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Original Article |

Gastroesophageal Reflux Disease Symptom Severity, Proton Pump Inhibitor Use, and Esophageal Carcinogenesis FREE

Katie S. Nason, MD, MPH; Promporn Paula Wichienkuer, MD, MPH; Omar Awais, MD; Matthew J. Schuchert, MD; James D. Luketich, MD; Robert W. O’Rourke, MD; John G. Hunter, MD; Cynthia D. Morris, PhD, MPH; Blair A. Jobe, MD
[+] Author Affiliations

Author Affiliations: Division of Thoracic and Foregut Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (Drs Nason, Awais, Schuchert, Luketich, and Jobe); and Departments of Public Health and Preventive Medicine (Dr Wichienkuer), Surgery (Drs O’Rourke, Hunter, and Jobe), and Informatics and Clinical Epidemiology (Dr Morris), Oregon Health & Science University, Portland.


Arch Surg. 2011;146(7):851-858. doi:10.1001/archsurg.2011.174.
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Published online

Hypothesis Screening for esophageal adenocarcinoma has focused on identifying Barrett esophagus (BE) in patients with severe, long-standing symptoms of gastroesophageal reflux disease (GERD). Unfortunately, 95% of patients who develop esophageal adenocarcinoma are unaware of the presence of BE before their cancer diagnosis, which means they never had been selected for screening. One possible explanation is that no correlation exists between the severity of GERD symptoms and cancer risk. We hypothesize that severe GERD symptoms are not associated with an increase in the prevalence of BE, dysplasia, or cancer in patients undergoing primary endoscopic screening.

Design Cross-sectional study.

Setting University hospital.

Patients A total of 769 patients with GERD.

Interventions Primary screening endoscopy performed from November 1, 2004, through June 7, 2007.

Main Outcomes Measures Symptom severity, proton pump inhibitor therapy, and esophageal adenocarcinogenesis (ie, BE, dysplasia, or cancer).

Results Endoscopy revealed adenocarcinogenesis in 122 patients. An increasing number of severe GERD symptoms correlated positively with endoscopic findings of esophagitis (odds ratio, 1.05; 95% confidence interval, 1.01-1.09). Conversely, an increasing number of severe GERD symptoms were associated with decreased odds of adenocarcinogenesis (odds ratio, 0.94; 95% confidence interval, 0.89-0.98). Patients taking proton pump inhibitors were 61.3% and 81.5% more likely to have adenocarcinogenesis if they reported no severe typical or atypical GERD symptoms, respectively, compared with patients taking proton pump inhibitors, who reported that all symptoms were severe.

Conclusions Medically treated patients with mild or absent GERD symptoms have significantly higher odds of adenocarcinogenesis compared with medically treated patients with severe GERD symptoms. This finding may explain the failure of the current screening paradigm in which the threshold for primary endoscopic examination is based on symptom severity.

Figures in this Article

On the basis of several epidemiologic studies in the late 1990s,15 recommendations have been made to screen white men older than 50 years with long-standing and severe symptoms of gastroesophageal reflux disease (GERD) for Barrett esophagus (BE), the known precursor lesion to esophageal adenocarcinoma.6 Despite these recommendations, 95% of patients who develop esophageal adenocarcinoma have not received endoscopic screening or been diagnosed as having BE, and most patients present with advanced disease and little chance for cure.7 Indications for screening1,811 historically included long-standing GERD and persistent severe symptoms despite adequate medical therapy, but these criteria have failed physicians in their attempt to stratify patients for prevention and early detection. In fact, the most recent guidelines state that screening has not been effective in even the highest-risk group and should, therefore, be “individualized to the patient.”11

One possible explanation for the failure of the current screening paradigm is that no correlation has been observed between the severity of GERD symptoms and cancer risk; because their symptoms are absent, insignificant, or atypical, these patients do not seek medical care or are not selected for endoscopic screening, and occult disease progression ensues. In addition, because proton pump inhibitors (PPIs) are extremely effective in reducing or eliminating symptoms, patients may be overlooked for screening under the false assumption that their disease is adequately treated. We hypothesize that severe GERD symptoms, particularly in patients who are taking PPIs, are not associated with an increase in the prevalence of BE, dysplasia, or cancer in patients undergoing primary endoscopic screening.

OVERVIEW

We performed an institutional review board–approved cross-sectional analysis of typical and atypical GERD symptoms and endoscopic findings in patients at Oregon Health & Science University (OHSU) and the Portland Veterans Administration Medical Center (PVAMC). All patients underwent primary screening endoscopy (ie, esophagogastroduodenoscopy), defined as the first ever esophagogastroduodenoscopy, and completed the validated GERD Health-Related Quality of Life questionnaire (GERD-HRQL)12 and the Reflux Symptom Index (RSI)13 from November 1, 2004, through June 7, 2007. Three distinct cohorts of patients were included to capture the full spectrum of possible GERD symptoms (Table 1).

Table Graphic Jump LocationTable 1. Number of Study Patients by Indication for Screening Endoscopya

The primary cohort was composed of adult patients referred to gastroenterology clinics who were subsequently scheduled for a clinically indicated upper endoscopy. Patients were enrolled regardless of the indication for the procedure. The second cohort of patients, all with typical GERD symptoms (ie, heartburn, regurgitation, or dysphagia) undergoing their first endoscopy or BE surveillance, had been targeted specifically for a randomized controlled trial studying small-caliber endoscopic screening without sedation.14 All patients in this cohort also had been scheduled for a clinically indicated upper endoscopic test (based on GERD symptoms) before being enrolled. The third cohort consisted of patients with atypical reflux symptoms (ie, hoarseness, throat-clearing, excess mucus, globus sensation, or cough) in the general otolaryngology clinics at OHSU and PVAMC who were enrolled in a BE prevalence study; all patients with nonmalignant ear, nose, and throat conditions completed the RSI at the time of their initial appointment. The patients who scored 2 or higher of 5 points for any 2 symptoms or 3 or higher of 5 points for any 1 symptom were approached for enrollment. Patients with a history of prior upper endoscopy or BE were excluded from all 3 cohorts. A total of 769 patients had GERD-HRQL and RSI questionnaires and a detailed medication history obtained; the questionnaires were administered prior to endoscopy.

