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World J Gastroenterol. Aug 14, 2010; 16(30): 3762-3772
Published online Aug 14, 2010. doi: 10.3748/wjg.v16.i30.3762
Pathophysiology and treatment of Barrett’s esophagus
Daniel S Oh, Steven R DeMeester
Daniel S Oh, Steven R DeMeester, Department of Surgery, The University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, United States
Author contributions: Both authors contributed to this paper.
Correspondence to: Steven R DeMeester, MD, Associate Professor, Department of Surgery, The University of Southern California, Keck School of Medicine, 1510 San Pablo St., Suite 514, Los Angeles, CA 90033, United States.
Telephone: +1-323-4429066 Fax: +1-323-4425872
Received: April 24, 2010
Revised: June 7, 2010
Accepted: June 14, 2010
Published online: August 14, 2010


Gastroesophageal reflux disease (GERD) affects an estimated 20% of the population in the United States. About 10%-15% of patients with GERD develop Barrett’s esophagus, which can progress to adenocarcinoma, currently the most prevalent type of esophageal cancer. The esophagus is normally lined by squamous mucosa, therefore, it is clear that for adenocarcinoma to develop, there must be a sequence of events that result in transformation of the normal squamous mucosa into columnar epithelium. This sequence begins with gastroesophageal reflux, and with continued injury metaplastic columnar epithelium develops. This article reviews the pathophysiology of Barrett’s esophagus and implications for its treatment. The effect of medical and surgical therapy of Barrett’s esophagus is compared.

Key Words: Gastroesophageal reflux disease, Barrett’s esophagus, Lower esophageal sphincter, Esophageal motility, Proton pump inhibitors, Antireflux surgery


Gastroesophageal reflux disease (GERD) affects an estimated 20% of the population, and with direct and indirect costs exceeding $10 billion annually, it is the costliest gastrointestinal disorder in the United States[1]. Much of this extraordinary sum goes to pay for increasingly more potent and widely prescribed medications to suppress gastric acid production. While these medications have been proven to relieve heartburn symptoms and heal esophagitis, they have not substantially altered the malignant complications of reflux disease. Adenocarcinoma of the esophagus, which occurs as a consequence of chronic gastroesophageal reflux, is increasing faster than any other cancer in the United States, and has surpassed squamous cell as the most prevalent type of esophageal cancer[2].

The esophagus is normally lined by squamous mucosa, therefore, it is clear that for adenocarcinoma to develop, there must be a sequence of events that results in transformation of the normal squamous mucosa into columnar epithelium. This sequence begins with gastroesophageal reflux, and with continued injury metaplastic columnar epithelium develops. Currently, in the Unites States, only an endoscopically visible segment of columnar mucosa that contains goblet cells on biopsy is considered to be premalignant, and patients with this condition are considered to have Barrett’s esophagus. Barrett’s esophagus is the precursor lesion for esophageal adenocarcinoma.


The prevalence of Barrett’s esophagus appears to be increasing in the Western world. It has been debated whether this represents a true rise in incidence or is secondary to a heightened awareness of the dangers of reflux disease among practitioners, and an increased use of upper endoscopy to evaluate patients with reflux symptoms[3]. The most convincing epidemiological evidence that the prevalence of Barrett’s esophagus is actually increasing comes from a recent study in the Netherlands using their Integrated Primary Care Information database, which contains > 500 000 computerized patient records. In that study, there was a linear increase in the diagnosis of Barrett’s esophagus that was even more pronounced if the increase was based on the number of upper endoscopies performed during the same time period (from 19.8/1000 upper endoscopies in 1997 to 40.4/1000 upper endoscopies in 2002)[4]. Epidemiological studies in England have also demonstrated an age-specific increase in the prevalence of Barrett’s esophagus per 100 upper endoscopies during the years 1982-1996[5].

