Risk of oesophageal cancer in Barrett's oesophagus and gastro-oesophageal reflux

BACKGROUND AND AIMS: While patients with Barrett's oesophagus develop oesophageal adenocarcinoma more frequently than the general population, it has controversially been suggested that gastro-oesophageal reflux (GORD) itself is a more important determinant of risk. In order to assess the validity of this suggestion, we examined the risk of oesophageal cancer in patients with Barrett's and with GORD compared with the general population in a community based cohort study. METHODS: Cohorts of patients with Barrett's (n = 1677), oesophagitis (n = 6392), and simple reflux (n = 6328), and a reference cohort (n = 13416) were selected from the General Practice Research Database. The last three cohorts were matched to the Barrett's cohort by general practitioner practice, age, and sex. Cox's regression analysis was used to calculate relative risks for oesophageal cancer. Standardised incidence ratio methodology was used to estimate the relative risks for oesophageal adenocarcinoma. RESULTS: A total of 137 oesophageal cancers were identified, of which 94 prevalent cases were excluded. The hazard ratios for oesophageal cancer were 10.6 (5.1-22.0), 2.2 (0.9-5.2), and 1.7 (0.7-4.5) in the Barrett's, oesophagitis, and reflux cohorts compared with the reference cohort, respectively. The corresponding relative risks for oesophageal adenocarcinoma were 29.8 (9.6-106), 4.5 (1.04-19.6), and 3.1 (0.6-14.2). CONCLUSION: Barrett's oesophagus increases the risk of oesophageal cancer approximately 10 times and oesophageal adenocarcinoma approximately 30 times compared with the general population. There is only a modestly increased risk of oesophageal cancer in patients with reflux who have no record of Barrett's oesophagus. Our findings therefore do not support the suggestion that gastro-oesophageal reflux disease itself predisposes to cancer.     

Risk of extra-oesophageal malignancies and colorectal cancer in Barrett's oesophagus and gastro-oesophageal reflux

BACKGROUND: The relationship between Barrett's oesophagus and colorectal cancer and other extra-oesophageal malignancies (EOM) has been a matter of controversy. These relationships have therefore been examined in a prospective study design in the General Practice Research Database. METHODS: Cohorts of patients having Barrett's oesophagus (n=1677), oesophagitis (n=6392), and simple reflux (n=6328), and a standard reference cohort representing the general population in the UK (n=13,416) were selected. The last three cohorts were matched to the Barrett's cohort by general practice, age and sex. Incident outcomes occurring beyond the first year of the follow-up were used for analyses. Hazard ratios and 95% confidence intervals were calculated using Cox's proportional hazards regression. The associations with cataract and oesophageal cancer were explored for comparison. RESULTS: Incident cases of 567 EOM (including 74 colorectal cancers), 448 cataract and 43 oesophageal cancers were used in the final analysis. The relative risks for colorectal cancer compared to the standard reference cohort were 1.16 (0.42-3.21) in the Barrett's cohort, 1.39 (0.76-2.54) in the oesophagitis cohort, and 0.93 (0.45-1.90) in the simple reflux cohort. The corresponding relative risks in the Barrett's cohort were 1.29 (0.90-1.85), 1.60 (1.10-2.32), and 10.56 (5.07-21.99) for EOM, cataract and oesophageal cancer, respectively. CONCLUSIONS: The risk of colorectal cancer was not higher in any of the Barrett's oesophagus, oesophagitis, or reflux cohorts compared to the general population. The explanations for the modest increase in the risk of EOM and cataract in the above cohorts are unclear but they may be mediated by ascertainment bias or shared risk factors.     

Effect of omeprazole 20 mg twice daily on duodenogastric and gastro-oesophageal bile reflux in Barrett's oesophagus

Background—Both acid and duodenal contents arethought to be responsible for the mucosal damage in Barrett'soesophagus, a condition often treated medically. However, little isknown about the effect of omeprazole on duodenogastric reflux (DGR) andduodenogastro-oesophageal reflux (DGOR).
Aims—To study the effect of omeprazole 20 mgtwice daily on DGR and DGOR, using the technique of ambulatorybilirubin monitoring.
Methods—Twenty three patients with Barrett'soesophagus underwent manometry followed by 24 hour oesophageal andgastric pH monitoring. In conjunction with pH monitoring, 11 patients(group 1) underwent oesophageal bilirubin monitoring and 12 patients (group 2) underwent gastric bilirubin monitoring, both before andduring treatment with omeprazole 20 mg twice daily.
Results—In both groups there was a significantreduction in oesophageal acid (pH<4) reflux (p<0.005) and asignificant increase in the time gastric pH was above 4 (p<0.005). Ingroup 1, median total oesophageal bilirubin exposure was significantlyreduced from 28.9% to 2.4% (p<0.005). In group 2, median totalgastric bilirubin exposure was significantly reduced from 24.9% to7.2% (p<0.005).
Conclusions—Treatment of Barrett's oesophaguswith omeprazole 20 mg twice daily results in a notable reduction in theexposure of the oesophagus to both acid and duodenal contents. Inaddition, delivery of duodenal contents to the upper gastric body is reduced.