SYMPTOM ASSESSMENT AND SEVERITY DEFINITIONS

The severity of each patient's typical and atypical GERD symptoms was quantified using the GERD-HRQL questionnaire12 and the RSI,13 respectively (Table 2). The former is a disease-specific instrument whose validity and reliability have been assessed compared with generic quality-of-life scales (ie, the 36-Item Short Form Health Survey)15 and to physiologic factors of GERD.16 The latter is used to assess the severity of atypical symptoms of GERD, specifically laryngopharyngeal reflux symptoms such as hoarseness and cough. The validity and reliability of this measure have been established for patients with laryngopharyngeal reflux who were treated with PPIs and antireflux surgery.13 The GERD-HRQL questionnaire and the RSI provide complementary information regarding GERD symptoms.

Table Graphic Jump LocationTable 2. Gastroesophageal Reflux Disease Symptom Questionnaires

Symptom severity was designated as “no symptoms,” “mild symptoms,” or “severe symptoms” based on the patient's response to each item in the GERD-HRQL questionnaire and the RSI (outlined in the severity schema in Table 3). On the basis of this classification system, the total number of severe GERD-HRQL (with 0-9 possible) and RSI (with 0-8 possible) symptoms were calculated independently as continuous variables. Finally, by combining the total number of severe symptoms from each (with dysphagia included only once; range, 0-16), a composite for each category of symptoms (ie, typical and atypical) was calculated.

ENDOSCOPIC EVALUATION

Endoscopy was performed by gastroenterologists at OHSU and PVAMC as part of standard clinical practice or by trained clinician investigators (R.W.O. and B.A.J.) within the studies outlined previously. All endoscopic findings were entered into the Clinical Outcomes Research Initiative database with details of patient history, including demographic and lifestyle variables and medical history. Barrett esophagus was suspected during endoscopy when the squamocolumnar junction was located proximal to the anatomical esophagogastric junction (ie, the most proximal extent of the gastric folds).17 Intestinal metaplasia of the gastric cardia mucosa was not considered BE. Biopsy specimens were obtained in 4 quadrants every 2 cm throughout the entire Barrett segment using large biopsy forceps.18,19 Esophageal biopsy specimens were evaluated by staff pathologists at OHSU and PVAMC. The diagnosis of BE required the unequivocal presence of goblet cells within the columnar epithelium. Standard diagnostic criteria were used to identify columnar epithelial dysplasia and invasive cancer.20 Esophagitis was documented using the Los Angeles classification system,21,22 and the hiatal hernia size was measured as the distance in centimeters between the crural impressions and the anatomical esophagogastric junction.

STATISTICAL ANALYSES

Statistical analyses were performed with SPSS for Windows (SPSS Inc, Chicago, Illinois) and SAS 9.1 TS Level 1M2 (SAS Institute Inc, Cary, North Carolina). Means, standard deviations, and ranges were presented for continuous variables. Proportions were presented for categorical variables. The value of 80 missing questionnaire responses for 62 study participants was estimated using the mean (rounded to the nearest integer) of each study participant's actual responses for that specific measure (ie, GERD-HRQL or RSI). This imputation allowed for the creation of summary GERD symptom severity measures, although it underestimated the variability of each participant's symptoms.

Associations between the outcome (ie, Barrett metaplasia, dysplasia, or adenocarcinoma) and covariates were assessed using the Pearson χ2 test and the Mantel-Haenszel test of trend, where appropriate. A multiple logistic regression model was created to model the relationship between symptom severity and the study outcome. Variables that were significant in univariate analysis with P < .25, known confounders (specifically, age, sex, and race/ethnicity), and probable biologic importance (specifically, presence of hiatal hernia and use of PPIs) were included in the model.

Pearson 2-tailed correlation statistics were calculated for all potential confounders. Of pairs that had at least moderate correlation (r > 0.70), only 1 variable was included in the preliminary model. Backward stepwise selection was used to derive the preliminary effects model. The criteria for variable removal was determined as a Wald statistic with P > .10. Interactions between each GERD symptom severity variable and age, sex, and the current use of PPIs were assessed and retained in the final model at P < .05. The final model's goodness of fit was assessed with the Hosmer-Lemeshow test.23 Duration of symptoms was available only for the patients within the second (ie, patients with typical GERD) and third (ie, patients with atypical GERD) cohorts. To determine the association among symptom severity, duration of symptoms, and the study outcome, the analysis was repeated with the primary cohort (ie, any reason for endoscopy) excluded.

DEMOGRAPHIC FACTORS ASSOCIATED WITH ESOPHAGEAL ADENOCARCINOGENESIS

Most patients were male (65.4%), white (94.3%), and non-Hispanic (97.8%). Typical GERD symptoms were present at the time of assessment in 67.1% of patients, and 57.2% were using a PPI at the time of primary endoscopy. One hundred seventy-nine of the 769 patients (23.3%) were found during endoscopy to have esophagitis, and 365 (47.5%) had a hiatal hernia with a mean (SD) size of 2.72 (1.72) cm.

