Clinical trial: chest pain caused by presumed gastro-oesophageal reflux in coronary artery disease - controlled study of lansoprazole vs. placebo.

BACKGROUND: Gastro-oesophageal reflux (GER) and coronary artery disease commonly co-exist. Coronary artery disease patients may mistake GER-induced pain for cardiac pain or GER might provoke angina. AIM: To investigate if GER might contribute to nocturnal/rest chest pain among coronary artery disease patients. METHODS: Double-blind placebo-controlled crossover study investigating effect of lansoprazole on chest pain; 125 patients with angiographically proven coronary artery disease enrolled with at least one weekly episode of nocturnal/rest pain, randomized to lansoprazole 30 mg daily or placebo with crossover after 4 weeks. Symptoms recorded and QOL assessed by Nottingham Health Profile Questionnaire; ST segment depression episodes counted from 24 h electrocardiographic monitoring in final week of both periods. STATISTICAL ANALYSIS: ANCOVA with period and carryover analysis. RESULTS: In all, 108 patients completed the study. There was a modest increase in pain-free days on lansoprazole vs. placebo (P < 0.02), with fewer days with pain at rest (P < 0.05) and at night (P < 0.009) on lansoprazole vs. placebo, but no significant differences in ST segment depression episodes (P = 0.64). There was a trend for reduction in the 'physical pain' QOL domain. CONCLUSIONS: Among coronary artery disease patients, lansoprazole modestly increases pain-free days and reduces rest/nocturnal pain. As lansoprazole did not affect ST segments, this may be by suppression of GER-provoked pain misinterpreted as angina, rather than acid-provoked ischaemia.

Meta analysis: Cancer risk in Barrett's oesophagus.

BACKGROUND: Risk of cancer in Barrett's oesophagus is reported to vary between studies and also between countries, where the studies were conducted as per several systematic reviews. Cancer incidence has implications on surveillance strategies. AIM: To perform a meta-analysis to determine the incidence of oesophageal cancer in Barrett's oesophagus. METHODS: Articles retrieved by MEDLINE search (English language, 1966-2004). Studies had to necessarily include verified Barrett's oesophagus surveillance patients, documented follow-up and cancer identified as the outcome measure. A random effects model of meta-analysis was chosen and results were expressed as mean (95% CI). RESULTS: Forty-one articles selected for conventional Barrett's oesophagus (length >3 cm); eight included short segment Barrett's oesophagus (one additional article including only short segment Barrett's oesophagus). Cancer incidence was 7/1000 (6-9) person-years duration of follow-up (pyd), with no detectable geographical variation [UK 7/1000 (4-12) pyd, USA 7/1000 (5-9) pyd and Europe 8/1000 (5-12) pyd]. Cancer incidence in the UK was 10/1000 (7-14), when two large studies were excluded. Cancer incidence in SSBO was 6/1000 (3-12) pyd. When short segment Barrett's oesophagus compared to conventional Barrett's oesophagus, there was a trend towards reduced cancer risk [OR 0.55, (95% CI: 0.19-1.6), P = 0.25]. CONCLUSION: We found no geographical variations in Barrett's oesophagus cancer risk, but observed a trend towards reduced cancer risk in short segment Barrett's oesophagus. There is a time trend of decreasing cancer incidence.

Normalization of oesophageal pH does not guarantee control of duodenogastro-oesophageal reflux in Barrett's oesophagus.

