John Dent

The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.

OBJECTIVES:A globally acceptable definition and classification of gastroesophageal reflux disease (GERD) is desirable for research and clinical practice. The aim of this initiative was to develop a consensus definition and classification that would be useful for patients, physicians, and regulatory agencies.METHODS:A modified Delphi process was employed to reach consensus using repeated iterative voting. A series of statements was developed by a working group of five experts after a systematic review of the literature in three databases (Embase, Cochrane trials register, Medline). Over a period of 2 yr, the statements were developed, modified, and approved through four rounds of voting. The voting group consisted of 44 experts from 18 countries. The final vote was conducted on a 6-point scale and consensus was defined a priori as agreement by two-thirds of the participants.RESULTS:The level of agreement strengthened throughout the process with two-thirds of the participants agreeing with 86%, 88%, 94%, and 100% of statements at each vote, respectively. At the final vote, 94% of the final 51 statements were approved by 90% of the Consensus Group, and 90% of statements were accepted with strong agreement or minor reservation. GERD was defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. The disease was subclassified into esophageal and extraesophageal syndromes. Novel aspects of the new definition include a patient-centered approach that is independent of endoscopic findings, subclassification of the disease into discrete syndromes, and the recognition of laryngitis, cough, asthma, and dental erosions as possible GERD syndromes. It also proposes a new definition for suspected and proven Barretts esophagus.CONCLUSIONS:Evidence-based global consensus definitions are possible despite differences in terminology and language, prevalence, and manifestations of the disease in different countries. A global consensus definition for GERD may simplify disease management, allow collaborative research, and make studies more generalizable, assisting patients, physicians, and regulatory agencies.

Mechanisms of Gastroesophageal Reflux in Patients with Reflux Esophagitis

We evaluated the mechanisms of gastroesophageal reflux in 10 patients with reflux esophagitis and compared the results with findings from 10 controls. The patients had more episodes of reflux (35 +/- 15 in 12 hours, as compared with 9 +/- 8 in the controls) and a lower pressure of the lower esophageal sphincter (13 +/- 8 mm Hg as compared with 29 +/- 9 in the controls) (P less than 0.001). Reflux occurred by three different mechanisms: transient complete relaxation of the lower esophageal sphincter, a transient increase in intra-abdominal pressure, or spontaneous free reflux associated with a low resting pressure of the lower esophageal sphincter. In controls 94 per cent of reflux episodes were caused by transient sphincter sphincter relaxation. In the patients 65 per cent of episodes of reflux accompanied transient sphincter relaxation, 17 per cent accompanied a transient increase in intra-abdominal pressure, and 18 per cent occurred as spontaneous free reflux. The predominant reflux mechanism in individual patients varied: some had normal resting sphincter pressure and reflux that occurred primarily during transient sphincter relaxation, whereas others with low resting sphincter pressures had spontaneous free reflux or reflux that occurred during an increase in intra-abdominal pressure.

Pathogenesis of Reflux Esophagitis

During the past decade considerable new information has accrued about reflux esphagitis and the physiology of esophageal motor function. Although numerous reports review the clinical, diagnostic, and therapeutic aspects of reflux esophagitis (1-6), few reports (7) focus primarily on the pathophysiology of esophagitis production. Our purpose here is to: (a) review critically recent findings relevant to the pathophysiology of reflux esophagitis, (b) analyze factors that may contribute to the production of reflux esophagitis, and (c) identify appropriate questions that merit further investigation. Throughout the report we will endeavor to alert the reader when the manuscript reflects our own opinion, speculation, or scientific bias as opposed to established observations. For this report the term reflux esophagitis is defined as esophageal inflammation caused by refluxed material. On endoscopy reflux esophagitis may cause visible discoloration, friability, ulceration, exudate, or luminal narrowing. In active reflux esophagitis, histologic sections demonstrate an acute polymorphonuclear or a mixed polymorphonuclear and round cell infiltrate, generally accompanied by epithelial erosion or ulceration. These gross or histologic findings are necessary for a specific diagnosis of reflux esophagitis. In some patients with clinical complaints suggesting GE reflux, the esophagus appears normal at endoscopy and no evidence of inflammation is present on biopsy. Biopsies