Several factors, including the use of PPIs, were associated with increased odds for the presence of esophageal adenocarcinogenesis (Table 4). One hundred twenty-two (15.9%) of the patients had esophageal adenocarcinogenesis: BE in 99 (12.9%) (99 of 769), esophageal dysplasia in 17 (2.2%), and esophageal adenocarcinoma in 6 (0.8%). Esophageal adenocarcinogenesis was present in 31 of 253 otolaryngology clinic patients (12.3%) and 91 of 516 gastroenterology clinic patients (17.6%) (P = .06). Typical and/or atypical GERD symptoms were present for longer than 10 years in 130 of 367 (35.4%).

Table Graphic Jump LocationTable 4. Sociodemographic Characteristics of Case and Control Individuals: Crude Odds for Esophageal Adenocarcinogenesis by Known and Potential Risk Factors
ASSOCIATION BETWEEN GERD SYMPTOM SEVERITY AND ESOPHAGITIS

Regardless of PPI use status, an increased number of severe GERD symptoms correlated positively with the identification of esophagitis (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.09) when compared with those with mild or no symptoms (Figure 1). However, when stratified by typical and atypical symptoms, only an increased number of severe typical GERD symptoms correlated positively with the presence of esophagitis (OR, 1.08; 95% CI, 1.02-1.1).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Correlation between the number of severe symptoms and the presence of erosive esophagitis. The odds of esophagitis increase as the number of severe symptoms increases. This finding is expected because esophageal acidification is responsible for the sensation of heartburn, and effective acid suppression has been proven to reduce or eliminate symptoms and heal erosions.24

ASSOCIATION BETWEEN GERD SYMPTOM SEVERITY AND ESOPHAGEAL ADENOCARCINOGENESIS

Patients with no severe symptoms were 63% (OR, 0.94; 95% CI, 0.89-0.98) more likely to have esophageal adenocarcinogenesis than patients reporting that all GERD symptoms were severe. This relationship persisted when typical and atypical symptoms were analyzed separately (OR, 0.92 [95% CI, 0.86-0.99]; and 0.91 [0.84-0.99], respectively).

GERD SYMPTOM SEVERITY, ODDS OF ESOPHAGEAL ADENOCARCINOGENESIS, AND PPI USE

After adjusting for age, sex, race/ethnicity, presence of hiatal hernia, clinic, and institution of recruitment, the total number of severe GERD symptoms was inversely and significantly associated with the odds of esophageal adenocarcinogenesis among patients using PPIs (OR, 0.90; 95% CI, 0.84-0.96). Within this model, no significant association was observed between symptom severity and adenocarcinogenesis in patients not using PPIs (OR, 1.06; 95% CI, 0.96-1.18) (Table 5 and Figure 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Correlation between the number of gastroesophageal reflux disease (GERD), typical, and atypical severe symptoms and the presence of esophageal adenocarcinogenesis in patients. As the number of severe typical or atypical reflux symptoms increased, a significantly decreased risk was observed for the presence of Barrett esophagitis, dysplasia, and cancer. This finding was most pronounced in patients taking proton pump inhibitors (PPIs).

Table Graphic Jump LocationTable 5. Adjusted Risk of Esophageal Adenocarcinogenesis by GERD Symptom Severity and PPI Usea

When analyzed by typical (OR, 0.90; 95% CI, 0.83-0.99) and atypical symptoms (0.81; 0.72-0.91), this inverse association persisted among PPI users. Patients taking PPIs were 61.3% and 81.5% more likely to have esophageal adenocarcinogenesis if they reported no severe typical or atypical GERD symptoms, respectively. In patients with atypical GERD symptoms who were not using PPIs, the converse was true. For these patients, the odds of esophageal adenocarcinogenesis at screening endoscopy increased by 29% (OR, 1.29; 95% CI, 1.09-1.54) as the number of severe GERD symptoms increased (Figure 3).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Correlation between the number of atypical severe symptoms and the presence of esophageal adenocarcinogenesis. Patients with an increasing number of severe atypical gastroesophageal reflux disease (GERD) symptoms who were not taking proton pump inhibitors (PPIs) composed the group most likely to have Barrett esophagitis, dysplasia, or cancer. This finding is surprising because most of these patients were recruited from otolaryngology clinics and rarely would have been targeted for screening endoscopy.

GERD SYMPTOM SEVERITY, ODDS OF ESOPHAGEAL ADENOCARCINOGENESIS, AND SYMPTOM DURATION

The association between the number of severe typical and/or atypical GERD symptoms and esophageal adenocarcinogenesis was then determined while controlling for duration of symptoms and PPI use. Patients with a 10-year or longer history of typical or atypical GERD symptoms were 3-fold more likely to have esophageal adenocarcinogenesis (OR, 3.02; 95% CI, 1.70-5.40) compared with a duration of symptoms of less than 10 years. Despite this, the inverse association with the total number of severe GERD symptoms persisted (OR, 0.82; 95% CI, 0.74-0.92). The relationship was even more pronounced when the analysis was stratified for duration of symptoms of more than 10 years in patients who were using PPIs (OR, 0.70; 95% CI, 0.58-0.84).

This study explored the relationship between typical and atypical GERD symptom severity and the odds of esophageal adenocarcinogenesis at the time of primary endoscopic screening. The results demonstrate that patients with minimal or no GERD symptoms who are using PPIs have increased odds of esophageal adenocarcinogenesis compared with those with severe symptoms, especially when GERD symptoms have been present for more than 10 years. These findings highlight one of many potential causes for the ineffectiveness of current screening efforts and implicate PPIs as a factor by which patients may be rendered asymptomatic in the face of continued mutagenic exposures.

