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 while 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, visceral and central hypersensitivity on symptom severity has greatly over-simplified the problem. That over-simplification has led to excessive use of PPIs for everything captured under the GERD umbrella and revealed 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.

For more than half a century, gastroesophageal reflux disease (GERD) has been viewed as a continuum of afflictions based on the degree of lower esophageal sphincter (LES) dysfunction. With minor dysfunction, perhaps a result of transient LES relaxations (TLESRs), patients develop symptomatic, but non-erosive gastroesophageal reflux disease (NERD). In contrast, those with severe dysfunction manifest by marked LES hypotonia, develop erosive esophagitis and/or Barrett's esophagus (BE). Pathophysiologically, progression along this continuum represents a deterioration of LES function with additional contributing factors such as hiatus hernia and ineffective esophageal motility. However, it is becoming clear that many presentations of GERD represent distinct phenotypes with unique predisposing cofactors and pathophysiology outside of this paradigm. For example, patients with reflux hypersensitivity may have normal LES function yet abnormalities of peripheral and/or central sensory processing. In contrast, patients with BE may have a relative esophageal hyposensitivity along with being Caucasian, male, and obese. Furthermore, long-term data suggest that patients with a NERD phenotype exhibit only minimal progression to erosive esophagitis and BE. Given this heterogeneity of what falls under the GERD umbrella it is reasonable that clinical management should target the unique pathophysiological features of each syndrome; one size does not fit all. Not every patient benefits from increased potency of acid inhibition and many are potentially harmed by surgical intervention. It is from that perspective that we will attempt to apply “precision medicine” to GERD. Table 1 lists some of the major GERD syndromes commonly faced in a GI referral practice along with some important differentiating clinical features. The list is not intended to be comprehensive, but rather illustrative of major GERD phenotypes with unique pathophysiological and management considerations as we have come to understand them. In discussing each of them, we will emphasize their unique features and challenges.

Table 1. Major GERD phenotypes along with clinically important modulating clinical considerations

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 mucosal breaks in the distal esophagus [2]. Highgrade esophagitis (LA C,D) most commonly affects white men with central adiposity [3] and its pathophysiology centers on gross incompetence of the esophagogastric junction (EGJ) manifest by a hypotensive LES, hiatal hernia, supine reflux, and poor acid clearance (Figure 1). The combination of supine reflux, poor acid clearance, and acidity from the acid pocket migrating across the squamocolumnar junction lead to greatly prolonged distal esophageal acid exposure. This is particularly problematic during sleep when there is a paucity of primary peristalsis, absent salivation, and relative hyposensitivity to esophageal acid exposure. Furthermore, the underlying irreversibility of these physiological defects mandates open-ended antisecretory therapy unless addressed with alternative strategies such as profound weight loss or antireflux surgery. Reflux-symptom association to heartburn is also greater in high-grade esophagitis compared to NERD even though they exhibit a relative insensitivity to esophageal acid exposure when tested by esophageal acid infusion [4]. Consistent with that, 11-47% of erosive esophagitis patients report neither heartburn nor regurgitation with older age, male gender and increased body mass index being risk factors for asymptomatic disease [5].

The pathophysiology of low-grade (LA grades A and B) esophagitis involves less severe impairment of the EGJ than does high-grade disease (Figure 1). Indeed, the finding of LA A esophagitis has been de-emphasized in recent literature because of the low likelihood of progression and possibility of spontaneous remission. In a 5-year follow-up study, one third of LA A patients were without erosive disease and not taking proton pump inhibitors (PPIs) while 38% remained at grade A without progression [6]. In another study of 109 esophagitis patients, none with low-grade esophagitis progressed to BE at follow-up [7]. Further analysis has suggested a more robust response to PPIs (>90%) than with higher grades of esophagitis. This is consistent with the findings of lower acid exposure times and more intact antireflux physiology in LA A patients, e.g. absence of hiatus hernia and relatively intact flap valve appearance [8]. Additional data de-emphasizing the significance of LA A esophagitis is the finding of this lesion in approximately 6% of asymptomatic individuals [9]. Considering these issues, the Lyon Consensus opined that LA A esophagitis was not definitive evidence of GERD [10]. That group also questioned the significance of LA B esophagitis because of interobserver variability in its diagnosis but in our opinion, when properly classified, LA B esophagitis is definitive evidence of GERD.

