CHAPTER 16 Helicobacter pylori and Gastroesophageal Reflux Disease Maria Pina Dore1 and David Y. Graham2 1 Instituto di Clinica Medica, University of Sassari, Italy, and Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA 2 Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA Key points • Helicobacter pylori infections and gastroesophageal reflux disease are both common and thus frequently occur together. • Helicobacter pylori does not cause gastroesophageal reflux disease directly or indirectly (i.e. it has no effect on the anti-reflux barrier). • Helicobacter pylori infection does not protect against gastroesophageal reflux disease, Barrett’s esophagus or adenocarcinoma of the esophagus. • Hypochlorhydria or achlorhydria associated with atrophic gastritis prevents symptom- atic reflux and gastroesophageal reflux disease sequelae such as erosive esophagitis, Barrett’s esophagus, and adenocarcinoma of the esophagus. It is also strongly associated with the risk of gastric cancer. • Proton pump inhibitor therapy in patients with Helicobacter pylori gastritis can result in acceleration of corpus gastritis and thus can theoretically increase the risk of gastric cancer. • Helicobacter pylori eradication does not significantly affect anti-secretory therapy for gastroesophageal reflux disease. • Patients considered for long-term proton pump inhibitor therapy should be tested for Helicobacter pylori and if present, the infection should be eradicated. Potential pitfalls • Failure to treat an Helicobacter pylori infection because of fear that doing so would increase the patient’s risk for gastroesophageal reflux disease and adenocarcinoma of the esophagus. • Failure to test for Helicobacter pylori in a patient in whom long-term proton pump inhibitor therapy is planned. • Failure to consider transient proton pump inhibitor-induced acid rebound for development of gastroesophageal reflux disease-like symptoms after discontinuing proton pump inhibitors given for a non-gastroesophageal reflux disease indication such as treatment to eradicate Helicobacter pylori. Practical Manual of Gastroesophageal Reflux Disease, First Edition. Edited by Marcelo F. Vela, Joel E. Richter and John E. Pandolfino. © 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd. 267 (c) 2014 John Wiley & Sons, Inc. All Rights Reserved. 268 Part 2: Gastroesophageal Reflux Disease Introduction Prior to the identification of Helicobacter pylori, peptic ulcer disease and gastric cancer were both known to be closely associated with the presence of gastritis; the discovery of H. pylori provided the link between them. Because H. pylori is a bacterial infection, it was thought likely that cure of the infection might result in prevention of gastric cancer and cure of the heretofore incurable peptic ulcer disease. Helicobacter pylori is now accepted as etiologically related to gastritis and the gastritis-associated diseases: duodenal ulcer, gastric ulcer and gastric cancer, both adenocarcinoma and primary gastric B-cell lymphoma. H. pylori infections are typically acquired in childhood with clinical disease occurring typically after a long latent period during which gastric damage occurs silently. The risk of a clinical outcome of the infection is approxi- mately 20% [1]. Different outcomes are associated with different patterns of gastritis: gastric ulcer and gastric cancer with atrophic pangastritis and low acid secretion (hypochlorhydria or achlorhydria), and duodenal ulcer with corpus-sparing gastritis (antral predominant gastritis) and high acid secretion. Because different outcomes are linked to markedly different pat- terns of gastritis, duodenal ulcer disease and gastric ulcer occur at entirely different ends of the spectrum of gastritis and it can be said that duodenal ulcer “protects” against gastric cancer and vice versa. Protection in this context means “inversely related to” and not any actual involvement (i.e. no one would fear that curing a duodenal ulcer would increase the risk of gastric cancer). This possible misuse of the concept of H. pylori infections “protecting” against other diseases will be discussed below. Within a decade of the culture of H. pylori, it was discovered how to reli- ably eradicate H. pylori infections which was also shown to result in the healing of the underlying gastritis. The hypothesis that cure of H. pylori infections would also cure peptic ulcer disease was also tested and proven to be correct. However, following H. pylori eradication, some patients were reported to have developed gastroesophageal reflux disease (GERD) [2,3]. At the time, the appearance of GERD following the cure of H. pylori-related duodenal ulcers was not expected although possibly it should have been. For