The importance of further defining potential risk factors for esophageal adenocarcinoma is clear. Since 1975, the incidence of this cancer has increased significantly.2527 Using the presence of long-standing severe GERD symptoms to guide screening strategies has failed to reduce the number of patients presenting with incurable disease. Some have suggested that the nearly epidemic use of antisecretory medications, coupled with the insensate nature of the Barrett epithelium,2831 may be reducing or eliminating GERD symptoms in the patients who are at highest risk, thus rendering them susceptible to occult disease progression. In addition, for a given degree of exposure to refluxate, the perception of GERD symptom severity may be highly variable among patients, which may contribute to occult disease progression in minimally symptomatic patients.

Although we are unable to determine causality from this study, the results have biologic plausibility. Acid suppression therapy is effective at eliminating symptoms despite unremitting reflux events.32 Vela and colleagues32 demonstrated that acid suppression in GERD patients did not result in a decrease in the total number of reflux episodes but rather in a shift from acidic to nonacidic reflux coupled with symptom resolution. In fact, as many as 50% of patients with BE who are taking PPIs will have persistent weak acid esophageal exposure despite complete symptom resolution.3335 Because bile acids become lipid soluble in the presence of a weak acid environment (ie, pH 3-5), they can move through the cell membrane, where they likely activate the caudal-related homeobox gene (Cdx-2 [GenBank NM_007673]) to promote BE.36,37

Lagergren and colleagues1 established symptomatic GERD as a risk factor for esophageal adenocarcinoma in their population-based, case-control study of esophageal adenocarcinoma cases in the 1990s. They established that long-standing and severe GERD symptoms were associated with an adjusted OR for esophageal adenocarcinoma of 43.5-fold compared with no symptoms. However, in their study, symptom severity was defined by symptom frequency as opposed to patient perception of severity. Although frequency most likely serves as a proxy for severity, it is not necessarily indicative of clinically severe GERD. Indeed, physicians and patients rarely consider mild symptoms, even if they occur frequently, as indicating severe GERD because the symptoms are tolerable and easily managed with medications.

Although cross-sectional and matched case-control studies3,8,38 of patients referred for upper endoscopy have shown that the age of onset, male sex, hiatal hernia, and duration of GERD symptoms are associated with BE, the relationship between the severity of GERD symptoms and BE has been less understood, and reports give conflicting results. For example, Locke and colleagues39 found no association between the presence of BE and GERD symptom severity in a large community-based population referred for esophagogastroduodenoscopy, although Eloubeidi and Provenzale40 discovered in their study of US Armed Services veterans that patients with BE were more likely to report less severe symptoms (adjusted OR, 0.13; 95% CI, 0.04-0.42) than patients with clinical GERD and no BE.

Of interest, in our study, patients with severe atypical symptoms who were not medically treated had significantly increased odds of esophageal adenocarcinogenesis compared with those with no severe symptoms. This finding is important because patients who are being evaluated for symptoms such as hoarseness, throat-clearing, excess mucus, globus sensation, or cough may not have reflux of gastrointestinal contents considered to be a possible cause of their symptoms. As such, they do not undergo esophageal screening and are not treated with PPIs. This group of patients may represent those who have little or no heartburn or regurgitation and are thus referred for evaluation to an otolaryngologist rather than a gastroenterologist. This supposition is supported by the fact that the prevalences of adenocarcinogenesis in otolaryngology and gastroenterology patients were statistically similar in this study.

As a cross-sectional investigation, this study reports only correlations at a single time point among the variables of interest, and it cannot establish causation. Given this limitation, this study reflects the patient population encountered clinically, with a wide range of GERD symptom severity at various stages of esophageal injury. In addition, the analysis did not control for all known risk factors for BE and esophageal adenocarcinoma, such as obesity41 and the duration of GERD symptoms.3,8 Inclusion of these potential confounders may have revealed a different relationship between GERD symptom severity and esophageal adenocarcinogenesis. Although the individual questionnaires are validated, the symptom severity scale developed for this study was not. However, given the lack of a commonly accepted measurement of GERD symptom severity, it was necessary to create internal scales to achieve the aims of this investigation.

Despite these concerns, this study exhibited a high degree of content validity. For example, the rate of esophageal adenocarcinogenesis discovered in this screening population was consistent with that reported for the general GERD population by other authors.4247 Also, previously established risk factors for esophageal adenocarcinogenesis, such as age, sex, ethnicity, and presence of hiatal hernia, were confirmed and reproduced in this study. Although this study is the first, to our knowledge, to examine the relationship among the severity of GERD symptoms, PPI use, and esophageal adenocarcinogenesis, others have demonstrated an increased risk of esophageal adenocarcinogenesis for patients taking PPIs. Those studies attributed this finding to confounding by intent, whereby PPI use was simply a marker for the severity of the patient's GERD rather than a direct causative factor.39,48,49 Finally, consistent with the published literature, our results demonstrated a positive correlation between symptom severity and the presence of esophagitis.24,50,51

In summary, patients with medically controlled GERD symptoms who underwent primary screening endoscopy had significantly increased odds of BE, dysplasia, and cancer compared with medically treated patients with severe GERD symptoms. Also, patients with untreated severe atypical symptoms are at increased risk for esophageal adenocarcinogenesis. These findings highlight potential causes for the ineffectiveness of the current esophageal cancer screening paradigm and suggest that, rather than recommending BE screening only in patients with long-standing, poorly controlled GERD, patients with long-standing but well-controlled symptoms of typical or atypical GERD may be a better population to target. In addition, patients who present initially to the otolaryngology clinic with severe atypical-predominate symptoms should be strongly considered for primary screening endoscopy.

