Phenotypes of Gastroesophageal Reflux Disease: Where Rome, Lyon, and Montreal Meet

Abstract

Gastroesophageal reflux disease (GERD) is now one of the most common diagnoses made in a gastroenterology practice. From a conventional pathophysiological perspective, GERD is conceptualized as incompetence of the antireflux barrier at the esophagogastric junction; the more severe that incompetence, the worse the disease. However, it is increasingly clear that many presentations of GERD represent distinct phenotypes with unique predisposing cofactors and pathophysiology outside of this paradigm. Three major consensus initiatives have grappled with this dilemma (the Montreal Consensus, The Rome Foundation, and the Lyon Consensus), each from a different perspective. Montreal struggled to define the disease, Rome sought to characterize its functional attributes, while Lyon examined its physiological attributes. Here, we merge the 3 perspectives, developing the concept that what has come to be known as GERD is actually a family of syndromes with a complex matrix of contributing pathophysiology. A corollary to this is that the concept of one size fits all to therapeutics does not apply, and that although escalating treatment with proton pump inhibitors (PPIs) may be pertinent to healing esophagitis, its applicability beyond that is highly questionable. Similarly, failing to recognize the modulating effects of anxiety, hypervigilance, and visceral and central hypersensitivity on symptom severity has greatly oversimplified the problem. That oversimplification has led to excessive use of PPIs for everything captured under the GERD umbrella and shown a broad spectrum of syndromes less amenable to PPI therapy in any dose. It is with this in mind that we delineate this precision medicine concept of GERD.

Keywords: Barrett's Esophagus; Esophagitis; Esophagus; Gastroesophageal Reflux Disease; Hiatus Hernia; Proton Pump Inhibitors.

Figure 1.

Conventional model of GERD pathogenesis detailing the progressive degradation of the EGJ as a barrier to gastroesophageal reflux. Coupled with this is the formation of a sliding hiatal hernia which both exacerbates that degradation and introduces the additional elements of supine reflux and prolonged esophageal acid clearance. More than anything else, it is these latter abnormalities that greatly exacerbate esophageal acid exposure leading to high-grade esophagitis. Conceptually, the blue boxes represent normal function, the green boxes detail the pathophysiological abnormalities leading to reflux symptoms and the red boxes detail the pathophysiological abnormalities leading to the mucosal pathology of GERD: high-grade esophagitis, strictures, etc.

Figure 2.

The diminishing efficacy of PPIs going from treatment for cardinal GERD symptoms (panel A), to atypical GERD symptoms (Panel B), to extra-esophageal syndromes (panel C). Where possible, treatment groups are subdivided by the presence or absence of esophagitis and, in the cases of panel B whether or not there was accompanying abnormal endoscopy or pH-metry. In panel C, although treated with high-dose PPIs, the participants were characterized as not having frequent heartburn on the basis of symptom assessment. NNT= number needed to treat to derive benefit from PPI treatment.

Figure 3.

Conceptual matrix of contributing physiology to the major GERD syndromes. For each syndrome, the length of the colored bars are estimates of the dominance played by each factor in its pathogenesis. Low-grade and high-grade esophagitis epitomize the conventional view of GERD pathophysiology as detailed in Figure 1, being mainly an imbalance between gastroesophageal reflux events and esophageal mucosal clearance and largely reflective of the increasing dominance of hiatal hernia with worsening disease. Long-segment Barrett’s has similar pathophysiology with additional contributions of bile reflux and a genetic predisposition (non-esophageal factors). At the other extreme the pathogenesis of functional heartburn and reflux hypersensitivity are dominated by visceral hypersensitivity and non-esophageal factors. In each case, the syndromes responsiveness to PPI therapy (Figure 2) is proportional to the dominance of the red bars (acid reflux).