Thus, there is evidence that the prevalence of Barrett’s esophagus is increasing, but it is clear that the true prevalence of Barrett’s esophagus in the population is unknown, and likely much higher than would be expected based on clinical cases diagnosed by upper endoscopy. In one of the few autopsy studies that has evaluated the prevalence of Barrett’s esophagus, Cameron et al[6] found 376 cases per 100 000 people in Olmsted County, MN, USA. This rate was five times higher than the clinical prevalence of Barrett’s esophagus in this same area (82.6 per 100 000). Further support for the concern about a large sub-clinical population of individuals with Barrett’s esophagus comes from a study done in veterans by Gerson et al[7]. They performed upper endoscopy in a group of patients who presented for routine sigmoidoscopy for colorectal cancer screening; none of whom had symptoms of reflux. Although there are obvious limitations to a study done primarily in older, white male military veterans, nonetheless, their finding that 25% of patients had Barrett’s esophagus is concerning because, on the basis of symptoms, none of these patients would have been recommended to have upper endoscopy. These observations suggest that the majority of individuals with Barrett’s esophagus go undiagnosed, either because they ignore minor reflux symptoms or, as the study in veterans suggests, they are truly asymptomatic.


The development of Barrett’s esophagus is likely a two-step process. The first step involves the transformation of normal esophageal squamous mucosa to a simple columnar epithelium called cardiac mucosa. This occurs in response to chronic injury produced by repetitive episodes of gastric juice refluxing onto the squamous mucosa. The change from squamous to cardiac mucosa likely occurs relatively quickly, within a few years, while the second step, the development of goblet cells indicative of intestinal metaplasia, proceeds slowly, probably over 5-10 years[8]. Once present, Barrett’s esophagus can progress to low- and high-grade dysplasia, and ultimately to adenocarcinoma. This entire process is commonly described as the Barrett’s metaplasia-dysplasia-carcinoma sequence.

Step one: Transition from squamous to columnar-lined esophagus

To understand what constitutes a columnar-lined esophagus an understanding of the anatomy and histology of the normal gastroesophageal junction is required. Unfortunately, the very definition of what is normal in this area remains controversial, with much debate centered on whether cardiac mucosa is normally present at the gastroesophageal junction. Although our understanding is gradually improving, Hayward’s remark in 1961 that “the lower end of the esophagus is a region where the pathology, the physiology, and even the anatomy are not quite clear” remains appropriate even today[9]. In one of the first reports describing the normal gastroesophageal junction, Hayward indicated that a junctional or buffer zone of columnar mucosa is normally interposed between the acid-secreting oxyntic gastric mucosa and the acid-sensitive squamous esophageal mucosa[9]. Although an appealing concept, Hayward provided no data in support of his theory, and did not discuss the role of the lower esophageal sphincter which had been demonstrated to exist before his publication. According to Hayward, this junctional mucosa is normally found in a length of up to 2 cm at the gastroesophageal junction. He also noted the following about this junctional mucosa: (1) it was histologically distinct from normal gastric fundic and pyloric epithelium; (2) it did not secrete acid or pepsin but was resistant to both; (3) it was not congenital but acquired; (4) it was mobile and varied in length - creeping progressively higher into the esophagus with continued gastroesophageal reflux; and (5) it was potentially reversible with correction of reflux. Furthermore, he pointed out that it was located in the esophagus, and that it developed in association with gastroesophageal reflux[9].

