Failure of oesophageal acid control in candidates for Barrett's oesophagus reversal on a very high dose of proton pump inhibitor

BACKGROUND: Normalization of oesophageal acid exposure using high dose proton pump inhibitors in patients who are candidates for ablation therapy has been suggested to be essential for successful Barrett's reversal. However, the success rate for achieving pH normalization has not been determined. METHODS: Patients with Barrett's oesophagus (2-6 cm in length) who were found to be eligible for ablation therapy using multipolar electrocoagulation were included in this prospective study. Patients underwent an upper endoscopy to determine Barrett's length and other anatomic characteristics. Biopsies were obtained to rule out dysplasia. Subsequently, patients were treated with omeprazole 40 mg b.d. Twenty-four hour oesophageal pH monitoring was performed after a mean period of 8.4 +/- 0.6 days of therapy. RESULTS: Twenty-five patients were enrolled into the study. The pH test was abnormal in four (16%) of the study subjects. An additional two (8%) patients had abnormal supine percentage time with pH less than 4. There was no significant difference in oesophageal acid control between patients with long vs. short segment Barrett's oesophagus. Elderly (> 60 years) patients tended to have less acid control than younger (相似文献   

Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence

BACKGROUND: There is little evidence that treatment of patients with Barrett's oesophagus with proton pump inhibitors over periods up to 6 years results in major regression of Barrett's oesophagus. AIM: To determine if longer periods of treatment with proton pump inhibitors lead to significant regression of Barrett's oesophagus, and to determine the incidence of oesophageal adenocarcinoma in the proton pump inhibitor-treated patients. METHODS: We analysed prospectively-collected data on Barrett's oesophagus patients treated with proton pump inhibitors for 1-13 years. RESULTS: 188 patients with Barrett's oesophagus and intestinal metaplasia, were treated for 1-13 years with a proton pump inhibitor (966 years of treatment; mean 5.1 years). No change in length was seen during treatment but 48% of patients developed squamous islands (25% after 1-3 years; 100% at 12-13 years). Squamous islands correlated with treatment duration and male sex but not with proton pump inhibitor dose or patient age. Six patients developed dysplasia and three males developed adenocarcinoma during treatment (cancer incidence 0.31%). CONCLUSIONS: Proton-pump inhibitor treatment over 1-13 years does not shorten the Barrett's oesophagus segment but squamous islands appear in many patients. The incidence of oesophageal adenocarcinoma was low in these proton pump inhibitor-treated patients compared with published series.     

Review article: approaches to Barrett's oesophagus treatment-the role of proton pump inhibitors and other interventions

Despite implementation of screening and surveillance strategies, a significantly large number of patients with Barrett's oesophagus remain undiagnosed. In those who are identified, the management options include acid reduction therapies with proton pump inhibitors or anti-reflux surgery. Endoscopic ablative therapies have also been attempted. In addition to having inherent procedure-related risks with ablative therapies, these alternatives may be limited by high rates of failure, need for continued acid suppressive therapy, metaplasia persistence under otherwise normal appearing tissue, need for procedural expertise, and continued risk for adenocarcinoma development. Therefore, a widely applicable chemoprevention strategy that cost-effectively reduces the rate of progression from oesophagitis to adenocarcinoma in high-risk patients and perhaps those at lower rates of risk is highly desirable. The AspECT trial currently underway is seeking to determine the effects of high- and low-dose proton pump inhibitor therapy with and without low-dose aspirin as Barrett's oesophagus chemoprevention.     

Oesophageal and gastric pH profiles in patients with gastro-oesophageal reflux disease and Barrett's oesophagus treated with proton pump inhibitors