Keywords:bilirubin monitoring; Barrett's oesophagus; omeprazole; pH monitoring; duodenogastric reflux; duodenogastro-oesophageal reflux

     

Proton pump inhibitor influence on reflux in Barrett's oesophagus

OBJECTIVES: It is important to identify factors responsible for the development of Barrett's oesophagus (BO). The effect of proton pump inhibitors (PPIs) on oesophageal clearance of both acid and alkaline reflux in these patients is uncertain and studies comparing BO patients and healthy controls (HCs) have not been performed earlier. METHODS: Two groups of patients were studied: 18 HCs and 12 BO patients. Oesophageal motility, acid reflux and duodenogastro-oesophageal reflux (DGOR) were measured using a three-pressure transducer catheter with an antimony pH tip, connected to a sodium ion selective electrode. All patients were studied both on and off PPIs. RESULTS: Without PPI therapy, BO patients had significantly more upright and supine acid reflux and upright DGOR compared with HCs. During acid reflux, HC demonstrated more peristalsis than BO [HC, % peristalsis=64 (9), BO=53 (8), P<0.01], but this was not seen during DGOR. [HC, % peristalsis=68 (14), BO=56 (11)]. In Barrett's patients, DGOR was significantly reduced with PPIs [off PPI, % upright DGOR=61 (17), on PPIs=19 (15), P<0.01], and no oesophageal motility differences were seen compared with results without PPIs. CONCLUSION: HCs demonstrate better oesophageal motility compared with BO patients to prevent acid and alkaline reflux. When acid reflux occurred, HCs had better coordinated motility to remove it. This increased coordination did not occur during DGOR, suggesting different stimulation mechanisms. PPI reduced DGOR in BO patients, without any change in oesophageal motility.     

Young patients with Barrett's oesophagus experience less reflux complaints

BACKGROUND/AIM: Barrett's oesophagus can be expected to be more resistant to the effects of acidic refluxate, and, hence, it can be postulated that patients with Barrett's oesophagus experience less reflux complaints. A cross-sectional study in consecutive patients presenting with Barrett's oesophagus and reflux oesophagitis was done in order to test this hypothesis. METHODS: Patients received a standardized questionnaire, and overall and specific symptom scores were assessed on a five-point Likert scale. RESULTS: Reflux oesophagitis was diagnosed in 128 patients and Barrett's oesophagus in 42. Patients with reflux oesophagitis had statistically significantly higher symptom scores than patients with Barrett's oesophagus (mean +/- SD): 9.1 +/- 6.3 vs. 6.2 +/- 5.4 (p = 0.01). The scores for heartburn and acid regurgitation were significantly higher in reflux oesophagitis, while there was a trend for epigastric pain, retrosternal pain, and vomitus. The symptom scores of patients with Barrett's oesophagus older than 60 years were not different from patients with reflux oesophagitis older than 60 years: 5.2 +/- 4.8 vs. 7.4 +/- 6.4. However, the symptom scores of patients younger than 60 years were significantly higher in those with reflux oesophagitis: 10.2 +/- 5.7 vs. 7.2 +/- 5.7 (p = 0.04). Odynophagia, heartburn, and acid regurgitation scored significantly higher in patients with reflux oesophagitis younger than 60 years as compared with Barrett patients younger than 60 years. CONCLUSIONS: Patients with Barrett's oesophagus indeed suffer less from reflux complaints. However, this is only true for those younger than 60 years.     