Now, over 40 years later, there is still dispute about the histology of the normal gastroesophageal junction, but it is clear that normally there is none or at most 4 mm of cardiac mucosa in the distal esophagus at the gastroesophageal junction[10-13]. Longer lengths of cardiac mucosa are acquired secondary to chronic gastroesophageal reflux[14,15]. Supporting evidence for the concept that cardiac mucosa is acquired comes from both clinical and experimental studies. Experimental evidence comes from a 1970 study by Bremner et al[16] in which a series of dogs underwent stripping of the distal esophageal squamous mucosa, with or without creation of a cardioplasty to destroy the function of the lower esophageal sphincter. Squamous re-epithelialization occurred in those animals without gastroesophageal reflux, whereas in the animals with reflux after cardioplasty, the esophagus was re-epithelialized by a columnar epithelium that lacked parietal cells - the equivalent of cardiac mucosa in humans[16]. There is also clinical evidence in humans that columnar mucosa can replace normal esophageal squamous epithelium in the setting of gastroesophageal reflux. Following an esophagectomy with gastric pull-up, reflux of gastric juice into the residual esophagus is common because there is no lower esophageal sphincter and a large hiatal hernia has been created. Postoperative endoscopy has revealed that many of these patients develop columnar epithelium that, on histology, is identical to cardiac mucosa proximal to the anastomosis in the residual esophagus, in what had pathologically been proven to be squamous mucosa at the time of the operation. Several series have revealed that this process is common, and occurs in ≥ 50% of patients after esophagectomy with gastric pull-up, and that the length of columnar mucosa increases with longer follow-up[8,17-20]. Furthermore, the cardiac mucosa that develops in these patients proximal to the esophagogastric anastomosis has been shown to be biochemically similar to cardiac mucosa found in non-operated patients at the native gastroesophageal junction[17]. Additional support for the concept that cardiac mucosa is acquired comes from the fact that it is not found anywhere else in the gastrointestinal tract, and when present at the gastroesophageal junction, it is always inflamed and demonstrates reactive changes unrelated to either Helicobacter pylori infection or mucosal pathology elsewhere in the stomach[21]. This is atypical for a normal epithelium. Lastly, the presence of cardiac mucosa can be correlated with objective markers of GERD, including an incompetent lower esophageal sphincter, increased esophageal acid exposure on 24-h pH monitoring, a hiatal hernia, and erosive esophagitis[15].

The earliest manifestation of GERD might in fact be the presence of microscopic foci of cardiac mucosa at the gastroesophageal junction. This leads to the question of why the finding of a microscopic length of cardiac mucosa at the gastroesophageal junction is so common even in patients without the typical reflux symptoms of heartburn or regurgitation. This is likely to be related to the pathophysiology of early reflux disease. Evidence is accumulating that reflux disease begins with gastric distention after large and particularly fatty meals. Gastric distension leads to effacement of the lower esophageal sphincter and exposure of the squamous mucosa at the distal extent of the sphincter to gastric juice. The pathophysiology of the gastroesophageal junction has been best studied by Fletcher and McColl. They have noted that the gastric distension that occurs with eating can cause the lower esophageal sphincter to unfold by almost 2 cm in normal volunteers[22]. Moreover, they have identified an unbuffered acid pocket at the gastroesophageal junction following a meal; a phenomenon that they have attributed to gastric juice floating upon a lipid layer after ingestion of fatty food. By pulling back a pH catheter before and after a meal, they have been able to show that the pH step-up that corresponds to the functioning lower esophageal sphincter moved proximally with gastric distension, secondary to unfolding of the distal portion of the sphincter. By measuring acid exposure with a pH catheter positioned at the squamocolumnar junction, and another located 5.5 cm proximal to the squamocolumnar junction, Fletcher et al[23] have demonstrated significantly greater acid exposure at the squamocolumnar junction (median total percentage time pH < 4 of 11.7% vs 1.8% at 5.5 cm proximal to the squamocolumnar junction). This study has confirmed the presence of significant acid exposure at the most distal intrasphincteric segment of the esophagus in patients with otherwise normal acid exposure proximally at 5.5 cm above the squamocolumnar junction. These findings were subsequently extended when it was demonstrated that salivary nitrite is rapidly converted into nitric oxide when it comes in contact with gastric acid that contains physiological levels of ascorbic acid, and this reaction has been found to be maximal at the gastroesophageal junction[24]. The levels of nitric oxide generated at the gastroesophageal junction are potentially mutagenic, and might play a role in the pathophysiology of this region.

It is likely that continued injury to the distal esophagus and lower esophageal sphincter leads to progressive loss of the abdominal length of the sphincter. What started as transient sphincter unfolding with gastric distension gradually progresses to permanent sphincter destruction. With destruction of the sphincter, reflux disease is allowed to explode into the esophagus, and can lead to an increase in the length of cardiac mucosa, either as tongues or as a circumferential replacement of the distal esophageal squamous mucosa. This leads to progressive migration of the squamocolumnar junction proximally[25,26]. Confirmation of esophageal submucosal glands deep to areas lined by cardiac mucosa provides clear evidence that the development of cardiac mucosa is occurring in the esophagus in areas previously covered with squamous mucosa and not in the proximal stomach[26].