BACKGROUND: Proton-pump inhibitors are effective at preventing the acid component of gastro-oesophageal refluxate from entering the oesophagus. It is not clear whether proton-pump inhibitors prevent duodenogastro-oesophageal reflux. AIM: To measure oesophageal exposure to duodenogastro-oesophageal refluxate while on proton-pump inhibitors in patients with Barrett's oesophagus. METHODS: Twenty-five patients (23 male) with Barrett's oesophagus underwent 24 h oesophageal pH and Bilitec 2000 monitoring while on omeprazole 40 mg/day (n = 19) or omeprazole 60 mg/day (n = 6). All patients were undergoing argon plasma ablation of their Barrett's epithelium as part of a clinical trial and the Bilitec measurements were only carried out after the ablation had been completed. RESULTS: 20 of 25 (80%) patients had a normal oesophageal pH profile. Fifteen of the 25 (60%) had abnormal oesophageal exposure to bile as measured by Bilitec 2000. Of the 20 patients who had a normal 24 h oesophageal pH profile, 11 (55%) had pathological exposure to bile in their oesophagus. CONCLUSION: Complete acid suppression does not guarantee elimination of duodenogastro-oesophageal reflux.

High-grade dysplasia in Barrett's oesophagus: natural history and review of clinical practice.

BACKGROUND: Management of high-grade dysplasia in Barrett's oesophagus is controversial: surgery carries an appreciable morbidity/mortality, high-grade dysplasia may not progress to cancer and endoscopic ablation is an emerging option. AIM: To review Barrett's oesophagus-related high-grade dysplasia management and outcome over a 10-year period. METHODS: This was a retrospective case note review of 36 patients identified from a pathology database. RESULTS: There were 31 men of mean age 67 years. Endoscopic surveillance identified nine. Median follow-up was 21 months. Seven patients had no further intervention because of age/comorbidity. The other 29 had repeat endoscopic biopsies, nine showing cancer (six oesophagectomized). Of the 20 remaining patients with persisting high-grade dysplasia, eight had surgery (histology showed cancer in six), seven continued endoscopic surveillance (high-grade dysplasia regressed in four) and five had 'curative' argon ablation. An intensive biopsy protocol was not followed in 55% of endoscopies. Prevalent cancers occurred in 44% with an annual incidence of 5% over 5 years. All cause mortality was 39% (14 of 36, eight of 14 from cancer). CONCLUSIONS: Management of high-grade dysplasia was not uniform. Unsuspected cancer was common in high-grade dysplasia patients undergoing surgery but 13% regressed under surveillance. High-grade dysplasia patients have a high mortality but 43% did not die from cancer.

Audit of a Barrett's epithelium surveillance database.

BACKGROUND: Barrett's epithelium is a premalignant condition in which endoscopic surveillance is recommended but remains contentious. AIM: To audit our Barrett's epithelium surveillance database and to calculate the incidence and natural history of dysplasia and cancer in this cohort. METHODS: A retrospective analysis of a computerised database of patients with columnar lined oesophagus containing specialised intestinal metaplasia was undertaken over a 5-year period. The surveillance protocol was annual endoscopy with 2-cm interval quadrantic biopsies with patients on continuous acid-suppression therapy. RESULTS: A total of 138 (102 men) patients underwent active surveillance. The mean age was 62.1 years and the mean Barrett's epithelium length was 5.9 cm. Ten patients had low-grade dysplasia, with a mean age of 73.5 years, a mean Barrett's epithelium length of 7.8 cm, a prevalence of 7.2% over 5 years and an incidence of 1.4% per annum. Low-grade dysplasia regressed in five patients, persisted in four patients, and was associated with a concurrent squamous carcinoma in one patient. Three patients had high-grade dysplasia at index endoscopy, with no incident cases. One progressed to adenocarcinoma after 2 years. A cancer incidence of one per 202 patient-years of surveillance was found, equivalent to 0.5% per year. CONCLUSION: Short-interval (1-year) endoscopic surveillance of Barrett's epithelium offers little reward. Low-grade dysplasia is uncommon, and no progression to adenocarcinoma was seen in this cohort. No incident high-grade dysplasia was observed. Prospective evaluation of a longer endoscopic surveillance interval in controlled clinical studies is warranted.

Efficacy and one year follow up of argon plasma coagulation therapy for ablation of Barrett's oesophagus: factors determining persistence and recurrence of Barrett's epithelium.

