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Gastroesophageal reflux disease revisited
Gastroenterol Clin N Am 31 (2002) S1–S10
Gastroesophageal reflux disease revisited Ronnie Fass, MD Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System (1-111G-1) and University of Arizona Health Sciences Center, 3601 South Sixth Avenue, Tucson, AZ, 85723 USA
For decades, gastroesophageal reflux disease (GERD) has been approached as a spectrum of disease. On one end of the spectrum are the patients with classic symptoms of GERD and normal esophageal mucosa. The other end of the spectrum is occupied by patients with GERD complications such as stricture, Barrett’s esophagus, and adenocarcinoma of the esophagus. Removing the spectrum concept and approaching the GERD population as three unique groups of patients (nonerosive reflux disease, erosive esophagitis, and Barrett’s esophagus) will dramatically shift our focus from esophageal mucosal injury to mechanisms leading to symptom generation in each group and foster specific therapeutic modalities that benefit each individual group of patients. The new paradigm suggests that each of the unique groups of GERD should be evaluated individually for the underlying mechanisms, therapeutic approaches, and potential complications. This process will enable us to better characterize each group and thus help to develop better strategies for diagnosis and treatment. For decades, gastroesophageal reflux disease (GERD) has been approached as a spectrum of disease. On one end of the spectrum are the patients with classic symptoms of GERD (heartburn and acid regurgitation) and normal esophageal mucosa (endoscopy negative reflux disease or nonerosive reflux disease) [1]. As we progress along the GERD spectrum, we encounter patients with erosive esophagitis (from mild to severe). The other end of the spectrum is occupied by patients with GERD complications such as stricture, Barrett’s esophagus, and adenocarcinoma of the esophagus [1,2]. DeVault and Castell [3] stated that GERD represents a wide spectrum of disease. El-Serag and Sonnenberg [4] suggested that GERD encompasses
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a broad clinical spectrum that ranges from regurgitation, pirosis, and epigastric pain without endoscopic lesions to erosive esophagitis accompanied by various complications such as esophageal ulcers, strictures, and Barrett’s metaplasia. The Genval Workshop Report [5] recommended that the term GERD should be used to include all individuals who are exposed to the risk of physical complications from gastroesophageal reflux or who experience clinically significant impairment of health-related well-being due to reflux-related symptoms. The usage of the term ‘‘spectrum’’ in medicine is to indicate a range of disease manifestations based on a similar pathophysiologic process [2]. The spectrum concept in GERD, however, focused our attention on esophageal mucosal injury as the most significant clinical outcome. It also suggests that patients may progress over time to develop erosive esophagitis and even complications such as Barrett’s esophagus and adenocarcinoma of the esophagus. Surprisingly, the GERD spectrum had a profound impact on our scientific and clinical perception of GERD and thus our approach toward its underlying mechanisms and treatment. The best example is the exclusive focus of clinical trials on treatment of patients with erosive esophagitis, completely ignoring those with nonerosive reflux disease (NERD) who account for the majority of GERD patients [6–11]. The false assumption was that results of therapeutic studies in patients with erosive esophagitis could be extrapolated to other GERD groups, specifically those with NERD. Studies that investigated the underlying mechanisms of GERD also focused primarily on conditions and factors that promote esophageal mucosal injury, with very little interest in symptom generation. The result was a significant progress in our understanding of the mechanisms that lead to reflux of gastric content into the esophagus and that promote mucosal injury, at the cost of making very little progress in identifying the factors (central or peripheral) that determine perception of acid reflux.