Nitrate and nitrosative chemistry within Barrett's oesophagus during acid reflux

BACKGROUND AND AIMS: When saliva, with its high nitrite content derived from the enterosalivary recirculation of dietary nitrate, meets acidic gastric juice, the nitrite is converted to nitrous acid, nitrosative species, and nitric oxide. In healthy volunteers this potentially mutagenic chemistry is focused at the gastric cardia. We have studied the location of this luminal chemistry in Barrett's patients during acid reflux. METHODS: Ten Barrett's patients were studied before and after administration of 2 mmol nitrate. Using microdialysis probes we measured nitrite, ascorbic acid, total vitamin C, and thiocyanate concentrations and pH simultaneously in the proximal oesophagus, Barrett's segment, hiatal sac, proximal stomach, and distal stomach. In a subgroup, real time nitric oxide concentrations were also measured. RESULTS: During acid reflux, Barrett's segment was the anatomical site with maximal potential for acid catalysed nitrosation, with its median concentration of nitrite exceeding that of ascorbic acid in two of 10 subjects before nitrate and in four of nine after nitrate. Thiocyanate, which catalyses acid nitrosation, was abundant at all anatomical sites. On entering the acidic Barrett's segment, there was a substantial fall in nitrite and the lowest ascorbic acid to total vitamin C ratio, indicative of reduction of salivary nitrite to nitric oxide at this anatomical site. Episodes of acid reflux were observed to generate nitric oxide concentrations of up to 60 muM within the Barrett's segment. CONCLUSION: The interaction between acidic gastric refluxate and nitrite rich saliva activates potentially mutagenic luminal nitrosative chemistry within Barrett's oesophagus.     

Neuromuscular function of the human lower oesophageal sphincter in reflux disease and Barrett's oesophagus

BACKGROUND: Columnar lined (Barrett's) oesophagus is often considered a sequel to chronic severe reflux disease. Aberrant lower oesophageal sphincter (LOS) motility associated with Barrett's oesophagus includes reduced basal LOS pressures. The aim of this study was to characterise neuromuscular function of the LOS in normal (squamous cell carcinoma (SCC) with uninvolved LOS) and reflux affected (Barrett's) oesophagus in vitro. METHODS: Strips of LOS muscle were prepared at biopsy following oesophagectomy from 16 patients with SCC and seven patients with oesophageal adenocarcinoma and Barrett's oesophagus associated with a history of reflux disease. LOS smooth muscle responses were recorded in response to electrical field stimulation (EFS), potassium chloride (KCl), DMPP, isoprenaline, capsaicin, bethanechol, and tachykinins. RESULTS: Basal LOS tone and LOS relaxations in response to isoprenaline, EFS, and DMPP were not significantly altered in the Barrett's group. After tetrodotoxin pretreatment, responses to KCl and DMPP were significantly reduced in the SCC but not in Barrett's LOS. Maximal contraction in response to bethanechol was significantly decreased in Barrett's LOS while substance P and NK-2 receptor mediated contraction was unaltered. Capsaicin, NK-1, and NK-3 receptor agonists exerted negligible effects on LOS tone. CONCLUSIONS: LOS muscle strips from patients with reflux associated Barrett's oesophagus exhibit a reduction in cholinergic muscle contraction while retaining similar features of basal tone, responses to tachykinins, and inhibitory muscle and neural function. Enteric inhibitory neurones in LOS muscle strips from patients with reflux associated Barrett's oesophagus display resistance to axonal sodium channel blockade. No evidence for functional NK-1 or NK-3 receptors or capsaicin sensitive axon collateral reflexes was observed in the human LOS.     

Surveillance in Barrett's oesophagus

Barrett's oesophagus is a premalignant condition with an increasing incidence of adenocarcinoma. There remains uncertainty based on the lack of accurate information, not least the necessity for, effectiveness of, and optimal interval for surveillance of known cases. The incidence of oesophageal cancer may not be as high as previously supposed, which could influence both surveillance intervals and cost effectiveness. Issues around patient selection have not been satisfactorily resolved; although most patients at risk are elderly and die of other causes, advanced oesophageal cancer is an unpleasant condition and the prevention of the morbidity associated with this by endoscopic therapy of early lesions may be a worthwhile goal. Many patients drop out of surveillance programmes; some of the reasons appear to centre on the lack of information and point to the need to educate our patients if we believe surveillance to be worthwhile.     

Evaluation of Helicobacter pylori in reflux oesophagitis and Barrett''s oesophagus.

