The pathogenesis of heartburn in nonerosive reflux disease: A unifying hypothesis
2005; Elsevier BV; Volume: 128; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2004.08.014
ISSN1528-0012
AutoresWilliam J. Barlow, Roy C. Orlando,
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoHeartburn is a symptom complex that has traditionally been accepted as an acid-mediated event and a reliable indicator of gastroesophageal reflux disease. Recently, however, these concepts have been questioned because patients with endoscopy-negative “heartburn” have lower response rates to acid suppression with proton pump inhibitors than do patients with endoscopy-positive “heartburn,” ie, erosive esophagitis. As explanation for this, 3 different mechanisms have been proposed to explain the occurrence of heartburn in the endoscopy-negative setting. They are: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. In this report, we review the observations in support of each concept and propose a means for reconciling them under one hypothesis: abnormal tissue resistance. Essential to this review and to the conclusions drawn about the pathogenesis of heartburn in nonerosive reflux disease is a reaffirmation of the definition of reflux-associated “heartburn” as an acid-mediated event requiring “relief by antacids” as a necessary component of the history. Heartburn is a symptom complex that has traditionally been accepted as an acid-mediated event and a reliable indicator of gastroesophageal reflux disease. Recently, however, these concepts have been questioned because patients with endoscopy-negative “heartburn” have lower response rates to acid suppression with proton pump inhibitors than do patients with endoscopy-positive “heartburn,” ie, erosive esophagitis. As explanation for this, 3 different mechanisms have been proposed to explain the occurrence of heartburn in the endoscopy-negative setting. They are: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. In this report, we review the observations in support of each concept and propose a means for reconciling them under one hypothesis: abnormal tissue resistance. Essential to this review and to the conclusions drawn about the pathogenesis of heartburn in nonerosive reflux disease is a reaffirmation of the definition of reflux-associated “heartburn” as an acid-mediated event requiring “relief by antacids” as a necessary component of the history. Gastroesophageal reflux disease (GERD) is a common disease, typically diagnosed by a history of recurrent heartburn. Heartburn, by definition, is a symptom complex characterized by a substernal discomfort or pain, usually burning in quality, which often starts near the epigastrium and radiates toward the mouth. It is worse following meals and on reclining and is characteristically relieved by antacid ingestion.1Orlando R.C. Reflux esophagitis.in: Yamada T. Alpers D.H. Owyang C. Powell D.W. Laine L. Textbook of gastroenterology. Lippincott Williams & Wilkins, Philadelphia1999: 1235-1263Google Scholar Based on upper endoscopy, patients with heartburn or GERD can be subdivided into 2 categories: those with and without erosive esophagitis. Those with erosive esophagitis on upper endoscopy (EGD) have identifiable mucosal breaks in the distal esophagus and those without erosive esophagitis—commonly designated as having nonerosive reflux disease (NERD)—have a grossly “normal-appearing” mucosa. Despite the obvious endoscopic differences, these subgroups are usually considered clinically indistinguishable.1Orlando R.C. Reflux esophagitis.in: Yamada T. Alpers D.H. Owyang C. Powell D.W. Laine L. Textbook of gastroenterology. Lippincott Williams & Wilkins, Philadelphia1999: 1235-1263Google ScholarThe pathogenesis of heartburn in erosive esophagitis is accepted as arising from the contact of refluxed gastric acid with damaged esophageal mucosa. Acid then produces heartburn by diffusion through visible mucosal breaks where it contacts and activates chemosensitive nociceptors within the esophageal mucosa. These same concepts, however, have not been accepted for the pathogenesis of heartburn in NERD, for the following reasons: (1) The normal esophagus on endoscopy in NERD offers no obvious route for acid entry and access to the nociceptors within the mucosa; (2) episodes of heartburn in NERD correlate poorly with acid reflux events on esophageal pH monitoring2Fass R. Epidemiology and pathophysiology of symptomatic gastroesophageal reflux disease.Am J Gastroenterol. 