Old paradigm Interestingly, there is very little data to support the spectrum concept. Recent studies have clearly demonstrated that patients with NERD do not represent a mild form of GERD. Symptom severity, frequency, or combination of both is similar in both NERD and erosive esophagitis [12]. The impact of symptoms on patient’s quality of life is also similar in both groups [13,14]. As with erosive esophagitis, most patients with NERD will relapse within 6 months if taken off antireflux treatment [13]. More surprising, however, were the results of therapeutic trials in NERD sufferers, demonstrating a symptom response rate to standard dose proton pump inhibitors (PPI) that was lower by up to 30% than what has been reported in patients with erosive esophagitis [1,15]. Lastly, patients with NERD that initially demonstrated a complete symptom relief on antireflux treatment relapse as NERD
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if taken off therapy [13]. Thus, NERD patients, even from a therapeutic point of view, do not appear to represent just a mild form of GERD. Progression of disease is a major concern for both GERD patients and physicians. The emphasis was that a subset of patients might develop complications such as peptic stricture, esophageal ulcer, Barrett’s esophagus, and even adenocarcinoma of the esophagus. A recent study raised the importance of symptom severity, frequency, and duration as strong predictive factors for the development of adenocarcinoma of the esophagus [16]. It is not clear, however, which type of GERD patients are at increased risk of developing esophageal cancer. There is no data to suggest that all GERD patients should be alarmed and thus concerned about the emergence of esophageal adenocarcinoma. Despite the suggestion by Lagergren and colleagues [16] that adenocarcinoma of the esophagus might develop de-novo (not necessarily from Barrett’s mucosa), there is no evidence to support this claim. In many cases of adenocarcinoma of the esophagus, the tumor is likely to outgrow the Barrett’s mucosa. The few retrospective limited studies that evaluated the natural course of NERD revealed very little progression to erosive esophagitis, let alone to Barrett’s esophagus [17–19]. It appears that most patients with NERD will stay NERD for the remainder of their lives. Similarly, there is no support in the literature that patients with erosive esophagitis, without Barrett’s mucosa underneath, will progress over time to develop overt Barrett’s esophagus [20]. Despite the popular assumption that Barrett’s esophagus develops in the background of esophageal mucosal injury in the form of erosive esophagitis, we have yet to see reliable reports that demonstrate this hypothetic histopathologic process. Except for few very old reports that did not include esophageal biopsies, there is no solid evidence that patients with erosive esophagitis will progress over time to develop metaplastic epithelium, and thus do not appear to be at increased risk for adenocarcinoma of the esophagus [21–24]. As with the NERD group, patients with erosive esophagitis almost always will relapse as erosive esophagitis when treatment that completely healed their erosions is discontinued [25]. This suggests that patients with erosive esophagitis will demonstrate esophageal mucosal injury if left untreated throughout their lifetime. Thus far, it appears that most of the GERD patients (NERD and erosive esophagitis) are unlikely to develop Barrett’s esophagus over time, let alone esophageal adenocarcinoma. Patients with Barrett’s esophagus, on the other hand, demonstrate very little, if any, evidence of regression or progression of the metaplastic epithelium over the years. There is no documentation of spontaneous regression of Barrett’s esophagus to either erosive esophagitis or NERD [1]. Patients with Barrett’s esophagus are almost always diagnosed on the first endoscopy rather than on follow-up endoscopies of nonerosive or erosive mucosa [26]. These patients also demonstrate a relative stability in their esophageal mucosal involvement, and the length of their Barrett’s mucosa remains unchanged during their lifetime. However,
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these are the patients that are at increased risk of developing esophageal cancer. Overall, there appears to be very little movement in between the different GERD groups (NERD, erosive esophagitis, and Barrett’s esophagus). Patients fit into one of the groups, probably based on their genetic makeup, and remain in this group during their lifetime (Fig. 1).
New paradigm Removing the spectrum concept and approaching the GERD population as three unique groups of patients (NERD, erosive esophagitis, and Barrett’s esophagus) will dramatically shift our focus from esophageal mucosal injury to symptoms (Fig. 2) [1]. If there is very little concern that patients with NERD will progress over time to develop erosive esophagitis, then the aim of antireflux treatment in this group is to ameliorate symptoms and improve quality of life. Furthermore, most patients with erosive esophagitis demonstrate low grades of mucosal injury and thus are unlikely to develop a GERD complication (stricture, ulcer, and so forth) [7,27,28]. Consequently, in these patients, symptoms also become the main focus of antireflux treatment. The new paradigm suggests that each of the unique groups of GERD should be evaluated individually for the underlying mechanisms, therapeutic approaches, and potential complications. This process will enable us to better characterize each group and thus help to develop better strategies for
Fig. 1. Patients tend to stay as nonerosive, erosive, or Barrett’s throughout their lifetime, suggesting a specific genetic makeup that predisposes them to develop one of the unique presentations of GERD.
