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Cameron Symposium on Barrett Esophagus and GERD
Pathogenesis of Gastroesophageal Reflux and Barrett Esophagus NAVTEJ S. BUTTAR, MBBS, AND GARY W. FALK, MD defense. This article is an overview of the dysfunction of the esophagogastric junction that leads to GERD. The role of the contents of the reflux and that of Helicobacter pylori infection in the pathogenesis of Barrett esophagus are also summarized. Mayo Clin Proc. 2001;76:226-234
Barrett esophagus is a metaplastic condition that affects the lower esophagus and is a complication of gastroesophageal reflux disease (GERD). Under normal circumstances, the reflux of gastric contents into the esophagus is prevented by a complex barrier at the esophagogastric junction. Dysfunction of the lower esophageal sphincter and the presence of a hiatal hernia lead to failure of this barrier. Esophageal mucosal damage results from the chronic exposure of the esophageal mucosa to gastroduodenal contents and the lack of an effective mucosal
EG = esophagogastric; GERD = gastroesophageal reflux disease; LES = lower esophageal sphincter; NANC = nonadrenergic, noncholinergic
G
as a zone of elevated intraluminal pressures at the EG junction. It is defined grossly as a contracted ring of muscle at the EG junction. Anatomically, it is a ring of thickened muscle at the EG junction. The ring is positioned so that it angles obliquely upward from the lesser to the greater curvature. Its thickness and width are greatest on the greater curve side. The ring is composed of 2 distinct smooth muscle components. One component is made up of short transverse clasps of muscle that form semicircles, the ends of which terminate on the anterior and posterior aspects of the EG junction. The other component of the sphincter is the sling of fibers that are along oblique loops of muscle fibers that loop around the greater curve side of the EG junction.1 Anatomically, these 2 smooth muscle components represent true LES as they are part of the esophageal wall. From the physiologic standpoint, due to their proximity to striated muscle fibers of diaphragmatic crura that can augment their tone, the smooth muscle part is often called the internal component, and the striated muscle part is called the external component of LES (Figure 1). The distal esophagus is anchored to the crural diaphragm by the phrenicoesophageal ligament. Normally, the length of the LES is 4 cm.2 Resting pressure of the LES is related to intrinsic muscle tone. This muscle is contracted at rest3,4 and remains so even when denervated.5,6 The innervation to the LES modulates its intrinsic tone. The LES has an intrinsic and extrinsic innervation. The extrinsic innervation is made up of both preganglionic parasympathetic fibers and postganglionic sympathetic fibers. The parasympathetic fibers arise in the dorsal motor nucleus of the vagus and travel with the vagus nerve to innervate postganglionic neurons in the myenteric plexus. Most of the sympathetic fibers that reach the LES do so by joining the vagus as it passes through the thoracic cavity. They termi-
astroesophageal reflux disease (GERD) is a spectrum of pathology ranging from esophagitis to the development of specialized intestinal metaplasia known as Barrett esophagus. The stomach and esophagus have distinct mucosal environments by virtue of a competent esophagogastric (EG) junction and mechanisms to alter rapidly any change in this environment. A failure that results in the change of the esophageal environment is poorly tolerated and may result in GERD. Following is a brief overview of the pathogenesis of GERD and Barrett esophagus. PATHOPHYSIOLOGY OF GERD Gastroesophageal reflux occurs when the normal antireflux barrier between the stomach and the esophagus, the EG junction, is impaired either transiently or permanently. Transient lower esophageal sphincter (LES) relaxation is the single most common functional abnormality that leads to failure of the antireflux barrier. The impaired EG junction allows a complex interaction between gastroduodenal contents and esophageal defense mechanisms that leads to GERD. The EG Junction The EG junction is critical in preventing the reflux of gastric contents. The barrier at the EG junction is maintained by the LES, defined physiologically by manometry From the Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic, Rochester, Minn (N.S.B.); and Center for Swallowing and Esophageal Disorders, Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio (G.W.F.). Individual reprints of this article are not available. The entire Alan J. Cameron Symposium on Barrett Esophagus and Gastroesophageal Reflux Disease will be available for purchase as a bound booklet from the Proceedings Editorial Office at a later date. Mayo Clin Proc. 2001;76:226-234
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Figure 1. Anatomy of the esophagogastric junction. The lower esophageal sphincter and the crural diaphragm constitute the intrinsic and extrinsic sphincters, respectively. The 2 sphincters are anatomically superimposed and are anchored to each other by the phrenicoesophageal ligament (reprinted with permission from Mittal and Balaban2).
nate in the myenteric plexus, and they play little role in control of the LES.7,8 Vagus nerve–mediated parasympathetic pathways can cause both LES relaxation and contraction. The majority of the vagus nerve comprises cholinergic preganglionic fibers that synapse with excitatory cholinergic pathways and inhibitory nonadrenergic, noncholinergic (NANC) pathways to mediate increases and decreases in muscle tone, respectively. In general, the relaxation responses to vagal stimulation are reduced by interfering with NANC neurotransmitters, such as nitric oxide9,10 or vasoactive intestinal polypeptide. Hexamethonium, which blocks nicotinic receptors at the autonomic ganglia, reduces both excitatory and inhibitory responses, but atropine, which is a cholinergic muscarinic receptor blocker, abolishes the excitatory response.11 Nitric oxide also mediates LES relaxation in response to swallowing.12,13 Two interdependent conditions can interfere with the physiologic functions of the EG junction. The LES dysfunction is a functional problem, and hiatal hernia is an anatomically determined functional disorder. LES Dysfunction.—Gastroesophageal reflux was once thought to be simply related to a marked reduction in basal LES tone. However, reflux across the EG junction related to LES dysfunction can occur by 1 of 3 mechanisms in patients with GERD: transient relaxation of the LES, transient increase of intra-abdominal pressure that overcomes the LES pressure, or spontaneous free reflux across a predominantly low-pressure LES zone.14 Dodds et al14 found that transient LES relaxation accounted for 65% of the
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reflux episodes in the reflux esophagitis patients and was the most common mechanism of GERD. Other investigators have also demonstrated that the transient LES relaxation is the single most common mechanism in GERD.15-17 Factors that increase the frequency of transient relaxation of the LES include gastric distention, high-fat meals, and the upright position.18-20 However, the reason reflux patients have more frequent transient LES relaxation than controls is unknown. While the importance of low basal LES tone has been deemphasized, a marked reduction of LES pressure can contribute to reflux in a subset of patients with especially severe disease. Dent et al16 found that the absence of LES pressure became a progressively more common mechanism of reflux with increasing severity of esophagitis. Others have confirmed these findings.21-23 The cause of low basal LES tone is unclear; however, a link between inflammation, arachidonic acid, and LES tone has been proposed based on an animal model in which the contraction and relaxation of LES could be induced in response to arachidonic acid and its metabolites.24 Hiatal Hernia.—A hiatal hernia is an acquired prolapse of a portion of the stomach through the diaphragmatic hiatus into the chest. The majority of hiatal hernias are of the sliding type in which the LES is displaced into the chest, above the diaphragmatic hiatus. There is a fine balance between the forces pulling the esophagus through the diaphragmatic hiatus into the thoracic cavity and the supporting structures that try to keep the EG junction at or below the diaphragmatic hiatus. An imbalance between these forces may lead to development of a hiatal hernia. The supporting structures are the phrenicoesophageal membrane and the diaphragmatic crura that tend to maintain the position of the EG junction at or below the diaphragmatic hiatus.25 The pulling forces are excessive contraction of the longitudinal muscle and shortening of the esophagus due to fibrosis. The supporting structures may vary from person to person and lose some of their elasticity with age.25 A hiatal hernia may contribute to gastroesophageal reflux by a variety of mechanisms. Gastric contents may be trapped in a hiatal hernia sac and then reflux proximally into the esophagus during a swallow-induced relaxation of the LES26 (Figure 2). Esophageal emptying can be impaired by a nonreducing large hiatal hernia.27 Large hiatal hernias may also displace the lower esophageal high-pressure zone proximally, and with increasing displacement, the length of high-pressure zone can decrease.28 Finally, a large hiatal hernia may widen the diaphragmatic hiatus, which may impair the ability of the crural diaphragm to function as an external sphincter.2 The importance of a hiatal hernia in GERD is therefore related to the anatomically determined functional impair-
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Figure 2. Mechanism of reflux due to hiatal hernia. A hiatal hernia is an acquired herniation of part of the stomach through the diaphragm (A). After an episode of reflux (B), an esophageal peristaltic contraction clears the bolus of acid from the esophagus (C) into the hiatal hernia (D). Subsequently, swallowinginduced relaxation of the lower esophageal sphincter results in reflux of acid from the hernial sac into the esophagus (E). This sequence can be repeated several times and results in markedly prolonged clearance of acid (reprinted with permission from Mittal and Balaban2).
