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Figure 1. Endoscopic Examination of Barrett Esophagus
Image description not available.
The endoscope is in the upper esophagus, looking downward to the lower esophageal sphincter. The tongues of darker salmon-colored mucosa projecting toward the endoscope represent a typical appearance of Barrett esophagus.
Figure 2. Algorithm for Initial Evaluation and Treatment of Patients With Gastroesophageal Reflux Disease Symptoms
Image description not available.
This diagram illustrates a step-down approach, initiating therapy with a proton pump inhibitor, as might be used for patient 1. Initial therapy with H2 receptor antagonists in patients not previously receiving these medications is also acceptable (a step-up approach).
1.
Locke III GR, Talley NJ, Fett SL, Zinsmeister AR, Melton III LJ. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.  Gastroenterology.1997;112:1448-1456.
2.
Revicki DA, Crawley JA, Zodet MW, Levine DS, Joelsson BO. Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease.  Aliment Pharmacol Ther.1999;13:1621-1630.
3.
Revicki DA, Wood M, Maton PN, Sorensen S. The impact of gastroesophageal reflux disease on health-related quality of life.  Am J Med.1998;104:252-258.
4.
Havelund T, Lind T, Wiklund I.  et al.  Quality of life in patients with heartburn but without esophagitis: effects of treatment with omeprazole.  Am J Gastroenterol.1999;94:1782-1789.
5.
Bloomston M, Zervos E, Gonzalez R, Albrink M, Rosemurgy A. Quality of life and antireflux medication use following laparoscopic Nissen fundoplication.  Am Surg.1998;64:509-513.
6.
Klinkenberg-Knol EC, Festen HP, Meuwissen SG. Pharmacological management of gastro-oesophageal reflux disease.  Drugs.1995;49:695-710.
7.
Smith PM, Kerr GD, Cockel R.  et al.  A comparison of omeprazole and ranitidine in the prevention of recurrence of benign esophageal stricture: Restore Investigator Group.  Gastroenterology.1994;107:1312-1318.
8.
Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.  N Engl J Med.1999;340:825-831.
9.
Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni Jr JF. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia.  JAMA.1995;274:474-477.
10.
Farrow DC, Vaughan TL, Sweeney C.  et al.  Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer.  Cancer Causes Control.2000;11:231-238.
11.
Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors.  Am J Dig Dis.1976;21:953-956.
12.
Valle C, Broglia F, Pistorio A, Tinelli C, Perego M. Prevalence and impact of symptoms suggestive of gastroesophageal reflux disease.  Dig Dis Sci.1999;44:1848-1852.
13.
DeVault KR, Castell DO.for the Practice Parameters Committee of the American College of Gastroenterology.  Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.  Am J Gastroenterol.1999;94:1434-1442.
14.
Fass R, Ofman JJ, Gralnek IM.  et al.  Clinical and economic assessment of the omeprazole test in patients with symptoms suggestive of gastroesophageal reflux disease.  Arch Intern Med.1999;159:2161-2168.
15.
Fass R, Ofman JJ, Sampliner RE, Camargo L, Wendel C, Fennerty MB. The omeprazole test is as sensitive as 24-h oesophageal pH monitoring in diagnosing gastro-oesophageal reflux disease in symptomatic patients with erosive oesophagitis.  Aliment Pharmacol Ther.2000;14:389-396.
16.
Adang RP, Vismans JF, Talmon JL, Hasman A, Ambergen AW, Stockbrugger RW. Appropriateness of indications for diagnostic upper gastrointestinal endoscopy: association with relevant endoscopic disease.  Gastrointest Endosc.1995;42:390-397.
17.
Eisen GM, Sandler RS, Murray S, Gottfried M. The relationship between gastroesophageal reflux disease and its complications with Barrett's esophagus.  Am J Gastroenterol.1997;92:27-31.
18.
Blot WJ, Devesa SS, Kneller RW, Fraumeni Jr JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia.  JAMA.1991;265:1287-1289.
