Andreas Leodolter

Progression of specialized intestinal metaplasia at the cardia to macroscopically evident Barrett's esophagus: an entity of concern in the ProGERD study

Abstract Objectives and aims. Histological Barretts esophagus, defined as specialized intestinal metaplasia (SIM+) at the cardia without endoscopic suspicion of columnar epithelium, is found frequently in biopsies at the gastro-esophageal junction although its clinical relevance is unknown. The authors aim was to evaluate prospectively the progression of SIM+ to macroscopically evident Barretts esophagus (BE/SIM+), and to identify risk factors for this progression. Methods. Data were obtained from a sub-group of patients (no visible BE at presentation, but SIM+) included in the ProGERD study, a prospective evaluation of the clinical course of GERD under routine clinical care. They had esomeprazole 20–40 mg/day for 2–8 weeks. Symptom assessment was performed annually, and endoscopy with biopsy was planned at baseline, after healing treatment and after 2 and/or 5 years. Results. 128 of 171 (74.8%) patients with unequivocal SIM at the z-line after healing were biopsied again after 2 and/or 5 years. At follow-up, 33 (25.8%) of these patients showed progression to BE/SIM+. Factors significantly associated with progression were smoking, a long history of GERD and severe esophagitis at baseline. Patients who had progressed to BE/SIM+ already at 2 years showed consistent findings at 5 years. Conclusion. More than 20% of GERD patients with SIM+ in this study were found to have BE/SIM+ within 2–5 years. This finding supports the hypothesis that SIM+ at the cardia could be the missing link explaining increased cancer risk in GERD patients without overt BE and merits further investigation in a prospective study.

NSAID-Associated Dyspepsia and Ulcers: A Prospective Cohort Study in Primary Care

Background and Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause dyspeptic complaints and lesions in the upper gastrointestinal tract. The true incidence of these side effects in the everyday situation remains uncertain. We therefore investigated as to how often patients on NSAIDs in the primary care setting must be expected to develop troublesome dyspepsia and/or ulcers in the upper gastrointestinal tract. Patients and Methods: Admitted to the study were consecutive patients requiring NSAID treatment for at least 2 weeks, who were free of treatment-requiring dyspeptic symptoms, and who were not receiving any prophylactic co-medication. After a minimum of 2 weeks of treatment with a NSAID, a standardized questionnaire and endoscopy of the upper gastrointestinal tract were obtained. Results: 104 patients (median age 53 years, 91 women) were recruited to the study. Four patients had to be excluded for protocol violations. NSAID treatment was applied mainly with diclofenac (n = 67), followed by ibuprofen (n = 22) and rofecoxib (n = 9). The main indication was degenerative complaints affecting the vertebral column and joints. Under treatment, 35% of the patients developed troublesome dyspepsia that required treatment. The frequency of dyspepsia was independent of the duration of NSAID use. Ulcer prevalence was 16% (duodenal ulcer: n = 5; gastric ulcer: n = 11; cardiac ulcer: n = 1). Relevant epigastric pain was experienced more frequently by ulcer patients than those with no ulcer (35 vs. 18%, p = n.s.), but their overall symptom frequency was no higher than in the latter. Predictors for the development of ulcer were smoking (odds ratio 5.11 [1.59–16.48]), regular use of alcohol (odds ratio 4.49 [1.34–15.07]) and duration of treatment less than 1 month (odds ratio 4.95 [1.06–23.09]). No ulcer complications occurred during the period under observation. Overall, 44% of the patients developed troublesome dyspepsia and/or ulcer. Conclusion: Primary care patients with an average risk profile frequently develop dyspeptic symptoms requiring treatment, and ulcers while on NSAIDs. Patients who developed an ulcer were not identifiable on the basis of symptoms or risk factors.