ment of the EG junction that leads to increased esophageal acid exposure. Although a hiatal hernia may or may not be an initiating factor at the inception of reflux disease, it clearly can act as a sustaining factor accounting for the chronicity of the disease. Furthermore, esophageal injury resulting from reflux may lead to increasing shortening and fibrosis of esophagus25 that may further increase the size of hiatal hernia and worsen the existing LES dysfunction (Figure 3). Effect of the Contents of Reflux The development of GERD is influenced by the composition of the material refluxed into the esophagus. Animal studies clearly demonstrate that acid and pepsin can cause mucosal damage.29 Although the esophageal mucosa is relatively resistant to acid, damage does occur at a high concentration (pH<2.0). In addition, duodenal contents, which include bile acids and the pancreatic enzyme trypsin, can also cause esophageal damage. Mucosal damage by bile acids depends on the conjugation state of the bile acids as well as the pH of the solution. Conjugated bile acids cause mucosal injury only at an acidic pH, whereas unconjugated bile acids as well as the pancreatic enzyme trypsin cause mucosal injury at a pH higher than 7.29 In humans, acid exposure in the distal esophagus as measured by 24-hour pH monitoring increases across the spectrum of GERD from nonerosive reflux disease to erosive reflux disease to Barrett esophagus and its complications.30,31 However, when compared with appropriate ageand sex-matched controls, acid and pepsin secretion is similar in patients with GERD, regardless of its severity.32 In patients with the classic acid hypersecretory condition, Zollinger-Ellison syndrome, endoscopic abnormalities of the esophagus are encountered more frequently than in the normal population.33 Others suggest that a subset of GERD patients may have acid hypersecretion, although these stud-
ies are not as well controlled.22,34,35 In summary, acid is required for esophageal injury, but acid hypersecretion does not appear to play an important role in GERD. Gastric Emptying Gastroesophageal reflux depends on an available reservoir of intragastric fluid. Delayed gastric emptying of liquids and solids is a potential mechanism that could increase the reservoir of gastric contents available to reflux. McCallum et al36 found that 41% of GERD patients had delayed emptying of a mixed solid-liquid meal. Others have also described delayed gastric emptying of a solid test meal.37 However, recent studies using more accurate methods demonstrated no difference in the rate of gastric emptying in GERD patients with or without esophageal mucosal injury and asymptomatic control groups.38,39 A more recent study of 87 GERD patients, 41 without esophagitis and 46 with reflux esophagitis (grade 1-3), found no difference in gastric emptying between the 2 groups.22 Thus, it appears that delayed gastric emptying is unlikely to be a major factor in the pathogenesis of GERD in most patients. It may, however, contribute to the development of GERD in a subset of patients. Esophageal Defenses Although many mechanisms may be involved in reflux, the common end result is exposure of esophageal mucosa to gastric and duodenal contents due to impaired function of the gastroesophageal barrier. This is countered by esophageal defense mechanisms, including esophageal clearance and mucosal resistance. Esophageal Clearance.—Esophageal acid clearance is one of the important defense mechanisms that protects against the development of esophageal mucosal injury. The efficiency of esophageal clearance determines the duration of esophageal exposure to noxious components of the gas-
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Figure 3. Potential mechanism of gastroesophageal reflux disease. Increased transient lower esophageal sphincter relaxation is the predominant mechanism of gastroesophageal reflux disease. A subset of patients with gastroesophageal reflux disease have hypotensive lower esophageal sphincter and usually have severe reflux disease.