19.
Kavic SM, Basson MD. Complications of endoscopy.  Am J Surg.2001;181:319-332.
20.
Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/US Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy.  Gastrointest Endosc.1991;37:421-427.
21.
Chan MF. Complications of upper gastrointestinal endoscopy.  Gastrointest Endosc Clin N Am.1996;6:287-303.
22.
Zubarik R, Eisen G, Mastropietro C.  et al.  Prospective analysis of complications 30 days after outpatient upper endoscopy.  Am J Gastroenterol.1999;94:1539-1545.
23.
Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate ingestion.  Am J Gastroenterol.1988;83:633-636.
24.
Pehl C, Pfeiffer A, Wendl B, Kaess H. The effect of decaffeination of coffee on gastro-oesophageal reflux in patients with reflux disease.  Aliment Pharmacol Ther.1997;11:483-486.
25.
Pehl C, Wendl B, Pfeiffer A, Schmidt T, Kaess H. Low-proof alcoholic beverages and gastroesophageal reflux.  Dig Dis Sci.1993;38:93-96.
26.
Klinkenberg-Knol EC, Nelis F, Dent J.  et al.  Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa.  Gastroenterology.2000;118:661-669.
27.
Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects.  Aliment Pharmacol Ther.1998;12:1079-1089.
28.
Koop H, Kuly S, Flug M.  et al.  Intragastric pH and serum gastrin during administration of different doses of pantoprazole in healthy subjects.  Eur J Gastroenterol Hepatol.1996;8:915-918.
29.
Sampliner RE. Effect of up to 3 years of high-dose lansoprazole on Barrett's esophagus.  Am J Gastroenterol.1994;89:1844-1848.
30.
Shaheen NJ, Crosby MA, Bozymski EM, Sandler RS. Is there publication bias in the reporting of cancer risk in Barrett's esophagus?  Gastroenterology.2000;119:333-338.
31.
O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry.  Am J Gastroenterol.1999;94:2037-2042.
32.
Spechler SJ, Robbins AH, Rubins HB.  et al.  Adenocarcinoma and Barrett's esophagus: an overrated risk?  Gastroenterology.1984;87:927-933.
33.
Schnell TG, Sontag SJ, Chejfec G.  et al.  Longterm nonsurgical management of Barrett's esophagus with high-grade dysplasia.  Gastroenterology.2001;120:1607-1609.
34.
Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus: the Practice Parameters Committee of the American College of Gastroenterology.  Am J Gastroenterol.1998;93:1028-1032.
35.
Isolauri J, Luostarinen M, Isolauri E, Reinikainen P, Viljakka M, Keyrilainen O. Natural course of gastroesophageal reflux disease: 17-22 year follow-up of 60 patients.  Am J Gastroenterol.1997;92:37-41.
36.
Schindlbeck NE, Klauser AG, Berghammer G, Londong W, Muller-Lissner SA. Three year follow up of patients with gastrooesophageal reflux disease.  Gut.1992;33:1016-1019.
37.
Hetzel DJ, Dent J, Reed WD.  et al.  Healing and relapse of severe peptic esophagitis after treatment with omeprazole.  Gastroenterology.1988;95:903-912.
38.
Marks RD, Richter JE, Rizzo J.  et al.  Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture and esophagitis.  Gastroenterology.1994;106:907-915.
39.
Coelho JC, Wiederkehr JC, Campos AC, Andrigueto PC. Conversions and complications of laparoscopic treatment of gastroesophageal reflux disease.  J Am Coll Surg.1999;189:356-361.
40.
Perdikis G, Hinder RA, Lund RJ, Raiser F, Katada N. Laparoscopic Nissen fundoplication: where do we stand?  Surg Laparosc Endosc.1997;7:17-21.
41.
Hinder RA, Filipi CJ, Wetscher G, Neary P, DeMeester TR, Perdikis G. Laparoscopic Nissen fundoplication is an effective treatment for gastroesophageal reflux disease.  Ann Surg.1994;220:472-481.
42.
Ye W, Chow WH, Lagergren J, Yin L, Nyren O. Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after anti-reflux surgery.  Gastroenterology.2001;121:1286-1293.
43.
Spechler SJ, Lee E, Ahnen D.  et al.  Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.  JAMA.2001;285:2331-2338.
Scientific Review and Clinical Applications
Clinician's Corner
April 17, 2002