INTRODUCTION: Barrett's epithelium (BE) has malignant potential. Neither acid suppression nor antireflux surgery produce consistent or complete regression of the metaplastic epithelium. Endoscopic thermoablation with argon plasma coagulation (APC) offers a different approach but factors influencing its outcome have not been systematically examined. AIM: To assess the efficacy of APC and factors influencing initial and one year outcome. METHODS: Fifty patients, mean age 61.4 years, mean BE length 5.9 cm (range 3-19), underwent APC therapy at four weekly intervals while receiving proton pump inhibitor (PPI) therapy. BE margins were marked by India ink tattooing and extent was documented by grid drawings, photography, and 2 cm interval quadrantic jumbo biopsies. Twenty four hour ambulatory oesophageal pH studies were done while on PPIs before and after APC therapy, and Bilitec bilirubin monitoring after APC completion. RESULTS: A total of 68% of patients achieved >90% BE ablation after a median of four APC sessions. Persistent BE (>10% original BE area) was associated with longer initial BE length despite more APC sessions. Persistent acid and bile reflux on PPIs, although commoner in this group, were not significantly different from those successfully ablated. Fifteen of 34 patients (44%) with successful macroscopic clearance had buried glands, present in 8.3% of a total of 338 biopsies. At the one year follow up, only 32% of those with initial successful ablation showed no recurrence. BE recurred or increased in most with mean segment length increases of 1.1 cm and 1.6 cm, respectively, in patients with previous full ablation and those with persistent BE. The presence of buried glands did not predict BE recurrence. Patients who reduced their PPI dose had significantly greater BE recurrence. CONCLUSIONS: APC is most effective for shorter segment BE ablation but "buried" glands do occur. Recurrence of BE is common at one year, especially in those with initial persistent and/or long segment BE and those who reduce their PPI dose.

Surveillance in Barrett's oesophagus: a personal view.

Barrett's oesophagus is defined as columnar-lined oesophagus of any length containing specialised intestinal metaplasia. Diagnosis depends on close corroboration between the endoscopist and histopathologist. It occurs in 10% of patients presenting endoscopically with reflux symptoms and has an adenocarcinoma incidence of 0.4% to 2%. Surveillance is performed to detect precancerous change (dysplasia) and early stage disease has a good surgical prognosis. Computer models suggest cost efficacy comparable to other health measures. However most patients with Barrett's do not die of oesophageal cancer and elective oesophagectomy has an appreciable mortality. Endoscopic ablation techniques and improved definition of high risk subgroups will help shape future surveillance programmes.

Bile acid therapy and markers of immune-mediated damage in primary biliary cirrhosis.

In primary biliary cirrhosis (PBC), liver damage results from both immune- and bile acid-mediated mechanisms. Therapies directed against the former have been either ineffective or toxic, while bile salt therapy is well tolerated but of uncertain long-term benefit. Because of slow disease progression, there is a need for surrogate markers of long-term efficacy. Candidates include markers of immune activation, such as soluble intercellular adhesion molecule-1 (sICAM-1) which shows promise in this respect. Using this marker, evidence has been presented to suggest an additive effect of the combination of ursodeoxycholic acid (UDCA) with azathioprine and prednisone in a short-term trial in PBC.

Measuring duodenogastro-oesophageal reflux (DGOR)

The importance of duodenogastro-oesophageal reflux (DGOR) in gastro-oesophageal reflux disease (GORD) is controversial. Most evidence points to a possible synergistic effect between refluxed acid and bile, which may be more frequent in patients with Barrett's oesophagus, particularly those with complications. Techniques for long-term measurement of DGOR include continuous aspiration, which is cumbersome and laborious, ambulatory spectrophotometric bilirubin measurement as a proxy for bile acids and sodium ion measurement using a sodium electrode. The two latter are the most promising techniques which are improving understanding of DGOR in clinical situations. Both have advantages and drawbacks. The Bilitec system for measuring bilirubin has been most studied and has been well validated. The sodium electrode has so far only been used for short-term monitoring but may be capable of development into a practical tool for longer-term monitoring of DGOR.

