Review article: gastro-oesophageal reflux disease--pathophysiological issues of clinical relevance

Gastro-oesophageal reflux disease is a multifactorial disorder in which the pathophysiological mechanisms are variably combined in different patients. Motor dysfunction of the lower oesophageal sphincter (LOS) and, possibly, the proximal stomach is a major cause of the increase in the number of reflux episodes. Transient LOS relaxation is the main mechanism of reflux in many patients with endoscopically negative disease, whereas a hypotensive LOS becomes relevant only in patients with oesophagitis. Alterations in primary and secondary peristalsis contribute to the increased oesophageal acid exposure by delaying clearance. The presence of a hiatus hernia, especially when voluminous and/or non-reducible, increases the number of reflux episodes by mechanically weakening the oesophago-gastric junction, and impairs oesophageal clearance. Hypersensitivity to acid is often present and contributes to the clinical manifestations of the disease, whereas oesophageal hypersensitivity, both to chemical and mechanical stimuli, plays a predominant role in a subset of patients. Increased concentrations of noxious compounds in the oesophageal refluxate may contribute to the development of anatomical lesions, but this is still a matter for debate. The clinical relevance of Helicobacter pylori infection and of mucosal defensive factors still needs to be fully elucidated.     

Effect of cisapride on nocturnal transient lower oesophageal sphincter relaxations and nocturnal gastro-oesophageal reflux in patients with oesophagitis: a double-blind, placebo-controlled study

AIM: To investigate the effect of cisapride, a selective 5-hydroxytryptamine-4 receptor agonist, on the frequency of nocturnal transient lower oesophageal sphincter relaxations and oesophageal acid exposure in patients with gastro-oesophageal reflux disease. METHODS: In a double-blind, placebo-controlled study, 10 patients with gastro-oesophageal reflux disease (six male and four female; mean age, 54 +/- 10.4 years) were randomly assigned to 5-day treatments with cisapride, 10 mg q.d.s., or placebo, separated by a 2-day washout period before the treatment crossover. Sleep stages, lower oesophageal sphincter tone and oesophageal pH were monitored overnight at the end of each treatment regimen. Gastric emptying was assessed before treatment. RESULTS: Cisapride decreased the frequency of transient lower oesophageal sphincter relaxations during sleep (1.2 +/- 0.2/h vs. 2.7 +/- 0.5/h with placebo; P=0.004) and oesophageal acid exposure (17.2 +/- 9.9% with placebo vs. 7.2 +/- 4.2% with cisapride; P=0.4). Cisapride increased lower oesophageal sphincter tone from 12.7 +/- 2.8 mmHg with placebo to 16.9 +/- 3.9 mmHg (P=0.03), and decreased heartburn episodes and antacid consumption. All patients had normal gastric retention data over 4 h. CONCLUSIONS: In patients with gastro-oesophageal reflux disease, cisapride significantly decreased the frequency of transient lower oesophageal sphincter relaxations during sleep and increased lower oesophageal sphincter pressure without changing gastric emptying. We hypothesize, therefore, that 5-hydroxytryptamine-4 mechanisms are important in the control of transient lower oesophageal sphincter relaxations in humans.     

Review article: the pathophysiology of gastro-oesophageal reflux disease

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is a common condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. AIM: To review the current knowledge on the underlying factors contributing to GERD, with particular emphasis on the most recent research. METHODS: Literature searches were conducted in Medline and EMBASE. The abstracts from recent large congresses were also reviewed to ensure coverage of the latest findings. RESULTS: The pathophysiological factors causing GERD can be split into those inducing greater exposure of the oesophagus to stomach contents, and those that provide increased perception of reflux or increased mucosal damage. Transient lower oesophageal sphincter relaxations, which are likely to be triggered by gastric distension, appear to be a key physiological cause of GERD. Excessive reflux may also be provoked by impaired oesophageal or gastric clearance mechanisms. Pre-epithelial, epithelial and post-epithelial defences all normally protect the oesophagus from injury, and may be compromised in individuals with GERD. Heartburn could also be caused by oesophageal hypersensitivity as a result of visceral neural pathway dysfunction. CONCLUSION: The pathophysiology of GERD is multifactorial, and abnormalities in the gastro-oesophageal junction, the stomach, the oesophagus and the nervous system may all contribute to this disease state.     