Gastroesophageal Reflux, Barrett Esophagus, and Esophageal CancerClinical Applications

Author Affiliations

Author Affiliations: Division of Digestive Diseases and Nutrition, the Center for Esophageal Diseases and Swallowing, and the Center For Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill.

 

Scientific Review and Clinical Applications Section Editor: Wendy Levinson, MD, Contributing Editor.

JAMA. 2002;287(15):1982-1986. doi:10.1001/jama.287.15.1982
Abstract

Gastroesophageal reflux disease (GERD), a condition commonly encountered in the primary care setting, is a risk factor for adenocarcinoma of the esophagus. Despite the ubiquity of the complaint, considerable uncertainty exists with respect to several basic questions, including when to perform endoscopy in patients with chronic reflux symptoms and how to address the cancer risk associated with GERD. These clinical vignettes illustrate common clinical questions encountered in caring for patients with GERD, especially as they relate to the issue of cancer risk. Applying data reviewed in the companion article, we propose practical answers to common clinical situations regarding care of patients with reflux. We also present an algorithm for treatment of patients with chronic GERD symptoms.

Gastroesophageal reflux disease (GERD) is one of the most common problems confronted by primary care physicians.1 The most common symptom of GERD is heartburn, but GERD may present with a variety of symptoms. Appropriate recognition and management of GERD relieves symptoms, increases quality of life, and forestalls complications of reflux disease, such as stricture formation.27 A major concern of patients and physicians is the increased risk of esophageal adenocarcinoma associated with reflux symptoms.810

The following cases illustrate common questions faced in caring for patients with GERD. The suggested treatment of the patients demonstrates one—but often not the only—approach to the individual's care. We have attempted to identify alternative diagnostic or therapeutic options that could be used when appropriate.

Patient 1

A 36-year-old Asian woman complains of 8 months of intermittent rising substernal chest burning, occurring approximately 3 times a week, worse at night and after large meals. Throughout the last 3 months, she has been taking nonprescription ranitidine and initially had good symptom relief, but now she is experiencing substantial periods of discomfort. She has been reading about reflux on the Internet and is especially concerned regarding the cancer risk with reflux.

Does This Patient Have Reflux?

This individual displays many of the classic features of uncomplicated gastroesophageal reflux. The description of her discomfort, the associated exacerbating factors, and the partial response of symptoms to H2 receptor antagonists (H2RAs) suggest that reflux disease is the most likely diagnosis.

Given the prevalence of reflux in the population1,11,12 and the typical nature of this patient's symptoms, further testing to confirm this diagnosis is not recommended.13 Instead, initiation of appropriate therapy can be used as a diagnostic test and a therapeutic measure.14,15 If this patient responds to an empirical trial of proton pump inhibitors with resolution of her symptoms, the diagnosis is confirmed and no further testing is necessary. In typical reflux presentations such as this, further diagnostic testing is reserved for patients demonstrating so-called alarm symptoms, such as dysphagia, bleeding, anemia, and weight loss,16 as well as those who do not respond as expected to empirical therapy.

Should I Recommend Endoscopy to Rule Out Barrett Esophagus or Adenocarcinoma of the Esophagus?

Barrett esophagus is an endoscopically detectable metaplastic change of the lining of the esophagus so that some portion is lined with specialized columnar epithelium instead of the normal squamous epithelium (Figure 1). With respect to this patient's cancer risk, several demographic and symptomatic features argue against further invasive measures to rule out esophageal adenocarcinoma or Barrett esophagus. Although symptom severity is not a reliable predictor of the presence of Barrett esophagus, the chronicity of symptoms is.17 Individuals who are symptomatic for more than 5 years are at increased risk compared with the general public and those with symptoms of shorter duration. Additionally, epidemiologic studies show that Barrett esophagus and adenocarcinoma of the esophagus are diseases most prevalent in white men.18 With respect to esophageal adenocarcinoma, the incidence in men is 4 times that in women and is approximately 8 times as likely in whites as in other races. The incidence of esophageal adenocarcinoma increases markedly with age, making a 36-year-old unlikely to be affected. Finally, and most important, the absolute risk of adenocarcinoma in patients with uncomplicated reflux symptoms is low, and screening endoscopy has not been demonstrated to further decrease this risk. For these reasons, the yield of endoscopic screening in this patient is low and may be outweighed by the small risk of complication from upper endoscopy.1922