BACKGROUND: One of the major pathophysiological abnormalities in patients with gastro-oesophageal reflux disease is thought to involve transient lower oesophageal sphincter (LOS) relaxations. One component of the neural mechanism controlling the LOS appears to be a reflex are whose afferent limb originates in the gastric fundus. As inflammation is known to be associated with neural activation an investigation was made to determine whether gastric infection with H pylori is altered in prevalence or distribution in patients with reflux disease. METHODS: Five groups of subjects referred for endoscopy-group 1: 25 controls (asymptomatic individuals with anaemia and normal endoscopy); group 2: 36 subjects with erosive oesophagitis alone (Savary-Millar grades I-III); group 3: 16 subjects with duodenal ulcer alone; group 4: 15 subjects with oesophagitis with duodenal ulcer; group 5: 16 subjects with Barrett's oesophagus. No patients were receiving acid suppressants or antibiotics. An antral biopsy specimen was taken for a rapid urease test, and two biopsy specimens were taken from the antrum, fundus, and oesophagus (inflamed and non-inflamed) for histological evidence of inflammation and presence of H pylori using a Giemsa stain. RESULTS: Nine (36%) controls had H pylori. Patients with duodenal ulcer alone had a significantly higher incidence of colonisation by H pylori than other groups (duodenal ulcer 15 (94%); oesophagitis 13 (36%); oesophagitis+duodenal ulcer 6 (40%); Barrett's oesophagus 4 (25%)). H pylori was not more common in oesophagitis. When H pylori colonised the gastric antrum it was usually found in the gastric fundus. There was no difference in anatomical distribution of H pylori in the different patient groups. In Barrett's oesophagus H pylori was found in two of 16 in the metaplastic epithelium. CONCLUSION: H pylori is not more common and its distribution does not differ in those with oesophagitis compared with control subjects, and is therefore unlikely to be aetiologically important in these patients. H pylori, however, can colonise Barrett's epithelium.     

Chemoprevention in Barrett's oesophagus

Barrett's oesophagus normally affects the distal oesophagus when metaplastic columnar lined epithelium replaces stratified squamous epithelium which predisposes to cancer development. This develops as a consequence of chronic gastroesophageal reflux (GORD). Those with Barrett's have a 40 fold increased risk of oesophageal adenocarcinoma [1]. There are is still a lack of understanding of the natural history of the cell of origin. This does hamper research into this area. We accept that there is a limitation in testing of the pathogenesis of Barrett's oesophagus due to a lack of a universally accepted animal model. The major questions surrounding Barrett's oesophagus include validity of surveillance strategies, the optimal treatment and more importantly an agent that can prevent progression to cancer without unacceptable side effects. The main chemopreventative agents that show promise are aspirin and proton pump inhibitors (PPIs). There are other agents such as green tea, berries and antioxidants and diet that have been suggested; we discuss the evidence available for these strategies. We hope for continued improvement in the clinical trial infrastructure to facilitate testing of new pharmacological and endoscopic interventions for Barrett's oesophagus.     

Nutcracker oesophagus: Association with chest pain and dysphagia controlling for gastro-oesophageal reflux

BACKGROUND: The association between nutcracker oesophagus, gastro-oesophageal reflux and their symptoms is controversial. AIM: To evaluate the association of nutcracker oesophagus with chest pain and dysphagia controlling for gastro-oesophageal reflux. METHODS: From a database of 935 consecutive patients investigated with oesophageal manometry and pH-metry, we selected all patients with nutcracker oesophagus including diffuse and segmental patterns. Patients with normal oesophageal peristalsis served as controls. Symptoms assessment, manometry testing and 24h oesophageal pH monitoring off acid-suppressive medications were performed following a standardized protocol. The associations between nutcracker oesophagus and symptoms were assessed by logistic regression analysis. RESULTS: Nutcracker oesophagus was found in 60 patients (6.4%), of which 30 had diffuse nutcracker oesophagus and 30 had segmental nutcracker oesophagus. The control group was composed by 656 patients with normal oesophageal peristalsis. Diffuse nutcracker oesophagus was associated with chest pain (odds ratio 4.3; 95% CI 1.9-9.9; P<0.0001) and dysphagia (odds ratio 5.3; 95% CI 2.3-12.2; P<0.0001), whereas segmental nutcracker oesophagus was associated with chest pain (odds ratio 2.8; 95% CI 1.1-6.9; P=0.026), controlling for total oesophageal acid exposure, age, sex and lower oesophageal sphincter (LOS) pressure. CONCLUSION: This study suggests that both diffuse and segmental nutcracker oesophagus should be regarded as meaningful abnormalities and not mere manometric curiosities.     

Relationship between spontaneous non-propagating pressure activity in the oesophagus and acid gastro-oesophageal reflux in pathological and non-pathological refluxers.