The precise details of the molecular mechanism by which squamous mucosa is transformed into cardiac mucosa remain unknown. However, there is likely to be a crucial interaction between normally sequestered esophageal stem cells and an intraluminal stimulus that drives this metaplastic process. Tobey et al[27] have demonstrated that exposure of esophageal squamous mucosa to gastric juice produces dilated intercellular spaces that allow molecules of up to 20 kDa to permeate down to the stem cells in the basal layer. Perhaps the sensation of heartburn occurs as a consequence of diffusion of hydrochloric acid through these intercellular spaces and stimulation of sensory afferent nerves[28]. These ultrastructural changes occur before gross or microscopic changes become apparent. Thus, one possibility is that factors present in the refluxed juice that gain access to the basal layer stem cells via these dilated intercellular spaces induce a phenotypic transformation such that cardiac columnar mucosal cells rather than squamous cells are produced.

Step two: Intestinalization of cardiac mucosa

Cardiac mucosa is thought to be an unstable epithelium, in part because of the severe inflammatory and reactive changes present on histology. It is hypothesized that cardiac mucosa progresses down one of two possible pathways, based on a combination of environmental and genetic factors. One pathway involves the expression of gastric genes and leads to the formation of parietal cells within glands below the cardiac mucosa. Gastric differentiation leads to a mucosa called oxyntocardiac mucosa, and this is thought to represent a regressive or favorable change because oxyntocardiac mucosa is not premalignant, and appears to be protected from developing intestinal metaplasia. In the second pathway, expression of intestinal genes causes the formation of goblet cells within cardiac mucosa. In contrast to gastric differentiation, intestinal differentiation represents a progressive or unfavorable change because this mucosa is premalignant. Both oxyntocardiac mucosa and Barrett’s esophagus have less inflammation than cardiac mucosa, which suggests that these mucosal types are more stable epithelia[29].

The development of goblet cells marks the transformation of cardiac mucosa into intestinal metaplasia. When an endoscopically visible length of this mucosa is present in the esophagus, the definition of Barrett’s esophagus has been met. While gastroesophageal reflux is known to be the primary factor responsible for the development of Barrett’s esophagus, the specific cellular events that lead to the transformation of cardiac mucosa into intestinalized cardiac mucosa are unknown. However, evidence is accumulating that intestinalization requires a specific condition or stimulus, and that Barrett’s esophagus occurs in a stepwise process. The first step, from squamous to cardiac mucosa, is likely to occur in response to acid reflux. The second step, development of intestinal metaplasia, is likely to occur in response to a different type of luminal insult. Numerous studies have demonstrated that, although isolated acid reflux can cause esophagitis, Barrett’s esophagus is associated with the presence of a mixture of acid and bile salts[30-32]. Furthermore, clinical experience dating back 30 years has suggested a role for refluxed bile in the development of intestinal metaplasia. In 1977, Hamilton and Yardley observed the development of columnar mucosa and intestinal metaplasia above the esophagogastric anastomosis in a group of patients after esophagectomy. They noted that “severe symptoms of gastroesophageal reflux and bile staining of the refluxed material were documented only in the group with Barrett’s. In addition, pyloroplasty had been performed more commonly in this group.”[33]. Recently, in two separate analyses of patients with reflux with and without Barrett’s esophagus, we found that the factor most associated with the presence of Barrett’s esophagus in both men and women with GERD was abnormal bilirubin reflux, as determined by Bilitec monitoring[34,35].

Fitzgerald et al[36] have reported several interesting observations on how the dynamics of mucosal exposure to luminal contents might affect columnar epithelial cell proliferation and differentiation. Using cultured human Barrett’s esophagus biopsy specimens, they have demonstrated that continuous exposure to acidic media at pH 3.5 resulted in increased villin expression (a marker for epithelial cell differentiation) and reduced cell proliferation. Villin expression was not detected when the culture medium was made more acidic (pH < 2.5). In contrast, a dramatic increase in proliferation occurred when the Barrett’s esophagus tissue was exposed to a short (1 h) pulse of acidic medium (pH 3.5) followed by a return to neutral pH. Clinically, this same group has noted that effective acid suppression results in a shift of the Barrett’s epithelium away from proliferation and toward differentiation[37]. However, the cellular consequences of duodeno-gastroesophageal reflux in the setting of gastric alkalization with acid suppression medications were not addressed in that study.