Review article: the role of non-acid reflux in gastro-oesophageal reflux disease

The role of acid in the pathogenesis of gastro‐oesophageal reflux disease (GERD) has been extensively studied and is well accepted. The role, if any, of non‐acid reflux, in particular duodenogastro‐oesophageal reflux, is much debated. The availability of new technology to detect non‐acid reflux has heightened interest in this question. This article reviews the following: How do we define non‐acid reflux? Does duodenogastro‐oesophageal reflux (alone or in combination) cause oesophageal injury, symptoms or both? What is its role in complicated GERD? What methods are available to assess non‐acid reflux? Does non‐acid reflux need treatment and if so what modalities are available?     

Review article: supra-oesophageal manifestations of gastro-oesophageal reflux disease

Supra-oesophageal manifestations of gastro-oesophageal reflux disease (GERD) are common and often under-appreciated, in part due to the absence of classic symptoms of heartburn and regurgitation. Patients with supra-oesophageal manifestations of GERD may report symptoms involving the pulmonary, otolaryngologic or pharyngeal systems. Endoscopy is often negative and therefore of limited diagnostic value in these patients, and while laryngoscopy and 24 h dual-channel intra-oesophageal pH-metry may have greater yields they are costly, invasive and time-consuming. Therefore, a trial of proton pump inhibitor therapy is now widely considered a first-line diagnostic test in those with suspected GERD-induced supra-oesophageal symptoms. The dose as well as duration of the proton pump inhibitor trial is dependent upon a patient's presenting symptoms. For example, GERD-related non-cardiac chest pain may be relieved with a short-term (e.g. 1 week) treatment with standard doses of a proton pump inhibitor. The use of high-dose twice daily proton pump inhibitor therapy for an extended period (e.g. 2-3 months) may be required before any discernible improvement in pulmonary symptoms or pharyngo-laryngitis is noted. Patients who do not experience symptom improvement following a proton pump inhibitor trial may require further diagnostic evaluations including 24 h oesophageal pH studies, while on acid anti-secretory therapy, to establish the absence of persistent acid reflux. The role of anti-reflux surgical or endoscopic interventions in those with supra-oesophageal manifestations of GERD remains to be established.     

Review article: extraoesophageal manifestations of gastro-oesophageal reflux disease

Although recent studies suggest that gastro-oesophageal reflux disease may frequently contribute to ear, nose and throat and respiratory diseases, the cause-and-effect relationship is far from proven. The review will address this controversial topic emphasizing recent literature raising concerns about the credibility of this association and our tests to make this diagnosis. The author believes these extraoesophageal symptoms suspected to be secondary to gastro-oesophageal reflux disease are an unresolved issue, but selective use of aggressive proton-pump inhibitor therapeutic trials may help to resolve this problem in our individual patients.     

Review article: respiratory manifestations of gastro-oesophageal reflux disease

Background  Respiratory manifestations represent one of the most prevalent and difficult-to-manage extra-oesophageal syndromes of gastro-oesophageal reflux disease.
Aims  To review the epidemiology, pathophysiological mechanisms and therapeutic outcomes of reflux-related respiratory disorders.
Methods  Search of the literature published in English using PubMed database.
Results  There is a discrepancy between the high prevalence of reflux in asthmatics and the limited efficacy of antireflux therapies. Asthma per se may cause reflux. Patients with difficult-to-treat asthma and/or nocturnal symptoms should be screened for reflux. Reflux can induce chronic cough through different mechanisms including micro-aspiration and both local and central reflexes. Cough and reflux may precipitate each other. A meta-analysis found no significant difference between placebo and proton pump inhibitors in the resolution of cough. Encouraging results have been reported, following antireflux surgery in patients selected on the basis of pH-impedance monitoring. Attention has been drawn to obstructive sleep apnoea syndrome.
Conclusions  The role of gastro-oesophageal reflux disease in the pathogenesis of miscellaneous respiratory disorders has been discussed for decades and established in asthma and cough. However, no major therapeutic advances have been reported recently. Future trials should concentrate on patient selection and the control of efficacy using recently developed technologies, such as pH-impedance monitoring.     