Gastro-oesophageal reflux in patients with coronary artery disease: how common is it and does it matter?

OBJECTIVE: To investigate the influence of spontaneous gastro-oesophageal reflux (GOR) on symptoms and cardiac ischaemia in patients with coronary artery disease. DESIGN: Simultaneous 24-h ambulatory oesophageal pH, 7-lead electrocardiographic (ECG) monitoring and symptom diary in patients taking their usual anti-anginal medication. SETTING: Regional cardiothoracic unit and gastroenterology unit of a teaching hospital. SUBJECTS: Twenty-four patients (20 males, 4 females, mean age 59 years) with post-myocardial infarction angina and angiographically proven coronary artery disease. MAIN OUTCOME MEASURES: Quantitation of acid gastro-oesophageal reflux (% total time pH < 4, number of reflux episodes, duration of reflux episodes), identification of ST segment elevation or depression of 1 mm or more on 24-h ECG recording and occurrence of chest pain ("heartburn' or "angina') within 5 min of GOR or ischaemic ST segment shift. RESULTS: There were 568 episodes of GOR, 28 of which were symptomatic. Abnormal GOR (% total time pH < 4 greater than 7%) occurred in 9 (38%) of the patients; all reflux parameters were increased in nitrate users compared to non-users (P < 0.05). Ischaemic ST-segment shift was seen on 113 occasions. Of a total of 41 chest pain episodes, 20 were related to GOR ("angina' with 8, "heartburn' with 12), while 8 coincided with both GOR and ST depression together ("angina' in 5, "heartburn' in 3). In addition to these eight episodes, coincidence of ST depression with GOR occurred on another nine occasions (all asymptomatic). CONCLUSION: GOR is common in patients with coronary artery disease and may be increased by drug therapy; GOR may occasionally be associated with myocardial ischaemia, but this is uncommonly symptomatic; GOR-induced pain is sometimes mistaken for angina. These effects were uncommon overall, but frequent in a few individuals and should be considered in the evaluation of patients with persistent chest pain despite seemingly adequate antianginal treatment.

Gastric DNA content in postgastrectomy patients. Relationship to mucosal dysplasia.

BACKGROUND: Gastric mucosal cellular DNA content was assessed in patients who had undergone gastric surgery for peptic ulcer disease more than 20 years previously, with the aim of examining the relationship between abnormal DNA content and gastric mucosal dysplasia, as well as determining the effect of different types of surgery on DNA content. METHODS: Sixty-five subjects underwent upper gastrointestinal endoscopy. In each, six biopsies were taken from the stoma or antrum and graded for severity of dysplasia. Cellular DNA was quantified using a microprocessor-controlled image analysis system with a fast densitometer card on Feulgen-stained slides. DNA histograms were evaluated using the 2c deviation index (2cDI) for proliferative activity and the 4c exceeding rate (4cER) and the 5c exceeding rate (5cER) as indices of malignant potential. RESULTS: In subjects with Billroth II operations, all the above DNA criteria were higher than in Billroth I (P < 0.05), vagotomy and pyloroplasty (P < 0.001), and controls (P < 0.0001). DNA values increased as dysplasia progressed in severity (2cDI, Rs = 0.67; 4cER, Rs = 0.61; 5cER, Rs = 0.72; respectively, P < 0.0001). Among subjects with no dysplasia, more aneuploid cells were found in the Billroth II group, (p < 0.005) compared with the other types of operation. CONCLUSIONS: Cellular DNA content is abnormal at an early stage in dysplasia and may even predate it. Increasing values of abnormal DNA content are related to the severity of dysplasia. DNA analysis may be a useful additional tool in surveillance programs to select high-risk patients for screening.

Direct assessment of the mechanism for a raised serum bile acid level in chronic liver disease.