It has been hypothesized that the mechanism by which acid and bile interact to cause Barrett’s esophagus is related to the ionized state of bile salts[38]. It appears that in a weakly acidic environment certain bile acids are particularly toxic. At pH 3-6, these bile salts are soluble and non-ionized, and can enter mucosal cells, accumulate, and cause direct cellular injury[39]. When the luminal pH is higher than the pKa, these same bile acids are ionized and cannot cross the phospholipid membrane. Further, when the luminal pH is lower, as normally it is in the stomach, bile acids precipitate out of solution and are harmless[40]. Thus, it is only at this critical pH range of 3-5 that certain bile acids become non-ionized and able to cross the cell membrane. Once inside the cell, the pH is 7 and the bile acids become ionized and are trapped inside the cell where they have been shown to result in mitochondrial injury, cellular toxicity and mutagenesis[41-44]. Consequently, this mid-range gastric pH of 3-5 is a danger zone for patients with duodeno-gastroesophageal reflux.

It remains uncertain whether the transformation of cardiac mucosa to intestinalized cardiac mucosa represents a phenotypic change secondary to the induction of genes, or a mutational event within the columnar cells. Mendes de Almeida and colleagues have demonstrated biochemically that both cardiac mucosa and intestinal metaplasia express sucrase-isomaltase and crypt cell antigen - two small intestine marker proteins; however, in that study only three patients with cardiac mucosa were evaluated[45]. Das has developed a murine monoclonal antibody (DAS-1) that reacts specifically with normal colonic epithelial cells, and subsequently he has found that it also reacts with an unknown epitope in Barrett’s mucosa[46]. Griffel et al[47] have reported that the DAS-1 antibody stained cardiac mucosa without intestinal metaplasia in seven patients, and that six of these patients later developed histological evidence of intestinalization on repeat biopsies. Likewise, we noted that the pattern of immunostaining with cytokeratins 7 and 20 was similar in cardiac mucosa and Barrett’s esophagus[48]. These findings suggest that, biochemically, cardiac mucosa and intestinal metaplasia are similar, and that cardiac mucosa is the precursor of intestinalized columnar epithelium, or Barrett’s esophagus.

Currently, the length of Barrett’s esophagus is divided into short (< 3 cm) and long (≥ 3 cm) segments based on the endoscopically determined length of the columnar streak or column in the distal esophagus. Clinically, patients with long-segment Barrett’s esophagus tend to have more severe reflux disease than those with short-segment disease. Patients with long-segment Barrett’s esophagus have a higher prevalence of hiatal hernia, more commonly have a defective lower esophageal sphincter, and demonstrate greater esophageal acid and bilirubin exposure on 24-h pH and Bilitec monitoring[30,49]. Despite the differences in length, there is evidence that short and long-segment Barrett’s esophagus are biochemically similar[48,50]. This is supported by the clinical observation that the risk of malignancy is similar for both short and long segments of Barrett’s esophagus[51].

The presence of goblet cells is the sine qua non of Barrett’s esophagus. The likelihood of finding intestinalization correlates with the length of the columnar segment. Once 4 cm of cardiac mucosa are present in the distal esophagus, nearly all patients will be found to have intestinal metaplasia on biopsy[49,52]. However, the location of goblet cells in a columnar-lined segment is not uniform, and often the entire length of columnar esophagus does not demonstrate intestinal metaplasia. Goblet cell density is greatest near the squamocolumnar junction and becomes more variable distally[29]. In other words, if intestinal metaplasia is present within a columnar-lined segment of the esophagus, it will always be present proximally at the squamocolumnar junction. Goblet cells might extend throughout the entire length of the columnar segment. The length of Barrett’s esophagus is determined by the endoscopic length of columnar mucosa and not by the length of mucosa showing intestinal metaplasia. In other words, a 6-cm segment of columnar mucosa with intestinal metaplasia only at the proximal 1 cm is still considered long-segment Barrett’s esophagus, but the clinical behavior of this long-segment Barrett’s might differ substantially from a 6-cm segment of columnar mucosa with intestinal metaplasia throughout the entire length. The current definition of Barrett’s esophagus does not take this into account.