troesophageal reflux. Under normal circumstances, gastric contents are cleared from the esophagus by normal peristalsis.40 Peristaltic dysfunction such as failed primary peristalsis and feeble peristaltic waves, which may result in impaired acid clearance, is common in GERD. Kahrilas et al41 found that peristaltic dysfunction was progressively more common with increasing severity of esophagitis and occurred in 25% of patients with mild esophagitis and 48% of patients with severe esophagitis. Whether peristaltic dysfunction is a primary defect or one due to acid-induced injury is not clear. Experiments done in animal models
have demonstrated that impaired contractility of the esophagus may occur in response to reflux.42 However, healing of esophagitis does not improve any of the motor abnormalities encountered in GERD.43,44 Esophageal peristalsis alone is not adequate for esophageal acid clearance. While acid volume is emptied from the esophagus after 1 or 2 peristaltic sequences, residual acid in the esophagus is neutralized by saliva in increments with each subsequent swallow.40 Aspirating saliva from the mouth results in failure to neutralize acid in the esophagus despite clearance of esophageal volume by normal peristal-
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sis. This points out the importance of saliva in esophageal acid clearance. Saliva also contains a number of growth factors such as epidermal growth factor, transforming growth factor α, and transforming growth factor β, which may help in healing and restitution of the esophageal lining. The role of salivary growth factor deficiency in patients with GERD and its complications has not been clearly elucidated.45 Mucosal Resistance.—Healthy esophageal mucosa has a variety of mechanisms to protect itself from injury. Continuous exposure of the healthy esophagus to 100-mmol/L hydrochloric acid (pH 1.1) for 30 minutes, as done in Bernstein test, does not produce signs of mucosal damage. The factors that contribute to such protection are divided into preepithelial, epithelial, and postepithelial defenses. Preepithelial defenses include the mucus and unstirred water layer along with surface bicarbonate ions. Epithelial defenses include the apical cell membrane, junctional barriers, intracellular and extracellular buffers, and pH regulatory processes. In healthy tissue, hydrogen ions cannot cross the apical surface membrane of epithelial cells. However, high luminal acidity can damage intercellular junctions and lead to acidification of the intercellular spaces. This exposes the basolateral aspect of the epithelial cells to hydrogen ions and can eventually lead to loss of osmoregulation and cell death. The postepithelial defenses include blood flow and tissue acid base balance. It is unclear at this time if the patients who are predisposed to gastroesophageal reflux–related injury have suboptimal mucosal defense.46 Dietary Factors and Smoking Dietary factors and smoking play an indirect role in the pathophysiology of GERD. Moderate alcohol consumption increases the exposure of the distal esophagus to acid and impairs the normal acid clearance in supine position.47,48 Alcohol can decrease LES pressure.49 The role of cigarette smoking in GERD is unclear.50-54 Cigarette smoking can increase the number of reflux episodes,50 increase esophageal acid exposure,52 and decrease LES pressure.53 Interestingly, smoking cessation does not affect esophageal acid exposure.51 PATHOGENESIS OF BARRETT ESOPHAGUS Barrett esophagus is the most serious complication of GERD because of its association with an increased risk of adenocarcinoma of the esophagus. Approximately 10% of patients with GERD symptoms have Barrett esophagus.48,55 Gastroesophageal reflux results in varying degrees of esophageal mucosal damage. Depending on the mucosal environment at the time of healing, patients may develop squamous or columnar epithelium. Why some patients with GERD develop Barrett esophagus whereas others do not is
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unclear. The following is an overview of pathogenesis of Barrett esophagus. Animal Models Bremner et al56 studied esophageal mucosal regeneration in a canine model of gastroesophageal reflux. In this study, the distal esophageal mucosa was excised, gastroesophageal reflux was induced (by creation of a hiatal hernia and destruction of the LES), and a subset of dogs was given histamine to further stimulate acid secretion. In the control group (with mucosal excision only), reepithelialization occurred with squamous epithelium. In the hiatal hernia group without acid hypersecretion, the mucosal defects were replaced by equal amounts of squamous and columnar epithelium. The mucosal defects of the hiatal hernia group with concomitant acid hypersecretion were almost completely replaced by columnar epithelium.56 In a recent study with a similar canine model, depth of experimental injury was considered to be a determinant of the type of epithelium that regenerates subsequently.57 Further work by Gillen et al58 examined the contents of reflux that contributed to the development of Barrett esophagus. In this study, mucosal defects in the distal esophagus of dogs were created. All dogs had gastroesophageal reflux by creation of a hiatal hernia and cardioplasty. A subgroup of dogs also had biliary diversion into the proximal stomach to create duodenogastroesophageal reflux. The dogs in the gastroesophageal reflux group as well as the duodenogastroesophageal reflux group developed columnar epithelium. However, when animals in the latter group were given cimetidine, no columnar epithelium developed. These results emphasize the importance of gastric acid reflux in the development of Barrett esophagus either alone or in combination with duodenal reflux. Acid and Pepsin In humans, Barrett esophagus is clearly associated with severe gastroesophageal reflux. Compared with patients with erosive and nonerosive GERD, patients with Barrett esophagus typically have greater esophageal acid exposure based on 24-hour pH monitoring.31,59-63 Part of the increase in acid exposure in patients with Barrett esophagus may be related to the almost uniform presence of a hiatal hernia, which is typically longer and associated with larger defects in the hiatus in patients with Barrett esophagus than in controls or patients with esophagitis alone.64 In addition, patients with Barrett esophagus have a lower basal LES pressure compared with patients with GERD without Barrett esophagus.62 It was once thought that patients with Barrett esophagus had a greater acid output, both basally and in response to pentagastrin stimulation, compared with normal individuals without reflux.65,66 However, more recent studies using appropriately matched controls found no
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difference in basal acid output or 24-hour and daytime patterns of gastric pH between healthy subjects and patients with Barrett esophagus.67,68 Patients with Barrett esophagus may be less sensitive to acid in the esophagus. Barrett esophagus patients have a positive Bernstein test less often than patients with uncomplicated reflux disease, and those with a positive test take longer to develop pain during acid perfusion.69 However, most patients with Barrett esophagus are elderly, and this observation may be due to an age-related decline in acid sensitivity.70 Finally, mucosal ablation of Barrett esophagus by a variety of techniques has been reported to heal with squamous rather than columnar epithelium when mucosal ablation is accompanied by vigorous acid suppression, whereas recurrent Barrett epithelium is more common in the absence of acid suppression.71-73 The role of pepsin has not been explored extensively in Barrett esophagus. Activation of pepsin requires a pH of less than 3; thus, separating the role of pepsin from acid alone is difficult. Hirschowitz67 could find no difference in pepsin output in patients with Barrett esophagus compared with age- and sex-matched controls. Reflux of gastric acid alone is not the only factor responsible for the pathogenesis of Barrett esophagus. Rather, a complex interaction of acid exposure, genetic susceptibility, environmental factors, and duodenogastroesophageal reflux may contribute to the pathogenesis of Barrett esophagus. Bile Reflux Excessive reflux of duodenal contents into the esophagus may contribute to the development of Barrett esophagus and its complications. Bile reflux is a term often used to describe the reflux of duodenal contents, which includes conjugated and unconjugated bile acids, lysolecithin, and pancreatic enzymes such as trypsin. A graded increase in fasting gastric bile acid concentrations occurs across the spectrum of nonerosive GERD, erosive GERD, Barrett esophagus, and Barrett esophagus complicated by ulcers, strictures, dysplasia, or carcinoma. This is also accompanied by increase in duodenogastroesophageal reflux.31,74,75 Duodenogastroesophageal reflux is increased in Barrett esophagus patients compared with age-matched controls, especially in patients with complications of Barrett esophagus such as ulcers, strictures, or dysplasia.76 Interestingly, increased duodenoesophageal reflux in these patients parallels increased acid reflux in the same patients. Thus, the majority of duodenogastroesophageal reflux episodes (70%-91%) occur in an acidic environment (pH<4).30,31 Taken together, these studies suggest the importance of both gastric and duodenal contents in the pathogenesis of Barrett esophagus.
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Cell of Origin The development of Barrett esophagus requires injury to the esophageal mucosa accompanied by an abnormal environment for epithelial repair as outlined above. The cell of origin is unclear; candidates include esophageal glandular cells, heterotopic gastric mucosa, or abnormal differentiation of a primordial stem cell. Barrett epithelium was initially thought to result from the upward migration of gastric epithelium after denudation of esophageal squamous epithelium. This hypothesis was disproved by the animal models outlined above. A cell with features of both squamous and columnar epithelium has been identified with scanning electron microscopy at the transition zone between normal esophageal squamous epithelium and the columnar epithelium of Barrett esophagus.77 Recent work by Boch et al78 focused on a new multilayered epithelium within Barrett epithelium that has histologic characteristics of both squamous and columnar epithelium. This epithelium concurrently expressed markers of both squamous and columnar cytokeratins, the cytoskeletal structural proteins present in all epithelia. In patients with Barrett esophagus without this multilayered epithelium, only markers to columnar cytokeratins were expressed, whereas squamous epithelium from the squamocolumnar junction expressed only squamous markers. These findings further support a multipotential stem cell as the origin of Barrett epithelium, although why this stem cell follows a columnar line of differentiation after esophageal injury from acid remains unclear.
