When are reflux episodes symptomatic?

Careful scrutiny of pH recordings and symptom diaries in patients having 24-hour pH-metry reveals that most reflux episodes are asymptomatic. Although this observation is well known and long recognized, the explanation for why one reflux episode leads to symptoms and others do not is incompletely understood. Forty-four patients with chronic typical gastroesophageal reflux disease (GERD) symptoms referred for ambulatory pH testing were studied. Antisecretory medication was stopped 2 weeks prior to the study. Two meals were taken during the study; one standardized (hamburger, fries, milk-shake) and one at the patient's discretion. A system onset marker noted the type, beginning and end of symptoms (heartburn, regurgitation, chest pain). Age, sex, upright/supine position, nadir pH, time pH < 4, and relationship to meals were compared for symptomatic/asymptomatic reflux episodes. An acid reflux event was defined as a drop in pH < 4 lasting > 5 seconds. The pH catheter detected 1464 reflux episodes. Only 93 (6.3%) were symptomatic. Forty-six of the 93 (49.4%) were associated with heartburn, 38 (40.9%) with regurgitation, and nine (9.7%) with chest pain. Nadir pH was significantly lower in symptomatic episodes. Nearly 50% of symptomatic reflux episodes occurred after meals, especially after non-standardized compared to standardized meal. Symptomatic episodes tended to be longer in duration and to occur in the supine position, while age/sex made no difference. Six percent of the reflux episodes were temporally associated with typical GERD symptoms. This association seems to be influenced by the acidity of the refluxate. Nearly half of the symptomatic reflux episodes occurred after eating.     

Characteristics of symptomatic reflux episodes in Japanese proton pump inhibitor-refractory non-erosive reflux disease patients

AIM: To clarify the pathogenesis of gastroesophageal reflux disease symptoms in non-erosive reflux disease(NERD) patients.METHODS: Thirty-five NERD patients with persistent symptoms, despite taking rabeprazole 10 mg twice daily for at least 8 wk, were included in this study. All patients underwent 24 h combined impedance- p H on rabeprazole. The symptom index(SI) was considered to be positive if ≥ 50%, and proximal reflux episodes were determined when reflux reached 15 cm above the proximal margin of the lower esophageal sphincter.RESULTS: In 14(40%) SI-positive patients, with liquid weakly acid reflux, the occurrence rate of reflux symptoms was significantly more frequent in proximal reflux episodes(46.7%) than in distal ones(5.7%)(P 0.001). With liquid acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes(38.5%) and distal ones(20.5%)(NS). With mixed liquid-gas weakly acid reflux, the occurrence rate of reflux symptoms in proximal reflux episodes was significantly more frequent(31.0%) than in distal reflux ones(3.3%)(P 0.001). With mixed liquid-gas acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes(29.4%) and distal ones(14.3%)(NS).CONCLUSION: The proximal extent of weakly acidic liquid and mixed liquid-gas reflux is a major factor associated with reflux perception in SI-positive patients on proton pump inhibitor therapy.     

Gastroesophageal reflux disease--from reflux episodes to mucosal inflammation

Gastroesophageal reflux disease (GERD) affects 20-30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.     

Characteristics of transient ischaemic episodes in patients with silent and symptomatic exercise-induced myocardial ischaemia

To evaluate transient ischaemic episodes during daily life inpatients with coronary artery disease and exercise-induced myocardialischaemia, 38 patients underwent ambulatory ST-segment monitoringover 48 h. Sixteen patients had painless ischaemia during exerciseand occasional angina, and 12 patients had symptomatic ischaemiaand frequent angina during daily life. Ten patients with provencoronary artery disease but normal exercise electrocardiogramsserved as controls. The extent of coronary artery lesions andthe prevalence of myocardial infarction were similar in allgroups. ST-segment monitoring revealed 817 min and 98 episodesof ST depression in 13/16 patients of the asymptomatic groupand 111 min and 21 episodes in 5/12 patients of the symptomaticgroup (P<0.03). Subjective scores for physical activity duringHolter monitoring were significantly higher in the first groupthan in the second. The majority of ischaemic episodes in bothgroups was asymptomatic. No ischaemic ST changes occurred incontrol patients. Results indicate a higher frequency of transientischaemic episodes related to a higher level of physical activityin patients with silent ischaemia than in patients with symptomaticexercise-induced ischaemia.     

