Gastroesophageal Reflux Disease Symptom Severity, Proton Pump Inhibitor Use, and Esophageal Carcinogenesis | Esophageal Disease | JAMA Surgery | JAMA Network
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    1 Comment for this article
    Proton Pump Inhibitors And Esophageal Adenocarcinoma
    Paul J. Rosch, MD | Clinical Professor of Medicine and Psychiatry New York Medical College
    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
    Original Article
    July 2011

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

    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

    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.