Pharyngeal (Zenker's) diverticulum is a disorder of upper esophageal sphincter opening

Pharyngeal coordination, sphincter opening, and flow pressures during swallowing were investigated in patients with pharyngeal (Zenkers) diverticula. Fourteen patients with diverticula and 9 healthy age-matched controls were studied using simultaneous videoradiography and manometry. Pharyngeal and upper esophageal sphincter pressures were recorded by a perfused side hole/sleeve assembly. Temporal relationships among swallowing events, extent of sphincter opening during swallowing, and intrabolus pressure during bolus passage across the sphincter were measured. The timing among pharyngeal contraction and sphincter relaxation, opening, and closure did not differ between patients and controls. Sphincter opening was significantly reduced in patients compared with controls in sagittal (P = 0.0003) and transverse (P = 0.005) planes. Manometric sphincter relaxation was normal in patients. Intrabolus pressure was significantly greater in patients than in controls (P = 0.001). It is concluded that Zenkers diverticulum is a disorder of diminished upper esophageal sphincter opening that is not caused by pharyngosphincteric incoordination or failed sphincter relaxation. Incomplete sphincter opening is likely to cause dysphagia. Increased hypopharyngeal pressures during swallowing are probably important in the pathogenesis of the diverticulum.

Integrity of cholinergic innervation to the lower esophageal sphincter in achalasia

The human lower esophageal sphincter (LES) is believed to be innervated by nonadrenergic, noncholinergic inhibitory nerves, and cholinergic excitatory nerves. In idiopathic achalasia, LES relaxation is abnormal because the inhibitory nerves to the sphincter are either absent or functionally impaired. The integrity of cholinergic excitatory nerves to the LES, however, has not been thoroughly evaluated. In 27 patients with untreated idiopathic achalasia, and 21 healthy volunteers, we investigated the hypothesis that postganglionic cholinergic nerves to the LES are functionally intact in achalasia. The LES responses to atropine, edrophonium, methacholine, amyl nitrite, and pentagastrin were assessed. In 2 achalasia patients, patterns of fasting motor activity in the LES were investigated during overnight manometric studies. Resting LES pressure was significantly greater in the achalasia patients, 41 +/- 4 mmHg (mean +/- SE), than in the normal subjects, 20 +/- 2 mmHg. Atropine significantly reduced LES pressure in both groups by 30%-75%. Edrophonium increased LES pressure in the achalasia patients but had negligible effect on the normal subjects. The LES in achalasia patients exhibited an increased sensitivity to both methacholine and pentagastrin compared with the normal subjects. In both patients who underwent an overnight manometric study, the LES exhibited cyclic phasic contractile activity synchronous with gastric contractions during the migrating motor complex. We conclude that the study findings support the hypothesis that postganglionic cholinergic LES innervation in achalasia patients is either normal or only minimally impaired, in contrast to the marked impairment of the inhibitory nerves governing LES relaxation.

Factors that influence induction of gastroesophageal reflux in normal human subjects