Efficacy and cost-effectiveness of the 13C-urea breath test as the primary diagnostic investigation for the detection of Helicobacter pylori infection compared to invasive and non-invasive diagnostic tests

Background Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans. There is a risk factor for gastric or duodenal ulcers, gastric cancer and MALT (Mucosa Associated Lymphoid Tissue)-Lymphomas. There are several invasive and non-invasive methods available for the diagnosis of H. pylori. The 13C-urea breath test is a non-invasive method recommended for monitoring H. pylori eradication therapy. However, this test is not yet used for primary assessment of H. pylori in Germany. Objectives What are the clinical and health economic benefits of the 13C-urea breath test in the primary assessment of H. pylori compared to other invasive and non-invasive methods? Methods A systematic literature search including a hand search was performed for studies investigating test criteria and cost-effectiveness of the 13C-urea breath test in comparison to other methods used in the primary assessment of H. pylori. Only studies that directly compared the 13C-urea breath test to other H. pylori-tests were included. For the medical part, biopsy-based tests were used as the gold standard. Results 30 medical studies are included. Compared to the immunoglobulin G (IgG) test, the sensitivity of the 13C-urea breath test is higher in twelve studies, lower in six studies and one study reports no differences. The specificity is higher in 13 studies, lower in three studies and two studies report no differences. Compared to the stool antigen test, the sensitivity of the 13C-urea breath test is higher in nine studies, lower in three studies and one study reports no difference. The specificity is higher in nine studies, lower in two studies and two studies report no differences. Compared to the urease test, the sensitivity of the 13C-urea breath test is higher in four studies, lower in three studies and four studies report no differences. The specificity is higher in five studies, lower in five studies and one study reports no difference. Compared to histology, the sensitivity of the 13C-urea breath test is higher in one study and lower in two studies. The specificity is higher in two studies and lower in one study. One study each compares the 13C-urea breath test to the 14C-urea breath test and the polymerase chain reaction (PCR) test, respectively, and reports no difference in sensitivity and specificity with the 14C-urea breath test, and lower sensitivity and higher specificity compared to PCR. The statistical significance of these differences is described for six of the 30 studies. Nine health economic evaluations are included in the Health Technology Assessment (HTA) report. Among these studies, the test-and-treat strategy using the 13C-urea breath test is compared to test-and-treat using serology in six analyses and to test and treat using the stool antigen test in three analyses. Thereby, test-and-treat using the breath test is shown to be cost-effective over the serology based strategy in three models and is dominated by a test-and-treat strategy using the stool antigen test in one model. A cost-effectiveness comparison between the urea breath test approach and the empirical antisecretory therapy is carried out in four studies. Of these, two studies report that the strategy using the urea breath test is cost-effective over the empirical antisecretory therapy. In two studies, test-and-treat using the 13C-urea breath test is compared to the empirical eradication therapy and in five studies to endoscopy-based strategies. The breath test approach dominates endoscopy in two studies and is dominated by this strategy in one study. Discussion All included medical and economic studies are limited to a greater or lesser extent. Additionally, the results of the studies are heterogeneous regarding medical and economic outcomes respectively. Thus, the majority of the medical studies do not report the statistical significance of the differences in sensitivity and specificity. In direct comparisons the 13C- urea breath test shows higher sensitivity and specificity than the IgG and stool antigen tests. In comparison to the urease test, results for sensitivity are inconsistent, and the specificity is slightly higher for the 13C-urea breath test. There are not enough results for comparisons between the 13C-urea breath test and the 14C-urea breath test, histology and PCR to describe tendencies. The included economic studies suggest that the test-and-treat strategy using the 13C-urea breath test is cost-effective compared to test-and-treat using serology as well as empirical antisecretory therapies. Due to a lack of valid studies, it is not possible to assess the breath test approach in comparison to test-and-treat using the stool antigen test and the empirical eradication therapy respectively, regarding the cost-effectiveness. The results of economic analyses comparing test-and-treat using the breath test to endoscopy strategies are too heterogeneous to draw any conclusions. Overall, none of the included economic models is able to completely capture the complexity of managing patients with dyspeptic complaints. Conclusions/Recommendations Based on available medical and economic studies, there is no sufficient evidence to recommend test and-treat using 13C-urea breath testing for the detection of H. pylori infection as the standard procedure for the management of uninvestigated dyspepsia in the German health care system. In addition, it must be considered that the DVGS guidelines of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DVGS) recommend endoscopy based methods for the management of patients with dyspeptic complaints.