example, by the mid-20th century it was well known that there was an association between the presence of duodenal ulcer and GERD and this find- ing was repeatedly confirmed in the West [4–13] and in Japan [14]. During this same time period, it was noted that the incidence of esophageal adeno- carcinoma appeared to be increasing. The fact that H. pylori caused inflam- mation, ulcers and cancer in the stomach led to questions about what, if any, was the role of H. pylori in GERD and in esophageal adenocarcinoma. This chapter will discuss whether there is a relationship between H. pylori and the frequency and severity of GERD as well as the sequelae of GERD (c) 2014 John Wiley & Sons, Inc. All Rights Reserved. Chapter 16: Helicobacter pylori and Gastroesophageal Reflux Disease 269 in different populations, attempt to provide an understanding of the path- ophysiology involved, and explain the role of H. pylori, if any, in “protection” against GERD and its sequelae such as Barrett’s esophagus and esophageal adenocarcinoma. Gastroesophageal reflux disease and Helicobacter pylori in the pre-Helicobacter pylori era Interest in GERD became prominent in the late 20th century. However, GERD was not a new problem but rather it became a disease du jour [15–17], as dyspepsia had long been recognized as particularly common in America [18] and heartburn, water-brash and pyrosis were all prevalent problems [19]. Antacids were widely and commonly used throughout the 19th and most of the 20th centuries. For example, in the 1970s over- the-counter antacids were used by at least half of US adults, with approx- imately a quarter of adults taking at least two doses per month and at least 5% of adults using antacids daily [20]. The introduction of H2 receptor antagonists (H2RAs) in the mid-1970s produced the first simple and effec- tive relief of ulcer pain and reliable ulcer healing and it was widely believed that ulcers were finally cured. Clinicians and third-party payers were, however, surprised to find that many patients with duodenal ulcer disease continued to use H2RAs despite healing of their ulcers. Despite the use of fiberoptic endoscopy to identify ulcers and confirm healing, GERD continued to be largely ignored. Evidence that GERD was given short shrift in the major gastroenterology textbooks can be easily found; for example, the major textbooks of gastrointestinal disease in the 1970s in the US did not recognize that GERD was a common manifestation of Zollinger–Ellison syndrome. The initial focus on GERD and how to study it was in part related to an interest manifested by pharmaceutical companies who saw GERD as a pos- sible way to expand their markets for proton pump inhibitors (PPIs) and to differentiate PPIs from H2RAs which dominated the market at that time. As noted above, over-the-counter antacid use among apparently other- wise healthy individuals was extremely common throughout this period but it was unclear why. In the early 1980s we studied why apparently healthy individuals were frequent users of antacids. We found that the pri- mary reason was GERD [20]. As interest in GERD increased, the gastroen- terology community found that the lessons learned in the study of peptic ulcer disease were not directly transferable to GERD. For example, as noted by our forefathers, peptic ulcer was an episodic condition whereas GERD was a chronic disease that required continuous therapy and that therapy was in large part symptomatic and not curative. (c) 2014 John Wiley & Sons, Inc. All Rights Reserved. 270 Part 2: Gastroesophageal Reflux Disease A Symptoms, complaints, complications B Symptoms and complaints Symptoms without complaints C Figure 16.1 The “iceberg” represents the populations of patients with gastroesophageal reflux [22]. The largest group are those with mild disease who self-medicate with over-the-counter drugs and rarely if ever visit doctors because of their symptoms. The smallest group are those who visit gastroenterologists because of severe disease requiring continuous high-dose therapy. A represents those with complications (e.g. symptoms and complications), B those with symptoms who seek medical care (e.g. symptoms and complaints), C those with symptoms who self-medicate and do not seek medical care (e.g. symptoms and no complaints). Adapted from Graham [16] with permission from Blackwell Publishing. In those days, most patients with GERD did not seek medical attention but rather used over-the counter drugs [20,21]. In contrast, those entering clinical trials were typically from the small subgroup with complicated ero- sive disease and as such, the results did not necessarily reflect the needs or responses of the average patient [22,23]. We proposed that the population