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

Moving beyond esophagitis to the domain of symptomatically defined disease, much attention has focused on clarifying just what constitutes the “typical reflux syndrome” in the Montreal Definition. Initially, this was defined as troublesome heartburn and/or regurgitation with the recognition that what is troublesome for one may not be troublesome for another and that neither symptom is specific for GERD. This is particularly true for the symptom of heartburn and subsequent analysis, culminating in the Rome IV consensus, has subdivided NERD into “true NERD”, reflux hypersensitivity, and functional heartburn based on a dichotomous normal/abnormal interpretation of esophageal acid exposure and reflux-symptom correlation from pH-metry or Impedance/pH-metry studies [11]. The underlying premise is that the physiological determinants of heartburn only partially overlap with the physiological determinants of reflux esophagitis. In particular, upright reflux and heightened esophageal sensitivity dominate with heartburn while supine reflux and prolonged esophageal acid exposure dominate in reflux esophagitis. NERD patients also have a different demographic profile than esophagitis patients with no predisposition based on race, central adiposity, or male gender. In fact, women have been shown to have greater esophageal afferent sensitivity than men, presumably predisposing them to the NERD phenotypes.

The physiological determinants of enhanced esophageal sensitivity have been extensively investigated focusing both on the structural integrity of the mucosa and the neural pathways mediating pain. With respect to mucosal integrity, a multitude of abnormalities have been reported in NERD phenotypes including dilated intercellular spaces detected by either light or electron microscopy, increased intrapapillary capillary loops observed with confocal microscopy or magnification endoscopy, and lower mucosal impedance detectable either during ambulatory reflux testing or with probes designed to be passed orally or through an endoscope [12, 13]. The underlying hypothesis is that the increased mucosal permeability facilitates exposure of subepithelial sensory nerves to refluxate. It has also been reported that the sensory nerves themselves are more superficial and therefore more vulnerable to chemostimulation, particularly in the proximal esophagus [14].

On the neural side, patients with NERD phenotypes can develop symptoms not only from esophageal acid exposure, but also by enhanced pain perception through both peripheral and central mechanisms. These abnormalities are most profound with functional heartburn in which case there is no demonstrable abnormality in esophageal acid exposure and least evident when NERD is defined on the basis of abnormal esophageal acid exposure, termed “true NERD” in Rome IV. Somewhere in the middle is reflux hypersensitivity, defined by reflux-induced typical reflux symptoms despite normal esophageal acid exposure. Consequently, reflux hypersensitivity is thought to be heavily dependent on peripheral and central sensitization. This may relate to lower stimulation thresholds for TRPV1 receptors in the esophageal mucosa, receptors that are also sensitive to heat and capsaicin, common symptom triggers in reflux hypersensitivity [15]. Acid sensing ion channel 3 sensitization has also been reported in such patients [15]. Other investigations suggest alterations in central pain perception with accelerated and enhanced pain transmission at the spinal level and attenuated descending inhibition [16]. Accordingly, stress and anxiety augment the central response to esophageal stimuli [17, 18]. Illustrative of this is a report of acoustic stress causing more rapid perception and increased symptom intensity during esophageal acid perfusion [19]. Experiments using functional brain MRI have also demonstrated enhanced pain center activity in patients with baseline neuroticism while undergoing esophageal distention [20].