Antireflux surgery for symptomatic gastroesophageal reflux

To determine the effects of Nissen fundoplication upon the symptoms of reflux and the diagnostic tests employed to evaluate reflux and to examine the relationship between gastroesophageal reflux and lower esophageal sphincter pressure before and after fundoplication, 10 patients with symptomatic reflux were studied before and after operation. Clinical evaluation, barium esophagography, endoscopy with mucosal biopsy, esophageal manometry, acid-perfusion and acid-reflux testing, and gastroesophageal scintiscanning were performed on each patient before and after surgery. Following fundoplication, marked symptomatic, radiographic, endoscopic, and histologic improvement was observed. Serial acid-reflux tests at increasing gastroesophageal pressure gradients returned to normal after surgery. Lower-esophageal-sphincter (LES) pressure increased from 8.2±1.3 to 12.0±1.5 mm Hg (P<0.01). In addition, surgery resulted in a significant decrease in the gastroesophageal reflux index from 17.4±2.4 to 2.7±1.1% (P<0.001). Surprisingly, the pre- and postoperative resting LES pressures did not correlate significantly with corresponding gastroesophageal reflux indices for individual patients. We conclude that increased LES pressure alone does not explain adequately the functional and clinical improvement which follows fundoplication.     

Characteristics of gastroesophageal reflux in symptomatic patients with and without excessive esophageal acid exposure

OBJECTIVE: In some patients with a physiological esophageal acid exposure, an association between reflux episodes and symptoms can be demonstrated. Besides acidity, other factors such as proximal extent may determine whether a reflux episode is perceived or not. We aimed to investigate the reflux profile of gastroesophageal reflux disease (GERD) patients with physiological acid exposure. METHODS: Twenty-four-hour impedance-pH monitoring was performed in 14 GERD patients with excessive acid exposure (pH+), 14 GERD patients with physiological acid exposure (pH-), and 14 controls. All patients had a positive symptom-reflux association during 24-h monitoring (SAP+). RESULTS: The incidence of acid reflux episodes in pH- SAP+ patients (25.5 +/- 4.9) and controls (20.2 +/- 3.9) was comparable, but lower than in pH+ SAP+ patients (69.8 +/- 7.3). However, no differences in number of weakly acidic reflux episodes were observed among pH- SAP+ patients, pH+ SAP+ patients, and controls (27.2 +/- 3.8 vs 26.8 +/- 4.6 and 21.0 +/- 3.7, respectively). The proportion of reflux episodes that reached the proximal esophagus was significantly higher in the pH+ SAP+ (33.5%) and pH- SAP+ (36.0%) patients than in the controls (19.5%). Volume clearance time was longer in pH+ SAP+ (12.5 [12.5-17.0] s) compared with pH- SAP+ patients (12.0 [11.0-16.5] s) and controls (9.5 [10.0-12.5] s) (P < 0.05). Acid clearance time was also longer in pH+ SAP+ patients (55.0 [32.0-64.0] s) compared with the pH- SAP+ (16.5 [11.4-40.0] s) and controls (14 [12.0-19.1] s) (P < 0.01). CONCLUSIONS: In pH- SAP+ patients, a higher proportion of reflux episodes reach the proximal esophagus than in controls. This can in part explain their symptoms.     

Effect of acid‐suppressive therapy on narrow band imaging findings in gastroesophageal reflux disease: a pilot study

Standard endoscopy is an insensitive test for gastroesophageal reflux disease (GERD). Narrow band imaging (NBI) endoscopy enhances visualization of the distal esophagus. NBI patterns like intrapapillary capillary loop (IPCL) dilatation, tortuosity, and increased number; microerosions; increased vascularity at the squamocolumnar junction (SCJ); ridge‐villous pattern below the SCJ; and presence of columnar islands in the distal esophagus have been suggested as features of GERD. We evaluated the effect of proton pump inhibitor (PPI) therapy on NBI findings in GERD patients. Patients prospectively underwent NBI upper endoscopy before and after PPI therapy. NBI findings were recorded at each endoscopy. Twenty‐one patients with GERD symptoms (mean age 60.0 years; males 90.5%; white 90.5%) were studied. After PPI therapy, there was a significant reduction in the proportion of patients with the following NBI features: IPCL tortuosity (90% vs. 4.8%, P < 0.0001), dilated IPCLs (86% vs. 9.5%, P < 0.0001), and increased vascularity at the SCJ (43% vs. 9.5%, P= 0.0082). PPI led to healing of all microerosions (71% vs. 0%, P < 0.0001) and disappearance of ridge‐villous patterns below the SCJ (14% vs. 0%, P < 0.0001). There was no significant change in the proportion of patients with increased numbers of IPCLs pre‐ and post‐PPI therapy (71% vs. 48%, P= 0.09) or columnar islands in the distal esophagus (38% vs. 29%, P= 0.31). In patients with GERD symptoms, NBI features suggestive of GERD respond to PPI; suggesting these features are truly acid‐mediated. These findings need to be confirmed by randomized controlled trials.     