The time course to develop goblet cells is uncertain, but it appears to take a minimum of 5-10 years[38,53]. Studies involving esophagectomy patients have indicated that cardiac mucosa develops rapidly, often within 1-2 years. Intestinalization of the columnar segment in these patients occurs significantly later, typically after another 3-5 years[18-20,33,54]. These findings might reflect an accelerated course of events because these patients often have significantly greater reflux of acid and bile than the typical patient with GERD. However, this clinically relevant human model does demonstrate the two-step process of Barrett’s esophagus, starting with columnarization followed by intestinalization in some patients.

The molecular mechanisms by which cardiac mucosa acquires goblet cells remain to be elucidated. However, there is increasing evidence that expression of the homeobox gene Cdx-2 plays a pivotal role. The expression of this gene increases with progression from squamous mucosa with esophagitis to cardiac mucosa, and is maximal in the setting of intestinal metaplasia[55-57]. Experimental work has suggested that Cdx-2 expression can be modulated by the pH of luminal material[58]. Furthermore, an individual’s response to an inflammatory stimulus might also participate in the mucosal adaptation to reflux disease. Fitzgerald et al[59] have demonstrated that esophagitis and Barrett’s esophagus have distinct cytokine profiles that reflect different inflammatory responses to reflux-induced injury. Moreover, even within a given Barrett’s esophagus segment, the inflammatory response is more severe at the proximal end near the squamocolumnar junction, which could explain the greater tendency for intestinalization to occur at this location[60]. Furthermore, the specific cytokine polymorphism of a given individual might also influence the development of Barrett’s esophagus. Preliminary work from Gough et al[61], for example, has demonstrated that specific polymorphisms of interleukin (IL)-1 receptor antagonist and IL-10 are more common in patients with Barrett’s esophagus than those with esophagitis. Thus, a genetically determined inflammatory response to reflux might influence the pathway of disease in each individual patient.


Barrett’s esophagus is a premalignant mucosa, and has an increased proliferation rate, decreased apoptosis, and an increased fraction of diploid and aneuploid cells compared to normal epithelium[13,62]. The combination of increased proliferation and decreased apoptosis allows genetic abnormalities to develop and accumulate, and drives the development of dysplasia and malignant transformation in Barrett’s esophagus[63]. Although non-dysplastic Barrett’s esophagus is a simple columnar epithelium with homogenous nuclei arranged close to the basement membrane, dysplasia results in both cytological and architectural abnormalities, including loss of nuclear polarity, pleomorphic appearance, and the development of glandular distortion[64]. By convention, there are four broad categories used by pathologists to describe the dysplastic process: (1) no dysplasia; (2) indefinite for dysplasia; (3) low-grade dysplasia; and (4) high-grade dysplasia. This classification system has been adapted for use in Barrett’s esophagus from that used in ulcerative colitis[65,66]. The most significant category, high-grade dysplasia, is characterized by carcinoma in situ with malignant cells that do not invade the lamina propria.

The grading of dysplasia has great clinical utility in stratifying risk of subsequent cancer in patients with Barrett’s esophagus, and to date, it is the most important predictive marker for the development of invasive adenocarcinoma. However, the ability to grade dysplasia remains a subjective endeavor, particularly outside specialized centers with expert gastrointestinal pathologists[67]. Even among focused gastrointestinal pathologists there is discordance, particularly with regard to the presence of low-grade dysplasia[68]. This lack of precision inherent in histopathological grading has stimulated efforts to identify more objective molecular and biochemical indicators of an increased risk for progression in patients with Barrett’s esophagus. It has been demonstrated that in medically treated patients with Barrett’s esophagus and low-grade dysplasia, the risk of progression is increased in patients with aneuploidy[69]. It is hoped that other molecular markers that are better able to predict which patients with Barrett’s esophagus are at increased risk for progression will be identified in the future.


