Summary by Daniel Frenkel MD
Please also see the clinical vignette presented before grand rounds on the 1st of April.
In his grand rounds lecture on April 1st 2009, Dr. Fritz Francois enlightened us to some novel aspects of gastroesophageal reflux disease (GERD). Despite simple and effective treatment approaches such as acid suppression medication, Dr. Francois explored “why the issues are still burning?” by discussing the changing face of GERD, the connection to obesity, and it’s association with Helicobacter Pylori.
What is GERD? As Dr. Francois explains, it is traditionally the reflux of gastric contents into the esophagus leading to symptoms and/or mucosal damage. However, it took a lot of debate from leading experts to arrive at a globally accepted definition for “GERD” and interestingly, some languages don’t have words to describe heartburn or refux, which has provided difficulty in identifying this disorder. From observational studies, GERD appears to be most common in North America with an increase in prevalence from 12% to >20% over the past decade. There haven’t been any studies looking at GERD or its complications in Africa, however, Dr. Francois points out that looking at racial and geographic differences may help elucidate some of the mystery of GERD.
The concern for the development of GERD is progression to adenocarcinoma since data from the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program has shown a 5-fold increase in esophageal adenocarcinoma over the past 25 years while squamous cell carcinoma is on the decline. An proposed paradigm for progression is movement from: normal epithelium à esophagitis à Barrett’s à Dysplasia à adenocarcinoma. According to cross-sectional surveys, there are no significant differences in weekly GERD symptoms among races, however, whites have a significant increase in esophagitis (2 times more likely) and Barrett’s esophagus (3-5 times more likely). Given this racial/ethnic discrepancy in reflux-associated pathology one is left asking is this paradigm correct and what predicts progression to esophagitis and beyond? Studies have identified several independent predictors of progression in GERD: male gender (RR4.3), smoking (RR 1.2), acid suppression (RR 0.54), and interestingly metabolic syndrome (RR 1.75). Therefore energy homeostasis shoud be evaluated as part of the pathophysiology of GERD.
Obesity is increasing throughout the world in both the developing and developed world. Increases in both BMI and abdominal diameter have been shown to correlate with increases in GERD, regardless of gender. In a meta-analysis, it was estimated that a BMI>25 was associated with GERD (OR 1.43), esophagitis (OR 1.76), Barrett’s esophagus (OR 2.46), and adenocarcinoma (OR 1.52). How can one connect obesity to GERD? Mechanisms include effects on esophageal motility, lower esophageal sphincter pressure, increased hiatal hernias, increased intragastric pressure, and physiologic factors.
The physiologic mechanism of swallowing involves decreased pressure of the lower esophageal sphincter at the initiation of the swallow, ahead of the transit of the bolus. Although this can expose the esophagus to gastric contents and reduce the pH, it is short-lived (less than 5 seconds) and the contents are cleared by the physiologic swallow mechanism. Transient lower esophageal sphincter relaxations (TLESRs), which is the physiologic mechanism of belching, are not initiated by a swallow mechanism, can last upwards of 30 seconds, and as a result gives greater occasion for the esophagus to be exposed to gastric contents for a longer period of time until the next swallow mechanism clears the esophagus. Studies have shown that increased BMI and waist circumference results in an increased number of TLESRs.
In addition to physical effects on the LES, adipose tissue is metabolically active and releases numerous molecules including leptin which may have a role in GERD. Leptin’s role is to decrease food intake while it’s counterpart Ghrelin, which is secreted by the stomach, promotes food intake. Grehlin significantly fluctuates with each meal while leptin although fluctuates with meals has a gradual increase throughout the day. Leptin receptors are present throughout the GI tract and in the stomach it has been shown to reduce acid secretion. However, leptin has been shown to induce proliferation of two esophageal adenocarcinoma lines. Could leptin be the link to the progression of GERD to adenocarcinoma, i.e. more receptors in the esophagus versus more leptin secreted? Dr. Francois presented some of his own data that demonstrated the number of leptin receptors was the same in the esophagus regardless of it’s mucosal state, however, in patient’s with Barrett’s there is an increase in leptin production in the stomach fundus (for every 2 fold increase in leptin there was a 3.4 fold increase in Barrett’s). Leptin may provide an alternative metabolic mechanism for the pathophysiology of GERD.
The final topic discussed by Dr. Francois is the role of H. Pylori in GERD. Studies have linked H. Pylori eradication with the development of esophagitis and those patient were also found to have weight gain. There are conflicting results on whether H. Pylori has any association with obesity but some studies have shown that patients with H. Pylori have higher levels of leptin and lower levels of grehlin. Dr. Francois’ own research, as well as other studies, have demonstrated that the eradication of H. Pylori reversed the levels of these adipokines and is associated with an increase in BMI.
Despite what we do know regarding GERD and its treatment, there are still questions that remain regarding its pathophysiology. Dr. Francois has highlighted a pathophysiologic difference amongst races as well as some novel associations between the eradication of H. Pylori, obesity, and GERD. These interesting connections may lead to a clearer understanding of the progression of GERD to adenocarcinoma and new targets for therapy.
Daniel Frenkel is a third year resident in Internal Medicine at NYU Medical Center