2003; 98: S2-S7Crossref PubMed Scopus (139) Google Scholar, 3Heading R.C. Epidemiology of oesophageal reflux disease.Scand J Gastroenterol. 1989; 24: 33-37PubMed Google Scholar; and (3), on pH monitoring, up to 50% of subjects with heartburn and negative endoscopy—ie, NERD—have normal acid contact time (ACT).4Schlesinger P.K. Donahue P.E. Schmid B. Layden T.J. Limitations of 24-hour intraesophageal pH monitoring in the hospital setting.Gastroenterology. 1985; 89: 797-804PubMed Google Scholar, 5Masclee A.A.M. DeBest A.C.A.M. DeGraaf R. Cluysenaer O.J.J. Jansen J.B.M.J. Ambulatory 24-hour pH-metry in the diagnosis of gastroesophageal reflux disease.Scand J Gastroenterol. 1990; 25: 225-230PubMed Google Scholar One approach that initially emerged in an attempt to reconcile the observations on pH monitoring and so to reestablish the role of acid reflux in heartburn in NERD was by the development of a scoring system. However, none of the 3 presently described systems—the symptom index, symptom sensitivity index, or symptom association probability—has been validated for the diagnosis of NERD.6Kahrilas P.J. Refractory heartburn.Gastroenterology. 2003; 124: 1941-1945Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar More recently, another means of reconciling these observations has emerged, and that is through consideration of alternative pathogenetic mechanisms for the development of heartburn in NERD, with the current candidates being esophageal visceral hypersensitivity (EVH), sustained esophageal contractions (SEC), and abnormal tissue resistance (ATR). This manuscript reviews these novel concepts and, through a reaffirmation that heartburn in NERD is an acid-mediated symptom characterized by “relief with antacids,” propose that all the observations can be reconciled under a single mechanism, namely ATR.Nonerosive reflux diseaseOur approach to examining the pathogenesis of heartburn in NERD first required that NERD be defined and that this definition be uniformly applied to clinical investigations to determine the applicability of their conclusions to the condition. The definition of NERD, as used herein, has 2 major requirements: (1) a history of “heartburn” in the absence of esophageal mucosal lesions on endoscopy and (2) supportive evidence that the symptom is acid-mediated, established by either prolonged ACT on pH monitoring, positive Bernstein test, or history that the reported heartburn is “relieved by antacids.” The validity of using the Bernstein test or pH monitoring for the diagnosis of NERD needs no elaboration because they are well-established methods for linking symptoms to esophageal acidity. However, the rationale for requiring that reflux-associated “heartburn” be qualified as being relieved by antacids and that, when acknowledged, this be accepted as evidence for NERD requires some explanation. There is now mounting evidence that the term “heartburn” has lost its value for the diagnosis of GERD through indiscriminate use of the term. Patients, for instance, have used the term to represent a variety of other unrelated digestive complaints, (eg, bloating and nausea), and physicians often truncate the term to accept as “heartburn” any recurrent substernal discomfort with characteristics inconsistent with a cardiac origin. Therefore, the requirement that reflux-associated “heartburn” be relieved by antacids adds an important qualifier in support of the symptom being acid mediated that is intuitive, historically supported by others with expertise in the field, and validated by clinical investigation as reliable for the diagnosis of GERD.7Pope II, C.E. Symptoms of esophageal disease.in: Sleisenger M.H. Fordtran J.S. Gastrointestinal disease Pathophysiology, diagnosis, management. 2nd ed. Saunders, Philadelphia1978: 197-198Google Scholar, 8Carlsson R. Dent J. Bolling-Sternevald E. Johnsson F. Junghard O. Lauritsen K. Riley S. Lundell L. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease.Scand J Gastroenterol. 1998; 33: 1023-1029Crossref PubMed Scopus (415) Google Scholar, 9Shaw M.J. Talley N.J. Beebe T.J. Rockwood T. Carlsson R. Adlis S. Fendrick A.M. Jones R. Dent J. Bytzer P. Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease.Am J Gastroenterol. 2001; 96: 52-57Crossref PubMed Google ScholarEsophageal visceral hypersensitivityEVH is 1 of the 3 mechanisms proposed to explain the pathogenesis of heartburn in NERD. The term, itself, implies the presence of an esophageal neuronal defect at the periperal or central level that creates heightened perception of an esophageal stimulus.10Sarkar S. Hobson A.R. Furlong P.L. Woolf C.J. Thompson D.G. Aziz Q. Central neural mechanisms mediating human visceral hypersensitivity.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G1196-G1202PubMed Google Scholar, 11Mehta A.J. Caestecker J.S. Camm A.J. Northfield T.C. Sensitization to painful distention and abnormal sensory perception in the esophagus.Gastroenterology. 1995; 108: 311-319Abstract Full Text PDF PubMed Scopus (93) Google Scholar EVH is recognized clinically by the presence of either allodynia or hyperalgesia. Allodynia is the perception of a stimulus at a level not perceived by a healthy subject and hyperalgesia is greater discomfort from a given stimulus than that experienced by a healthy subject. Based on these definitions, the esophagus in NERD can be said to be hypersensitive to acid because NERD subjects are typically Bernstein “positive,” and healthy subjects, despite similar esophageal acidity, are Bernstein “negative.”12Bernstein L.M. Baker L.A. A clinical test for esophagitis.Gastroenterology. 1958; 34: 760-781Abstract Full Text PDF PubMed Scopus (366) Google Scholar (Note: The Bernstein test involves esophageal perfusion with 0.1 N HCl, (ie, pH 1.1, for up to 30 minutes) and is recorded as “positive” when symptoms occur that mimic those experienced spontaneously.13Sandler R.S. Bernstein (acid perfusion) test.in: Drossman D.A. Manual of gastroenterologic procedures. 2nd ed. Raven, New York1987: 55-58Google Scholar) Recently, Fass et al performed a Bernstein test on a group of patients with GERD and reaffirmed the presence of acid hypersensitivity.14Fass R. Nailiboff B. Higa L. Johnson C. Kodner A. Munakata J. Ngo J. Mayer E.A. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.Gastroenterology. 1998; 115: 1363-1373Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar Notably, 27% of the GERD patients in this study had NERD; the diagnosis of NERD being established by history of heartburn, negative endoscopy, and abnormal pH monitoring. Moreover, although typical in that chemosensitivity to acid was heightened based on Bernstein testing, the esophagus of the same subjects was not hypersensitive to mechanical stimulation based on intraesophageal balloon distention. The finding that the esophagus in NERD is hypersensitive to mechanical stimulation (balloon distention) was initially reported by Trimble et al.15Trimble K.C. Pryde A. Heading R.C. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux Evidence for a spectrum of visceral sensitivity in GORD.Gut. 1995; 37: 7-12Crossref PubMed Scopus (241) Google Scholar However, the applicability of the observations to NERD remains questionable because the diagnosis was established in endoscopy-negative subjects with heartburn whose relationship to esophageal acidity was confirmed on the basis of a positive sensitivity index (symptoms correlating with an acidic event ≥50% on pH monitoring). Notably, total ACT on pH monitoring was normal in these subjects, and the history of heartburn lacked documentation of relief by antacids. Because the sensitivity index itself is inherently inaccurate and lacks validation, the conclusion that the mechanical hypersensitivity was present in NERD remains unclear. Moreover, Trimble et al had an internal “control” group of 11 GERD patients (4 with erosive esophagitis) whose diagnosis was established by the presence of abnormal pH monitoring, and these subjects, like those of Fass et al,14Fass R. Nailiboff B. Higa L. Johnson C. Kodner A. Munakata J. Ngo J. Mayer E.A. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.Gastroenterology. 1998; 115: 1363-1373Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar had no evidence of mechanical hypersensitivity in that response to balloon distention was similar to the healthy control subjects. The conclusion that mechanical hypersensitivity to intraesophageal balloon distention is a feature of NERD was also reported by Rodriguez-Stanley et al, and this observation was found to be independent of normal or abnormal ACT on pH monitoring.16Rodriguez-Stanley S. Robinson M. Earnest D.L. Meerveld B.G. Miner P.B. Esophageal hypersensitvity may be a major cause of heartburn.Am J Gastroenterol. 1999; 94: 628-631Crossref PubMed Google Scholar Furthermore. although NERD in this instance was well documented in ∼80% of subjects—heartburn relieved by antacids + endoscopy negative + Bernstein test positive in ∼90%—the conclusion that mechanical hypersensitivity was present remains unsettled. This was because patient responses were compared directly with historically (healthy) controls, who had balloon distention performed by other investigators at another institution. Therefore, the data currently support hypersensitivity to chemical (acid), but not mechanical, stimuli in NERD, and this is offered as an explanation for heartburn correlating poorly with luminal acidity in NERD, as well as for the development of heartburn in NERD despite normal ACT on pH monitoring.It is important to recognize, however, that acid hypersensitivity in NERD is itself an observation and not a mechanism. Acid hypersensitivity, therefore, suggests but does not prove the existence of EVH, (ie, the presence of primary neuronal dysfunction). In particular, acid hypersensitivity in NERD cannot distinguish between inappropriately heightened perception because of underlying neuronal dysfunction and appropriately heightened perception because of microscopic mucosal defects that result in greater access of luminal acidity to nociceptors within the esophageal mucosa (see ATR below).Sustained esophageal contractionsSEC are another mechanism proposed to explain the pathogenesis of heartburn in NERD. SEC, which represent prolonged contractions of the esophageal longitudinal smooth muscle, can be detected in vivo in humans as an increase in wall thickness by high frequency endoscopic ultrasonography.17Pehlivanov N. Liu J. Kassab G.S. Puckett J.L. Mittal R.K. Relationship between esophageal muscle thickness and intraluminal pressure An ultrasonographic study.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G1093-G1098PubMed Google Scholar The concept that SEC are the cause of heartburn in NERD evolved from observations in a dozen patients with GERD. GERD was diagnosed by a history of retrosternal burning in the absence of other identifiable causes. Relief with antacids and endoscopy findings were not presented; however, pH monitoring was reportedly abnormal for the group as a whole. SEC were identified for all subjects during continuous intraluminal ultrasonography and correlated with the symptom of heartburn and acid reflux on pH montoring. During the study, there were 40 episodes of heartburn in 11 subjects, and SEC—with mean duration of 45 seconds (range, 18–148 seconds)—preceded heartburn in 28 (70%) subjects.18Pehlivanov N. Liu J. Mittal R.K. Sustained esophageal contraction A motor correlate of heartburn symptom.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G743-G751PubMed Google Scholar In addition, because SEC in these patients correlated better with retrosternal burning than did acid reflux, if causal SEC would offer an explanation for the lack of correlation of heartburn and acid reflux on pH monitoring. In another test of this hypothesis, 15 subjects were monitored for SEC while undergoing a Bernstein test. In 6 of 8 (75%) subjects who were Bernstein positive, symptoms were accompanied by SEC, whereas an SEC was only observed in 1 of 7 (14%) subjects who were Bernstein negative.18Pehlivanov N. Liu J. Mittal R.K. Sustained esophageal contraction A motor correlate of heartburn symptom.