Helicobacter pylori Infection The role of H pylori in the development of Barrett esophagus has been the subject of intense interest.79,80 Hospitalization and death rates for distal gastric cancer and duodenal ulcer disease have decreased since 1970, while those for GERD and esophageal adenocarcinoma have increased during that same time period.81 It is tempting to link these opposing time trends to the decline in the prevalence of H pylori infection in the Western world.82 While most studies find no causal relationship between H pylori infection and Barrett esophagus, some evidence suggests a possible protective role of H pylori infection.83-85 What accounts for a potential protective effect of infection with H pylori? Corpus-predominant gastritis is associated with decreased acid secretion as well as a decreased risk for the development of Barrett esophagus.86 The protective effect of H pylori infection may also be related to colonization with cagA-positive H pylori strains. Several recent reports are consistent with these observations. Vicari et al84 found that the prevalence of cagApositive H pylori strains was decreased in patients with Barrett esophagus and Barrett esophagus with adenocarci-
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noma or dysplasia compared with a control population. Similarly, Chow et al87 reported that carriage of cagApositive strains was associated with an increased risk for distal gastric cancers but with a reduced risk for esophageal and gastric cardia adenocarcinomas. Changes in gastric reflux modulated by H pylori colonization may account for the observations in patients susceptible to GERD (hiatal hernia, LES dysfunction, esophageal dysmotility). Patients without H pylori infection or those infected with cagA-negative strains have little or no corpus inflammation with normal or high intragastric acidity, which, in susceptible individuals, promotes the development of reflux or its complications. However, colonization with cagA-positive strains of H pylori and its associated severe corpus inflammation result in less acidic gastric reflux, which may be protective against the development of GERD and its complications.88 CONCLUSION Barrett esophagus is closely associated with reflux and is a long-term, serious complication of reflux. The reflux of gastric and duodenal contents into the esophagus is prevented by a complex barrier that exists at the EG junction. The failure of this barrier chronically exposes the lower esophageal mucosa to gastric and duodenal contents. The interaction of these offending factors with the factors providing mucosal defense leads to mucosal damage and development of Barrett esophagus. A better understanding of the pathogenesis of both GERD and Barrett esophagus is anticipated in the coming years. REFERENCES 1.
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Champion G, Richter JE, Vaezi MF, Singh S, Alexander R. Duodenogastroesophageal reflux: relationship to pH and importance in Barrett’s esophagus. Gastroenterology. 1994;107:747754. Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology. 1991;101:1149-1158. Miller LS, Vinayek R, Frucht H, Gardner JD, Jensen RT, Maton PN. Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology. 1990;98:341-346. Collen MJ, Johnson DA, Sheridan MJ. Basal acid output and gastric acid hypersecretion in gastroesophageal reflux disease: correlation with ranitidine therapy. Dig Dis Sci. 1994;39:410417. Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. Gastroenterology. 1990;98:654-661. McCallum RW, Berkowitz DM, Lerner E. Gastric emptying in patients with gastroesophageal reflux. Gastroenterology. 1981;80: 285-291. Maddern GJ, Chatterton BE, Collins PJ, Horowitz M, Shearman DJ, Jamieson GG. Solid and liquid gastric emptying in patients with gastro-oesophageal reflux. Br J Surg. 1985;72:344-347. Shay SS, Eggli D, McDonald C, Johnson LF. Gastric emptying of solid food in patients with gastroesophageal reflux. Gastroenterology. 1987;92:459-465. Keshavarzian A, Bushnell DL, Sontag S, Yegelwel EJ, Smid K. Gastric emptying in patients with severe reflux esophagitis. Am J Gastroenterol. 1991;86:738-742. Helm JF, Dodds WJ, Pelc LR, Palmer DW, Hogan WJ, Teeter BC. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med. 1984;310:284-288. Kahrilas PJ, Dodds WJ, Hogan WJ, Kern M, Arndorfer RC, Reece A. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology. 1986;91:897-904. Eastwood GL, Castell DO, Higgs RH. Experimental esophagitis in cats impairs lower esophageal sphincter pressure. Gastroenterology. 1975;69:146-153. Eckardt VF. Does healing of esophagitis improve esophageal motor function? Dig Dis Sci. 1988;33:161-165. Howard JM, Reynolds RP, Frei JV, et al. Macroscopic healing of esophagitis does not improve esophageal motility. Dig Dis Sci. 1994;39:648-654. Kongara KR, Soffer EE. Saliva and esophageal protection. Am J Gastroenterol. 1999;94:1446-1452. Orlando RC. Mechanisms of reflux-induced epithelial injuries in the esophagus. Am J Med. 2000;108(suppl 4a):104S-108S. Vitale GC, Cheadle WG, Patel B, Sadek SA, Michel ME, Cuschieri A. The effect of alcohol on nocturnal gastroesophageal reflux. JAMA. 1987;258:2077-2079. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis. 1976;21: 953-956. Mayer EM, Grabowski CJ, Fisher RS. Effects of graded doses of alcohol upon esophageal motor function. Gastroenterology. 1978; 75:1133-1136. Schindlbeck NE, Heinrich C, Dendorfer A, Pace F, Muller-Lissner SA. Influence of smoking and esophageal intubation on esophageal pH-metry. Gastroenterology. 1987;92:1994-1997. Waring JP, Eastwood TF, Austin JM, Sanowski RA. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux. Am J Gastroenterol. 1989;84:1076-1078. Kadakia SC, Kikendall JW, Maydonovitch C, Johnson LF. Effect of cigarette smoking on gastroesophageal reflux measured by 24-h ambulatory esophageal pH monitoring. Am J Gastroenterol. 1995;90:1785-1790.