BACKGROUND: Acid plays a significant role in the development of gastro-oesophageal reflux symptoms and tissue damage. It is generally assumed that acid suppressive therapy with proton pump inhibitors improves or eliminates symptoms of gastro-oesophageal reflux disease by normalizing intra-oesophageal pH. However, the degree of acid suppression induced by proton pump inhibitor therapy in patients with gastro-oesophageal reflux disease and/or Barrett's oesophagus has not been adequately studied. AIM: To assess the efficacy of proton pump inhibitors in normalizing intra-oesophageal and intra-gastric pH in patients with gastro-oesophageal reflux disease with and without Barrett's oesophagus who have been rendered symptom-free by acid-suppressive therapy. METHODS: Patients with gastro-oesophageal reflux disease and Barrett's oesophagus were prospectively evaluated by dual sensor 24-h pH monitoring while receiving proton pump inhibitor therapy for complete control of gastro-oesophageal reflux disease symptoms. Analyses and comparisons of intra-oesophageal and intra-gastric pH profiles on therapy were then made. RESULTS: One hundred and ten patients, 98 men and 12 women, with gastro-oesophageal reflux disease (n = 62) and/or Barrett's oesophagus (n = 48), were studied. All tolerated proton pump inhibitors well and were asymptomatic at the time of the study. Thirty-six (58%) patients with gastro-oesophageal reflux disease and 24 (50%) patients with Barrett's oesophagus (P = 0.4) normalized their intra-oesophageal pH profiles on proton pump inhibitors. Compared with patients with gastro-oesophageal reflux disease, patients with Barrett's oesophagus were more likely to have higher degree of pathologic acid reflux despite proton pump inhibitor therapy (DeMeester score 50.5 +/- 8.2 vs. 31.4 +/- 4.6, P = 0.03) and exhibited less intra-gastric acid suppression (% total pH < 4.0: 53.9 +/- 2.7 vs. 39.9 +/- 2.6, P = 0.0004), particularly supine (% pH < 4.0: 62.1 +/- 3.4 vs. 44.8 +/- 3.4, P = 0.0006). CONCLUSIONS: Gastro-oesophageal reflux disease patients with or without Barrett's oesophagus continue to exhibit pathologic gastro-oesophageal reflux disease and low intra-gastric pH despite proton pump inhibitor therapy that accomplishes complete reflux symptom control. Further, intra-oesophageal and intra-gastric pH control is significantly more difficult to achieve in patients with Barrett's oesophagus. These findings may have significant therapeutic implications.     

The effects of high-dose esomeprazole on gastric and oesophageal acid exposure and molecular markers in Barrett's oesophagus

Aliment Pharmacol Ther 2010; 32: 1023–1030

Summary

Background Acid reflux is often difficult to control medically. Aim To assess the effect of 40 mg twice daily esomeprazole (high‐dose) on gastric and oesophageal pH and symptoms, and biomarkers relevant to adenocarcinoma, in patients with Barrett’s oesophagus (BO). Methods Eighteen patients, treated with proton pump inhibitors as prescribed by their treating doctor, had their therapy increased to high‐dose esomeprazole for 6 months. Results At entry into the study, 9/18 patients had excessive 24‐h oesophageal acid exposure, and gastric pH remained <4 for >16 h in 8/18. With high‐dose esomeprazole, excessive acid exposure occurred in 2/18 patients, and gastric pH <4 was decreased from 38% of overall recording time and 53% of the nocturnal period to 15% and 17%, respectively (P < 0.001). There was a reduction in self‐assessed symptoms of heartburn (P = 0.0005) and regurgitation (P < 0.0001), and inflammation and proliferation in the Barrett’s mucosa. There was no significant change in p53, MGMT or COX‐2 expression, or in aberrant DNA methylation. Conclusions High‐dose esomeprazole achieved higher levels of gastric acid suppression and control of oesophageal acid reflux and symptoms, with significant decreases in inflammation and epithelial proliferation. There was no reversal of aberrant DNA methylation.     

Exposure to proton pump inhibitors and risk of pancreatic cancer: a meta-analysis

ABSTRACT

Objectives: To estimate the pancreatic cancer risk among subjects exposed versus not exposed to proton pump inhibitors.

Methods: The authors searched PubMed, EMBASE, Scopus, Cochrane Library, and clinicaltrials.gov to identify relevant studies. The authors quantified pancreatic cancer risk among subjects exposed versus not exposed to PPIs, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) in overall and sensitivity analyses.

Results: One randomized trial, two cohort, four case-control, and five nested case-control studies with 700,178 subjects (73,985 cases; 626,193 controls) were retained. PPI exposure was associated with pancreatic cancer risk (OR = 1.75, 95%CI = 1.12–2.72, I² = 99%); confirmed in sensitivity analyses for high-quality studies, observational studies, case-control studies, studies with pancreatic cancer as the primary outcome, and in sensitivity analyses for diabetes and obesity but not for pancreatitis and smoking. This association was independent of the duration and Defined Daily Dose of PPI exposure. Rabeprazole had a singular significant association with pancreatic cancer (OR = 5.40, 95%CI = 1.98–14.703, I² = 87.9%).

Conclusion: The class of PPIs is associated with a 1.75-fold increase in pancreatic cancer risk, confirmed in sensitivity analyses.     

