesis of obesity-related GERD.

Diagnosis of Gastroesophageal Reflux Disease (GERD)

BACKGROUND: Gastroesophageal reflux disease (GERD) affects approximately 20–40% of individuals in Europe and North America and represents a disorder associated with "losses" (loss of life quality, esophageal function and morphology). METHODS: Review of level of evidence III–IV papers on diagnosis of GERD. RESULTS: GERD symptoms (heartburn, regurgitation, dysphagia, cough, wheezing) are associated with pathologic acidic and/or nonacidic gastroesophageal reflux, impaired esophageal motility and lower esophageal sphincter function and pathologic morphology: stricture, ulcus, ring web formation; columnar lined esophagus (CLE); intestinal metaplasia (i.e. Barrett esophagus) which may progress towards dysplasia and adenocarcinoma of the esophagus. Symptom correlation with data obtained by combined pH- and intraluminal impedance monitoring represents a sensitive tool for assessment of presence or absence of GERD and should be offered to those with GERD symptoms and normal pH-monitoring. Endoscopy should include biopsy sampling of a normal appearing esophago-gastric junction for exclusion of microscopic CLE with or without intestinal metaplasia and/or dysplasia. The value of high-resolution manometry for diagnosis of GERD is still under investigation. CONCLUSIONS: Patient history, physical examination and assessment of life quality are of major importance for diagnosis of GERD. Novel technologies have profoundly contributed towards those responsible being able to ascertain whether symptoms are in fact being caused by gastroesophageal reflux.

Achalasia: physiology and etiopathogenesis

Achalasia is a disorder of esophageal motility that has been well documented for over 300 years. Despite this, the initiating factor or factors and the underlying mechanisms leading to the characteristic features of achalasia, the absence of distal esophageal peristalsis and abnormal lower esophageal sphincter relaxation, are still not well understood. Recent work has shed light on changes in neurotransmission and cell signaling in the lower esophagus and lower esophageal sphincter that lead to achalasia. A number of recent reviews have thoroughly discussed diagnostic and therapeutic modalities and the reader is referred to these for in-depth review of these topics. The focus of this review will be on our current understanding of the physiology of esophageal peristalsis and lower esophageal sphincter function as it relates to achalasia and on available evidence for etiology and proposed pathophysiologic mechanisms.

Lower Esophageal Sphincter Function in the Neonate

After completing this article, readers should be able to: 1. Describe the functions of the lower esophageal sphincter. 2. Delineate the circumstances in which gastroesophageal reflux can occur in infants. 3. Explain the role of transient lower esophageal sphincter relaxation in neonatal gastroesophageal reflux. The lower esophageal sphincter (LES) is a region of smooth muscle thickening at the esophagogastric junction. The primary function of the LES is to control flow of luminal contents between the esophagus and stomach and to serve as a physical barrier against the occurrence of gastroesophageal reflux (GER) (ie, retrograde flow of gastric contents from the stomach into the esophagus). The LES is primarily controlled by parasympathetic (vagus) nerve pathways, which regulate contraction (predominantly cholinergic) and reflex relaxation (predominantly nonadrenergic noncholinergic). The LES is supported extrinsically by the crural diaphragm, which acts as an “external” sphincter. Basal LES pressure (LESP), which can be measured by passing a manometric catheter through the LES high-pressure zone, is generated by a combination of smooth muscle tone and the external compressive squeeze of the crural diaphragm. Measurements of LESP have shown that LES tone varies over time, depending on prandial state, and is influenced by many factors, including postprandial cholecystokinin release, the migratory motor complex, respiratory effort, straining, physical activity, and methylxanthine therapy. As such, the measurement of LESP at a single point in time may be poorly representative of the “true” LESP profile. The functioning of the LES as a competent antireflux barrier is very important to the developing neonate. GER occurs more frequently in the neonate than in older children and typically is recognized during episodes of regurgitation that are very common in infants. This “physiologic GER” or benign feeding-related regurgitation usually resolves spontaneously and is not necessarily symptomatic of GER disease. Pathologic GER (GER disease) may be suggested by reflux …