The effect of baclofen on gastro-oesophageal reflux,lower oesophageal sphincter function and reflux symptoms in patients with reflux disease

BACKGROUND: Baclofen decreases gastro-oesophageal reflux episodes in healthy subjects by reducing the incidence of transient lower oesophageal sphincter relaxations. AIM: To investigate the effect of baclofen on reflux symptoms, oesophageal pH and lower oesophageal sphincter manometry in patients with gastro-oesophageal reflux disease. METHODS: A double-blind, placebo-controlled, two-way crossover design was used to study the effect of baclofen on heartburn and regurgitation 3 h after a provocation test meal in 37 patients with gastro-oesophageal reflux disease. Additionally, in 20 of these patients, the effect of baclofen on oesophageal pH, transient lower oesophageal sphincter relaxations and basal lower oesophageal sphincter pressure was studied. RESULTS: Baclofen significantly decreased the acid reflux time and the incidence of gastro-oesophageal reflux episodes (8.3 +/- 8.8% vs. 12.4 +/- 12.0%, P = 0.03 and 10.9 +/- 7.3 per 3 h vs. 18.7 +/- 12.4 per 3 h). The incidence of transient lower oesophageal sphincter relaxations was significantly lower with baclofen than with placebo (15.1 +/- 6.4 per 3 h vs. 22.8 +/- 5.4 per 3 h, P < 0.0001). Lower oesophageal sphincter pressure and the percentage of transient lower oesophageal sphincter relaxations associated with reflux were not affected by baclofen. No significant effect on symptom scores was observed. CONCLUSIONS: Baclofen decreases post-prandial acid reflux in patients with gastro-oesophageal reflux disease by reducing the incidence of transient lower oesophageal sphincter relaxations. No effect of a single dose of baclofen on reflux symptoms could be demonstrated in this 3-h post-prandial study.     

Review article: endoscopic treatments for gastro-oesophageal reflux disease

A number of endoscopic techniques have been described for the treatment of reflux disease. These include endoscopic plicators, which place submucosal or transmural sutures around the lower oesophageal sphincter, the Stretta procedure, which places minute areas of thermal injury in the muscle of the lower oesophageal sphincter and cardia, and injection techniques, in which inert substances are injected into the mucosa or the muscle of the lower oesophagus. The mechanism of action of these procedures has been studied to varying degrees. The Stretta procedure is the only endoscopic technique that has been shown to be effective in a sham-controlled trial. Complication rates are generally low, but serious complications have been reported in some cases. The results with some of these techniques are promising, but all procedures described to date are limited by the absence of large, rigorously controlled trials against a form of treatment that has been proven to be both safe and effective (medical therapy). Future studies will need to use controls, validated outcome measures and pre-determined end-points and to provide comparative and long-term data.     

Review article: gastro-oesophageal reflux disease and psychological comorbidity

Background  A growing number of studies have shown the impact of psychological comorbidities on gastro-oesophageal reflux disease (GERD) patients' symptom reports and healthcare-seeking behaviour.
Aim  To review the reported relationship between GERD and psychological comorbidity.
Methods  Review of the literature on GERD and psychological comorbidity.
Results  Psychological comorbidity is common among GERD patients and appears to afflict all GERD phenotypes. Sexual and physical abuse is also common in GERD patients. Stress enhances perception of oesophageal acid exposure. Treatment for GERD, especially in those who are not responsive to antireflux treatment, may require further evaluation for psychological comorbidity.
Conclusions  Psychological comorbidity is very common in GERD patients and is likely to play an important role in response, or failure of response, to proton pump inhibitor treatment.     

Review article: the role of surgery in gastro-oesophageal reflux disease

BACKGROUND: Rates for laparoscopic fundoplication are declining in the United States and there is no consensus on the indications for referral to surgery in gastro-oesophageal reflux disease. AIM: To highlight recent studies on the outcomes of laparoscopic fundoplication in adults that cast doubt on the traditional indications for surgery in reflux disease. RESULTS: Patients who are well maintained on medical therapy have more to lose with surgical intervention than to gain, and should not be offered surgery. Likewise, the notion that surgery prevents oesophageal cancer is a hypothesis that is not supported by current evidence, therefore surgical intervention should not be offered to these patients. The only clear-cut candidates for surgery include: patients with anatomic abnormalities such as a large hiatus hernia, or those with persistent regurgitation that causes troublesome symptoms despite medical therapy; and carefully selected patients with extra-oesophageal disorders who have symptoms of reflux disease such as heartburn and regurgitation, an incomplete response to medical therapy and persistent plus demonstrable reflux on pH or impedance testing that is associated with their symptoms. Patients should be aware of the high likelihood of needing continued acid inhibitory therapy following surgery and the possibility of side-effects. CONCLUSION: Only a few carefully selected patients should undergo fundoplication for reflux disease.