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Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking. Gut. 1990;31:4-10. Pehl C, Pfeiffer A, Wendl B, Nagy I, Kaess H. Effect of smoking on the results of esophageal pH measurement in clinical routine. J Clin Gastroenterol. 1997;25:503-506. Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med. 1986;315:362-371. Bremner CG, Lynch VP, Ellis FH Jr. Barrett’s esophagus: congenital or acquired? an experimental study of esophageal mucosal regeneration in the dog. Surgery. 1970;68:209-216. Li H, Walsh TN, O’Dowd G, Gillen P, Byrne PJ, Hennessy TP. Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett’s esophagus. Surgery. 1994;115:176-181. Gillen P, Keeling P, Byrne PJ, West AB, Hennessy TP. Experimental columnar metaplasia in the canine oesophagus. Br J Surg. 1988;75:113-115. Coenraad M, Masclee AA, Straathof JW, Ganesh S, Griffioen G, Lamers CB. Is Barrett’s esophagus characterized by more pronounced acid reflux than severe esophagitis? Am J Gastroenterol. 1998;93:1068-1072. Iascone C, DeMeester TR, Little AG, Skinner DB. Barrett’s esophagus: functional assessment, proposed pathogenesis, and surgical therapy. Arch Surg. 1983;118:543-549. Neumann CS, Cooper BT. 24 hour ambulatory oesophageal pH monitoring in uncomplicated Barrett’s oesophagus. Gut. 1994;35: 1352-1355. Singh P, Taylor RH, Colin-Jones DG. Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett’s metaplasia is present. Am J Gastroenterol. 1994;89:349-356. Oberg S, DeMeester TR, Peters JH, et al. The extent of Barrett’s esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure. J Thorac Cardiovasc Surg.1999;117:572-580. Cameron AJ. Barrett’s esophagus: prevalence and size of hiatal hernia. Am J Gastroenterol. 1999;94:2054-2059. Mulholland MW, Reid BJ, Levine DS, Rubin CE. Elevated gastric acid secretion in patients with Barrett’s metaplastic epithelium. Dig Dis Sci. 1989;34:1329-1334. Collen MJ, Johnson DA. Correlation between basal acid output and daily ranitidine dose required for therapy in Barrett’s esophagus. Dig Dis Sci. 1992;37:570-576. Hirschowitz BI. Gastric acid and pepsin secretion in patients with Barrett’s esophagus and appropriate controls. Dig Dis Sci. 1996; 41:1384-1391. Savarino V, Mela GS, Zentilin P, et al. Time pattern of gastric acidity in Barrett’s esophagus. Dig Dis Sci. 1996;41:1379-1383. Johnson DA, Winters C, Spurling TJ, Chobanian SJ, Cattau EL Jr. Esophageal acid sensitivity in Barrett’s esophagus. J Clin Gastroenterol. 1987;9:23-27. Grade A, Pulliam G, Johnson C, Garewal H, Sampliner RE, Fass R. Reduced chemoreceptor sensitivity in patients with Barrett’s esophagus may be related to age and not to the presence of Barrett’s epithelium. Am J Gastroenterol. 1997;92:2040-2043. Brandt LJ, Kauvar DR. Laser-induced transient regression of Barrett’s epithelium. Gastrointest Endosc. 1992;38:619-622. Van Laethem JL, Cremer M, Peny MO, Delhaye M, Deviere J. Eradication of Barrett’s mucosa with argon plasma coagulation and acid suppression: immediate and mid term results. Gut. 1998; 43:747-751. Haag S, Nandurkar S, Talley NJ. Regression of Barrett’s esophagus: the role of acid suppression, surgery, and ablative methods. Gastrointest Endosc. 1999;50:229-240. Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology. 1996;111:1192-1199.
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Gillen P, Keeling P, Byrne PJ, Healy M, O’Moore RR, Hennessy TP. Implication of duodenogastric reflux in the pathogenesis of Barrett’s oesophagus. Br J Surg. 1988;75:540-543. Attwood SE, DeMeester TR, Bremner CG, Barlow AP, Hinder RA. Alkaline gastroesophageal reflux: implications in the development of complications in Barrett’s columnar-lined lower esophagus. Surgery. 1989;106:764-770. Shields HM, Zwas F, Antonioli DA, Doos WG, Kim S, Spechler SJ. Detection by scanning electron microscopy of a distinctive esophageal surface cell at the junction of squamous and Barrett’s epithelium. Dig Dis Sci. 1993;38:97-108. Boch JA, Shields HM, Antonioli DA, Zwas F, Sawhney RA, Trier JS. Distribution of cytokeratin markers in Barrett’s specialized columnar epithelium. Gastroenterology. 1997;112:760765. O’Connor HJ. Review article: Helicobacter pylori and gastrooesophageal reflux disease-clinical implications and management. Aliment Pharmacol Ther. 1999;13:117-127. O’Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett’s esophagus: report on the Cleveland Clinic Barrett’s Esophagus Registry. Am J Gastroenterol. 1999;94: 2037-2042.
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El-Serag HB, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease. Gut. 1998;43:327-333. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA. The cohort effect and Helicobacter pylori. J Infect Dis. 1993;168:219-221. Varanasi RV, Fantry GT, Wilson KT. Decreased prevalence of Helicobacter pylori infection in gastroesophageal reflux disease. Helicobacter. 1998;3:188-194. Vicari JJ, Peek RM, Falk GW, et al. The seroprevalence of cagApositive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology. 1998;115:50-57. Werdmuller BF, Loffeld RJ. Helicobacter pylori infection has no role in the pathogenesis of reflux esophagitis. Dig Dis Sci. 1997; 42:103-105. El-Serag HB, Sonnenberg A, Jamal MM, Inadomi JM, Crooks LA, Feddersen RM. Corpus gastritis is protective against reflux oesophagitis. Gut. 1999;45:181-185. Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res. 1998;58:588-590. Richter JE, Falk GW, Vaezi MF. Helicobacter pylori and gastroesophageal reflux disease: the bug may not be all bad. Am J Gastroenterol. 1998;93:1800-1802.
The Alan J. Cameron Symposium on Barrett Esophagus and Gastroesophageal Reflux Disease will continue in the March issue.
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Cameron Symposium on Barrett Esophagus and GERD
Pathogenesis of Gastroesophageal Reflux and Barrett Esophagus NAVTEJ S. BUTTAR, MBBS, AND GARY W. FALK, MD defense. This article is an overview of the dysfunction of the esophagogastric junction that leads to GERD. The role of the contents of the reflux and that of Helicobacter pylori infection in the pathogenesis of Barrett esophagus are also summarized. Mayo Clin Proc. 2001;76:226-234
Barrett esophagus is a metaplastic condition that affects the lower esophagus and is a complication of gastroesophageal reflux disease (GERD). Under normal circumstances, the reflux of gastric contents into the esophagus is prevented by a complex barrier at the esophagogastric junction. Dysfunction of the lower esophageal sphincter and the presence of a hiatal hernia lead to failure of this barrier. Esophageal mucosal damage results from the chronic exposure of the esophageal mucosa to gastroduodenal contents and the lack of an effective mucosal
EG = esophagogastric; GERD = gastroesophageal reflux disease; LES = lower esophageal sphincter; NANC = nonadrenergic, noncholinergic
G
as a zone of elevated intraluminal pressures at the EG junction. It is defined grossly as a contracted ring of muscle at the EG junction. Anatomically, it is a ring of thickened muscle at the EG junction. The ring is positioned so that it angles obliquely upward from the lesser to the greater curvature. Its thickness and width are greatest on the greater curve side. The ring is composed of 2 distinct smooth muscle components. One component is made up of short transverse clasps of muscle that form semicircles, the ends of which terminate on the anterior and posterior aspects of the EG junction. The other component of the sphincter is the sling of fibers that are along oblique loops of muscle fibers that loop around the greater curve side of the EG junction.1 Anatomically, these 2 smooth muscle components represent true LES as they are part of the esophageal wall. From the physiologic standpoint, due to their proximity to striated muscle fibers of diaphragmatic crura that can augment their tone, the smooth muscle part is often called the internal component, and the striated muscle part is called the external component of LES (Figure 1). The distal esophagus is anchored to the crural diaphragm by the phrenicoesophageal ligament. Normally, the length of the LES is 4 cm.2 Resting pressure of the LES is related to intrinsic muscle tone. This muscle is contracted at rest3,4 and remains so even when denervated.5,6 The innervation to the LES modulates its intrinsic tone. The LES has an intrinsic and extrinsic innervation. The extrinsic innervation is made up of both preganglionic parasympathetic fibers and postganglionic sympathetic fibers. The parasympathetic fibers arise in the dorsal motor nucleus of the vagus and travel with the vagus nerve to innervate postganglionic neurons in the myenteric plexus. Most of the sympathetic fibers that reach the LES do so by joining the vagus as it passes through the thoracic cavity. They termi-
astroesophageal reflux disease (GERD) is a spectrum of pathology ranging from esophagitis to the development of specialized intestinal metaplasia known as Barrett esophagus. The stomach and esophagus have distinct mucosal environments by virtue of a competent esophagogastric (EG) junction and mechanisms to alter rapidly any change in this environment. A failure that results in the change of the esophageal environment is poorly tolerated and may result in GERD. Following is a brief overview of the pathogenesis of GERD and Barrett esophagus. PATHOPHYSIOLOGY OF GERD Gastroesophageal reflux occurs when the normal antireflux barrier between the stomach and the esophagus, the EG junction, is impaired either transiently or permanently. Transient lower esophageal sphincter (LES) relaxation is the single most common functional abnormality that leads to failure of the antireflux barrier. The impaired EG junction allows a complex interaction between gastroduodenal contents and esophageal defense mechanisms that leads to GERD. The EG Junction The EG junction is critical in preventing the reflux of gastric contents. The barrier at the EG junction is maintained by the LES, defined physiologically by manometry From the Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic, Rochester, Minn (N.S.B.); and Center for Swallowing and Esophageal Disorders, Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio (G.W.F.). Individual reprints of this article are not available. The entire Alan J. Cameron Symposium on Barrett Esophagus and Gastroesophageal Reflux Disease will be available for purchase as a bound booklet from the Proceedings Editorial Office at a later date. Mayo Clin Proc. 2001;76:226-234
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© 2001 Mayo Foundation for Medical Education and Research
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Figure 1. Anatomy of the esophagogastric junction. The lower esophageal sphincter and the crural diaphragm constitute the intrinsic and extrinsic sphincters, respectively. The 2 sphincters are anatomically superimposed and are anchored to each other by the phrenicoesophageal ligament (reprinted with permission from Mittal and Balaban2).