BACKGROUND: Impaired hepatic uptake is the major cause of raised serum bile acid levels in liver disease, but confirmation in humans by direct measurement is lacking. The synthetic gamma-labelled bile acid 75Se-homocholic acid taurine (75SeHCAT) provides a tool for the direct measurement of hepatic bile acid handling. OBJECTIVE: To determine the interrelationships among hepatic handling of 75SeHCAT, the kinetics of its disappearance from plasma and serum bile acid levels in patients with chronic liver disease. DESIGN: We studied 12 patients with primary biliary cirrhosis and 14 with cirrhosis arising from other causes. Fasting serum bile acid levels were measured enzymatically. After intravenous administration of 75SeHCAT, we determined plasma disappearance rates (initial K1, late K2) from serial blood samples and hepatic uptake and excretory rates directly from dynamic abdominal gamma-camera scanning. Both scanning and sampling were carried out over a period of 90 min. RESULTS: Serum bile acid concentrations correlated with K1 and with hepatic uptake (Rs = -0.53, P < 0.01; Rs = -0.47, P < 0.02, respectively) but neither with K2 nor with the excretory rate. K1 and uptake were reduced (P < 0.05) in patients with high serum bile acid levels and in those with varices. Serum bile acid levels were higher in patients with varices (P < 0.05), which might suggest that portosystemic shunting occurred. However, this is unlikely because the varices were not independent of liver function. CONCLUSION: Hepatic bile acid uptake and excretion are independent processes. Hepatic uptake is related to initial, whereas hepatic excretion is related to late, plasma disappearance. Impaired hepatic uptake is a major determinant of the rise in serum bile acid levels in chronic liver disease.

Sensitization to painful distention and abnormal sensory perception in the esophagus.

BACKGROUND/AIMS: The mechanism of abnormal esophageal sensory perception in patients with unexplained chest pain is unknown. The aim of this study was to test the following two hypotheses: (1) similar to cutaneous nociceptors, esophageal stretch receptors can be sensitized by a noxious chemical stimulus, and (2) patients with esophageal chest pain have sensitized receptors. METHODS: Twenty-five patients with noncardiac chest pain underwent esophageal manometry, provocation tests, and 24-hour pH monitoring. Eleven patients had positive and 14 had negative results of esophageal provocation tests. Esophageal perception and pain thresholds for balloon stretch (in milliliters) and electrical stimulation (in milliamperes) were determined in patients and 7 healthy controls performed before and after randomized, double-blind esophageal perfusion with normal saline or 0.1N HCl. RESULTS: The basal balloon pain threshold was lower in patients with positive results of esophageal tests than in either those patients with negative results of esophageal tests or controls (P < 0.05). After acid perfusion, balloon perception and pain thresholds decreased in patients with negative results of esophageal tests (P < 0.05) and in controls (P < 0.05) but not in patients with positive results of esophageal tests. No change occurred after saline perfusion nor in electrical pain thresholds in any group after the perfusion of either fluid. CONCLUSIONS: In patients with negative results of esophageal tests and in controls, the pain threshold to balloon distention is lowered by acid. The lack of such effect in patients with positive results of esophageal tests implies that pain receptors may already be sensitized.

Effect of famotidine on oesophageal sensitivity in gastro-oesophageal reflux disease.

Gastric acid suppression could improve heartburn by healing oesophagitis or by reduction of oesophageal sensitivity to acid. To independently assess changes in oesophageal sensitivity, it would be necessary to study patients with reflux disease but no oesophagitis. The aim of this study was to investigate the effect of acid suppression on oesophageal sensitivity and to assess the time course of any measured effect. Twenty seven patients were recruited, of whom 25 completed the study (14 men and 11 women, mean (SD) age 50 (15) years). All had classic symptoms of gastro-oesophageal reflux but normal results of upper gastrointestinal endoscopy and oesophageal mucosal histological tests. Each had abnormal 24 hour pH studies and a positive acid perfusion tests. Subjects were assigned double blind to placebo (n = 11) or famotidine 40 mg twice daily (n = 14) for four weeks. Acid perfusion tests were carried out at 0, 4, 5, and 8 weeks and time to heartburn recorded. Time to heartburn (mean (SEM)) was 124 (78) seconds in the famotidine and 187 (154) in the placebo group at week 0 (NS). Compared with baseline, significant increases in time to heartburn was found with famotidine at weeks 4 (383 (102), p < 0.01) and 5 (344 (92), p < 0.01) but not week 8 (336 (90) seconds). No significant effects were found with placebo (219 (41), 146 (23), and 144 (25) seconds for weeks 4, 5, and 8). Heartburn symptom score decreased significantly with famotidine (mean scores 3.6, 1.9, 2.1, and 2.6 at weeks 0, 4, 5, and 8 (p=0.001)) and showed a significant negative correlation with time to heartburn (r(s)=-0.60; p<0.0001). It is concluded that oesophageal sensitivity to acid is reduced by famotidine independent of and effect on oesophagitis; the effect wanes one to four weeks after the end of treatment and correlates with change in heartburn score.

Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid.

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA) is clinically beneficial in chronic cholestatic liver disease, but the underlying mechanisms are unclear. It has been suggested that intrahepatic retention of endogenous hydrophobic bile acids contributes to cholestasis and that the hydrophilic bile acid UDCA reduces this retention; the aim of our study was to test these hypotheses. METHODS: Twelve patients with primary biliary cirrhosis (PBC) and 5 with primary sclerosing cholangitis (PSC) were studied before and during UDCA (10 mg.kg-1.day-1) and compared with 11 healthy controls. Following intravenous 75Se labeled homocholic acid taurine (75SeHCAT) in the fasting state, abdominal gamma camera imaging was performed for 90 minutes. Initial hepatic uptake, transit time, net, and absolute excretory rates for 75SeHCAT were measured. RESULTS: Mean initial hepatic uptake was not different between patients and controls (17.2% and 19.9% dose/minute, not significant). However, net and absolute excretory rates were significantly reduced in patients (1.4% vs. 3.7% dose/minute, P < 0.0001; and 2.35% vs. 3.96% dose/minute, P < 0.02, respectively), and hepatic transit time was prolonged (18.7 minutes vs. 11.6 minutes, P < 0.002). UDCA improved net and absolute hepatic excretory rates and transit time (1.43% to 1.96% dose/minute, P < 0.001; 2.35% to 3.15% dose/minute, P < 0.005 and 18.7 to 14.7 minutes, P < 0.001, respectively). However, UDCA did not alter initial hepatic uptake. CONCLUSIONS: In PBC and PSC, there is a defect in hepatic bile acid excretion but not in uptake, implying bile acid retention. This retention is reduced by UDCA.

Determinants of pregnancy heartburn.

OBJECTIVE: To study the prevalence and severity of reflux symptoms in pregnancy. DESIGN: Self-administered questionnaire detailing age, race, gestational age, parity, weight, height, symptoms and severity of gastro-oesophageal reflux. SETTING: An antenatal clinic in a teaching hospital. SUBJECTS: 607 consecutive women at various stages of pregnancy were recruited during attendance at antenatal clinic. RESULTS: The prevalence of heartburn increased with gestational age (22% in the first, 39% in the second, and 72% in the third trimester; P < 0.0001), as did severity of heartburn (P < 0.0001). Pharyngeal regurgitation as a symptom showed little increase during advancing pregnancy. Symptoms of heartburn rapidly increased towards the end of the second trimester. The decrease in heartburn traditionally expected during the last three weeks of pregnancy (fetal head descent) was not observed. Logistic regression analysis showed increased risk of suffering heartburn with increasing gestational age (P < 0.0001), pre-pregnancy heartburn (P < 0.0001), parity (P < 0.0001) and inversely with maternal age (P < 0.05) but not with body mass index before pregnancy, race, or weight gain in pregnancy. CONCLUSION: Heartburn, but less so pharyngeal regurgitation, increases in prevalence and severity with gestational age and parity. We speculate that hormone-related impairment of distal oesophageal clearance mechanisms may have a crucial bearing on whether heartburn develops in those individuals at greatest risk.