Review article: a role for gastrointestinal prokinetic agents in the treatment of reflux oesophagitis?

Gastro-oesophageal reflux disease may result from a host of factors. Medical therapy has largely been aimed at neutralizing acid or decreasing acid production but improvement of upper-gastrointestinal motility may prove to be a valuable treatment modality as well. This paper reviews the current state of knowledge of the pathogenesis of reflux disease and concentrates upon promotility treatment with domperidone, metoclopramide and cisapride.     

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: a drug therapy for the prevention of variceal haemorrhage

The development of varices is a major complication of cirrhosis, and variceal haemorrhage has a high mortality. There have been major advances in the primary and secondary prevention of variceal haemorrhage over the last 20 years involving endoscopic, radiological and pharmacological approaches. This review concentrates principally on drug therapy, particularly on the numerous haemodynamic studies. Many of these drugs have not been studied in clinical trials, but provide data about the underlying pathogenesis of portal hypertension. Also covered in this review are the randomized controlled trials and meta-analyses that involve a large number of patients. These trials involve relatively few drugs such as non-selective beta-blockers and nitrates. Correlations between haemodynamic and clinical parameters are discussed. Despite the recent increase in the use of alternative endoscopic therapies, an effective and well tolerated drug remains a clinically important research goal.     

Review article: oesophageal dilation in adults with eosinophilic oesophagitis

Aliment Pharmacol Ther 2011; 33: 748–757

Summary

Background Eosinophilic oesophagitis is a chronic inflammatory disorder of the oesophagus, characterised by the proton pump inhibitor‐refractory accumulation of eosinophils in the oesophageal epithelium (>15 intraepithelial eosinophils/high powered field). Adults present with solid food dysphagia and recurrent food impactions. Oesophageal remodelling produces the characteristic endoscopic feature of adult eosinophilic oesophagitis including strictures, rings and a narrow calibre oesophagus. Aim To evaluate the safety and efficacy of oesophageal dilation as the initial therapy for adults with eosinophilic oesophagitis. Methods Medline search from 1975 to November 2010 for all reports of the treatment of patients with eosinophilic oesophagitis using search words: eosinophilic oesophagitis treatment, dilation and eosinophilic oesophagitis, steroids and eosinophilic oesophagitis. Results Our systematic review found that 92% of patients treated with oesophageal dilation had improvement in their dysphagia symptoms for up to 1–2 years. Three case series clearly showed clinical resolution of dysphagia symptoms, independent of the degree of eosinophil infiltration, which was unchanged after dilation. Postprocedure pain for several days is common, due to some degree of mucosal tear, but true perforation very rare (<0.1%). Conclusions Oesophageal dilation is an acceptable option for healthy adult eosinophilic oesophagitis patients with anatomic narrowing, possibly followed by a course of topical steroids to reduce inflammation and retard remodelling. Future studies should include a head‐to‐head comparison of topical steroids and oesophageal dilation, bougie vs through‐the‐scope balloon dilation and maintenance topical steroids compared with on‐demand treatment.     

Review article: the pathogenesis and management of eosinophilic oesophagitis

BACKGROUND: Eosinophilic oesophagitis is a clinicopathological disease affecting both children and adults that is characterized by symptoms of gastro-oesophageal reflux disease (feeding refusal, vomiting, heartburn, dysphagia and food impaction) and dense oesophageal eosinophilia both of which are unresponsive to proton pump inhibition. AIM: To present a review of the recent literature examining the pathogenesis and treatments of eosinophilic oesophagitis. METHODS: We performed a PubMed search for eosinophilic oesophagitis, pathogenesis and treatments. RESULTS: Translational and basic studies suggest that this disease is sparked by food or by aeroallergens. To date, effective treatments include systemic/topical corticosteroids, specific food elimination or an elemental diet. While several studies identified oesophageal strictures as potential complications of unbridled eosinophilia, the natural history of the disease is still not certain. Recent studies suggest a role for interleukin-5 and eotaxin-3 in the pathogenesis of eosinophilic oesophagitis and suggest an impact of future targeted therapeutic agents. CONCLUSIONS: Eosinophilic oesophagitis represents a immune-mediated disease of undetermined pathogenesis. While many patients develop clinicopathological findings following ingestion of foods, others do not. Natural history studies will be critical to defining future treatment paradigms.     

Review article: drug hepatotoxicity

Background Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. Aims (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre‐existing liver disease and in the post‐liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. Methods A Medline search was performed to identify relevant literature using search terms including ‘drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics’. Results Amoxicillin‐clavulanic acid is one of the most frequently implicated causes of drug‐induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co‐infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. Conclusions Drug‐induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.     