nate in the myenteric plexus, and they play little role in control of the LES.7,8 Vagus nerve–mediated parasympathetic pathways can cause both LES relaxation and contraction. The majority of the vagus nerve comprises cholinergic preganglionic fibers that synapse with excitatory cholinergic pathways and inhibitory nonadrenergic, noncholinergic (NANC) pathways to mediate increases and decreases in muscle tone, respectively. In general, the relaxation responses to vagal stimulation are reduced by interfering with NANC neurotransmitters, such as nitric oxide9,10 or vasoactive intestinal polypeptide. Hexamethonium, which blocks nicotinic receptors at the autonomic ganglia, reduces both excitatory and inhibitory responses, but atropine, which is a cholinergic muscarinic receptor blocker, abolishes the excitatory response.11 Nitric oxide also mediates LES relaxation in response to swallowing.12,13 Two interdependent conditions can interfere with the physiologic functions of the EG junction. The LES dysfunction is a functional problem, and hiatal hernia is an anatomically determined functional disorder. LES Dysfunction.—Gastroesophageal reflux was once thought to be simply related to a marked reduction in basal LES tone. However, reflux across the EG junction related to LES dysfunction can occur by 1 of 3 mechanisms in patients with GERD: transient relaxation of the LES, transient increase of intra-abdominal pressure that overcomes the LES pressure, or spontaneous free reflux across a predominantly low-pressure LES zone.14 Dodds et al14 found that transient LES relaxation accounted for 65% of the
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reflux episodes in the reflux esophagitis patients and was the most common mechanism of GERD. Other investigators have also demonstrated that the transient LES relaxation is the single most common mechanism in GERD.15-17 Factors that increase the frequency of transient relaxation of the LES include gastric distention, high-fat meals, and the upright position.18-20 However, the reason reflux patients have more frequent transient LES relaxation than controls is unknown. While the importance of low basal LES tone has been deemphasized, a marked reduction of LES pressure can contribute to reflux in a subset of patients with especially severe disease. Dent et al16 found that the absence of LES pressure became a progressively more common mechanism of reflux with increasing severity of esophagitis. Others have confirmed these findings.21-23 The cause of low basal LES tone is unclear; however, a link between inflammation, arachidonic acid, and LES tone has been proposed based on an animal model in which the contraction and relaxation of LES could be induced in response to arachidonic acid and its metabolites.24 Hiatal Hernia.—A hiatal hernia is an acquired prolapse of a portion of the stomach through the diaphragmatic hiatus into the chest. The majority of hiatal hernias are of the sliding type in which the LES is displaced into the chest, above the diaphragmatic hiatus. There is a fine balance between the forces pulling the esophagus through the diaphragmatic hiatus into the thoracic cavity and the supporting structures that try to keep the EG junction at or below the diaphragmatic hiatus. An imbalance between these forces may lead to development of a hiatal hernia. The supporting structures are the phrenicoesophageal membrane and the diaphragmatic crura that tend to maintain the position of the EG junction at or below the diaphragmatic hiatus.25 The pulling forces are excessive contraction of the longitudinal muscle and shortening of the esophagus due to fibrosis. The supporting structures may vary from person to person and lose some of their elasticity with age.25 A hiatal hernia may contribute to gastroesophageal reflux by a variety of mechanisms. Gastric contents may be trapped in a hiatal hernia sac and then reflux proximally into the esophagus during a swallow-induced relaxation of the LES26 (Figure 2). Esophageal emptying can be impaired by a nonreducing large hiatal hernia.27 Large hiatal hernias may also displace the lower esophageal high-pressure zone proximally, and with increasing displacement, the length of high-pressure zone can decrease.28 Finally, a large hiatal hernia may widen the diaphragmatic hiatus, which may impair the ability of the crural diaphragm to function as an external sphincter.2 The importance of a hiatal hernia in GERD is therefore related to the anatomically determined functional impair-
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Figure 2. Mechanism of reflux due to hiatal hernia. A hiatal hernia is an acquired herniation of part of the stomach through the diaphragm (A). After an episode of reflux (B), an esophageal peristaltic contraction clears the bolus of acid from the esophagus (C) into the hiatal hernia (D). Subsequently, swallowinginduced relaxation of the lower esophageal sphincter results in reflux of acid from the hernial sac into the esophagus (E). This sequence can be repeated several times and results in markedly prolonged clearance of acid (reprinted with permission from Mittal and Balaban2).
