Diagnosis of gastro-oesophageal reflux disease is enhanced by adding oesophageal histology and excluding epigastric pain.

BACKGROUND: The diagnosis of gastro-oesophageal reflux disease (GERD) in clinical practice is limited by the sensitivity and specificity of symptoms and diagnostic testing. AIM: To determine if adding histology as a criterion and excluding patients with epigastric pain enhances the diagnosis for GERD. METHODS: Patients with frequent upper gastrointestinal symptoms who had not taken a proton pump inhibitor in the previous 2 months and who had evaluable distal oesophageal biopsies were included (Diamond study: NCT00291746). Epithelial hyperplasia was identified when total epithelial thickness was at least 430 µm. Investigation-based GERD criteria were: presence of erosive oesophagitis, pathological oesophageal acid exposure and/or positive symptom-acid association probability. Symptoms were assessed using the Reflux Disease Questionnaire and a pre-specified checklist. RESULTS: Overall, 127 (55%) of the 231 included patients met investigation-based GERD criteria and 195 (84%) met symptom-based criteria. Epithelial hyperplasia was present in 89 individuals, of whom 61 (69%) met investigation-based criteria and 83 (93%) met symptom-based criteria. Adding epithelial hyperplasia as a criterion increased the number of patients diagnosed with GERD on investigation by 28 [12%; number needed to diagnose (NND): 8], to 155 (67%). The proportion of patients with a symptom-based GERD diagnosis who met investigation-based criteria including epithelial hyperplasia was significantly greater when concomitant epigastric pain was absent than when it was present (P < 0.05; NND: 8). CONCLUSIONS: Histology increases diagnosis of GERD and should be performed when clinical suspicion is high and endoscopy is negative. Excluding patients with epigastric pain enhances sensitivity for the diagnosis of GERD.

Cluster analysis of risk factor genetic polymorphisms in Alzheimer's disease.

Multiple genetic variants may contribute to the risk of developing Alzheimer's disease. We have analyzed polymorphisms in 9 genes to determine whether particular combinations would contribute to this risk. The genes were APOE, LDLr, CST3, CTSD, TNF, BACE1, MAPT, STH, eNOS, and TFCP2. Three risk groups for the disease were identified. Risk group I was younger, was heterozygous for the CST3 (GA), CTSD2936 (AG), TNF -308 (AG) genetic variants. Risk group II was older, was homozygous for the -427 APOE promoter polymorphism (TT), and heterozygous for the MAPT deletion and for the STH variant (QR). Group III had both the youngest and oldest subjects, were heterozygous for the -863 (AC) and -1031 (CT) TNF promoter polymorphisms. All three groups carried the APOE 4 allele and were heterozygous for both BACE1 polymorphisms. The control groups were carriers of the APOE 3 allele and were homozygous for the BACE1 genetic variants.

Duplicate breath testing to confirm eradication of Helicobacter pylori: incremental benefit and cost in 419 patients.

BACKGROUND: Current standards for establishing a cure of H. pylori infection require two breath tests taken at least 4 weeks apart, to be negative. AIM: To determine the incremental cost and accuracy of repeating a urea breath test (UBT) in clinical practice. METHODS: We identified 419 patients with documented Helicobacter pylori infection who received eradication therapy and then had two breath tests, one 4 weeks and the second at least 8 weeks after the completion of treatment. H. pylori infection was documented at baseline by a positive rapid urease test and histology. RESULTS: In patients with successful eradication of H. pylori infection (n = 317), the mean +/- standard deviation delta over baseline (DOB) value before treatment was 43 +/- 29 ppm. Following treatment, the mean DOB in cured was 0.56 +/- 2.1 ppm at 1 month and was similar to the value obtained at the second breath (0.68 +/- 1; P = 0.39), which was performed 60 +/- 71 days after the first UBT. In patients remaining infected (n = 102), the mean DOB at baseline was 47 +/- 20 ppm. Four weeks after treatment, the DOB was 40 +/- 32 ppm. The second UBT was performed 94 +/- 72 days after the first and the DOB was significantly greater than the first (47 +/- 28; P = 0.040). There was no discordant result between the first breath test and second breath test. At a cost of 30 euros/breath test, the incremental cost of a second breath test was 12 570 euros in this cohort with no incremental clinical benefit. CONCLUSIONS: A single UBT, 4 weeks after treatment is as effective as two serial breath tests in confirming H. pylori eradication. The incremental cost of the second breath test is very high with no incremental clinical benefit.

Diagnostic utility of alarm features for colorectal cancer: systematic review and meta-analysis.