Lower esophageal sphincter analysis using computerized manometry in patients with chagasic megaesophagus

Due to the introduction of computer technology into manometry laboratories, three-dimensional manometric images of the lower esophageal sphincter can be constructed based on radially oriented pressures, a method termed 'computerized axial manometry.' Calculation of the sphincter pressure vector volume using this method is superior to standard manometric techniques in assessing lower esophageal sphincter function in patients with gastroesophageal reflux disease and idiopathic achalasia. Despite similarities between idiopathic achalasia and chagasic esophagopathy found using clinical, radiological, and manometric studies, controversy around lower esophageal sphincter pressure persists. The goal of this study was to analyze esophageal motor disorders in Chagas' megaesophagus using computerized axial manometry. Twenty patients with chagasic megaesophagus (5 men, 15 women, and average age 50.1 years, range 17-64) were prospectively studied. For three-dimensional imaging construction of the lower esophageal sphincter, a low-complacency perfusion system and an eight-channel manometry probe with four radial channels placed in the same level were used. For probe traction, the continuous pull-through technique was used. Results showed that the lower esophageal sphincter of patients with chagasic megaesophagus have significantly elevated pressure, length, asymmetry, and vector volumes compared to those of normal volunteers (P < 0.05). Aperistalsis of the esophageal body waves was observed in all patients and contraction amplitude was lower than that in normal patients. We conclude that patients with chagasic megaesophagus have hypertonic lower esophageal sphincter and aperistalsis of the esophageal body.

Cholecystectomy and oesophageal reflux: a prospective evaluation.

The effect of cholecystectomy on oesophageal function was examined prospectively. Of 37 patients studied, 17 (46 per cent) were still symptomatic 3-4 months after surgery. Thirteen patients (35 per cent) had abnormal oesophageal pH profiles before cholecystectomy, increasing to 27 (73 per cent) afterwards (P < 0.002). The mean (s.e.m.) DeMeester acid reflux score increased from 15.2(2.1) to 34.2(5.2) (P < 0.001) after operation. Lower oesophageal sphincter function, as measured by the sphincter function index, was significantly reduced in the patients with abnormal pH profiles after operation (P < 0.01). Mean(s.e.m.) supine gastric alkaline shift (proportion of time at pH > 4) increased from 9.2(2.0) to 17.7(3.7) per cent (P < 0.02) and the incidence of gastritis from eight patients (22 per cent) to 23 (62 per cent) (P < 0.001). These data suggest that cholecystectomy results in gastro-oesophageal reflux that appears to be related to compromised sphincter competence.

The sphinctometer: A new device for measurement of lower oesophageal sphincter function

Current evidence suggests that lower oesophageal sphincter (LOS) competence depends upon both pressure and length. Existing devices can measure length and pressure, but not simultaneously. This methodological problem is a fundamental drawback to understanding LOS function and its role in oesophageal disease. A 'sphinctometer' has been developed, consisting of an oil-filled 3-mm diameter Silastic chamber, 6 cm in length, incorporating a pressure microtransducer designed to provide an integrated pressure reading as a function of length. Its performance has been tested in vitro using human cadaver oesophagus in a specially constructed chamber in which sphincter length and pressure can be varied independently. Comparisons were made with a conventional pull-through technique. Sphinctometer response was linear throughout the LOS pressure range of 0 to 50 mmHg at a fixed LOS length (RS = 0.99; P less than 0.001). Sphinctometer response was also linear at fixed LOS pressure for sphincter lengths from 1 to 6 cm (RS = 0.99; P less than 0.001). This device thus appeared suitable for monitoring function of the human LOS, and has subsequently been successfully incorporated into an ambulatory system for patient use.