Review article: endpoints used in functional dyspepsia drug therapy trials

Aliment Pharmacol Ther 2011; 33: 634–649

Summary

Background The measurement of patient‐reported outcomes (PRO) in treatment trials for functional gastrointestinal disorders is a matter of controversy. Aim To focus on instruments and endpoints that have been used to evaluate the efficacy of therapeutic agents in functional dyspepsia (FD) trials, also considering the newly defined Rome III FD criteria. Methods A Medline search was conducted to identify relevant studies pertaining to FD treatment, with particular emphasis on the studies to date which have used validated outcome measures. Results Currently available outcome measures are heterogeneous across studies. They include global binary endpoints, analogue or categorical scoring scales, uni‐ or multi‐dimensional disease specific questionnaires, global outcome evaluations and quality of life questionnaires. Across the available outcome measures, substantial heterogeneity is found, not only in the type of endpoint measure, but also in the number and types of symptoms that are considered to be part of the FD symptom complex. Especially based on content validity, none of the existing questionnaires or endpoints can be considered sufficiently validated to be recommended unequivocally as the primary outcome measure for FD trials according to the Rome III criteria. On the other hand, existing well‐validated multi‐dimensional questionnaires that include many non‐FD symptoms can be narrowed down to evaluate only the cardinal symptoms according to Rome III. Conclusions There is an urgent need to develop Rome III‐based patient‐reported outcomes for functional dyspepsia. Well‐validated multi‐dimensional questionnaires may serve as a guidance for this purpose, and could also be considered for use in ongoing clinical trials.     

Review article: assessment of drug therapy in inflammatory bowel disease

This review article surveys the clinical and laboratory parameters used to assess and quantitate inflammation in ulcerative colitis and Crohn's disease, with particular reference to their usage in controlled trials of drugs in inflammatory bowel disease.     

Review article: Helicobacter pylori and reflux disease

The falling prevalence of Helicobacter pylori infection and related diseases (peptic ulcer disease, gastric cancer) in developed countries has been paralleled by an increased recognition of gastro-oesophageal reflux and its complications. These epidemiological data do not support a role for H. pylori in the pathogenesis of reflux disease, but suggest a negative association with the increasing incidence of oesophageal diseases. This has led some investigators to propose a 'protective' role of H. pylori infection against the development of oesophageal diseases. In these patients, pre-existing lower oesophageal sphincter dysfunction, susceptibility to reflux, unmasking of latent reflux and the patterns and severity of gastritis are probably important factors contributing to the development of oesophageal diseases. The most likely mechanism by which H. pylori infection may protect against reflux is by decreasing the potency of the gastric refluxate in patients with corpus-predominant gastritis. The prevalence of H. pylori infection in patients with reflux disease is probably no greater than that in those without reflux, and there are conflicting data indicating that reflux symptoms or erosive oesophagitis develop after H. pylori eradication. It is also unclear whether H. pylori augments the antisecretory effects of proton pump inhibitors or accelerates the development of atrophic gastritis.     

Review article: gastro-oesophageal reflux and laryngeal symptoms

There is some evidence from clinical, experimental and multiprobe ambulatory pH studies that gastro-oesophageal reflux is more common in patients with laryngeal symptoms and could potentially play a role in the causation of these symptoms. The proportion of unselected patients with laryngeal symptoms who have gastro-oesophageal reflux as the primary aetiology may be overestimated in some series. The symptom that has been most evaluated is hoarseness, but even for this symptom the proportion of patients who have significant reflux varies widely. There is even less agreement for other symptoms, and the data on globus sensation remains confused. It is likely that these patients present to ear, nose and throat (ENT) clinics because of the relative insensitivity of the oesophageal mucosa to acid exposure. Given the lack of specificity for routine diagnostic tests for gastro-oesophageal reflux, it is necessary to perform ambulatory pH monitoring for a secure diagnosis in these patients. Treatment studies have been surprisingly few and inadequate in design. It is suspected that there is a strong placebo response for these symptoms. No clear information on efflcacy can be provided until placebo-controlled randomised studies are available.     

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: indications for anti-reflux surgery in gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD) is a complex multifactorial disorder whose treatment is based on knowledge of its pathophysiology, natural history and evolution. Recently the relationship between the severest degrees of cardial incontinence and hiatus hernia has been emphasized, which causes the impairment of the mechanical properties of the gastro-oesophageal barrier and of oesophageal acid clearing. Among different types of hiatus hernia, those characterized by the permanent axial orad migration of the oesophago-gastric (EG) junction (nonreducible hiatus hernia) are correlated with severe GERD. Barium swallow may adequately differentiate hiatal insufficiency, concentric hiatus hernia and short oesophagus which are the steps of migration across or above the diaphragm. When associated with panmural oesophagitis and fibrosis of the oesophageal wall, these conditions may be the cause of recurrence of hiatus hernia and reflux after laparoscopic standard anti-reflux surgical procedures; in the presence of nonreducibility of the EG junction below the diaphragm without tension, dedicated surgical procedures are necessary. It is currently agreed that surgical therapy is indicated for patients affected by severe GERD who are not compliant with long-term medical therapy, require high dosages of drugs and are too young for lifetime medical treatment. While the existence of severe GERD correlated with an irreversible anatomical disorder represents an elective indication for surgery, warrants further investigation. Accurate identification of the functional and anatomical abnormalities underlying GERD is mandatory in order to decide whether medical or surgical therapy should be implemented, and to tailor the surgical technique, laparoscopic or open, to each patient.     

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.