Although it is widely accepted that Barrett’s esophagus is a premalignant condition, the degree of risk remains uncertain. A meta-analysis by Shaheen et al[70] of 25 articles published between 1984 and 1998 concluded that the incidence of adenocarcinoma in patients with Barrett’s esophagus was approximately 0.5% per patient-year, with a range from 0.2% to 2.9%. However, these studies were done in patients being treated for reflux, including those that had antireflux surgery, and thus these estimates might not reflect the true natural history of Barrett’s esophagus progression. Known risk factors for progression to dysplasia and cancer include hiatal hernia size, the length of Barrett’s esophagus, patient age, and the presence of cellular and molecular abnormalities, including abnormal ploidy status and p16 or p53 gene abnormalities[69,71-74].

The natural history of dysplasia is not well characterized, but the risk of malignancy increases with the development of low- and high-grade dysplasia. The best data have come from Reid et al[69], and in a carefully followed group of patients. they reported that low-grade dysplasia progressed to cancer in 4% over 5 years, whereas high-grade dysplasia led to cancer in 61% at 5 years. It is also clear that progression is variable, with some patients progressing at a steady pace over several years, while others have stable non-dysplastic or low-grade dysplasia in Barrett’s esophagus for many years, and then rapidly develop high-grade dysplasia and cancer. Theisen et al[75] conducted a review of patients who received follow-up through the entire sequence of Barrett’s esophagus, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma to better understand the chronology of these events. In a group of 28 patients that presented with adenocarcinoma, a median of 24 mo passed from the initial diagnosis of Barrett’s esophagus. Progression from low-grade to high-grade dysplasia occurred over a median of 11 mo. Once high-grade dysplasia was diagnosed, the median time to diagnosis of cancer was 3 mo. Although this timeline was variable for each individual, in the cohort of patients that had progression of Barrett’s esophagus to cancer, the process occurred within 3 years. However, because most Barrett’s esophagus patients do not progress onto dysplasia and cancer, the cohort in this retrospective study might not be applicable to all patients. Furthermore, because few of these patients had been in long-term Barrett’s esophagus surveillance programs, it is not possible to separate prevalent from incident cancers in this group, and the actual month and year that Barrett’s esophagus developed in each patient is also unknown. Thus, information on progression of Barrett’s esophagus is largely anecdotal.

Medical therapy of Barrett’s esophagus

There are three goals for treating patients with Barrett’s esophagus: (1) stop reflux; (2) promote or induce healing or regression of the metaplastic epithelium such that the high-risk mucosa (intestinal metaplasia) is eliminated; and (3) halt progression to dysplasia and cancer. Most patients with Barrett’s esophagus are treated medically; however, adequate medical therapy is difficult because of the degree of impairment of the lower esophageal sphincter and the poor esophageal body motility that are frequently present. This is likely to be the reason why the least controlled symptom in patients with Barrett’s esophagus receiving medical treatment is regurgitation[76]. Medical treatment options are limited to dietary and lifestyle modifications, pro-motility agents, and acid-suppression therapy. Sampliner and the Practice Parameters Committee of the American College of Gastroenterology have stated that “the goal of therapy of Barrett’s esophagus should be the control of the symptoms of GERD”, and that “symptom relief is an appropriate endpoint for the therapy of Barrett’s esophagus”[77]. However, this viewpoint flies in the face of logic. Gastroesophageal reflux causes both Barrett’s esophagus and esophageal cancer. Symptoms are not part of the pathophysiology of the disease. Rather, they are merely the variably expressed byproduct of reflux. Many patients with Barrett’s esophagus have few or no reflux symptoms; probably as a consequence of an altered sensitivity of the metaplastic epithelium to refluxed acid. Consequently, the eradication of symptoms, if present, cannot be equated with elimination of reflux. Katzka and Castell[78] have demonstrated that standard-dose omeprazole (20 mg/d) failed to suppress acid sufficiently to keep gastric pH neutral for a full 24 h in patients with Barrett’s esophagus. Furthermore, increasing the dose of the omeprazole until all symptoms were alleviated was an unreliable measure of effective therapy, since 80% of patients studied with 24-h pH still had abnormal distal esophageal acid exposure[78]. Sampliner likewise found that high-dose proton pump inhibitor administration (lansoprazole, 60 mg/d) failed to normalize the 24-h pH test in over a third of patients with Barrett’s esophagus who were tested while on therapy[76]. Even if complete suppression of acid could be achieved 24 h/d, 7 d/wk, for 350 d/year, impedance studies have shown that the number of reflux events is unchanged. Acid reflux events are merely converted to non- or weak acid reflux events, because the physiological abnormalities that lead to reflux are unaddressed by medical acid suppression therapy[79,80]. The role of continued weak or non-acid reflux in the progression of Barrett’s esophagus is undefined, but it may explain the paucity of evidence that acid suppression therapy alters the natural history of Barrett’s esophagus.