Lack of predictors of normalization of oesophageal acid exposure in Barrett's oesophagus

BACKGROUND: Barrett's oesophagus patients may continue to have abnormal oesophageal acid exposure on proton pump inhibitor therapy. The effect of factors such as Barrett's oesophagus length, hiatal hernia size and Helicobacter pylori infection on intra-oesophageal pH in Barrett's oesophagus patients has not been adequately studied. AIM: To evaluate oesophageal acid exposure in a large Barrett's oesophagus population on b.d. proton pump inhibitor therapy and determine clinical factors predicting normalization of intra-oesophageal pH on therapy. METHODS: Barrett's oesophagus patients were studied using 24 h pH monitoring to evaluate intra-oesophageal acid suppression on b.d. dosing of rabeprazole. RESULTS: Forty-six Barrett's oesophagus patients completed the study. Median total percentage time pH < 4 was 1.05% (range: 0-29.9%) in the entire group and respective values for upright and supine percentage time pH < 4 were 1.15% and 0%. However, 34 of the Barrett's oesophagus patients (73.9%) had a normal pH study (median total percentage time pH < 4: 0.2%) and 12 patients (26.1%) had an abnormal result (median total percentage time pH < 4: 9.3%). There were no significant differences between patients with a normal and abnormal 24 h pH result with respect to age, Barrett's oesophagus length, hiatal hernia size and presence of H. pylori infection. CONCLUSIONS: Approximately 25% of Barrett's oesophagus patients continue to have abnormal total intra-oesophageal pH profiles despite b.d. proton pump inhibitor therapy. Factors such as age, Barrett's oesophagus length and hiatal hernia size cannot be used to predict persistent abnormal intra-oesophageal pH on proton pump inhibitor.     

Reflux patterns in patients with short-segment Barrett's oesophagus: a study using impedance-pH monitoring off and on proton pump inhibitor therapy

Background  In short-segment Barrett's oesophagus (SSBO) heartburn may be absent and oesophageal acid exposure time (OAET) assessed with pH-only monitoring may be normal. By detecting reflux episodes independently of their acidity, multichannel intraluminal impedance-pH (MII-pH) monitoring allows a comprehensive characterization of reflux events, either off or on proton pump inhibitor (PPI) therapy.
Aim  To assess reflux parameters by MII-pH monitoring in newly diagnosed SSBO, at baseline and as modified with PPI therapy.
Methods  Short-segment Barrett's oesophagus was defined by oesophageal intestinal metaplasia up to 3 cm in length. 24-h MII-pH monitoring was performed before and during PPI therapy.
Results  Fifty patients were studied prospectively. Normal OAET was found at baseline in 15 patients (30%), 8 and 2 of whom with a higher than normal number of acid and weakly acidic refluxes, respectively. Overall, abnormal reflux parameters were detected by MII-pH monitoring in 90% of patients. Reflux events were prevalent in the upright period. On PPI therapy, acid refluxes decreased and a correspondent increase in weakly acidic refluxes was observed (median from 48.5 to 9 and from 16 to 57.5, respectively) ( P  <   0.001).
Conclusions  Acid refluxes, mainly in the upright period, characterize SSBO. PPI therapy transforms acid refluxes into weakly acidic refluxes.     

Comparison of the main oesophageal pathophysiological characteristics between short- and long-segment Barrett's oesophagus

AIM: To assess the oesophageal manometric characteristics and 24-h pH profiles of patients with both short-segment and long-segment Barrett's oesophagus and compare them with those of patients with reflux oesophagitis and controls. METHODS: Seventy-nine patients who had undergone upper digestive endoscopy were recruited: 16 had short-segment Barrett's oesophagus, 13 had long-segment Barrett's oesophagus, 25 had grade III oesophagitis according to the Savary-Miller classification and 25 were used as controls. The diagnosis of Barrett's oesophagus was based on the histological detection of specialized intestinal metaplasia, which extended < 3 cm into the oesophagus in patients with short-segment disease and > 3 cm in patients with long-segment disease. All subjects underwent oesophageal manometry and basal 24-h oesophageal pH monitoring. RESULTS: The lower oesophageal sphincter pressure was significantly lower in patients with reflux oesophagitis and short-segment and long-segment Barrett's oesophagus than in controls (P=0.0004-0.0001), but there was no difference among the three reflux groups. The peristaltic wave amplitude of patients with long-segment Barrett's oesophagus was significantly lower than that of controls (P=0.002) and patients with short-segment Barrett's oesophagus (P=0.02), but was no different from that of patients with reflux oesophagitis. The percentage of non-propagated wet swallows was significantly higher in patients with reflux oesophagitis and short-segment and long-segment Barrett's oesophagus when compared with that of controls (P=0.0004-0.0001). The total percentage of time the oesophagus was exposed to pH < 4.0 was significantly higher in patients with reflux oesophagitis and short-segment and long-segment Barrett's oesophagus (P=0.0001) than in controls, and was higher in patients with long-segment disease than in those with short-segment disease (P=0.01). CONCLUSIONS: Long-segment Barrett's oesophagus is characterized by a greater impairment of peristaltic wave amplitude and a higher oesophageal acid exposure than is short-segment Barrett's oesophagus. However, both forms are linked to increased acid reflux.