Findings from recent studies indicate that transient relaxation of the lower esophageal sphincter (LES) is an important contributory mechanism to spontaneous episodes of gastroesophageal reflux (GER) in normal subjects as well as in patients with reflux esophagitis. Our study aim was to evaluate the interrelationship between reduction of LES pressure and elevation of intraabdominal pressure in the induction of GER in healthy subjects. Seven volunteers were studied supine after gastric loading with 0.1 N HCl. A pH probe recorded acid GER. Leg raising (LR) or abdominal compression (AC) were used as stress maneuvers to increase intraabdominal pressure, either alone or in combination with stimuli that concurrently lowered LES pressure, namely multiple rapid swallows (RS) or intraesophageal balloon distention (BD). Each individual stimulus and stimulus combination was tested three times, giving a total of 24 test maneuvers per subject. The test maneuvers elicited 2–12 GERs in each subject. The GER incidence for single maneuvers was: AC, 0%; LR, 0%; RS, 19%; and BD, 24%. LR in combination with RS or BD did not increase the incidence of GER above that induced by RS or BD alone. In contrast, AC concurrent with RS and BD increased the incidence of GER to 52% and 81%, respectively. For all test conditions, a prerequisite for the occurrence of GER was a fall in LES pressure to a minimal value of 3 mm Hg or less. GER never occurred when LES pressure was ≥4 mm Hg, even during intervals of increased intraabdominal pressure. We conclude that (1) virtually complete absence of LES pressure is an essential prerequisite for the induction of GER; (2) during intervals of negligible LES pressure, elevation of intraabdominal pressure increases the prevalence of GER;and (3) LR by normal subjects induces a substantial increase in the abdominal pressure but does not increase GER, probably due to a pinch-cock effect of the diaphragmatic hiatus on the intrahiatal esophageal segment.

Disordered gastric emptying: mechanical basis, assessment and treatment.

The recent use of scintigraphic methods has demonstrated that disordered gastric emptying occurs frequently. Delayed gastric emptying is more common than rapid gastric emptying. While the prevalence of deranged gastric emptying depends on the population studied, the measurement technique and the criteria used to define abnormality, there is in general reasonable concordance among the results of different studies. For example, delayed emptying of solid meals is seen in about 50% of patients with diabetes mellitus (whether insulin dependent or non-insulin dependent) and 40% of patients presenting with unexplained upper abdominal symptoms (Jian et al, 1985; Horowitz et al, 1986a, 1989a; Keshavarzian et al, 1987). Some of the disorders that have been demonstrated to result in either delayed or accelerated gastric emptying are listed in Table 1. Gastroparesis may be transient or chronic. Acute gastroparesis may develop secondary to gastroenteritis or metabolic disorders. Helicobacter pylori is, however, not associated with gastroparesis (Barnett et al, 1989). A considerable number of drugs, such as morphine, anticholinergics, P-adrenergic agonists, L-dopa, some anorectic drugs and tricyclic antidepressants, delay gastric emptying (Nimmo, 1976; Horowitz et al, 1985a). Cigarette smoking significantly delays gastric emptying (Johnson et al, 1991). Despite the limited number of histopathological studies on human tissue (Yoshida et al, 1988)) most causes of chronic gastroparesis not attributable to the effects of surgery are presumed to be associated with structural abnormalities in either the gastric or small intestinal smooth muscle, or its nervous innervation (Horowitz et al, 1986b, 1987a,b,c). Limited data (Achem-Karam et al, 1985; Labo et al, 1986) suggest that abnormalities in the secretion of

Upper esophageal sphincter tone and reactivity to stress in patients with a history of globus sensation

Anxiety and abnormal upper esophageal sphincter function have been ascribed ill- defined roles in the etiology of globus sensation. In this study, we examined the psychological profile and effect of acute mental stress (dichotic listening task) on UES tone in seven patients reporting to the clinic with globus sensation and 13 healthy controls. Alterations in heart rate, blood pressure, frontalis EMG, and skin conductance confirmed the effectiveness of the stress test in patients and controls. During resting conditions, UES pressure (mean±SE) in patients (40.4±4.6 mm Hg) did not differ significantly from controls (46.5±4.7 mm Hg). In response to stress, UES pressure rose by 31% in patients (P=0.04) and by 25% in controls (P=0.002). The stress- induced rise in UES pressure in patients (9.5±3.8 mm Hg) was not significantly different to that observed in controls (11.8±3.0 mm Hg). Psychological profiles of globus patients presenting to the clinic revealed them to be more introverted, anxious, neurotic, and depressed than normal controls. We conclude that in patients with a history of globus sensation, resting UES pressure and its response to stress is normal. Although individuals presenting to the clinic with globus sensation showed increased levels of psychoneurosis, acute, predictable stress is not a factor in the genesis of globus sensation. UES hyperresponsiveness to other stimuli or subjective intolerance to changes in UES pressure could account for symptoms of globus sensation.