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G743-G751PubMed Google Scholar Notably, the positive correlation between SEC and heartburn in GERD are paralleled in another report by an equally strong (75%) correlation between SEC and spontaneous chest pain in patients with atypical chest complaints.19Balaban D.H. Yamamoto Y. Liu J. Pehlivanov N. Wisniewski R. DeSilvey D. Mittal R.K. Sustained esophageal contraction A marker of esophageal chest pain identified by intraluminal ultrasonography.Gastroenterology. 1999; 116: 29-37Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Moreover, in patients with atypical chest complaints, SEC accompanied chest pain in 5 patients responding positively to edrophonium and were absent in all patients who were edrophonium negative. Taken together, these data suggest that SEC correlate with chest pain of esophageal origin and that this is the case irrespective of the nature of the provocation, yet it remains unclear whether SEC, either via neuronal compression or localized neuronal ischemia, are actually causal for either or both types of symptoms. For instance, the evidence in favor of causality for reflux-associated heartburn include the following: (1) association with spontaneously occurring “heartburn,” (2) association with heartburn precipitated by Bernstein testing, and (3) appearance shortly before the onset of symptoms. Conversely, causality can be questioned based on the following: (1) lack of specificity (SEC occurring with high frequency irrespective of the provocation); (2) brevity (short duration [seconds] of SEC, making it difficult to reconcile with duration of heartburn or its relief by antacids); (3) variable association with heartburn (SEC being absent in 30% and having resolved before the onset of symptoms in another 25% of events17Pehlivanov N. Liu J. Kassab G.S. Puckett J.L. Mittal R.K. Relationship between esophageal muscle thickness and intraluminal pressure An ultrasonographic study.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G1093-G1098PubMed Google Scholar); and (4) failure of atropine to reduce the frequency or severity of heartburn while reducing esophageal wall thickness by ∼25%.20Dodds W.J. Dent J. Hogan W.J. Arndorfer R.C. Effect of atropine on esophageal motor function in humans.Am J Physiol. 1981; 240: G290-G296PubMed Google Scholar, 21Mittal R. Gui A. Liu J. The sustained esophageal contraction associated with heartburn of a positive Bernstein test is mediated through a non-cholinergic pathway.Gastroenterology. 2001; 120: A2149Google ScholarAbnormal tissue resistanceATR is the third mechanism proposed to explain the pathogenesis of heartburn in NERD. In this context “abnormal tissue resistance” refers specifically to “abnormal esophageal epithelial barrier function.” In the esophagus, the main structural components of the barrier are the apical membranes and junctional complexes of the cells comprising the stratum corneum.22Orlando R.C. Lacy E.R. Tobey N.A. Cowart K. Barriers to paracellular permeability in rabbit esophageal epithelium.Gastroenterology. 1992; 102: 910-923PubMed Google Scholar These protect by preventing the diffusion of ingested and refluxed luminal contents from penetrating into the esophageal mucosa. In animal models of NERD, created by exposing the esophageal mucosa to acid or acid-pepsin, acid and acid-pepsin damage the esophagus by initially attacking the junctional complex.23Tobey N.A. Hosseini S.S. Caymaz-Bor C. Wyatt H.R. Orlando G.S. Orlando R.C. The role of pepsin in acid injury to esophageal epithelium.Am J Gastroenterology. 2001; 96: 3062-3070Crossref PubMed Google Scholar, 24Orlando R.C. Powell D.W. Carney C.N. Pathophysiology of acute acid injury in rabbit esophageal epithelium.J Clin Invest. 1981; 68: 286-293Crossref PubMed Scopus (132) Google Scholar, 25Orlando R.C. Gastroesophageal reflux disease Offensive factors and tissue resistance.in: Orlando R.C. Gastroesophageal reflux disease. Marcel Dekker, New York2000: 165-192Crossref Google Scholar Damage to the junctions results in (and is identified by) reductions in both the esophageal potential difference (PD) and transmural electrical resistance and increases in paracellular permeability to water, electrolytes, and small molecules. Moreover, and as a consequence of the increase in salt and water flow across the junctions, dilated intercellular spaces develop within the squamous epithelium.24Orlando R.C. Powell D.W. Carney C.N. Pathophysiology of acute acid injury in rabbit esophageal epithelium.J Clin Invest. 