Larger-scale prospective studies, ideally having a validated measure of symptom severity, will enable us to determine the prevalence of BE stratified by symptom duration, antisecretory medication use, and current symptoms severity and lead to stronger guidance in recommendations for screening endoscopy.

Correspondence: Blair A. Jobe, MD, Division of Thoracic and Foregut Surgery, Universty of Pittsburgh, Shadyside Medical Building, 5200 Centre Ave, Ste 715, Pittsburgh, PA 15232 (jobeba@upmc.edu).

Accepted for Publication: June 7, 2010.

Author Contributions:Study concept and design: Wichienkuer, Awais, Morris, and Jobe. Acquisition of data: O’Rourke, Hunter, Morris, and Jobe. Analysis and interpretation of data: Nason, Wichienkuer, Schuchert, Luketich, O’Rourke, Morris, and Jobe. Drafting of the manuscript: Nason and Jobe. Critical revision of the manuscript for important intellectual content: Nason, Awais, Schuchert, Luketich, O’Rourke, Hunter, Morris, and Jobe. Statistical analysis: Nason, Wichienkuer, and Morris. Obtained funding: Hunter and Jobe. Administrative, technical, and material support: Nason, O’Rourke, Hunter, and Jobe. Study supervision: Hunter and Jobe.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Robert Anthony McHugh Research Fund for the Prevention and Early Detection of Esophageal Cancer, American Surgical Association Foundation Fellowship Award (Dr O’Rourke); and by National Institutes of Health (NIH) grants UL1 RR024140, K23 DK066165-01, and R21 DK081161 (Dr Jobe); by NIH grant K08 DK074397 (Dr O’Rourke); and by NIH grant U01 DK57132.

Previous Presentation: These data were presented at the 81st Annual Meeting of the Pacific Coast Surgical Association Meeting; February 14, 2010; Kapalua, Hawaii.

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PubMed   |  Link to Article
Fass R, Yalam JM, Camargo L, Johnson C, Garewal HS, Sampliner RE. Increased esophageal chemoreceptor sensitivity to acid in patients after successful reversal of Barrett's esophagus.  Dig Dis Sci. 1997;42(9):1853-1858
PubMed   |  Link to Article
Grade A, Pulliam G, Johnson C, Garewal H, Sampliner RE, Fass R. Reduced chemoreceptor sensitivity in patients with Barrett's esophagus may be related to age and not to the presence of Barrett's epithelium.  Am J Gastroenterol. 1997;92(11):2040-2043
PubMed
Niemantsverdriet EC, Timmer R, Breumelhof R, Smout AJ. The roles of excessive gastro-oesophageal reflux, disordered oesophageal motility and decreased mucosal sensitivity in the pathogenesis of Barrett's oesophagus.  Eur J Gastroenterol Hepatol. 1997;9(5):515-519
PubMed   |  Link to Article
Vela MF, Camacho-Lobato L, Srinivasan R, Tutuian R, Katz PO, Castell DO.  Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole.  Gastroenterology. 2001;120(7):1599-1606
PubMed   |  Link to Article
Gerson LB, Boparai V, Ullah N, Triadafilopoulos G. Oesophageal and gastric pH profiles in patients with gastro-oesophageal reflux disease and Barrett's oesophagus treated with proton pump inhibitors.  Aliment Pharmacol Ther. 2004;20(6):637-643
PubMed   |  Link to Article
Vallböhmer D, DeMeester SR, Peters JH,  et al.  Cdx-2 expression in squamous and metaplastic columnar epithelia of the esophagus.  Dis Esophagus. 2006;19(4):260-266
PubMed   |  Link to Article
Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression.  Gastroenterology. 1999;117(2):327-335
PubMed   |  Link to Article
Burnat G, Rau T, Elshimi E, Hahn EG, Konturek PC. Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett's esophageal mucosa and adenocarcinoma cell line.  Scand J Gastroenterol. 2007;42(12):1460-1465
PubMed   |  Link to Article
Kazumori H, Ishihara S, Rumi MAK, Kadowaki Y, Kinoshita Y. Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett's epithelium.  Gut. 2006;55(1):16-25
PubMed   |  Link to Article
Gerson LB, Edson R, Lavori PW, Triadafilopoulos G. Use of a simple symptom questionnaire to predict Barrett's esophagus in patients with symptoms of gastroesophageal reflux.  Am J Gastroenterol. 2001;96(7):2005-2012
PubMed   |  Link to Article
Locke GR, Zinsmeister AR, Talley NJ. Can symptoms predict endoscopic findings in GERD?  Gastrointest Endosc. 2003;58(5):661-670
PubMed   |  Link to Article
Eloubeidi MA, Provenzale D. Clinical and demographic predictors of Barrett's esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans.  J Clin Gastroenterol. 2001;33(4):306-309
PubMed   |  Link to Article
Lagergren J, Bergström R, Nyrén O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia.  Ann Intern Med. 1999;130(11):883-890
PubMed
Salem SB, Kushner Y, Marcus V, Mayrand S, Fallone CA, Barkun AN. The potential impact of contemporary developments in the management of patients with gastroesophageal reflux disease undergoing an initial gastroscopy.  Can J Gastroenterol. 2009;23(2):99-104
PubMed
Nandurkar S, Locke GR III, Murray JA,  et al.  Rates of endoscopy and endoscopic findings among people with frequent symptoms of gastroesophageal reflux in the community.  Am J Gastroenterol. 2005;100(7):1459-1465
PubMed   |  Link to Article
Dickman R, Mattek N, Holub J, Peters D, Fass R. Prevalence of upper gastrointestinal tract findings in patients with noncardiac chest pain versus those with gastroesophageal reflux disease (GERD)-related symptoms: results from a national endoscopic database.  Am J Gastroenterol. 2007;102(6):1173-1179
PubMed   |  Link to Article
Fan X, Snyder N. Prevalence of Barrett's esophagus in patients with or without GERD symptoms: role of race, age, and gender.  Dig Dis Sci. 2009;54(3):572-577
PubMed   |  Link to Article
Poelmans J, Feenstra L, Demedts I, Rutgeerts P, Tack J. The yield of upper gastrointestinal endoscopy in patients with suspected reflux-related chronic ear, nose, and throat symptoms.  Am J Gastroenterol. 2004;99(8):1419-1426
PubMed   |  Link to Article
Toruner M, Soykan I, Ensari A, Kuzu I, Yurdaydin C, Özden A. Barrett's esophagus: prevalence and its relationship with dyspeptic symptoms.  J Gastroenterol Hepatol. 2004;19(5):535-540
PubMed   |  Link to Article
Duan L, Wu AH, Sullivan-Halley J, Bernstein L. Antacid drug use and risk of esophageal and gastric adenocarcinomas in Los Angeles County.  Cancer Epidemiol Biomarkers Prev. 2009;18(2):526-533
PubMed   |  Link to Article
García Rodríguez LA, Lagergren J, Lindblad M. Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK.  Gut. 2006;55(11):1538-1544
PubMed   |  Link to Article
Okamoto K, Iwakiri R, Mori M,  et al.  Clinical symptoms in endoscopic reflux esophagitis: evaluation in 8031 adult subjects.  Dig Dis Sci. 2003;48(12):2237-2241
PubMed   |  Link to Article
Vakil NB, Traxler B, Levine D. Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment.  Clin Gastroenterol Hepatol. 2004;2(8):665-668
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Correlation between the number of severe symptoms and the presence of erosive esophagitis. The odds of esophagitis increase as the number of severe symptoms increases. This finding is expected because esophageal acidification is responsible for the sensation of heartburn, and effective acid suppression has been proven to reduce or eliminate symptoms and heal erosions.24