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Fig. 2. GERD as a spectrum represents the old paradigm that should be replaced by a new paradigm: GERD is composed of three unique groups of patients—NERD, erosive esophagitis, and Barrett’s esophagus.
diagnosis and treatment. In addition, the new paradigm encourages us to further study the underlying mechanisms that lead to symptoms in patients with GERD. Until now, mechanistic studies in GERD have focused primarily on the causes of acid reflux. Transient lower esophageal sphincter relaxation, reduced basal lower esophageal sphincter pressure, and stress reflux have been identified as the culprits for acid reflux [29–31]. The factors that determine perception of intraesophageal stimuli such as acid, however, are yet to be elucidated. Only 2% to 3% of acid reflux events reach conscious level and thus are perceived by GERD patients [32]. In normal subjects, acid reflux events commonly occur, primarily after meals, but result in no symptoms. What determines the perception of a specific acid reflux event should be the primary focus of current GERD research. By identifying the potential central and peripheral factors responsible for enhancing perception of intraluminal events, better therapy might be tailored to the different groups of GERD. The author and colleagues [33] recently proposed that central and peripheral factors can modulate esophageal perception of intraesophageal stimuli that are physiologic or pathologic, acidic or nonacidic. Anxiety, stress, sleep, and other central factors have been demonstrated to enhance perception of intraesophageal events [34–36]. Intestinal nutrients and, specifically, intraduodenal fat have been also associated with increased perception of intraluminal stimuli [37]. Currently, we are aware of the fact that the esophagus has a limited repertoire of symptoms. Symptoms do not appear to be stimulus specific as has been previously suggested. It is clear today that acid-related and nonacidrelated stimuli can result in heartburn symptom [26,38,39]. Thus, some
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patients with heartburn that lack erosive esophagitis may represent a subgroup with classic heartburn that is not related to gastric reflux (acidic or nonacidic) but rather to some type of esophageal motor event. Recent work has suggested that prolonged longitudinal muscle contraction in the esophagus may be the motor corollary of heartburn [40,44]. In the NERD group, research should be focused on the different mechanisms for heartburn symptoms that this group encompasses. It is obvious that NERD represents a heterogeneous group of patients that differ in the reasons for their typical GERD symptoms. Clinical predictive factors should be determined that could be used to identify the different subgroups in clinical practice. In addition, understanding the different subgroups may help us to develop more specific and effective therapeutic modalities. Patients with NERD and abnormal acid exposure demonstrate the highest symptom response rate to antireflux treatment among the NERD subgroup. In fact, studies have demonstrated that the higher the esophageal acid exposure in the distal esophagus, the greater the symptom response to proton pump inhibitor (PPI) therapy [28]. In contrast, NERD patients with normal pH testing represent a more challenging group of patients that has been recently termed functional heartburn [41]. The causes for their heartburn may be diverse. A significant number of these patients appear to have a hypersensitivity to acid reflux within the physiologic range that normally does not elicit any GERD symptoms [42]. Others might have sensitivity to changes in esophageal pH that never traverse pH 4. Unlike the early perception, it appears that the definition of an acid reflux event (pH\4) is not necessarily detrimental for the generation of heartburn symptoms [33,43]. In some patients, smaller changes in esophageal pH are sufficient to trigger classic GERD symptoms [33]. Lastly, a significant group of functional heartburn patients might have nonacid-related stimuli that are responsible for their GERD symptoms. Reflux of nonacidic volume or even motor events are likely the cause of GERD-like symptoms in these patients [26,38,39]. The different subgroups respond differently to antireflux treatment [44]. Unlike patients with NERD and abnormal 24-hour esophageal pH monitoring, patients with functional heartburn may need higher doses of PPIs or, potentially, pain modulators for symptom control. Although patients with erosive esophagitis appear to be a much more homogeneous group of patients, there are several unsettled issues that need to be further investigated. There is sufficient data to show that failure of standard dose PPI therapy to heal erosive esophagitis is related to the extent of esophageal mucosal injury [16,45]. In other words, the greater the grading of erosive esophagitis, the lower the percentage of patients that demonstrate complete healing of erosive esophagitis on a PPI. More intriguing is the fact that up to 15% of the patients with complete healing of their esophageal inflammation continue to report GERD symptoms on standard-dose PPI [45]. The latter suggests that symptomatic failure in patients with erosive esophagitis is not necessarily tied to mucosal healing failure. Furthermore,