1981; 68: 286-293Crossref PubMed Scopus (132) Google Scholar, 26Carney C.N. Orlando R.C. Powell D.W. Dotson M.M. Morphologic alterations in early acid-induced epithelial injury of the rabbit esophagus.Lab Invest. 1981; 45: 198-208PubMed Google Scholar, 27Tobey N.A. Hosseini S.S. Argote C.M. DobrucaliAM Awayda M.S. Orlando R.C. Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophagal epithelium.Am J Gastroenterol. 2004; 99: 13-22Crossref PubMed Scopus (218) Google Scholar Noteworthy, dilated intercellular spaces are not only a recognized feature of experimental acid injury in animal models, but this same lesion has been established as a morphologic feature in GERD, both nonerosive and erosive types (Figure 1).28Tobey N.A. Carson J.L. Alkiek R.A. Orlando R.C. Dilated intercellular spaces A morphological feature of acid reflux-damaged human esophageal epithelium.Gastroenterology. 1996; 111: 1200-1205Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, 29Solcia E. Villani L. Luinetti O. Trespi E. Strada E. Tinelli C. Fiocca R. Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease.Virchows Arch. 2000; 436: 207-216Crossref PubMed Scopus (101) Google Scholar, 30Calabrese C. Fabbri A. Bortolotti M. Cenacchi G. Areni A. Scialpi C. Miglioli M. Di Febo G. Dilated intercellular spaces as a marker of oesophageal damage Comparative results in gastro-oesophageal reflux disease with and without bile reflux.Aliment Pharmacol Ther. 2003; 18: 525-532Crossref PubMed Scopus (124) Google Scholar This suggests that, as in experimental models, ATR because of damaged junctions is an early lesion in GERD and a fundamental defect in NERD. Support for this concept can also be found in humans by monitoring the response of the esophageal PD to acid perfusion in vivo. In NERD and healthy subjects, basal esophageal PD values are similar; however, during acid perfusion, the PD in NERD either rises higher or falls lower than the PD values observed in healthy subjects.31Orlando R.C. Powell D.W. Studies of esophageal epithelial electrolyte transport and potential difference in man.in: Allen A. Flemstrm G. Garner A. Silen W. Turnberg L. Mechanisms of mucosal protection in the upper gastrointestinal tract. Raven, New York1984: 75-80Google Scholar, 32Orlando R.C. Powell D.W. Bryson J.C. Kinard III, H.B. Carney C.N. Jones J.D. Bozymski E.M. Esophageal potential difference measurements in esophageal disease.Gastroenterology. 1982; 83: 1026-1032PubMed Scopus (40) Google Scholar, 33Carlsson R. Fandriks L. Jonsson C. Lundell L. Orlando R.C. Is the esophageal squamous epithelial barrier function impaired in patients with gastroesophageal reflux disease?.Scand J Gastroenterol. 1999; 5: 454-458Google Scholar Because both changes reflect increased ion permeability in the tissue, these findings are consistent with ATR in NERD. Notably, the term ATR in NERD neither establishes etiology for the damage to the intercellular junctions nor that the defective junctions are the primary cause of NERD. Indeed, there is evidence to indicate that ATR in NERD is a secondary event because dilated intercellular spaces as a marker of junctional damage have been noted to return to normal following treatment.34Calabrese C. Areni A. Miglioli M. DeFebo G. Omeprazole and ultrastructural modifications occurring in reflux esophagitis.Gastroenterology. 2002; 122: 837Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarThe presence of ATR in NERD has potentially important ramifications for symptoms, given that Robles-Chillidia et al35Robles-Chillida E.M. Rodrigo J. Mayo I. Arnedo A. Gomez A. Ultrastructure of free-ending nerve fibers in oesophageal epithelium.J Anat. 1981; 133: 227PubMed Google Scholar and Rodrigo et al36Rodrigo J. Hernandez D.J. Vidal M.A. Pedrosa J.A. Vegetative innervation of the esophagus III. Intraepithelial endings.Acta Anat. 1975; 92: 242Crossref PubMed Google Scholar have localized the sensory neurons in Macaque esophageal epithelium to the intercellular spaces and these to within 3 cell layers of the lumen. In addition, the studies of Kollarik and Undem37Kollarik M. Undem B.J. Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea pig.J Physiol. 2002; 543.2: 591-600Crossref Scopus (172) Google Scholar in guinea pig trachea, a tissue neurally and embrologically similar to esophagus, and Steen et al38Steen K.H. Steen A.E. Reeh P.W. A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro.J Neurosci. 1995; 15: 3982-3989Crossref PubMed Google Scholar and Steen and Reeh39Steen K.H. Reeh P.W. Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in humans.Neurosci Lett. 1993; 154: 113-116Crossref PubMed Scopus (169) Google Scholar in human and rat skin, another organ lined by stratified squamous epithelia, are notable because they document that the sensory nerves contain chemosensitive nociceptors capable of responding to an acidic environment and, in the Steen and Reeh39Steen K.H. Reeh P.W. Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in humans.Neurosci Lett. 1993; 154: 113-116Crossref PubMed Scopus (169) Google Scholar investigation, responding with pain. Moreover, the level of acidity that activated the nociceptors was over a pH range of only 5.2–6.9. Although signaling at such modest pH levels may appear surprising, given the magnitude of the pH declines that can occur within the lumen, on reappraisal, the signaling is appropriate if it is to serve a protective function. This is because acidity of this magnitude, (ie, pH <6.5), is destructive to squamous cells when in contact with the basolateral cell membrane.40Tobey N.A. Powell D.W. Schreiner V.J. Orlando R.C. Serosal bicarbonate protects against acid injury to rabbit esophagus.Gastroenterology. 1989; 96: 1466-1477PubMed Google Scholar From this, we surmise that heartburn develops in NERD because of the existence of ATR. ATR leads to reflux-associated heartburn because the increased paracellular permeability because of junctional damage permits refluxed gastric acid entry to the intercellular space and access to the acid-sensitive nociceptors (Figure 2).Figure 2Unifying hypothesis: The presence of abnormal tissue resistance—demonstrated by defects within the intercellular junctional complex between cells of the surface layers of esophageal (stratified squamous) epithelium—is shown to enable the ready diffusion of refluxed gastric acid (H+) into the intercellular space. Within this space, it encounters and activates chemosensitive nociceptors whose signals are transmitted via the spinal cord to the brain for symptom (heartburn) perception. Activation of the same nociceptors are also capable of initiating a short reflex arc to esophageal (longitudinal) smooth muscle as means of precipitating a sustained esophageal contraction.View Large Image Figure ViewerDownload (PPT)ATR: as unifying hypothesisATR also has potential appeal as the underlying pathogenetic mechanism for reflux-associated heartburn in NERD because it can reconcile the observations used to support the causality of EVH and SEC. For instance, ATR embraces EVH in NERD from the perspective of luminal acidity but counters the suggestion that acid hypersensitivity is due to inappropriate neuronal signaling with the concept that ATR results in appropriate activation of esophageal nociceptors by diffusion of luminal acid into (and acidification of) the intercellular space (Figure 2). Furthermore, because Mehta et al11Mehta A.J. Caestecker J.S. Camm A.J. Northfield T.C. Sensitization to painful distention and abnormal sensory perception in the esophagus.Gastroenterology. 1995; 108: 311-319Abstract Full Text PDF PubMed Scopus (93) Google Scholar and Hu et al41Hu W.H. Martin C.J. Talley N.J. Intraesophageal acid perfusion sensitizes the esophagus to mechanical distension A barostat study.Am J Gastroenterol. 2000; 95: 2189-2194Crossref PubMed Google Scholar have shown the development of mechanical hypersensitivity to balloon distention following acid perfusion in the healthy human esophagus, acid activation of the esophageal nociceptors because of ATR could explain the proposed, but yet unproven, development of mechanosensitization in NERD. Similarly, ATR embra
Referência(s)