Appropriate treatment for this patient consists of counseling about the pathophysiology of reflux and a review of conservative measures sometimes helpful in avoiding reflux symptoms. These conservative measures, listed in BOX 1, may decrease distal esophageal acid exposures.2325 Additionally, adding a pharmacological intervention would be reasonable. Because the patient has had an incomplete symptomatic response to H2RAs, therapy with a proton pump inhibitor could be initiated at standard daily dosing. Alternatively, in this patient, increasing the dose of H2RA as an initial step is also acceptable. A discussion of the risk factors and demographics of esophageal adenocarcinoma and the risks and benefits of endoscopic screening should help the patient understand why this measure is not recommended in her situation. Finally, close follow-up to ensure response of symptoms to therapy and to allow the tapering of pharmacological therapy to the lowest dose at which the patient is symptom free should be arranged. Figure 2 demonstrates a suggested algorithm for the use of endoscopy and pharmacological therapy for patients with classic reflux symptoms. This figure demonstrates a step-down approach to pharmacological therapy, starting with a proton pump inhibitor and decreasing acid suppression to the lowest dosage of either proton pump inhibitor or, preferably, H2RA that keeps the subject symptom free. Step-up approaches, starting with H2RAs and intensifying therapy as necessary, are also acceptable in patients who have not tried H2RA before evaluation.

Box 1. Conservative Measures in Reflux Disease

Elevate the head of the bed on 15-cm blocks.
Avoid eating within 4 hours before sleep.
Avoid eating large meals and chocolate.
Avoid consuming caffeinated products.
Avoid peppermint.
Avoid fatty foods.
Quit smoking.
Lose weight if overweight.

Patient 2

A 65-year-old white man visits your office for follow-up for chronic reflux symptoms. He had an endoscopy 3 years ago, at which time 5 cm of Barrett mucosa without dysplasia was discovered. He otherwise is well, with no weight loss or dysphagia. He has been receiving therapy with a proton pump inhibitor daily for the last 6 years and is worried about the long-term effects of these medications on his system.

Are There Adverse Effects of Long-term Proton Pump Inhibition?

When omeprazole, the first proton pump inhibitor, was introduced into the US market, there was concern that the potency of the drug and the increase in serum gastrin levels associated with its use might lead to the development of gastrinomas. Now, despite the ubiquitous nature of these agents and more than 15 years of experience with them, no increased cancer risk associated with proton pump inhibitor use has been demonstrated. The drugs appear to be safe, even when taken long-term and at doses higher than those initially approved for the healing of erosive esophagitis.26 Routine monitoring of serum gastrin levels is not recommended and may, in fact, cause the physician and patient some distress if they are checked, because they are often elevated in those undergoing therapy.2729

What Is the Appropriate Follow-up for This Patient's Barrett Esophagus?

Because of the dearth of data supporting surveillance endoscopy in Barrett esophagus, any consideration of enrolling a patient in an endoscopic surveillance program should be preceded by a frank discussion of the risks and benefits of surveillance. At the end of this discussion, the patient should understand the rationale behind endoscopic surveillance (to detect cancer in a preclinical and potentially more curable stage), the absolute risk of esophageal adenocarcinoma (approximately 1 in 200-300 patient-years),3032 the risk of serial upper endoscopy (1 major complication in approximately 1000 procedures),19 the treatment options if dysplasia occurs within the Barrett esophagus (esophagectomy, closer surveillance to detect early cancer,33 and enrollment in an experimental ablative protocol),34 and the lack of endoscopic-surveillance evidence showing a survival benefit in those with Barrett esophagus. If after this discussion the patient opts for enrollment in an endoscopic surveillance program, referral to a gastroenterologist or surgeon for upper endoscopy with biopsies is warranted.34

Patient 3

A 36-year-old man presents for follow-up of 2 years of reflux disease. His condition, made manifest by substernal chest burning, is well controlled by twice-daily proton pump inhibitors, for which he pays out of pocket. He wonders how long he will have to take these medications and whether there are other treatment options for him. He has heard that cancer can be associated with reflux, and his neighbor recently underwent a surgical antireflux procedure. He wonders if this procedure would protect him from cancer.

What Is the Natural History of Treated and Untreated Reflux Disease?

Longitudinal studies of reflux disease demonstrate that, for most patients, the condition is chronic.26,35,36 Furthermore, in most of those who develop erosive esophagitis, maintenance therapy will be necessary after healing to avoid recurrence of esophagitis.26,37 However, many patients requiring proton pump inhibitors to heal mucosal disease can continue taking H2RAs. Therefore, in individuals with erosive disease, an 8-week course of proton pump inhibitors to heal mucosal lesions may be followed by an attempt to continue giving the patient H2RAs. In reflux patients who again become symptomatic while receiving H2RAs, long-term maintenance therapy with proton pump inhibitors may be initiated. In addition to good relief of symptoms and high healing rates of erosive esophagitis, proton pump inhibitor treatment effectively delays the development of peptic strictures in patients with a history of strictures.7,38 However, medical therapy has not been demonstrated to avert the development of Barrett esophagus or decrease the risk of cancer in individuals with long-term reflux symptoms.