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the extent of erosive esophagitis prior to treatment has not been shown to be predictive of symptomatic failure in patients that healed their erosive esophagitis. The mechanisms responsible for refractoriness of symptoms in these patients are not well understood, but hypersensitivity to acid or the presence of nonacidic reflux are some of the potential answers. Recent data further support the concept that erosive esophagitis is not the intermediate step for Barrett’s esophagus development [46,47]. Erosive esophagitis and Barrett’s esophagus appear to be two different diseases. The esophageal lesion that precedes the development of Barrett’s esophagus has still remained elusive; however, patients with Barrett’s esophagus clearly demonstrate a variety of mechanistic and therapeutic issues that are unique to this premalignant lesion. Acid reflux, although important in Barrett’s evolution and symptom generation, is probably just one of several other noxious factors that are responsible for the different clinical aspects of the lesion [48–50]. Failure to cause significant regression of Barrett’s epithelium by high dose of a PPI may suggest that abnormal acid exposure in the distal esophagus is not necessarily needed to maintain the lesion [51]. It is also likely that acid reflux is not an important factor in the neoplastic transformation of the lesion [52] and may explain the absence of medical studies that demonstrate prevention of progression to adenocarcinoma of the esophagus in Barrett’s esophagus patients receiving antireflux treatment. Despite claims by surgical groups that antireflux surgery may prevent the emergence of adenocarcinoma of the esophagus from Barrett’s mucosa, a recent rigorous meta-analysis that evaluated this literature concluded that presently, there is no evidence to support the surgical claim [53]. The complications appear to be different among the GERD groups as well. Patients with NERD compose most of the patients with atypical/extraesophageal manifestations of GERD [54]. Regardless of the term ‘‘extraesophageal manifestations of GERD,’’ hoarseness, chronic cough, asthma, and others are in actuality complications of GERD. Only patients with severe erosive esophagitis are at increased risk of developing peptic stricture, esophageal ulceration, and bleeding [28,55,56]. Finally, only Barrett’s esophagus has been identified as the precursor of adenocarcinoma of the esophagus; thus, only patients that harbor this lesion are at increased risk of developing esophageal cancer (Fig. 2) [20].
Summary GERD should be viewed as three distinct groups of patients: NERD, erosive esophagitis, and Barrett’s esophagus. This new paradigm will shift our focus to mechanisms leading to symptom generation in each group and foster specific therapeutic modalities that benefit each individual group of patients.
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[22] Goldman MC, Beckman RC. Barrett syndrome. Case report with discussion about concepts of pathogenesis. Gastroenterology 1960;39:104–10. [23] Halverson JF, Semb BKH. The ‘‘Barrett syndrome’’ (the columnar-lined lower esophagus): an acquired condition secondary to reflux esophagitis. Acta Chir Scand 1975;141:682–7. [24] Mossberg SM. The columnar-lined esophagus (Barrett syndrome)—an acquired condition? Gastroenterology 1966;50:671–6. [25] Bate CM, Booth SN, Crowe JP, et al. Omeprazole 10 mg or 20 mg once daily in the prevention of recurrence of reflux oesophagitis. Gut 1995;36:492–8. [26] Sifrim D, Holloway R, Silny J, et al. Acid, nonacid, and gas reflux in patients with gastroesophageal reflux disease during ambulatory 24-hour pH—impedance recordings. Gastroenterology 2001;120(7):1588–98. [27] Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97(3): 575–83. [28] Marks RD, Richter JE, Rizzo J, et al. Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture and esophagitis. Gastroenterology 1994;106(4):907–15. [29] Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547–52. [30] Kahrilas PF, Shi G, Manka M, et al. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology 2000;118:688–95. [31] Lin S, Ke M, Xu J, et al. Impaired esophageal emptying in reflux disease. Am J Gastroenterol 1994;89:1003–6. [32] Richter JE, Bradley LA. Psychophysiological interactions in esophageal diseases. Semin Gastrointest Dis 1995;7:169–84. [33] Fass R, Fennerty MB, Vakil N. Nonerosive reflux disease—current concepts and dilemmas. Am J Gastroenterol 2001;96(2):303–14. [34] Bradley LA, Richter JE, Pulliam TJ, et al. The relationship between stress and symptoms of gastroesophageal reflux: the influence of physiological factors. Am J Gastroenterol 1993; 88:11–9. [35] Cook IJ, Collins SM. Does acute emotional stress influence frequency or duration of gastroesophageal reflux in human subjects [abstract]? Gastroenterology 1986;90:1380. [36] Fass R, Malagon IB, Naliboff B, et al. Effect of psychologically induced stress on symptom perception and autonomic nervous system repose of patients (PTS) with erosive esophagitis (EE) and non-erosive reflux disease (NERD) [abstract]. Gastroenterology 2000;118(4): A637 #3250. [37] Meyer JH, Lembo A, Elashoff JD, et al. Duodenal fat intensifies the perception of heartburn. Gut 2001;49:624–8. [38] Fass R, Naliboff B, Higa L, et al. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology 1998;115(6): 1363–73. [39] Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120(7):1599–606. [40] Pehlivanov ND, Liu J, Mittal R. Sustained esophageal contraction: a motor correlate of heartburn symptom [abstract]. Gastroenterology 1999;116:G4613. [41] The Rome II International Working Teams. Functional heartburn. In: Drossman DA, Corazziari E, Talley NJ, et al, editors. Rome II: the functional gastrointestinal disorders. 2nd edition. Lawrence: Allen Press; 2000. p. 275–8. [42] Fass R, Tougas G. Functional heartburn—the stimulus, the pain and the brain. Gut, in press. [43] Johnson LF. Methods of data analysis. In: Richter JE, editor. Ambulatory esophageal pH monitoring. Baltimore, MD: Williams & Wilkins; 1997. p. 65–76.