ment of the EG junction that leads to increased esophageal acid exposure. Although a hiatal hernia may or may not be an initiating factor at the inception of reflux disease, it clearly can act as a sustaining factor accounting for the chronicity of the disease. Furthermore, esophageal injury resulting from reflux may lead to increasing shortening and fibrosis of esophagus25 that may further increase the size of hiatal hernia and worsen the existing LES dysfunction (Figure 3). Effect of the Contents of Reflux The development of GERD is influenced by the composition of the material refluxed into the esophagus. Animal studies clearly demonstrate that acid and pepsin can cause mucosal damage.29 Although the esophageal mucosa is relatively resistant to acid, damage does occur at a high concentration (pH<2.0). In addition, duodenal contents, which include bile acids and the pancreatic enzyme trypsin, can also cause esophageal damage. Mucosal damage by bile acids depends on the conjugation state of the bile acids as well as the pH of the solution. Conjugated bile acids cause mucosal injury only at an acidic pH, whereas unconjugated bile acids as well as the pancreatic enzyme trypsin cause mucosal injury at a pH higher than 7.29 In humans, acid exposure in the distal esophagus as measured by 24-hour pH monitoring increases across the spectrum of GERD from nonerosive reflux disease to erosive reflux disease to Barrett esophagus and its complications.30,31 However, when compared with appropriate ageand sex-matched controls, acid and pepsin secretion is similar in patients with GERD, regardless of its severity.32 In patients with the classic acid hypersecretory condition, Zollinger-Ellison syndrome, endoscopic abnormalities of the esophagus are encountered more frequently than in the normal population.33 Others suggest that a subset of GERD patients may have acid hypersecretion, although these stud-
ies are not as well controlled.22,34,35 In summary, acid is required for esophageal injury, but acid hypersecretion does not appear to play an important role in GERD. Gastric Emptying Gastroesophageal reflux depends on an available reservoir of intragastric fluid. Delayed gastric emptying of liquids and solids is a potential mechanism that could increase the reservoir of gastric contents available to reflux. McCallum et al36 found that 41% of GERD patients had delayed emptying of a mixed solid-liquid meal. Others have also described delayed gastric emptying of a solid test meal.37 However, recent studies using more accurate methods demonstrated no difference in the rate of gastric emptying in GERD patients with or without esophageal mucosal injury and asymptomatic control groups.38,39 A more recent study of 87 GERD patients, 41 without esophagitis and 46 with reflux esophagitis (grade 1-3), found no difference in gastric emptying between the 2 groups.22 Thus, it appears that delayed gastric emptying is unlikely to be a major factor in the pathogenesis of GERD in most patients. It may, however, contribute to the development of GERD in a subset of patients. Esophageal Defenses Although many mechanisms may be involved in reflux, the common end result is exposure of esophageal mucosa to gastric and duodenal contents due to impaired function of the gastroesophageal barrier. This is countered by esophageal defense mechanisms, including esophageal clearance and mucosal resistance. Esophageal Clearance.—Esophageal acid clearance is one of the important defense mechanisms that protects against the development of esophageal mucosal injury. The efficiency of esophageal clearance determines the duration of esophageal exposure to noxious components of the gas-
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Figure 3. Potential mechanism of gastroesophageal reflux disease. Increased transient lower esophageal sphincter relaxation is the predominant mechanism of gastroesophageal reflux disease. A subset of patients with gastroesophageal reflux disease have hypotensive lower esophageal sphincter and usually have severe reflux disease.
troesophageal reflux. Under normal circumstances, gastric contents are cleared from the esophagus by normal peristalsis.40 Peristaltic dysfunction such as failed primary peristalsis and feeble peristaltic waves, which may result in impaired acid clearance, is common in GERD. Kahrilas et al41 found that peristaltic dysfunction was progressively more common with increasing severity of esophagitis and occurred in 25% of patients with mild esophagitis and 48% of patients with severe esophagitis. Whether peristaltic dysfunction is a primary defect or one due to acid-induced injury is not clear. Experiments done in animal models
have demonstrated that impaired contractility of the esophagus may occur in response to reflux.42 However, healing of esophagitis does not improve any of the motor abnormalities encountered in GERD.43,44 Esophageal peristalsis alone is not adequate for esophageal acid clearance. While acid volume is emptied from the esophagus after 1 or 2 peristaltic sequences, residual acid in the esophagus is neutralized by saliva in increments with each subsequent swallow.40 Aspirating saliva from the mouth results in failure to neutralize acid in the esophagus despite clearance of esophageal volume by normal peristal-
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sis. This points out the importance of saliva in esophageal acid clearance. Saliva also contains a number of growth factors such as epidermal growth factor, transforming growth factor α, and transforming growth factor β, which may help in healing and restitution of the esophageal lining. The role of salivary growth factor deficiency in patients with GERD and its complications has not been clearly elucidated.45 Mucosal Resistance.—Healthy esophageal mucosa has a variety of mechanisms to protect itself from injury. Continuous exposure of the healthy esophagus to 100-mmol/L hydrochloric acid (pH 1.1) for 30 minutes, as done in Bernstein test, does not produce signs of mucosal damage. The factors that contribute to such protection are divided into preepithelial, epithelial, and postepithelial defenses. Preepithelial defenses include the mucus and unstirred water layer along with surface bicarbonate ions. Epithelial defenses include the apical cell membrane, junctional barriers, intracellular and extracellular buffers, and pH regulatory processes. In healthy tissue, hydrogen ions cannot cross the apical surface membrane of epithelial cells. However, high luminal acidity can damage intercellular junctions and lead to acidification of the intercellular spaces. This exposes the basolateral aspect of the epithelial cells to hydrogen ions and can eventually lead to loss of osmoregulation and cell death. The postepithelial defenses include blood flow and tissue acid base balance. It is unclear at this time if the patients who are predisposed to gastroesophageal reflux–related injury have suboptimal mucosal defense.46 Dietary Factors and Smoking Dietary factors and smoking play an indirect role in the pathophysiology of GERD. Moderate alcohol consumption increases the exposure of the distal esophagus to acid and impairs the normal acid clearance in supine position.47,48 Alcohol can decrease LES pressure.49 The role of cigarette smoking in GERD is unclear.50-54 Cigarette smoking can increase the number of reflux episodes,50 increase esophageal acid exposure,52 and decrease LES pressure.53 Interestingly, smoking cessation does not affect esophageal acid exposure.51 PATHOGENESIS OF BARRETT ESOPHAGUS Barrett esophagus is the most serious complication of GERD because of its association with an increased risk of adenocarcinoma of the esophagus. Approximately 10% of patients with GERD symptoms have Barrett esophagus.48,55 Gastroesophageal reflux results in varying degrees of esophageal mucosal damage. Depending on the mucosal environment at the time of healing, patients may develop squamous or columnar epithelium. Why some patients with GERD develop Barrett esophagus whereas others do not is