The above observations go a long way in explaining the variability and controversy surrounding treatment efficacy in NERD patients compared to esophagitis patients. In a metaanalysis of studies comparing NERD and esophagitis, when NERD was defined by both endoscopy and positive pH-metry (as opposed to only endoscopy and symptom assessment), the response rate to PPIs was similar for both groups [21]. The implication is that many NERD patients included in treatment studies not vetted by pH-metry had hypersensitive esophagus or functional heartburn making them less responsive to antisecretory therapy. The correlate is that, given the predisposition to esophageal pain sensitization, therapies targeting heartburn perception may benefit some NERD patients. These may include tricyclic antidepressants, selective serotonin receptor inhibitors, or gabapentin as well as non-pharmacologic therapies such as cognitive behavioral therapy, acupuncture, meditation and exercise. Consequently, both pathophysiologically and therapeutically, NERD patients can share features of low-grade esophagitis, reflux hypersensitivity, or functional heartburn depending on how NERD is 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 cytokines accompanying metabolic syndrome in its pathogenesis and would be additive to the deleterious effect of increased intraabdominal pressure [24]. BE patients are overwhelmingly more likely to be Caucasian men suggesting genetic susceptibility and/or hormonal protection [25,26]. As with high-grade esophagitis, BE patients are relatively hyposensitive to esophageal acid infusion compared to other GERD phenotypes. The clinical correlate of this is the paucity or absence of reflux symptoms reported by many BE patients and about 50% of esophageal adenocarcinoma (EAC) patients [27, 28].

At a more basic level is the question of why the undifferentiated esophageal stem cell is rerouted to the columnar morphology unique to BE. This is likely attributable to a series of epigenetic changes consequent from prolonged exposure to acid and bile refluxate [29]. Genetic changes found in Barrett's epithelium include abnormalities of p53, p16, hedgehog, and CDX2 [30]. Of interest, persistence of CDX2, a marker of intestinal differentiation, has been demonstrated in neosquamous mucosa after BE ablation [31]. Transdifferentiation between mature squamous cells and BE has also been proposed based on the demonstration of bile and acid triggered mesenchymal transition in BE patients [32].

Despite BE being viewed as an important clinical endpoint, its real significance is in its predisposition to becoming dysplastic and malignant; the ultimate problem is EAC. Moreover, even though BE increases the risk of EAC, that is a rare outcome and BE is not associated with a measurable decrement in life expectancy [33]. Furthermore, only a small fraction of EAC patients are observed to progress through the classical sequence of erosive esophagitis, BE, dysplasia, cancer. In other words, most EAC is prevalent and not incident disease [34]. In fact, in a landmark Scandinavian population-based epidemiology study 40% of EAC patients reported no prior history of frequent heartburn and 38% had no identifiable BE at the time of resection or autopsy [27]. Confirming this, a subsequent large study reported that approximately half of prevalent EACs presented without BE or reflux symptoms [28]. Undoubtedly, many of these patients evolved to EAC though an accelerated or independent pathway of intestinal metaplasia at the EGJ with minimal endoscopic evidence of BE; entities referred to as short segment BE, ultra-short segment BE, or even intestinal metaplasia at the EGJ. These entities are quite common, encompassing an estimated 20% of the population undergoing upper endoscopy and are not necessarily associated with symptomatic GERD [35]. Taken together, these observations suggest that the current strategies of managing EAC risk based solely on stratified GERD severity will have little impact on overall EAC mortality. Certainly, some early cancers will be detected, but most will evade detection until they become symptomatic with dysphagia and are beyond cure. This dilemma has fostered interest in chemoprevention as an alternative strategy and some progress has been made along that front with a recently published trial demonstrating reduction in all-cause mortality in a population of BE patients treated with high-dose esomeprazole and low-dose aspirin over a ten-year period [36]. Ultimately, however, the use of a widely available cost-effective screening tool whose application does not depend on a GERD symptom profile will be required [37].

Regurgitation-Dominant Reflux Disease

Regurgitation-dominant disease is a distinct GERD phenotype because of its reduced response to therapy compared to heartburn-dominant disease [38, 39]. This makes intuitive sense as 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 the hypopharynx and can be tasted. This can occur regardless of the presence of acid and is accentuated in a recumbent posture. Although rarely used as an entry criterion in clinical trials, troublesome regurgitation (occurring 3-7 days per week) is common in GERD, reported in 13% of patients in an observational multicenter study and disturbing sleep in up to 60% of these patients [40]. Meta-analyses of treatment trials have consistently shown PPI therapy to be 10-20% less effective in relieving regurgitation than in relieving heartburn. On the other hand, surgical or endoscopic fundoplication and magnetic sphincter augmentation have been more effective than PPIs in relieving regurgitation in randomized controlled trials [41, 42].