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Correlation between the number of gastroesophageal reflux disease (GERD), typical, and atypical severe symptoms and the presence of esophageal adenocarcinogenesis in patients. As the number of severe typical or atypical reflux symptoms increased, a significantly decreased risk was observed for the presence of Barrett esophagitis, dysplasia, and cancer. This finding was most pronounced in patients taking proton pump inhibitors (PPIs).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Correlation between the number of atypical severe symptoms and the presence of esophageal adenocarcinogenesis. Patients with an increasing number of severe atypical gastroesophageal reflux disease (GERD) symptoms who were not taking proton pump inhibitors (PPIs) composed the group most likely to have Barrett esophagitis, dysplasia, or cancer. This finding is surprising because most of these patients were recruited from otolaryngology clinics and rarely would have been targeted for screening endoscopy.

Tables

Table Graphic Jump LocationTable 1. Number of Study Patients by Indication for Screening Endoscopya
Table Graphic Jump LocationTable 2. Gastroesophageal Reflux Disease Symptom Questionnaires
Table Graphic Jump LocationTable 4. Sociodemographic Characteristics of Case and Control Individuals: Crude Odds for Esophageal Adenocarcinogenesis by Known and Potential Risk Factors
Table Graphic Jump LocationTable 5. Adjusted Risk of Esophageal Adenocarcinogenesis by GERD Symptom Severity and PPI Usea