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[44] Watson RGP, Tham TCK, Johnson BT, et al. Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux: the ‘‘sensitive oesophagus.’’ Gut 1997;40:587–90. [45] Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001;96(3):656–65. [46] Cameron AJ, Arora AS. Barrett’s esophagus and reflux esophagitis: is there a missing link? Am J Gastroenterol 2002;97(2):273–8. [47] Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, et al. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut 2002; 50:451–9. [48] Cuomo R, Koek G, Sifrim D, et al. Analysis of ambulatory duodenogastroesophageal reflux monitoring. Dig Dis Sci 2000;45:2463–9. [49] Menges M, Muller M, Zeitz M. Increased acid and bile reflux in Barrett’s esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy. Am J Gastroenterol 2001;96:331–7. [50] Vaezi M, Richter J. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1996;111:1192–9. [51] Haag S, Nandurkar S, Talley NJ. Regression of Barrett’s esophagus: the role of acid suppression, surgery, and ablative methods. Gastrointest Endosc 1999;50(2):229–40. [52] Fass R, Sampliner RE, Spechler SJ. The relationship between esophageal acid exposure, dysplasia and extent of columnar metaplasia in Barrett’s esophagus [abstract]. Gastroenterology 2000;118(4, suppl 2):A685 #3761. [53] Corey K, Schmitz SM, Shaheen NJ. Does a surgical anti-reflux procedure decrease the incidence of esophageal adenocarcinoma in Barrett’s esophagus? A meta-analysis. Gastroenterology 2002;122(4):A292 #M1390. [54] Richter JE. Extraesophageal presentations of gastroesophageal reflux disease: an overview. Am J Gastroenterol 2000;95(8, suppl 2000):S1–S3. [55] El-Serag HB, Sonnenberg A. Association of esophagitis and esophageal strictures with diseases treated with nonsteroidal anti-inflammatory drugs. Am J Gastroenterol 1997; 92(1):52–6. [56] Marks RD, Richter JE. Peptic strictures of the esophagus. Am J Gastroenterol 1993; 88(8):1160–73.
Gastroesophageal reflux disease revisited Ronnie Fass, MD Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System (1-111G-1) and University of Arizona Health Sciences Center, 3601 South Sixth Avenue, Tucson, AZ, 85723 USA
For decades, gastroesophageal reflux disease (GERD) has been approached as a spectrum of disease. On one end of the spectrum are the patients with classic symptoms of GERD and normal esophageal mucosa. The other end of the spectrum is occupied by patients with GERD complications such as stricture, Barrett’s esophagus, and adenocarcinoma of the esophagus. Removing the spectrum concept and approaching the GERD population as three unique groups of patients (nonerosive reflux disease, erosive esophagitis, and Barrett’s esophagus) will dramatically shift our focus from esophageal mucosal injury to mechanisms leading to symptom generation in each group and foster specific therapeutic modalities that benefit each individual group of patients. The new paradigm suggests that each of the unique groups of GERD should be evaluated individually for the underlying mechanisms, therapeutic approaches, and potential complications. This process will enable us to better characterize each group and thus help to develop better strategies for diagnosis and treatment. For decades, gastroesophageal reflux disease (GERD) has been approached as a spectrum of disease. On one end of the spectrum are the patients with classic symptoms of GERD (heartburn and acid regurgitation) and normal esophageal mucosa (endoscopy negative reflux disease or nonerosive reflux disease) [1]. As we progress along the GERD spectrum, we encounter patients with erosive esophagitis (from mild to severe). The other end of the spectrum is occupied by patients with GERD complications such as stricture, Barrett’s esophagus, and adenocarcinoma of the esophagus [1,2]. DeVault and Castell [3] stated that GERD represents a wide spectrum of disease. El-Serag and Sonnenberg [4] suggested that GERD encompasses
E-mail address: [email protected] 0889-8553/02/$ – see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 8 9 - 8 5 5 3 ( 0 2 ) 0 0 0 4 6 - 8
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a broad clinical spectrum that ranges from regurgitation, pirosis, and epigastric pain without endoscopic lesions to erosive esophagitis accompanied by various complications such as esophageal ulcers, strictures, and Barrett’s metaplasia. The Genval Workshop Report [5] recommended that the term GERD should be used to include all individuals who are exposed to the risk of physical complications from gastroesophageal reflux or who experience clinically significant impairment of health-related well-being due to reflux-related symptoms. The usage of the term ‘‘spectrum’’ in medicine is to indicate a range of disease manifestations based on a similar pathophysiologic process [2]. The spectrum concept in GERD, however, focused our attention on esophageal mucosal injury as the most significant clinical outcome. It also suggests that patients may progress over time to develop erosive esophagitis and even complications such as Barrett’s esophagus and adenocarcinoma of the esophagus. Surprisingly, the GERD spectrum had a profound impact on our scientific and clinical perception of GERD and thus our approach toward its underlying mechanisms and treatment. The best example is the exclusive focus of clinical trials on treatment of patients