OBJECTIVE: Colorectal cancer is the second most common cause of cancer death in Europe and North America. Alarm features are used to prioritize access to urgent investigation, but there is little information concerning their utility in the diagnosis of colorectal cancer. METHODS: A systematic review and meta-analysis of the published literature was carried out to assess the diagnostic accuracy of alarm features in predicting colorectal cancer. Primary or secondary care-based studies in unselected cohorts of adult patients with lower gastrointestinal symptoms were identified by searching MEDLINE, EMBASE and CINAHL (up to October 2007). The main outcome measures were accuracy of alarm features or statistical models in predicting the presence of colorectal cancer after investigation. Data were pooled to estimate sensitivity, specificity, and positive and negative likelihood ratios. The quality of the included studies was assessed according to predefined criteria. RESULTS: Of 11 169 studies identified, 205 were retrieved for evaluation. Fifteen studies were eligible for inclusion, evaluating 19 443 patients, with a pooled prevalence of colorectal carcinoma of 6% (95% CI 5% to 8%). Pooled sensitivity of alarm features was poor (5% to 64%) but specificity was >95% for dark red rectal bleeding and abdominal mass, suggesting that the presence of either rules the diagnosis of colorectal cancer in. Statistical models had a sensitivity of 90%, but poor specificity. CONCLUSIONS: Most alarm features had poor sensitivity and specificity for the diagnosis of colorectal carcinoma, whilst statistical models performed better in terms of sensitivity. Future studies should examine the utility of dark red rectal bleeding and abdominal mass, and concentrate on maximising specificity when validating statistical models.

[The Montreal definition and classification of gastroesophageal reflux disease: a global, evidence-based consensus paper]. / Die Montreal-Definition und -Klassifikation der gastroösophagealen Refluxkrankheit: Ein globales evidenzbasiertes Konsensus-Papier.

AIM: A world-wide recognised and accepted definition and classification of gastroesophageal reflux disease (GERD) would be highly desirable for research and clinical practice. The purpose of this project was to develop such a generally accepted definition and classification that could be used equally by patients, physicians, and supervisory bodies. METHODS: In order to ensure a consensus among the participating experts a modified delphi process with a step-wise selection modality was employed. For this the working group of five persons formulated a series of statements on the basis of a systematic search of the literature using three databases (Embase, Cochrane-Study register, Medline). Then these statements were developed further for two years, revised and finally passed as consensus. The consensus group consisted of 44 experts from 18 countries. Each key vote was held on the basis of a six-point scale. A "consensus" was considered to have been reached when two-thirds of the participants voted in favour of the respective statement. RESULTS: The level of agreement between the experts increased in the course of the multistep decision process, in the individual voting steps requiring at least two-thirds of the participants, the results were at first 86%, then 88% through to 94% and finally 100% in favour of the chosen statement. In the final voting, 94% of the final 51 statements were accepted by 90% of the consensus group. 90% of all statements were accepted unanimously or with only minor reservations. GERD was defined as a disease that is associated with troublesome symptoms and/or complications on account of reflux of stomach contents into the esophagus. The complaints are divided into esophageal and extra-esophageal syndromes. Among the novel aspects of this definition are the patient-orientated approach that is independent of endoscopic findings, the classification of the ailment into independent syndromes as well as the consideration of laryngitis, cough, asthma and dental problems as possible GERD syndromes. Furthermore, a new definition of suspected or demonstrated Barrett's esophagus is proposed. CONCLUSION: Irrespective of country-specific differences in terminology, language, prevalence and manifestations of this disease, evidence-based, world-wide valid consensus definitions are possible. A global consensus definition of GERD will simplify disease management, make mutual research possible and help in the design of generally valid studies. This will not only help the patient but also the physician and supervisory bodies.

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.

Gastroesophageal reflux disease is a progressive disease.

It is controversial whether gastrooesophageal reflux disease represents a spectrum disease from a nonerosive to a complicated one, or whether it is a categorial disease, i.e. it can be divided into three categories, such as nonerosive gastrooesophageal reflux disease, erosive gastrooesophageal reflux disease and Barrett's esophagus (BE) with little or no transition from one category to the other. This controversy might be of general interest, because it has some implications in the management of the patient. However, literature data concerning the natural history of gastrooesophageal reflux disease are very limited, and in particular very few papers have dealt with the issue of describing the natural history of patients with nonerosive gastrooesophageal reflux disease. Aim of the present review is to reassess these scanty data, and to try to demonstrate that progression from milder to more severe forms of gastrooesophageal reflux disease is possible and documented.

Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report.

BACKGROUND: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000. AIMS: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer. RESULTS: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility. CONCLUSION: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

Pretreatment endoscopy--pro & contra: is endoscopy needed before treatment in all patients with gastroesophageal reflux disease?