References

Lagergren J, Bergström R, Lindgren A, Nyrén O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.  N Engl J Med. 1999;340(11):825-831
PubMed   |  Link to Article
Chow WH, Blot WJ, Vaughan TL,  et al.  Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia.  J Natl Cancer Inst. 1998;90(2):150-155
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Lieberman DA, Oehlke M, Helfand M.Gastroenterology Outcomes Research Group in Endoscopy.  Risk factors for Barrett's esophagus in community-based practice: GORGE consortium.  Am J Gastroenterol. 1997;92(8):1293-1297
PubMed
Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barrett's esophagus: a prospective study of 170 patients followed 4.8 years.  Am J Gastroenterol. 1997;92(2):212-215
PubMed
Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma.  Cancer Epidemiol Biomarkers Prev. 1995;4(2):85-92
PubMed
Baquet CR, Commiskey P, Mack K, Meltzer S, Mishra SI. Esophageal cancer epidemiology in blacks and whites: racial and gender disparities in incidence, mortality, survival rates and histology.  J Natl Med Assoc. 2005;97(11):1471-1478
PubMed
Dulai GS, Guha S, Kahn KL, Gornbein J, Weinstein WM. Preoperative prevalence of Barrett's esophagus in esophageal adenocarcinoma: a systematic review.  Gastroenterology. 2002;122(1):26-33
PubMed   |  Link to Article
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(1):27-31
PubMed
Sampliner RE.Practice Parameters Committee of the American College of Gastroenterology.  Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus.  Am J Gastroenterol. 2002;97(8):1888-1895
PubMed   |  Link to Article
Sampliner RE.Practice Parameters Committee of the American College of Gastroenterology.  Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus.  Am J Gastroenterol. 1998;93(7):1028-1032
PubMed   |  Link to Article
Wang KK, Sampliner RE.Practice Parameters Committee of the American College of Gastroenterology.  Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus.  Am J Gastroenterol. 2008;103(3):788-797
PubMed   |  Link to Article
Velanovich V. The development of the GERD-HRQL symptom severity instrument.  Dis Esophagus. 2007;20(2):130-134
PubMed   |  Link to Article
Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI).  J Voice. 2002;16(2):274-277
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Jobe BA, Hunter JG, Chang EY,  et al.  Office-based unsedated small-caliber endoscopy is equivalent to conventional sedated endoscopy in screening and surveillance for Barrett's esophagus: a randomized and blinded comparison.  Am J Gastroenterol. 2006;101(12):2693-2703
PubMed   |  Link to Article
Velanovich V. Comparison of generic (SF-36) vs. disease-specific (GERD-HRQL) quality-of-life scales for gastroesophageal reflux disease.  J Gastrointest Surg. 1998;2(2):141-145
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Velanovich V, Karmy-Jones R. Measuring gastroesophageal reflux disease: relationship between the Health-Related Quality of Life score and physiologic parameters.  Am Surg. 1998;64(7):649-653
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Wallner B, Sylvan A, Janunger K-G. Endoscopic assessment of the “Z-line” (squamocolumnar junction) appearance: reproducibility of the ZAP classification among endoscopists.  Gastrointest Endosc. 2002;55(1):65-69
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Reid BJ, Blount PL, Feng Z, Levine DS. Optimizing endoscopic biopsy detection of early cancers in Barrett's high-grade dysplasia.  Am J Gastroenterol. 2000;95(11):3089-3096
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Levine DS, Blount PL, Rudolph RE, Reid BJ. Safety of a systematic endoscopic biopsy protocol in patients with Barrett's esophagus.  Am J Gastroenterol. 2000;95(5):1152-1157
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Lewin KJ, Appleman HD. Tumors of the esophagus and stomach. In: Atlas of Tumor Pathology. Vol 18. Washington, DC: Armed Forces Institute of Pathology, American Registry of Pathology; 1996
Nasseri-Moghaddam S, Razjouyan H, Nouraei M,  et al.  Inter- and intra-observer variability of the Los Angeles classification: a reassessment [published correction appears in Arch Iran Med. 2007;10(3):429].  Arch Iran Med. 2007;10(1):48-53
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Lundell LR, Dent J, Bennett JR,  et al.  Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification.  Gut. 1999;45(2):172-180
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Hosmer DW, Lemeshow S. Applied Logistic Regression. Hoboken, NJ: John Wiley & Sons, Inc; 2000
Pilotto A, Franceschi M, Leandro G,  et al.  Clinical features of reflux esophagitis in older people: a study of 840 consecutive patients.  J Am Geriatr Soc. 2006;54(10):1537-1542
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Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States.  Cancer. 1998;83(10):2049-2053
PubMed   |  Link to Article
Brown LM, Devesa SS, Chow W-H. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age.  J Natl Cancer Inst. 2008;100(16):1184-1187
PubMed   |  Link to Article
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007.  CA Cancer J Clin. 2007;57(1):43-66
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Korkmaz M, Tarhan E, Unal H, Selcuk H, Yilmaz U, Ozluoglu L. Esophageal mucosal sensitivity: possible links with clinical presentations in patients with erosive esophagitis and laryngopharyngeal reflux.  Dig Dis Sci. 2007;52(2):451-456
PubMed   |  Link to Article
Fass R, Yalam JM, Camargo L, Johnson C, Garewal HS, Sampliner RE. Increased esophageal chemoreceptor sensitivity to acid in patients after successful reversal of Barrett's esophagus.  Dig Dis Sci. 1997;42(9):1853-1858
PubMed   |  Link to Article
Grade A, Pulliam G, Johnson C, Garewal H, Sampliner RE, Fass R. Reduced chemoreceptor sensitivity in patients with Barrett's esophagus may be related to age and not to the presence of Barrett's epithelium.  Am J Gastroenterol. 1997;92(11):2040-2043
PubMed
Niemantsverdriet EC, Timmer R, Breumelhof R, Smout AJ. The roles of excessive gastro-oesophageal reflux, disordered oesophageal motility and decreased mucosal sensitivity in the pathogenesis of Barrett's oesophagus.  Eur J Gastroenterol Hepatol. 1997;9(5):515-519
PubMed   |  Link to Article
Vela MF, Camacho-Lobato L, Srinivasan R, Tutuian R, Katz PO, Castell DO.  Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole.  Gastroenterology. 2001;120(7):1599-1606
PubMed   |  Link to Article
Gerson LB, Boparai V, Ullah N, Triadafilopoulos G. Oesophageal and gastric pH profiles in patients with gastro-oesophageal reflux disease and Barrett's oesophagus treated with proton pump inhibitors.  Aliment Pharmacol Ther. 2004;20(6):637-643
PubMed   |  Link to Article
Vallböhmer D, DeMeester SR, Peters JH,  et al.  Cdx-2 expression in squamous and metaplastic columnar epithelia of the esophagus.  Dis Esophagus. 2006;19(4):260-266
PubMed   |  Link to Article
Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression.  Gastroenterology. 1999;117(2):327-335
PubMed   |  Link to Article
Burnat G, Rau T, Elshimi E, Hahn EG, Konturek PC. Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett's esophageal mucosa and adenocarcinoma cell line.  Scand J Gastroenterol. 2007;42(12):1460-1465
PubMed   |  Link to Article
Kazumori H, Ishihara S, Rumi MAK, Kadowaki Y, Kinoshita Y. Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett's epithelium.  Gut. 2006;55(1):16-25
PubMed   |  Link to Article
Gerson LB, Edson R, Lavori PW, Triadafilopoulos G. Use of a simple symptom questionnaire to predict Barrett's esophagus in patients with symptoms of gastroesophageal reflux.  Am J Gastroenterol. 2001;96(7):2005-2012
PubMed   |  Link to Article
Locke GR, Zinsmeister AR, Talley NJ. Can symptoms predict endoscopic findings in GERD?  Gastrointest Endosc. 2003;58(5):661-670
PubMed   |  Link to Article
Eloubeidi MA, Provenzale D. Clinical and demographic predictors of Barrett's esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans.  J Clin Gastroenterol. 2001;33(4):306-309
PubMed   |  Link to Article
Lagergren J, Bergström R, Nyrén O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia.  Ann Intern Med. 1999;130(11):883-890
PubMed
Salem SB, Kushner Y, Marcus V, Mayrand S, Fallone CA, Barkun AN. The potential impact of contemporary developments in the management of patients with gastroesophageal reflux disease undergoing an initial gastroscopy.  Can J Gastroenterol. 2009;23(2):99-104
PubMed
Nandurkar S, Locke GR III, Murray JA,  et al.  Rates of endoscopy and endoscopic findings among people with frequent symptoms of gastroesophageal reflux in the community.  Am J Gastroenterol. 2005;100(7):1459-1465
PubMed   |  Link to Article
Dickman R, Mattek N, Holub J, Peters D, Fass R. Prevalence of upper gastrointestinal tract findings in patients with noncardiac chest pain versus those with gastroesophageal reflux disease (GERD)-related symptoms: results from a national endoscopic database.  Am J Gastroenterol. 2007;102(6):1173-1179
PubMed   |  Link to Article
Fan X, Snyder N. Prevalence of Barrett's esophagus in patients with or without GERD symptoms: role of race, age, and gender.  Dig Dis Sci. 2009;54(3):572-577
PubMed   |  Link to Article
Poelmans J, Feenstra L, Demedts I, Rutgeerts P, Tack J. The yield of upper gastrointestinal endoscopy in patients with suspected reflux-related chronic ear, nose, and throat symptoms.  Am J Gastroenterol. 2004;99(8):1419-1426
PubMed   |  Link to Article
Toruner M, Soykan I, Ensari A, Kuzu I, Yurdaydin C, Özden A. Barrett's esophagus: prevalence and its relationship with dyspeptic symptoms.  J Gastroenterol Hepatol. 2004;19(5):535-540
PubMed   |  Link to Article
Duan L, Wu AH, Sullivan-Halley J, Bernstein L. Antacid drug use and risk of esophageal and gastric adenocarcinomas in Los Angeles County.  Cancer Epidemiol Biomarkers Prev. 2009;18(2):526-533
PubMed   |  Link to Article
García Rodríguez LA, Lagergren J, Lindblad M. Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK.  Gut. 2006;55(11):1538-1544
PubMed   |  Link to Article
Okamoto K, Iwakiri R, Mori M,  et al.  Clinical symptoms in endoscopic reflux esophagitis: evaluation in 8031 adult subjects.  Dig Dis Sci. 2003;48(12):2237-2241
PubMed   |  Link to Article
Vakil NB, Traxler B, Levine D. Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment.  Clin Gastroenterol Hepatol. 2004;2(8):665-668
PubMed   |  Link to Article