with erosive esophagitis, completely ignoring those with nonerosive reflux disease (NERD) who account for the majority of GERD patients [6–11]. The false assumption was that results of therapeutic studies in patients with erosive esophagitis could be extrapolated to other GERD groups, specifically those with NERD. Studies that investigated the underlying mechanisms of GERD also focused primarily on conditions and factors that promote esophageal mucosal injury, with very little interest in symptom generation. The result was a significant progress in our understanding of the mechanisms that lead to reflux of gastric content into the esophagus and that promote mucosal injury, at the cost of making very little progress in identifying the factors (central or peripheral) that determine perception of acid reflux.
Old paradigm Interestingly, there is very little data to support the spectrum concept. Recent studies have clearly demonstrated that patients with NERD do not represent a mild form of GERD. Symptom severity, frequency, or combination of both is similar in both NERD and erosive esophagitis [12]. The impact of symptoms on patient’s quality of life is also similar in both groups [13,14]. As with erosive esophagitis, most patients with NERD will relapse within 6 months if taken off antireflux treatment [13]. More surprising, however, were the results of therapeutic trials in NERD sufferers, demonstrating a symptom response rate to standard dose proton pump inhibitors (PPI) that was lower by up to 30% than what has been reported in patients with erosive esophagitis [1,15]. Lastly, patients with NERD that initially demonstrated a complete symptom relief on antireflux treatment relapse as NERD
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if taken off therapy [13]. Thus, NERD patients, even from a therapeutic point of view, do not appear to represent just a mild form of GERD. Progression of disease is a major concern for both GERD patients and physicians. The emphasis was that a subset of patients might develop complications such as peptic stricture, esophageal ulcer, Barrett’s esophagus, and even adenocarcinoma of the esophagus. A recent study raised the importance of symptom severity, frequency, and duration as strong predictive factors for the development of adenocarcinoma of the esophagus [16]. It is not clear, however, which type of GERD patients are at increased risk of developing esophageal cancer. There is no data to suggest that all GERD patients should be alarmed and thus concerned about the emergence of esophageal adenocarcinoma. Despite the suggestion by Lagergren and colleagues [16] that adenocarcinoma of the esophagus might develop de-novo (not necessarily from Barrett’s mucosa), there is no evidence to support this claim. In many cases of adenocarcinoma of the esophagus, the tumor is likely to outgrow the Barrett’s mucosa. The few retrospective limited studies that evaluated the natural course of NERD revealed very little progression to erosive esophagitis, let alone to Barrett’s esophagus [17–19]. It appears that most patients with NERD will stay NERD for the remainder of their lives. Similarly, there is no support in the literature that patients with erosive esophagitis, without Barrett’s mucosa underneath, will progress over time to develop overt Barrett’s esophagus [20]. Despite the popular assumption that Barrett’s esophagus develops in the background of esophageal mucosal injury in the form of erosive esophagitis, we have yet to see reliable reports that demonstrate this hypothetic histopathologic process. Except for few very old reports that did not include esophageal biopsies, there is no solid evidence that patients with erosive esophagitis will progress over time to develop metaplastic epithelium, and thus do not appear to be at increased risk for adenocarcinoma of the esophagus [21–24]. As with the NERD group, patients with erosive esophagitis almost always will relapse as erosive esophagitis when treatment that completely healed their erosions is discontinued [25]. This suggests that patients with erosive esophagitis will demonstrate esophageal mucosal injury if left untreated throughout their lifetime. Thus far, it appears that most of the GERD patients (NERD and erosive esophagitis) are unlikely to develop Barrett’s esophagus over time, let alone esophageal adenocarcinoma. Patients with Barrett’s esophagus, on the other hand, demonstrate very little, if any, evidence of regression or progression of the metaplastic epithelium over the years. There is no documentation of spontaneous regression of Barrett’s esophagus to either erosive esophagitis or NERD [1]. Patients with Barrett’s esophagus are almost always diagnosed on the first endoscopy rather than on follow-up endoscopies of nonerosive or erosive mucosa [26]. These patients also demonstrate a relative stability in their esophageal mucosal involvement, and the length of their Barrett’s mucosa remains unchanged during their lifetime. However,
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these are the patients that are at increased risk of developing esophageal cancer. Overall, there appears to be very little movement in between the different GERD groups (NERD, erosive esophagitis, and Barrett’s esophagus). Patients fit into one of the groups, probably based on their genetic makeup, and remain in this group during their lifetime (Fig. 1).