Felodipine does not increase the reflux episodes in patients with gastroesophageal reflux disease

BACKGROUND/AIMS: Calcium channel blocking agents have been reported to increase the risk of gastroesophageal reflux. However, whether felodipine, a newer calcium channel blocker, increases reflux episodes and decreases esophageal acid clearance in patients with gastroesophageal reflux disease has never been studied. Therefore, the aim of this study was to evaluate whether felodipine increases the incidence of gastroesophageal reflux in patients with gastroesophageal reflux disorder. METHODOLOGY: Nine patients with gastroesophageal reflux disease, 6 men and 3 women, with a mean age of 62.6 +/- 14.4 years (range: 37-80 years) were studied. They received ambulatory esophageal pH monitoring for 45.7-48 hours (mean: 47.1 +/- 0.8 hours). Various pH parameters were evaluated during a similar interval of monitoring time before and after receiving 5 mg of felodipine. RESULTS: No significant difference was noted in any pH parameter by the Wilcoxon signed Ranks test, including reflux episodes (P = 0.552), reflux episodes longer than 5 min (P = 0.683), esophageal acid clearance (P = 0.663) and fraction time of pH < 4 (P = 0.752) before and after the use of felodipine. CONCLUSIONS: Felodipine does not increase reflux episodes or impair esophageal acid clearance in patients with gastroesophageal reflux disease.     

Acid gastro-oesophageal reflux episodes as related to the quality of preceding peristalsis. A study in normal subjects

It has earlier been demonstrated after long-term monitoring of pH and peristalsis in the oesophagus that episodes of acid gastro-oesophageal reflux occur in normal volunteers. To determine whether there is a connection between gastro-oesophageal reflux and prior peristalsis, pH and peristalsis were monitored for 12 h in 26 asymptomatic subjects. The recorded peristalsis was divided into brief bursts of peristaltic contractions (less than or equal to 60 sec) and more prolonged continuous activity. Peristaltic periods were limited to prior and subsequent peristalsis by a non-peristaltic course of greater than 30 sec. Continuous peristalsis was defined as a sequence of peristaltic contractions with a mutual distance between individual peristaltic waves of greater than or equal to 30 sec. A total of 81 episodes of reflux were recorded, of which 67 were preceded by peristaltic activity. Brief bursts of peristalsis, unrelated to reflux episodes, were frequently terminated by bolus-transporting peristaltic waves (p less than 0.001). When the last contraction before reflux was considered, an increased frequency of non-propagating peristalsis was found (p less than 0.01). In addition, a closer time relationship was observed between peristalsis and reflux if the last contraction was of the upper segmentary type, as compared with propagating activity (p less than 0.001). In conclusion, reflectory sphincter relaxation producing reflux may possibly be triggered by contractions in the upper part of the oseophagus, not followed by a bolus-transporting peristaltic wave.     

Precipitating causes of acid reflux episodes in ambulant patients with gastro-oesophageal reflux disease.

Previous studies of the mechanisms that precipitate acid reflux episodes have used short term hospital based measurements. A 24 hour pH and motility recording system, incorporating a sphincter monitoring device, has been developed to study naturally occurring acid reflux episodes in control subjects and patient groups with different grades of oesophagitis. Lower oesophageal sphincter relaxations related to episodes of acid reflux were common in control subjects (67% of episodes) but became more difficult to detect as the grade of oesophagitis increased (grade 0/1 - 67%, grade 2/3 - 35%, grade 4 - 13%). A variety of events that produced recognisable transdiaphragmatic pressure patterns were associated with acid reflux episodes. In control subjects 74% of acid reflux episodes were precipitated by belching but this mechanism became less evident as the grade of oesophagitis increased (grade 0/1 - 43%, grade 2/3 - 40%, grade 4 - 29%). Activities that produced a pressure gradient across the diaphragm became increasingly important as events precipitating acid reflux as oesophagitis became more severe (controls--2%, grade 0/1 - 15%, grade 2/3 - 11%, grade 4 - 22%). This study has shown the pressure events surrounding acid reflux in fully ambulant patients with gastro-oesophageal reflux disease.     