Somatic DNA Hypomethylation in H. pylori -Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer

Objectives:Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk.Methods:We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer-free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method.Results:GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 × 10−12), irrespective of the tumor location or patients’ country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 × 10−5) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC.Conclusions:Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes.

Nighttime Heartburn in Patients with Gastroesophageal Reflux Disease under Routine Care

Background: Gastroesophageal reflux disease (GERD) is a common disorder. The aim of our study was to describe the prevalence of nighttime heartburn and its associations with esophagitis, Barrett’s esophagus, and extra-esophageal symptoms. Methods: Data were collected as part of the ongoing Progression of Gastroesophageal Reflux Disease (ProGERD) study. Based on endoscopy results, patients were categorized as having nonerosive GERD, erosive GERD, or Barrett’s esophagus. ORs and 95% CIs derived from logistic regression analysis were calculated for the association between nighttime heartburn and GERD complications. Results: The overall prevalence of nighttime heartburn for at least 1 of 3 years was 49%, and 21% of patients reported nighttime heartburn in all 3 years. According to multivariate analysis, chronic nighttime heartburn was associated with globus sensation (OR 1.79, 95% CI 1.29–2.47) and erosive GERD (OR 1.67, 95% CI 1.29–2.15). Compared to continuous proton pump inhibitor (PPI) intake, noncontinuous PPI therapy (OR 2.26, 95% CI 1.73–2.96) and medication other than PPIs (OR 2.46, 95% CI 1.67–3.62) were also associated with chronic nighttime heartburn. Conclusions: The prevalence of nighttime heartburn in GERD patients under routine care was high, even in patients on continuous PPI therapy. Nighttime heartburn was not associated with Barrett’s esophagus or most extra-esophageal symptoms.

On-Demand Therapy Is a Valid Strategy in GERD Patients: Pros and Cons

On-demand proton pump inhibitor (PPI) therapy is an attractive option for long-term management of gastroesophageal reflux disease (GERD). Controlled trials in non-erosive reflux disease (NERD) patients have shown sufficient symptom control in most patients with a high rate of willingness to continue treatment and substantial saving on PPI expenditure. However, due to the slow onset of action of PPIs, rescue antacids are often used when symptoms recur and several patients continue to experience some degree of heartburn. On-demand treatment is less cost-saving in patients with esophagitis, and symptomatic/endoscopic relapses occur frequently in severe grades. Data on the prevention of long-term sequelae of on-demand treatment are scarce, only indirect evidence being available. It is suggested that PPI continuous maintenance is more appropriate than on-demand therapy in patients with severe esophagitis, in those with Barrett’s esophagus where chronic PPIs may reduce incidence of dysplasia, in uninvestigated elderly patients where esophagitis is more prevalent and it is more frequently complicated with gastrointestinal bleeding and possibly in uninvestigated or NERD patients with frequent clinical relapses. Finally, more appropriate outcome variables should be used in future trials in order to assess efficacy of on-demand treatment adequately.