The role of endoscopy in reflux disease has changed from being primarily diagnostic to one of risk management. Objective studies of routine endoscopy have shown little change in outcomes after the examination. Screening and surveillance for Barrett's esophagus is still an unconfirmed strategy. In most developed countries, including western Europe and North America, middle-aged patients (over the age of 50) with gastroesophageal reflux disease would benefit more from colonoscopy than upper endoscopy.

The cost-effectiveness of biomarkers for predicting the development of oesophageal adenocarcinoma.

BACKGROUND: The recommended surveillance strategy for oesophageal adenocarcinoma may prevent as few as 50% of cancer deaths. Tissue biomarkers have been proposed to identify high-risk patients. AIM: To determine performance characteristics of an ideal biomarker, or panel of biomarkers, that would make its use more cost-effective than the current surveillance strategy. METHODS: We created a Markov model using data from published literature, and performed a cost-utility analysis. The population consisted of 50-year-old Caucasian men with gastro-oesophageal reflux, who were monitored until age 80. We examined strategies of observation only, current practice (dysplasia-guided surveillance), surveillance every 3 months for patients with a positive biomarker (biomarker-guided surveillance), and oesophagectomy immediately for a positive biomarker (biomarker-guided oesophagectomy). The primary outcome was the threshold cost and performance characteristics needed for a biomarker to be more cost-effective than current practice. RESULTS: Regardless of the cost, the biomarker needs to be at least 95% specific for biomarker-guided oesophagectomy to be cost-effective. For biomarker-guided surveillance to be cost-effective, a $100 biomarker could be 80% sensitive and specific. CONCLUSIONS: Biomarkers predicting the development of oesophageal adenocarcinoma would need to be fairly accurate and inexpensive to be cost-effective. These results should guide the development of biomarkers for oesophageal adenocarcinoma.

Review article: new pharmacological agents for the treatment of gastro-oesophageal reflux disease.

Proton pump inhibitors, which act at the terminal point of acid secretion--the H+, K+-ATPase--are currently the most effective pharmacological treatments available for reflux disease. Despite the efficacy of the proton pump inhibitors, there is still potential for clinical improvement in gastro-oesophageal reflux disease pharmacotherapy. Faster onset of complete acid inhibition and improved duration of efficacy are two potential areas for improvement A number of novel pharmaceutical agents are currently undergoing clinical evaluation for the treatment of gastro-oesophageal reflux disease. These include transient lower oesophageal sphincter relaxation-reducing agents, serotonergic agents/prokinetics, potassium-competitive acid blockers, mucosal protectants, histamine H3 agonists and anti-gastrin agents. One or more of these drug groups may represent the future medical therapy for gastro-oesophageal reflux disease, should they prove effective in the clinical setting. This review summarizes the state of the art with these agents.

Symptom evaluation in reflux disease: workshop background, processes, terminology, recommendations, and discussion outputs.

There has been no published indepth systematic evaluation of the best approaches to symptom evaluation in gastro-oesophageal reflux disease (GORD). A two day international multidisciplinary workshop was therefore held in Marrakech, Morocco, in September 2002 to address these issues. The aim of the workshop was to critically review the data regarding the reliability, processes, and priorities for symptom evaluation in GORD patients. The workshop was designed to give outputs that could be readily reported and to arrive at specific recommendations on best practice in symptom evaluation in reflux disease.

Effect of Helicobacter pylori eradication on development of dyspeptic and reflux disease in healthy asymptomatic subjects.

BACKGROUND AND AIM: There are few data on the course of Helicobacter pylori infection in asymptomatic subjects. The aim of this study was to assess the effect of eradication therapy on the development of dyspeptic and gastro-oesophageal reflux disease in a cohort of asymptomatic individuals observed over a prolonged period. METHODS: A total of 169 blood donors infected with H pylori who had volunteered for studies on eradication in 1990 formed the cohort. To be included in this cohort subjects had to have no symptoms, as determined by a validated symptom questionnaire at the baseline visit. Eighty eight subjects were infected with H pylori while 81 had successfully undergone eradication therapy. Subjects were followed up (annually) using the same symptom questionnaire and in 2000 they underwent repeat endoscopy. RESULTS: Thirteen subjects developed symptoms during follow up. The incidence of symptoms in H pylori positive subjects was 1.893/100 person-years of follow up and in H pylori negative individuals 0.163/100 person-years of follow up. H pylori infected subjects were significantly more likely to develop symptoms (log rank test, p=0.003) as well as those infected with CagA positive strains (log rank test, p=0.017). The development of symptomatic gastro-oesophageal reflux disease was no different in individuals with and without eradication (odds ratio 0.57 (95% confidence interval 0.26-1.24); p=0.163). CONCLUSIONS: H pylori eradication prevents the development of dyspeptic symptoms and peptic ulcer disease in healthy asymptomatic blood donors and is not associated with an increase in the incidence of symptomatic gastro-oesophageal reflux disease.