New paradigm Removing the spectrum concept and approaching the GERD population as three unique groups of patients (NERD, erosive esophagitis, and Barrett’s esophagus) will dramatically shift our focus from esophageal mucosal injury to symptoms (Fig. 2) [1]. If there is very little concern that patients with NERD will progress over time to develop erosive esophagitis, then the aim of antireflux treatment in this group is to ameliorate symptoms and improve quality of life. Furthermore, most patients with erosive esophagitis demonstrate low grades of mucosal injury and thus are unlikely to develop a GERD complication (stricture, ulcer, and so forth) [7,27,28]. Consequently, in these patients, symptoms also become the main focus of antireflux treatment. The new paradigm suggests that each of the unique groups of GERD should be evaluated individually for the underlying mechanisms, therapeutic approaches, and potential complications. This process will enable us to better characterize each group and thus help to develop better strategies for
Fig. 1. Patients tend to stay as nonerosive, erosive, or Barrett’s throughout their lifetime, suggesting a specific genetic makeup that predisposes them to develop one of the unique presentations of GERD.
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Fig. 2. GERD as a spectrum represents the old paradigm that should be replaced by a new paradigm: GERD is composed of three unique groups of patients—NERD, erosive esophagitis, and Barrett’s esophagus.
diagnosis and treatment. In addition, the new paradigm encourages us to further study the underlying mechanisms that lead to symptoms in patients with GERD. Until now, mechanistic studies in GERD have focused primarily on the causes of acid reflux. Transient lower esophageal sphincter relaxation, reduced basal lower esophageal sphincter pressure, and stress reflux have been identified as the culprits for acid reflux [29–31]. The factors that determine perception of intraesophageal stimuli such as acid, however, are yet to be elucidated. Only 2% to 3% of acid reflux events reach conscious level and thus are perceived by GERD patients [32]. In normal subjects, acid reflux events commonly occur, primarily after meals, but result in no symptoms. What determines the perception of a specific acid reflux event should be the primary focus of current GERD research. By identifying the potential central and peripheral factors responsible for enhancing perception of intraluminal events, better therapy might be tailored to the different groups of GERD. The author and colleagues [33] recently proposed that central and peripheral factors can modulate esophageal perception of intraesophageal stimuli that are physiologic or pathologic, acidic or nonacidic. Anxiety, stress, sleep, and other central factors have been demonstrated to enhance perception of intraesophageal events [34–36]. Intestinal nutrients and, specifically, intraduodenal fat have been also associated with increased perception of intraluminal stimuli [37]. Currently, we are aware of the fact that the esophagus has a limited repertoire of symptoms. Symptoms do not appear to be stimulus specific as has been previously suggested. It is clear today that acid-related and nonacidrelated stimuli can result in heartburn symptom [26,38,39]. Thus, some
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patients with heartburn that lack erosive esophagitis may represent a subgroup with classic heartburn that is not related to gastric reflux (acidic or nonacidic) but rather to some type of esophageal motor event. Recent work has suggested that prolonged longitudinal muscle contraction in the esophagus may be the motor corollary of heartburn [40,44]. In the NERD group, research should be focused on the different mechanisms for heartburn symptoms that this group encompasses. It is obvious that NERD represents a heterogeneous group of patients that differ in the reasons for their typical GERD symptoms. Clinical predictive factors should be determined that could be used to identify the different subgroups in clinical practice. In addition, understanding the different subgroups may help us to develop more specific and effective therapeutic modalities. Patients with NERD and abnormal acid exposure demonstrate the highest symptom response rate to antireflux treatment among the NERD subgroup. In fact, studies have demonstrated that the higher the esophageal acid exposure in the distal esophagus, the greater the symptom response to proton pump inhibitor (PPI) therapy [28]. In contrast, NERD patients with normal pH testing represent a more challenging group of patients that has been recently termed functional heartburn [41]. The causes for their heartburn may be diverse. A significant number of these patients