Impact of Endoscopic Suturing of the Gastroesophageal Junction on Lower Esophageal Sphincter Function and Gastroesophageal Reflux in Patients with Reflux Disease

OBJECTIVES:Plication of the gastroesophageal junction by endoscopic suturing has been reported to improve symptoms and reduce acid exposure in patients with gastroesophageal reflux disease (GERD). The mechanisms underlying these effects are not well defined. The aims of our study were to determine the impact of endoscopic suturing of the gastroesophageal junction on lower esophageal sphincter (LES) function in patients with GERD.METHODS:In 15 patients (7 males) with GERD (heartburn, % time esophageal pH < 4 greater than 4%, ± history of erosive esophagitis within 6 months), two plications were performed circumferentially 1 cm below the gastroesophageal junction. Endoscopy and combined postprandial esophageal manometry and pH monitoring were performed before and 6 months after treatment; 24-h ambulatory pH monitoring and symptom assessment were also performed before, and at 6 and 12 months after treatment.RESULTS:Six months after treatment, the rate of transient LES relaxations (tLESRs) was decreased by 37% (p < 0.05) and basal LES pressure had increased from 4.3 ± 2.2 mmHg to 6.2 ± 2.1 mmHg (p < 0.05). The rate of postprandial reflux events and acid exposure time were not altered. Endoscopic suturing significantly reduced 24-h esophageal acid exposure from 9.6% (9.0–12.1) to 7.4% (3.9–10.1) at 6 months, due predominantly to a reduction in upright acid exposure. The reduction in total 24-h acid exposure was sustained to 12 months. At repeat endoscopy, only one plication was evident in 6 patients (40%) at 6 months. Seven patients (47%) remained off medications at 6 and 12 months follow-up.CONCLUSIONS:In patients with GERD, endoscopic suturing of the gastroesophageal junction results in a reduction in the rate of tLESRs, and an increase in basal LES pressure. These changes in LES function result in only a modest reduction in gastroesophageal reflux.

Optimizing acid suppression for treatment of acid-related diseases

Gastric acid is of central importance in the pathogenesis of duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. Pharmacological reduction of acid secretion is, therefore, the mainstay of current treatment, but the optimal degree of acid suppression remains incompletely understood. This paper considers the ideal ways of assessing and reporting the pharmacological effectiveness of acid-inhibiting drugs and relating such data to clinical efficacy. Twenty-four-hour intragastric pH measurements are widely used for this purpose, although this technique cannot measure secretion quantitatively. Data on suppression of 24-hr intragastric acidity for groups of subjects have been successfully correlated with healing rates for duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. Three primary determinants of healing have been derived from antisecretory data. These are the degree of suppression of acidity, the duration of suppression of acidity, and the duration of treatment. The order of importance of these determinants varies depending on the disease. Data on 24-hr intragastric acidity should be accompanied whenever possible by data on 24-hr plasma gastrin levels, as the relationship between suppression of acidity and a rise in gastrin varies widely between individuals. It is not possible to predict the plasma gastrin level from the intragastric pH or any other measurement of intragastric acidity. Comparative data sets in groups of subjects may provide useful information. Proton pump inhibitors produce a greater and longer-lasting degree of suppression of acidity than conventional doses of H2-receptor antagonists. For this reason, they are more effective in healing duodenal ulcer and gastric ulcer. However, in view of the importance of duration of treatment, healing rates with the H2-receptor antagonists approach those obtained with proton pump inhibitors if treatment is continued for a longer time. In gastroesophageal reflux disease in particular, although the optimal degree of acid suppression is not yet defined, the consistently superior performance of proton pump inhibitors demonstrates that increased suppression of acidity is clinically beneficial.