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Proton Pump Inhibitors And Esophageal Adenocarcinoma
Posted on September 27, 2011
Paul J. Rosch, MD
Clinical Professor of Medicine and Psychiatry New York Medical College
Conflict of Interest: None Declared
The finding by Nason et al1 that patients who took more proton pump inhibitors (PPIs) to prevent or treat GERD had higher rates of esophageal adenocarcinoma, supports the view that in addition to osteoporotic fractures and Clostridium difficile infections, protracted use of these drugs could also increase risk of cancer.2,3 In addition, the unexplained dramatic rise in this previously uncommon malignancy mirrors the increased use of PPIs. One possibility is that pancreatic enzymes, which would normally be inactivated by hydrochloric acid, are now able to cause esophageal irritation and dysplasia. As also previously suggested, "this may not develop from direct superficial injury but rather from stimulation of esophageal cytokines that attract inflammatory cells to submucosal tissues."2 GERD patients usually show no mucosal damage on endoscopy, and in animal studies, no gross or microscopic evidence of inflammation in the esophageal mucosa was seen following exposure to acute stress, hydrochloric acid, ethanol, aspirin, or prednisolone.4 The earliest changes seen much later were dilated esophageal epithelial intercellular spaces that were not prevented by pretreatment with esomeprazole (Nexium), suggesting that they were not due to acid reflux.5
While PPI's were originally used for only 4-6 weeks to treat GERD, many patients take them for much longer, especially those without GERD in whom biopsies show dysplastic changes consistent with Barrett's esophagus. These and others may be prescribed PPIs perpetually, despite the lack of evidence that this prevents or delays the development of esophageal adenocarcinoma. Surgery for GERD similarly does not reduce risk for this malignancy, further highlighting the need for more long-term studies.
References: 1. Nason KS, Wichienkuer PP, Awais O, et al. Gastroesophageal reflux disease symptom severity, proton pump inhibitor use, and esophageal carcinogenesis. Arch Surg. 2011; 146 (7): 851-858. 2. Rosch PJ. Could Proton Pump Inhibitors Cause Cancer? Arch Intern Med. 2010; 170(19):1775-1776. 3. Poulsen AH, Christensen S, McLaughlin JK, et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer. 2009; 100(9):1503-1507. 4. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009;137(5):1776-1784. 5. Zhang DH, Zhou LY, Dong XY, et al. Factors influencing intercellular spaces in the rat esophageal epithelium. World J Gastroenterol. 2010;16(9):1063-1069

Conflict of Interest: None declared
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