Does a Surgical Antireflux Procedure Decrease the Risk of Cancer in Individuals With Long-term Reflux Symptoms?

Although a surgical antireflux procedure is a safe and effective treatment for GERD in appropriately selected patients, it should not be pursued to decrease the risk of cancer in patients with reflux symptoms. Although the risk of mortality from a laparoscopic antireflux procedure is low (approximately 0.2%),3941 it is still likely higher than the lifetime risk of death from adenocarcinoma in patients with chronic reflux disease because of the rareness of this cancer in the GERD population. Also, although it is intuitive to expect that decreasing exposure of the esophagus to gastric acid might halt the development of neoplasia, no data suggest that surgical antireflux procedures decrease the already low risk of esophageal adenocarcinoma among patients with GERD. The limited data that do exist suggest that surgical antireflux procedures do not decrease the cancer risk in subjects with GERD.8,42,43 Whether surgical antireflux procedures decrease the incidence of cancer in the subgroup with Barrett esophagus is a debated and unsettled issue. However, for patients with typical reflux symptoms, cancer prevention should not be the impetus for a surgical antireflux procedure.

CONCLUSIONS

Despite the commonness of GERD, it is often undiagnosed or undertreated in practice. In patients with classic substernal chest burning, further diagnostic testing is usually unnecessary, and empiric therapy with antisecretory medications may be instituted. Testing is appropriate for individuals who display alarm symptoms and those who do not respond as expected to therapy. The cancer risk in patients with GERD is low, and screening endoscopy has not been demonstrated to be effective in decreasing cancer incidence or increasing life expectancy. Potent anti-acid medications, such as proton pump inhibitors, make total relief of symptoms attainable in most patients. Long-term therapy with proton pump inhibitors may be necessary and, given the available evidence, appears safe and well tolerated. Surgical antireflux procedures are effective in appropriately chosen patients but should not be pursued solely in an attempt to decrease the already low risk of esophageal cancer in those with reflux.

Several other resources for physicians and patients to learn more about the evaluation and management of gastroesophageal reflux disease are available on the Internet (BOX 2).

Box 2. Resources

For Patients

American College of Gastroenterology's Web site, available at:
http://www.acg.gi.org/acg-dev/patientinfo/frame_gerd.html

National Institutes of Health's information page, available at:
http://www.niddk.nih.gov/health/digest/pubs/heartbrn/heartbrn.htm

Mayo Clinic's heartburn information site, available at:
http://www.mayoclinic.com/findinformation/diseasesandconditions/invoke.cfm?id=DS00095

National Library of Medicine's online tutorial, available at:
http://www.nlm.nih.gov/medlineplus/tutorials/gerd/id159101.html

For Physicians

American College of Gastroenterology's physician forum on GERD, available at:
http://www.acg.gi.org/phyforum/gifocus/2evi.html

American College of Gastroenterology's guidelines for the diagnosis and treatment of GERD, available at:
http://www-east.elsevier.com/ajg/issues/9406/ajg1123fla.htm

