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

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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.

Section snippets

Syndromes Defined by Heartburn and/or Reflux Esophagitis

Recognizing the complexity of the GERD universe, the Montreal Definition of GERD introduced an umbrella definition stipulating that GERD could be consequent from gastric reflux causing either troublesome symptoms or complications.1 Under that umbrella definition were esophageal syndromes including reflux esophagitis and the typical reflux syndrome. Focus first on reflux esophagitis characterized in the Los Angeles (LA) classification as A, B, C, or D by the severity of endoscopically defined

Barrett’s Esophagus

A considerable body of data supports the conclusion that BE results from chronic excessive exposure to gastroesophageal refluxate: (1) markedly increased esophageal acid exposure as on pH-metry; (2) high-grade erosive esophagitis often precedes the development of BE; and (3) shared associations of BE and high-grade esophagitis with LES hypotension, hiatus hernia, ineffective esophageal motility, and central obesity.22,23 The association with central obesity potentially implicates the systemic

Regurgitation-Dominant Reflux Disease

Regurgitation-dominant disease is a distinct GERD phenotype because of its reduced response to therapy compared with heartburn-dominant disease.38,39 This makes intuitive sense because the mechanisms by which regurgitation occurs are somewhat distinct. Specifically, gross failure of the EGJ with or without a hiatal hernia facilitates flow of gastric content into the esophagus of sufficient volume such that either fluid movement is perceived within the esophagus or the refluxate gains entry to

Extraesophageal Manifestations of Gastroesophageal Reflux Disease

Management of putative extraesophageal manifestations of GERD is challenging given the protean manifestations often proposed. Critical questions that need to be addressed with these patients are as follows: (1) Does the patient have abnormal reflux and how can that be detected? (2) Is reflux causing the extraesophageal symptom? (3) By what mechanism is this occurring? Unfortunately, it is much easier to formulate these questions than it is to answer them.

Conventional physiological testing for

Chest Pain

GERD-related chest pain represents another phenotype in which establishing causality is often tenuous and by association. This has several explanations. Not least among them is the differential diagnosis of chest pain, which is broad, with reflux being the ultimate cause in only a minority.64 When present, the clinical characteristics of esophageal chest pain can be indistinguishable from those in coronary artery disease. The best and often difficult means of establishing causation is by

Conclusions

Many terms in medicine that are singularly meant to reflect a specific process, in fact, comprise multiple facets of variable proportions with interactions among themselves and with other distinct pathophysiologies. We have proposed that GERD is one of these terms. Figure 3 attempts to conceptualize this for some of the GERD syndromes that we have discussed. Evidently GERD is a family of syndromes with a complex matrix of contributing pathophysiology. Consequently, the concept of one size fits

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    Conflicts of interest These authors disclose the following: John E. Pandolfino has consulted for Medtronic, Sandhill Scientific, and Ethicon, has received grants from Medtronic, has served as a speaker for Medtronic, Sandhill Scientific, Takeda, and Ethicon, and has received stock options from Crospon; and Peter J. Kahrilas has consulted for Ironwood Pharmaceuticals and Bayer. The remaining author discloses no conflicts.

    Funding Supported by R01 DK092217 from the US Public Health Service (P.J.K. and J.E.P.).

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