An important masquerader of regurgitation-dominant GERD is rumination. Clinical distinctions are that while regurgitation is often acidic, postprandial, and prompted by actions such as bending over or lifting, rumination is generally bland, occurs while eating, and is prompted by subconsciously overpowering the EGJ with tightening of the abdominal musculature. This can be detected manometrically by abrupt increases in intragastric pressure and physiologically by transient increases in the tone of the abdominal wall muscles [43]. Although ostensibly a different syndrome than GERD, rumination syndrome overlaps with upright GERD in that both are associated with a reversal of the esophagogastric pressure gradient resulting in flow of gastric content into the esophagus [44, 45]. This similar pathophysiology is underscored by the demonstrated efficacy of diaphragmatic breathing, a maneuver that normalizes the transphincteric pressure gradient, in both syndromes [44, 46]. On the other hand, rumination is PPI unresponsive, given that it is completely independent of gastric acid secretion. It is optimally treated with the combination of cognitive behavioral therapy and learning the technique of diaphragmatic breathing [47]. That being said, one controlled trial demonstrated improvement with baclofen and another small series reported benefit from fundoplication [48, 49]. However, given the alternative options, the latter is rarely indicated. Finally, gastroparesis is commonly associated with heartburn and regurgitation which correlate with the severity of impaired gastric emptying [50].

Extraesophageal Manifestations of GERD

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: 1) Does the patient have abnormal reflux and how can that be detected? 2) Is reflux causing the extraesophageal symptom?, and 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 reflux interrogates the distal esophagus, but this may be insensitive with respect to extraesophageal syndromes because of heightened vulnerability of pharyngeal and airway structures. Hence, investigators have attempted to adapt pH-metry to monitor pharyngeal reflux by placing the pH sensor in or near the hypopharynx. However, for a number of technical and practical reasons, the accuracy of pharyngeal pH-metry is questionable, evident by the poor concordance between pharyngeal and esophageal pH drops during simultaneous monitoring [51]. An alternative strategy is to measure pepsin in saliva as an indicator of gastric juice refluxing into the mouth. Unfortunately, despite an initial report suggesting utility of a commercially available pepsin assay (PepTest, RD Biomed, Hull, UK), attempts at confirming that result concluded that the test had poor sensitivity (38%) and specificity (60%) for differentiating among well-characterized GERD phenotypes and controls [52]. Consequently, despite their theoretical limitations, we are left with conventional pH-metry and pH/impedance-metry as the only validated tests appropriate for clinical application.

Apart from the diagnostic limitations summarized above, there are also real limitations of therapeutics for extraesophageal GERD syndromes. Focusing on the syndromes that have been explored in the most detail, controlled PPI trials have been conducted in patients with poorly controlled asthma, reflux laryngitis, and postnasal drip [53-55]. For the most part, these have been convincingly negative as summarized in Figure 2 [38, 53, 54, 56-59]. From these experiences, certain general principles emerge in managing putative extraesophageal GERD syndromes. First, it is uncommon for reflux to be the dominant cause of extraesophageal syndromes in patients not also experiencing typical esophageal symptoms. More likely, reflux may be one of multiple causative cofactors. Consequently, effective management generally involves a multidisciplinary approach aimed at identifying causal cofactors and adjunctive treatments. A second theme is that pH-metry is more useful when it is normal, excluding reflux as a cause rather than when it is equivocal, leaving that door open. A third principle is that although fundoplication effectively eliminates reflux, it has substantial potential for adverse outcomes and no high quality data exist supporting its efficacy in these syndromes. In brief, diagnostics are more helpful in ruling out GERD than ruling it in and there is a real tendency to over-treat these patients, be that with PPIs or antireflux surgery.

gastroesophageal reflux clinical

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

Devising a rational approach to evaluating patients with potential extraesophageal manifestations is challenging. Although helpful when found, erosive esophagitis is a rare finding at endoscopy; in one study of laryngitis patients, none had more that LA grade A esophagitis [60]. Ambulatory pH or pH-impedance metry are the mainstay of evaluation, but there is little consensus on how to interpret these studies in this context given the absence of any high quality treatment outcome data. Consequently, the representation of extraesophageal manifestations as an established phenotype of GERD continues to be tenuous in many patients. Clearly there are anecdotal reports of patients with reflux leading to pulmonary fibrosis, bronchiectasis, chronic cough, asthma or laryngeal dysfunction, but identification, let alone treatment, of GERD as a contributor to these extraesophageal syndromes remains problematic.