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unclear. The following is an overview of pathogenesis of Barrett esophagus. Animal Models Bremner et al56 studied esophageal mucosal regeneration in a canine model of gastroesophageal reflux. In this study, the distal esophageal mucosa was excised, gastroesophageal reflux was induced (by creation of a hiatal hernia and destruction of the LES), and a subset of dogs was given histamine to further stimulate acid secretion. In the control group (with mucosal excision only), reepithelialization occurred with squamous epithelium. In the hiatal hernia group without acid hypersecretion, the mucosal defects were replaced by equal amounts of squamous and columnar epithelium. The mucosal defects of the hiatal hernia group with concomitant acid hypersecretion were almost completely replaced by columnar epithelium.56 In a recent study with a similar canine model, depth of experimental injury was considered to be a determinant of the type of epithelium that regenerates subsequently.57 Further work by Gillen et al58 examined the contents of reflux that contributed to the development of Barrett esophagus. In this study, mucosal defects in the distal esophagus of dogs were created. All dogs had gastroesophageal reflux by creation of a hiatal hernia and cardioplasty. A subgroup of dogs also had biliary diversion into the proximal stomach to create duodenogastroesophageal reflux. The dogs in the gastroesophageal reflux group as well as the duodenogastroesophageal reflux group developed columnar epithelium. However, when animals in the latter group were given cimetidine, no columnar epithelium developed. These results emphasize the importance of gastric acid reflux in the development of Barrett esophagus either alone or in combination with duodenal reflux. Acid and Pepsin In humans, Barrett esophagus is clearly associated with severe gastroesophageal reflux. Compared with patients with erosive and nonerosive GERD, patients with Barrett esophagus typically have greater esophageal acid exposure based on 24-hour pH monitoring.31,59-63 Part of the increase in acid exposure in patients with Barrett esophagus may be related to the almost uniform presence of a hiatal hernia, which is typically longer and associated with larger defects in the hiatus in patients with Barrett esophagus than in controls or patients with esophagitis alone.64 In addition, patients with Barrett esophagus have a lower basal LES pressure compared with patients with GERD without Barrett esophagus.62 It was once thought that patients with Barrett esophagus had a greater acid output, both basally and in response to pentagastrin stimulation, compared with normal individuals without reflux.65,66 However, more recent studies using appropriately matched controls found no
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difference in basal acid output or 24-hour and daytime patterns of gastric pH between healthy subjects and patients with Barrett esophagus.67,68 Patients with Barrett esophagus may be less sensitive to acid in the esophagus. Barrett esophagus patients have a positive Bernstein test less often than patients with uncomplicated reflux disease, and those with a positive test take longer to develop pain during acid perfusion.69 However, most patients with Barrett esophagus are elderly, and this observation may be due to an age-related decline in acid sensitivity.70 Finally, mucosal ablation of Barrett esophagus by a variety of techniques has been reported to heal with squamous rather than columnar epithelium when mucosal ablation is accompanied by vigorous acid suppression, whereas recurrent Barrett epithelium is more common in the absence of acid suppression.71-73 The role of pepsin has not been explored extensively in Barrett esophagus. Activation of pepsin requires a pH of less than 3; thus, separating the role of pepsin from acid alone is difficult. Hirschowitz67 could find no difference in pepsin output in patients with Barrett esophagus compared with age- and sex-matched controls. Reflux of gastric acid alone is not the only factor responsible for the pathogenesis of Barrett esophagus. Rather, a complex interaction of acid exposure, genetic susceptibility, environmental factors, and duodenogastroesophageal reflux may contribute to the pathogenesis of Barrett esophagus. Bile Reflux Excessive reflux of duodenal contents into the esophagus may contribute to the development of Barrett esophagus and its complications. Bile reflux is a term often used to describe the reflux of duodenal contents, which includes conjugated and unconjugated bile acids, lysolecithin, and pancreatic enzymes such as trypsin. A graded increase in fasting gastric bile acid concentrations occurs across the spectrum of nonerosive GERD, erosive GERD, Barrett esophagus, and Barrett esophagus complicated by ulcers, strictures, dysplasia, or carcinoma. This is also accompanied by increase in duodenogastroesophageal reflux.31,74,75 Duodenogastroesophageal reflux is increased in Barrett esophagus patients compared with age-matched controls, especially in patients with complications of Barrett esophagus such as ulcers, strictures, or dysplasia.76 Interestingly, increased duodenoesophageal reflux in these patients parallels increased acid reflux in the same patients. Thus, the majority of duodenogastroesophageal reflux episodes (70%-91%) occur in an acidic environment (pH<4).30,31 Taken together, these studies suggest the importance of both gastric and duodenal contents in the pathogenesis of Barrett esophagus.
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Cell of Origin The development of Barrett esophagus requires injury to the esophageal mucosa accompanied by an abnormal environment for epithelial repair as outlined above. The cell of origin is unclear; candidates include esophageal glandular cells, heterotopic gastric mucosa, or abnormal differentiation of a primordial stem cell. Barrett epithelium was initially thought to result from the upward migration of gastric epithelium after denudation of esophageal squamous epithelium. This hypothesis was disproved by the animal models outlined above. A cell with features of both squamous and columnar epithelium has been identified with scanning electron microscopy at the transition zone between normal esophageal squamous epithelium and the columnar epithelium of Barrett esophagus.77 Recent work by Boch et al78 focused on a new multilayered epithelium within Barrett epithelium that has histologic characteristics of both squamous and columnar epithelium. This epithelium concurrently expressed markers of both squamous and columnar cytokeratins, the cytoskeletal structural proteins present in all epithelia. In patients with Barrett esophagus without this multilayered epithelium, only markers to columnar cytokeratins were expressed, whereas squamous epithelium from the squamocolumnar junction expressed only squamous markers. These findings further support a multipotential stem cell as the origin of Barrett epithelium, although why this stem cell follows a columnar line of differentiation after esophageal injury from acid remains unclear.
Helicobacter pylori Infection The role of H pylori in the development of Barrett esophagus has been the subject of intense interest.79,80 Hospitalization and death rates for distal gastric cancer and duodenal ulcer disease have decreased since 1970, while those for GERD and esophageal adenocarcinoma have increased during that same time period.81 It is tempting to link these opposing time trends to the decline in the prevalence of H pylori infection in the Western world.82 While most studies find no causal relationship between H pylori infection and Barrett esophagus, some evidence suggests a possible protective role of H pylori infection.83-85 What accounts for a potential protective effect of infection with H pylori? Corpus-predominant gastritis is associated with decreased acid secretion as well as a decreased risk for the development of Barrett esophagus.86 The protective effect of H pylori infection may also be related to colonization with cagA-positive H pylori strains. Several recent reports are consistent with these observations. Vicari et al84 found that the prevalence of cagApositive H pylori strains was decreased in patients with Barrett esophagus and Barrett esophagus with adenocarci-
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noma or dysplasia compared with a control population. Similarly, Chow et al87 reported that carriage of cagApositive strains was associated with an increased risk for distal gastric cancers but with a reduced risk for esophageal and gastric cardia adenocarcinomas. Changes in gastric reflux modulated by H pylori colonization may account for the observations in patients susceptible to GERD (hiatal hernia, LES dysfunction, esophageal dysmotility). Patients without H pylori infection or those infected with cagA-negative strains have little or no corpus inflammation with normal or high intragastric acidity, which, in susceptible individuals, promotes the development of reflux or its complications. However, colonization with cagA-positive strains of H pylori and its associated severe corpus inflammation result in less acidic gastric reflux, which may be protective against the development of GERD and its complications.88 CONCLUSION Barrett esophagus is closely associated with reflux and is a long-term, serious complication of reflux. The reflux of gastric and duodenal contents into the esophagus is prevented by a complex barrier that exists at the EG junction. The failure of this barrier chronically exposes the lower esophageal mucosa to gastric and duodenal contents. The interaction of these offending factors with the factors providing mucosal defense leads to mucosal damage and development of Barrett esophagus. A better understanding of the pathogenesis of both GERD and Barrett esophagus is anticipated in the coming years. REFERENCES 1.
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The Alan J. Cameron Symposium on Barrett Esophagus and Gastroesophageal Reflux Disease will continue in the March issue.
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