References
1.
Locke III GR, Talley NJ, Fett SL, Zinsmeister AR, Melton III LJ. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.  Gastroenterology.1997;112:1448-1456.
2.
Revicki DA, Crawley JA, Zodet MW, Levine DS, Joelsson BO. Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease.  Aliment Pharmacol Ther.1999;13:1621-1630.
3.
Revicki DA, Wood M, Maton PN, Sorensen S. The impact of gastroesophageal reflux disease on health-related quality of life.  Am J Med.1998;104:252-258.
4.
Havelund T, Lind T, Wiklund I.  et al.  Quality of life in patients with heartburn but without esophagitis: effects of treatment with omeprazole.  Am J Gastroenterol.1999;94:1782-1789.
5.
Bloomston M, Zervos E, Gonzalez R, Albrink M, Rosemurgy A. Quality of life and antireflux medication use following laparoscopic Nissen fundoplication.  Am Surg.1998;64:509-513.
6.
Klinkenberg-Knol EC, Festen HP, Meuwissen SG. Pharmacological management of gastro-oesophageal reflux disease.  Drugs.1995;49:695-710.
7.
Smith PM, Kerr GD, Cockel R.  et al.  A comparison of omeprazole and ranitidine in the prevention of recurrence of benign esophageal stricture: Restore Investigator Group.  Gastroenterology.1994;107:1312-1318.
8.
Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.  N Engl J Med.1999;340:825-831.
9.
Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni Jr JF. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia.  JAMA.1995;274:474-477.
10.
Farrow DC, Vaughan TL, Sweeney C.  et al.  Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer.  Cancer Causes Control.2000;11:231-238.
11.
Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors.  Am J Dig Dis.1976;21:953-956.
12.
Valle C, Broglia F, Pistorio A, Tinelli C, Perego M. Prevalence and impact of symptoms suggestive of gastroesophageal reflux disease.  Dig Dis Sci.1999;44:1848-1852.
13.
DeVault KR, Castell DO.for the Practice Parameters Committee of the American College of Gastroenterology.  Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.  Am J Gastroenterol.1999;94:1434-1442.
14.
Fass R, Ofman JJ, Gralnek IM.  et al.  Clinical and economic assessment of the omeprazole test in patients with symptoms suggestive of gastroesophageal reflux disease.  Arch Intern Med.1999;159:2161-2168.
15.
Fass R, Ofman JJ, Sampliner RE, Camargo L, Wendel C, Fennerty MB. The omeprazole test is as sensitive as 24-h oesophageal pH monitoring in diagnosing gastro-oesophageal reflux disease in symptomatic patients with erosive oesophagitis.  Aliment Pharmacol Ther.2000;14:389-396.
16.
Adang RP, Vismans JF, Talmon JL, Hasman A, Ambergen AW, Stockbrugger RW. Appropriateness of indications for diagnostic upper gastrointestinal endoscopy: association with relevant endoscopic disease.  Gastrointest Endosc.1995;42:390-397.
17.
Eisen GM, Sandler RS, Murray S, Gottfried M. The relationship between gastroesophageal reflux disease and its complications with Barrett's esophagus.  Am J Gastroenterol.1997;92:27-31.
18.
Blot WJ, Devesa SS, Kneller RW, Fraumeni Jr JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia.  JAMA.1991;265:1287-1289.
19.
Kavic SM, Basson MD. Complications of endoscopy.  Am J Surg.2001;181:319-332.
20.
Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/US Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy.  Gastrointest Endosc.1991;37:421-427.
21.
Chan MF. Complications of upper gastrointestinal endoscopy.  Gastrointest Endosc Clin N Am.1996;6:287-303.
22.
Zubarik R, Eisen G, Mastropietro C.  et al.  Prospective analysis of complications 30 days after outpatient upper endoscopy.  Am J Gastroenterol.1999;94:1539-1545.
23.
Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate ingestion.  Am J Gastroenterol.1988;83:633-636.
24.
Pehl C, Pfeiffer A, Wendl B, Kaess H. The effect of decaffeination of coffee on gastro-oesophageal reflux in patients with reflux disease.  Aliment Pharmacol Ther.1997;11:483-486.
25.
Pehl C, Wendl B, Pfeiffer A, Schmidt T, Kaess H. Low-proof alcoholic beverages and gastroesophageal reflux.  Dig Dis Sci.1993;38:93-96.
26.
Klinkenberg-Knol EC, Nelis F, Dent J.  et al.  Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa.  Gastroenterology.2000;118:661-669.
27.
Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects.  Aliment Pharmacol Ther.1998;12:1079-1089.
28.
Koop H, Kuly S, Flug M.  et al.  Intragastric pH and serum gastrin during administration of different doses of pantoprazole in healthy subjects.  Eur J Gastroenterol Hepatol.1996;8:915-918.
29.
Sampliner RE. Effect of up to 3 years of high-dose lansoprazole on Barrett's esophagus.  Am J Gastroenterol.1994;89:1844-1848.
30.
Shaheen NJ, Crosby MA, Bozymski EM, Sandler RS. Is there publication bias in the reporting of cancer risk in Barrett's esophagus?  Gastroenterology.2000;119:333-338.
31.
O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry.  Am J Gastroenterol.1999;94:2037-2042.
32.
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