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: test and treat or treat and test in reflux disease?

The role of diagnostic testing in reflux disease is in evolution. There is little question that patients with dysphagia, bleeding or other 'alarm' symptoms, should undergo early endoscopy. A substantial proportion of patients presenting with reflux symptoms have endoscopy negative reflux disease. pH testing is both inconvenient and lacks the sensitivity and specificity required for a 'gold standard'. Empirical trials of therapy using proton pump inhibitors have shown that a trial of treatment may be the most accurate way of diagnosing gastro-oesophageal reflux disease (GERD) and may the optimal strategy from a cost-effectiveness standpoint. On the other hand, the increasing rate of oesophageal adenocarcinoma has raised questions about the possible value of screening endoscopy to determine if Barrett's oesophagus is present. The role of endoscopic testing in the average patient is therefore shifting from a diagnostic modality to one that helps manage risk by identifying Barrett's oesophagus.

A rapid, low-dose, 13C-urea tablet for the detection of Helicobacter pylori infection before and after treatment.

BACKGROUND: A new urea breath test (UBT) has been described which uses a tablet formulation of 13C-urea with citric acid and allows breath sampling to be performed as early as 10 min after ingestion of the tablet. AIM: To assess the diagnostic accuracy of tablet-based 13C-UBTs (50 and 100 mg 13C-urea) before and after Helicobacter pylori eradication treatment, compared with an endoscopy gold standard and a conventional 13C-UBT (75 mg 13C-urea). METHODS: Two hundred dyspeptic patients underwent endoscopy, followed by tablet-based 13C-UBTs (50 and 100 mg 13C-urea) and a conventional 13C-UBT (75 mg 13C-urea). H. pylori-infected patients were prescribed treatment and asked to return 4-6 weeks after the end of therapy for repeat endoscopy and 13C-UBTs. RESULTS: One hundred and thirteen patients were infected with H. pylori. The sensitivity and specificity of the conventional 13C-UBT were both 100%; the sensitivity and specificity of the 100-mg tablet-based 13C-UBT were 100% and 98.85%, respectively. For the 50-mg tablet-based 13C-UBT, cut-off values of the difference over baseline of between 1.65 and 3.15 provided a sensitivity and specificity of 100%. At follow-up, the sensitivity and specificity of the conventional and 100-mg tablet-based 13C-UBTs were both 100%. For the 50-mg tablet-based 13C-UBT, cut-off values of the difference over baseline of between 1.49 and 1.56 gave a sensitivity and specificity of 100%. CONCLUSIONS: New 10-min 13C-UBTs using tablet formulations of 13C-urea with citric acid are reliable for the assessment of H. pylori status pre- and post-treatment.

Health-related anxiety and the effect of open-access endoscopy in US patients with dyspepsia.

BACKGROUND: The role of endoscopy in dyspepsia is the subject of debate. The detection of lesions is infrequent, but patients may benefit from the knowledge that the examination is normal. We sought to determine the prevalence of health-related anxiety in dyspeptic patients referred for open-access endoscopy and to investigate the effect of endoscopy on health-related anxiety. METHODS: Consecutive patients referred for open-access endoscopy from primary care were studied using a validated questionnaire for health-related anxiety before and after endoscopy, at 1 month and 6 months. Symptoms were assessed using a validated questionnaire at 1 and 6 months. RESULTS: One hundred and nine patients were studied (69 women and 40 men; mean age, 49 +/- 15 years). Thirty-six of the 109 patients (33%) had high anxiety scores at baseline (mean score, 41 +/- 1), which decreased after endoscopy to 35 +/- 1 (P < 0.05). The changes persisted at 1 month (33 +/- 1) and 6 months (33 +/- 1). Endoscopic findings were as follows: normal examination, 120; erosive oesophagitis, 11 (Grade A); erosive duodenitis (all Helicobacter pylori-negative), 6. Scales for preoccupation with health and fear of illness and death showed significant improvement after endoscopy, and the effects were preserved for 6 months. Anxiety scores in our population were substantially higher than in a corresponding UK population. CONCLUSIONS: Health-related anxiety is common in dyspeptic patients referred for endoscopy. Endoscopy decreases the preoccupation with health and fear of illness and death in patients with severe anxiety, and the effects persist for 6 months.

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.