appear to have a hypersensitivity to acid reflux within the physiologic range that normally does not elicit any GERD symptoms [42]. Others might have sensitivity to changes in esophageal pH that never traverse pH 4. Unlike the early perception, it appears that the definition of an acid reflux event (pH\4) is not necessarily detrimental for the generation of heartburn symptoms [33,43]. In some patients, smaller changes in esophageal pH are sufficient to trigger classic GERD symptoms [33]. Lastly, a significant group of functional heartburn patients might have nonacid-related stimuli that are responsible for their GERD symptoms. Reflux of nonacidic volume or even motor events are likely the cause of GERD-like symptoms in these patients [26,38,39]. The different subgroups respond differently to antireflux treatment [44]. Unlike patients with NERD and abnormal 24-hour esophageal pH monitoring, patients with functional heartburn may need higher doses of PPIs or, potentially, pain modulators for symptom control. Although patients with erosive esophagitis appear to be a much more homogeneous group of patients, there are several unsettled issues that need to be further investigated. There is sufficient data to show that failure of standard dose PPI therapy to heal erosive esophagitis is related to the extent of esophageal mucosal injury [16,45]. In other words, the greater the grading of erosive esophagitis, the lower the percentage of patients that demonstrate complete healing of erosive esophagitis on a PPI. More intriguing is the fact that up to 15% of the patients with complete healing of their esophageal inflammation continue to report GERD symptoms on standard-dose PPI [45]. The latter suggests that symptomatic failure in patients with erosive esophagitis is not necessarily tied to mucosal healing failure. Furthermore,
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the extent of erosive esophagitis prior to treatment has not been shown to be predictive of symptomatic failure in patients that healed their erosive esophagitis. The mechanisms responsible for refractoriness of symptoms in these patients are not well understood, but hypersensitivity to acid or the presence of nonacidic reflux are some of the potential answers. Recent data further support the concept that erosive esophagitis is not the intermediate step for Barrett’s esophagus development [46,47]. Erosive esophagitis and Barrett’s esophagus appear to be two different diseases. The esophageal lesion that precedes the development of Barrett’s esophagus has still remained elusive; however, patients with Barrett’s esophagus clearly demonstrate a variety of mechanistic and therapeutic issues that are unique to this premalignant lesion. Acid reflux, although important in Barrett’s evolution and symptom generation, is probably just one of several other noxious factors that are responsible for the different clinical aspects of the lesion [48–50]. Failure to cause significant regression of Barrett’s epithelium by high dose of a PPI may suggest that abnormal acid exposure in the distal esophagus is not necessarily needed to maintain the lesion [51]. It is also likely that acid reflux is not an important factor in the neoplastic transformation of the lesion [52] and may explain the absence of medical studies that demonstrate prevention of progression to adenocarcinoma of the esophagus in Barrett’s esophagus patients receiving antireflux treatment. Despite claims by surgical groups that antireflux surgery may prevent the emergence of adenocarcinoma of the esophagus from Barrett’s mucosa, a recent rigorous meta-analysis that evaluated this literature concluded that presently, there is no evidence to support the surgical claim [53]. The complications appear to be different among the GERD groups as well. Patients with NERD compose most of the patients with atypical/extraesophageal manifestations of GERD [54]. Regardless of the term ‘‘extraesophageal manifestations of GERD,’’ hoarseness, chronic cough, asthma, and others are in actuality complications of GERD. Only patients with severe erosive esophagitis are at increased risk of developing peptic stricture, esophageal ulceration, and bleeding [28,55,56]. Finally, only Barrett’s esophagus has been identified as the precursor of adenocarcinoma of the esophagus; thus, only patients that harbor this lesion are at increased risk of developing esophageal cancer (Fig. 2) [20].
Summary GERD should be viewed as three distinct groups of patients: NERD, erosive esophagitis, and Barrett’s esophagus. This new paradigm will shift our focus to mechanisms leading to symptom generation in each group and foster specific therapeutic modalities that benefit each individual group of patients.
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