W1849 Clinical Course of Extra-Esophageal Disorders in Gastroesophageal Reflux Disease During Routine Care: A 5-Year Follow-Up Study

P>0.05).All 5 GERD bleeders required endoscopy treatment had multiple esophageal ulcers(LA class C or D).The majority of the GERD bleeders 63/84 had multiple esophageal ulcers. Other risk factors for patients with bleeding GERD were identified. Barretts esophagus was found in 11/58 (19%) of GERD bleeders (26/84 had LA class D were unable to diagnose Barretts) comparing to 10% in general GERD patients, odd ratio was 1.9 (P<0.05). NSAID use found in 13/84 (15%), odd ratio was 2.5 (P<0.05). 18/84 of the GERD bleeders were taking maintenance treatment for GERD at the time of the bleeding. Only 6/84 GERD bleeder had abdominal pain or reflux symptomes on admission. CONCLUSIONS:AUGIB is a serious complication of GERD.It required admission to hospital, blood transfusion and endoscopic treatment.Barretts esophagus,NSAID use, and multiple esophageal ulcers were significant risk factors for GERD bleeding.REFERENCES:(1)PJKahrilas, NEnglJMed 2008;359:1700-7. (2)Boonpongmanee et al Gastrointestinal Endosc 2004;59:788-94

Medizinischer und gesundheitsökonomischer Nutzen der Untersuchung auf Helicobacter pylori-Besiedlung mittels 13C-Harnstoff-Atemtest in der Primärdiagnostik im Vergleich zu invasiven und nichtinvasiven diagnostischen Verfahren

Helicobacter pylori (H. pylori) is one of themost common bacterial infections in humans. There is a risk factor for gastric or duodenal ulcers, Marc Nocon Alexander Kuhlmann Andreas Leodolter Stephanie Roll gastric cancer and MALT (Mucosa Associated Lymphoid Tissue)Lymphomas. There are several invasive and non-invasive methods Christoph Vauth available for the diagnosis of H. pylori. The C-urea breath test is a nonStefan N. Willich invasive method recommended for monitoring H. pylori eradication Wolfgang Greiner therapy. However, this test is not yet used for primary assessment of H. pylori in Germany.

Factors that influence heartburn relapse in patients with reflux esophagitis

inhibitor during the healing phase of the EXPO study [1]. Methods: In this multicentre, randomised, double-blind trial (study code: SH-NEG-0008), patients with endoscopically confirmed RE and a history of gastroesophageal reflux disease (GERD) symptoms were randomised to once-daily esomeprazole 40mg (n=1562) or pantoprazole 40mg (n=1589) for 4–8 weeks. Multiple logistic regression analysis was performed to identify factors with a significant influence on resolution of heartburn after 4 weeks’ healing therapy. Factors were selected by a single-factor analysis of treatment, age, sex, BMI, baseline endoscopic severity of RE (LA grade), Helicobacter pylori status, Barrett’s esophagus, hiatus hernia, baseline GERD symptoms and duration of GERD symptom history. Only those factors identified as significant (P<0.05) in the single-factor model were included in the multiple analysis. Resolution of heartburn was defined as absence of heartburn (according to investigator assessment) during the week prior to the 4-week visit. Results: The multiple analysis showed that esomeprazole gave a higher rate of heartburn resolution than pantoprazole after 4 weeks’ healing treatment (odds ratio [OR] 1.31 [95% CI: 1.12, 1.54]; P<0.001); positive H. pylori status (OR 1.44 [95% CI: 1.19, 1.74]; P<0.001) and older age (OR 1.013 [95% CI: 1.007, 1.019]; P<0.001) were also associated with an increased likelihood of resolution of heartburn. In contrast, women (OR 0.74 [95% CI: 0.63, 0.88]; P<0.001) and patients with acid regurgitation (OR 0.77 [95% CI: 0.61, 0.98]; P<0.05) or epigastric pain (OR 0.68 (95% CI: 0.57, 0.82]; P<0.001) were significantly less likely to achieve heartburn resolution at the end of 4 weeks’ treatment. Dysphagia and history of GERD symptoms were also included in the multiple analysis. Conclusions: Use of esomeprazole gives a higher rate of heartburn resolution than pantoprazole during healing therapy for RE. Certain patients, such as women and those with epigastric pain, have a decreased likelihood of heartburn resolution.