Objective evaluation of symptomatic alkaline reflux after antrectomy

The purpose of this study was to compare the endoscopic and histologic findings in gastric mucosa, the total bile acids in the gastric contents, and the gastric emptying of a solid food in symptomatic and asymptomatic patients after vagotomy and antrectomy. Eleven male patients with typical symptoms of alkaline reflux were compared to six asymptomatic patients. There were no significant differences between the groups in output or concentrations of bile acid in fasting gastric juices. Evidence for gastritis by endoscopic or histologic features was present in asymptomatic as well as symptomatic patients. Gastric emptying of radiolabeled liver was faster in the symptomatic group, but the difference was not significant. In conclusion, these tests do not distinguish between patients with symptoms of alkaline reflux and asymptomatic patients after vagotomy and antrectomy.     

Optimal management of severe symptomatic gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is a common disorder, and empirical proton pump inhibitor (PPI) treatment is often the first step of management; however, up to 40% of patients remain symptomatic despite PPI treatment. Refractory reflux refers to continued symptoms despite an adequate trial of PPI, and management remains challenging. The differential diagnosis is important; other oesophageal (e.g. eosinophilic oesophagitis) and gastroduodenal disorders (e.g. functional dyspepsia) should be ruled out, as this changes management. A combination of clinical assessment, endoscopic evaluation and in selected cases oesophageal function testing can help characterize patients with refractory reflux symptoms into oesophageal phenotypes so appropriate therapy can be more optimally targeted. Medical options then may include adding a H2 receptor antagonist, alginates, baclofen or antidepressant therapy, and there is emerging evidence for bile acid sequestrants and diaphragmatic breathing. The demonstration of a temporal association of symptoms with reflux events on pH-impedance testing (reflux hypersensitivity) serves to focus the management on modulating oesophageal perception and reducing the reflux burden, or identifies those with no obvious pathophysiologic abnormalities (functional heartburn). Anti-reflux surgery based on randomized controlled trial evidence has a role in reflux hypersensitivity or continued pathological acid reflux despite PPI in carefully considered, fully worked up cases that have failed medical therapy; approximately two of three cases will respond but there is a small risk of complications. In patients with persistent volume reflux despite medical therapy, given the lack of alternatives, anti-reflux surgery is a consideration. Promising newer approaches include endoscopic techniques. This review aims to summarize current diagnostic approaches and critically evaluates the evidence for the efficacy of available treatments.     

Pharyngeal reflux episodes at pH 5 in healthy volunteers

OBJECTIVE: The clinically used cut-off limit in reflux disease is pH 4. Yet, earlier studies have shown a poor correlation between pharyngeal reflux episodes and symptoms or laryngeal findings, and treatment results have been suboptimal. Moreover, recent data suggest that pepsin is still active at pH 5. The aim of this study was to evaluate the occurrence of pharyngeal pH 5 reflux episodes in healthy controls and to correlate these to the pH monitoring results with a cut-off limit of pH 4. MATERIAL AND METHODS: The results of double-probe 24-h pH monitoring from 35 healthy controls were reanalysed concerning the occurrence of pH decreases to pH 5. RESULTS: Pharyngeal pH 5 reflux episodes occurred in 32 healthy controls (91%). The median number of pharyngeal reflux episodes at pH 5 was 4.0. The vast majority of these reflux episodes (92%) occurred in the upright position, especially in the postprandial period. The median time pH < 5 in the pharynx was 0.1% while the upper limit of normality was 1.5%. Pharyngeal pH 5 reflux episodes were 5 times more common than pH 4 reflux episodes. There was a significant positive correlation between hypopharyngeal and oesophageal acid exposure time at both pH 4 and 5 (p<0.01). CONCLUSIONS: Pharyngeal pH 5 reflux episodes are present in most healthy adults, mainly in upright position and in the postprandial period. The importance of these episodes for the occurrence of laryngeal symptoms and signs and for treatment response needs to be prospectively assessed.     

Acid reflux and asthma

The association between asthma and gastroesophageal reflux (GER) has been further delineated with recent clinical investigations. The prevalence of GER development in asthmatics is higher than in control populations. Furthermore, asthmatics with GER have a higher risk of asthma hospitalization. Asthma medications may be one of the promoting factors for GER development in asthmatics. Inhaled albuterol decreases lower esophageal sphincter (LES) pressure and esophageal contraction amplitude. Furthermore, oral prednisone results in increased esophageal acid contact times. Respiratory symptoms also correlate with esophageal acid events. The role of neurogenic inflammation in asthma-induced bronchoconstriction is also being further developed. Therapy of GER may improve asthma outcomes in selected asthmatics. Currently, there are no double-blind, placebo-controlled, multicenter trials reporting asthma outcomes with antireflux therapy.