An exception to deemphasizing the relationship of GERD to an extraesophageal syndrome is with lung transplantation which, despite difficulties in establishing cause and effect, has important unique considerations. First is that the sequelae of untreated GERD after lung transplant may lead to accelerated mortality from allograft injury [61]. Second, particularly with interstitial pulmonary fibrosis, GERD has been implicated with the primary lung disease and not preemptively managing GERD postoperatively could lead to recurrence in the implanted lung [62]. Third, is the concern that post-transplant allograft injury results from reflux-aspiration even with PPIs prompting the use of either pre-, or post-transplant fundoplication [63]. Other data, however, suggest that PPIs may be effective at prolonging allograft survival [64].

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, the differential diagnosis of chest pain is broad with reflux being the ultimate cause in only a minority [65]. 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 recording acid reflux concurrently with the onset of chest pain during pH-metry. In fact, it was in this application that reflux-symptom correlation paradigms were initially validated. A study of 177 patients evaluated for non-cardiac chest pain with pHmetry reported abnormal esophageal acid exposure in 35%, predicted by male gender, older age and Caucasian race [66]. Furthermore, abnormal pH-metry was more likely in patients with heartburn, regurgitation and hiatal hernia. In other words, similar to the case of extraesophageal manifestations, an atypical esophageal symptom is more likely attributable to GERD when typical symptoms are also present. Notably, only 20 patients in that study had a positive symptom correlation to esophageal acid exposure. Similar findings were reported in another study of 120 non-cardiac chest pain patients; 40% had abnormal esophageal acid exposure and patients with typical reflux symptoms were more likely to have a positive refluxsymptom association (52 vs. 31%) [65]. Moreover, those with reflux-induced chest pain exhibited reflux episodes with more sustained and lower pH drops extending up to the proximal esophagus. These data suggest an important clinical distinction between non-cardiac chest pain without typical esophageal symptoms and esophageal chest pain accompanied by typical esophageal symptoms. Evident in Figure 2, the former is poorly responsive to PPI therapy while the latter exhibits a number needed to treat of less than 2 with PPI therapy.

Although Figure 2 suggests a good response to PPI therapy for chest pain patients with accompanying typical esophageal symptoms, there is an important caveat to that. These studies used a 50% reduction in pain as the definition of success as opposed to complete elimination which was the common definition of success in studies addressing heartburn relief. This lower threshold of success opens the door for a greater placebo response. This reduced threshold also suggests that esophageal hypersensitivity may be an important co-factor in the genesis of esophageal chest pain particularly when it persists despite PPI therapy. Experimental data supporting that contention are the demonstration of a lower threshold for eliciting pain with either balloon distention or esophageal acid infusion among chest pain patients [67]. There are also data demonstrating that patients with esophageal chest pain may have perturbed esophageal mucosal integrity potentially exposing sensory afferents to luminal stimuli [14, 68]. Notably, Rome IV distinguishes functional chest pain from chest pain attributable to GERD with or without esophageal hypersensitivity [11].

Conclusion

Many terms in medicine that are singularly meant to reflect a specific process are, in fact, comprised of multiple facets of variable proportions with interactions amongst 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 all to therapeutics does not apply. While an escalating step-up approach with antisecretory medications may be pertinent to healing esophagitis, its applicability beyond that is highly questionable. Failure to recognize this limitation has resulted in extreme over-usage of antisecretory agents in general and especially PPIs. Similarly, failing to recognize the modulating effects of anxiety, hypervigilance, visceral and central hypersensitivity on symptom severity has greatly over-simplified the problem. Quite clearly, not all GERD is the same and it is time to apply a personalized approach to management, understanding the nuances of its varied presentations. The problem of erosive esophagitis was solved with PPIs, but the general application of PPIs to everything captured under the GERD umbrella revealed the broad spectrum of syndromes much less amenable to PPI therapy in any dose. It is with this in mind that we put forth this precision medicine concept for the management of GERD.

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 esponsiveness to PPI therapy (Figure 2) is proportional to the dominance of the red bars (acid reflux)

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