To evaluate the oesophageal motor activity preceding episodes of reflux, 10 pathological and 10 non-pathological refluxers and 26 normal subjects were investigated. The pressure events in spontaneous short periods of pressure activity (less than or equal to 60 sec) and in long activity periods were registered. The last contraction before reflux was more frequently found non-propagating than the last contraction of pressure periods not followed by reflux (p less than 0.01). The interval from the last contraction to reflux was shortest, if the contraction terminated in, or confined to the upper part of the oesophagus (p less than 0.001). Increased proportion of reflux episodes were preceded by an upper segmentary contraction (p less than 0.05) and a short activity period (p less than 0.02) in patients with pathological reflux in comparison with non-pathological refluxers. Spontaneously occurring sphincter relaxations might be triggered by preceding non-propagated contractile activity. The relative number of reflux episodes preceded by non-propagated pressure activity seems to be increased in patients with frequent episodes of acid reflux, compared with patients with infrequent episodes, or with normal subjects.     

Definition of Barrett's oesophagus

Barrett's oesophagus is the eponym applied to the columnar epithelium-lined lower oesophagus. In 1976, Paull et al. described three types of columnar epithelia lining the distal oesophagus: a junctional or cardiac-type epithelium, a gastric fundic-type epithelium and a distinctive type of intestinal metaplasia referred to as specialized columnar epithelium. Even the normal oesophagus can be lined by 2 cm of columnar epithelium. To avoid the problem of false-positive diagnoses, arbitrary criteria for the extent of oesophageal columnar lining necessary to include patients in studies of Barrett's oesophagus were established in the early 1980s. The latter criteria require a circumferential segment of columnar lined epithelium of 2 or 3 cm in length. There are, however, a number of technical and conceptual problems related to this approach. The traditional definition excludes shorter segments and tongues of columnar lined epithelium. Only the specialized columnar epithelium defined by intestinal type goblet cells carries an inherent risk of malignancy. Therefore, a number of investigators currently define Barrett's oesophagus as any amount of columnar mucosa in the lower esophagus that has histologic evidence of goblet cells (highlighted in biopsies using the alcian blue pH 2.5 stain). Recently, short segments of specialized intestinal metaplasia in the distal oesophagus ("short segment Barrett's oesophagus") have attracted considerable attention. It has also become clear that intestinal metaplasia can occur at a normally located gastro-oesophageal junction. The etiology and clinical significance (in terms of possible relationship to the adenocarcinoma of the cardia) of this "intestinal metaplasia of the gastric cardia" and its potential relationship to Barrett's oesophagus are not yet completely understood.     

Persistent acid reflux and symptoms in patients with Barrett's oesophagus on proton-pump inhibitor therapy

OBJECTIVES: To assess both acid gastro-oesophageal reflux (GOR) suppression in patients with Barrett's oesophagus on proton-pump inhibitors (PPI) and the predictive value of symptoms.DESIGN A prospective study of patients with Barrett's epithelium (> 3 cm, containing specialized intestinal metaplasia).PATIENTS AND METHODS: Forty-five patients with Barrett's epithelium were recruited. Therapy was adjusted to omeprazole 20 mg twice daily. Oesophageal manometry and 24 h pH studies were performed on treatment. Heartburn score was calculated before and after PPI dose adjustment. In patients with persisting acid reflux, omeprazole dose was increased to 20 mg three times daily and pH studies repeated. Adequacy of GOR suppression, assessed by pH monitoring, was related to heartburn score (0-3). RESULTS: Twenty of the 45 patients were symptomatic (mean score 1.9) on pre-study treatment (mainly omeprazole < 20 mg once daily); on omeprazole 20 mg twice daily, only six patients remained symptomatic (mean score 1.6). Ten patients (22%) had persisting GOR on omeprazole 20 mg twice daily (median % total time with pH < 4 was 8%). Abnormal nocturnal reflux was found in nine and abnormal daytime reflux in only four patients. Heartburn persisted in three of these 10 patients (30%). Those remaining symptomatic had more daytime acid reflux than the asymptomatic patients with persistent reflux (median percentage daytime at pH < 4 was 13.6% vs 0.6%, respectively; P < 0.01). By increasing the omeprazole dose to 20 mg three times daily, only three of the 10 had persistent acid reflux. CONCLUSIONS: Persistent acid reflux on PPI therapy is common in patients with Barrett's oesophagus. Although nocturnal acid reflux is the most common finding, symptoms tended to occur in those with abnormal daytime reflux. Symptom resolution does not guarantee acid reflux control.