The second and third goals of therapy in patients with Barrett’s esophagus are to eliminate the high-risk mucosa, i.e. intestinal metaplasia, and prevent progression to dysplasia and cancer. Medical therapy has not been shown to achieve either of these goals reliably. Several reports have concluded that medical therapy does not cause regression of intestinal metaplasia[81-83]. This might be different in patients with short-segment Barrett’s esophagus. Weston et al[84] have described the loss of goblet cells from lengths of intestinal metaplasia < 2 cm in 32% of patients treated medically for 1-3 years. In contrast, only two of 29 patients (7%) with lengths of intestinal metaplasia ≥ 3 cm had loss of goblet cells.

With respect to the efficacy of medical therapy in preventing progression of Barrett’s esophagus to dysplasia and cancer, there is speculation that prolonged, and perhaps inadequate acid suppression might actually promote the development of Barrett’s esophagus and its complications[32]. Lagergren et al[85] have recently reported that the risk of esophageal adenocarcinoma was increased nearly eightfold among persons in whom heartburn, regurgitation, or both occurred at least once weekly compared to persons without these symptoms. They noted that the risk of esophageal adenocarcinoma was three times higher among patients who used medication for symptoms of reflux compared to those who did not use any antireflux medication[85]. Others, including Ortiz et al[82] and Hameeteman et al[86] have also linked medical therapy for Barrett’s esophagus with progression to dysplasia and adenocarcinoma. In the study by Hameeteman et al[86] from the Netherlands, 50 patients with a columnar-lined esophagus were treated medically and followed from 1.5 to 14 years (mean 5.2 years). Of these 50 patients, initially only 34 had intestinal metaplasia on biopsy of the columnar mucosa. At completion of the study, 37 patients had intestinal metaplasia, which indicated that three patients developed Barrett’s esophagus during the 5-year study period. In addition, at the start of the study, six patients had low-grade dysplasia and one had high-grade dysplasia. By the end of the 5-year study, 10 patients had low-grade dysplasia, three had high-grade dysplasia, and five had adenocarcinoma[86]. Similarly, Sharma et al[87] followed 32 medically treated patients with short segment Barrett’s esophagus (mean length: 1.5 cm) for a mean of 36.9 mo, and found a 5.7% annual incidence of progression to dysplasia. During the 98 patient-years of follow-up in their series, two patients developed high-grade dysplasia, and one of these patients progressed to cancer. Recall that the expected rate of cancer is 1 per 100 patient-years of follow-up. All patients in the study by Sharma and colleagues were treated with omeprazole, ranitidine, and/or promotility agents. They commented that most patients developed dysplasia while on acid suppression medication, and they concluded that medical treatment does not prevent the development of dysplasia. A recent retrospective observational study in patients with Barrett’s esophagus suggested that proton pump inhibitor use was associated with a reduced incidence of high-grade dysplasia or adenocarcinoma compared to patients not taking such medication, but there was no difference in the incidence of dysplasia between groups[88].

Antireflux surgery for Barrett’s esophagus

In contrast to the ongoing weak or non-acid reflux that occurs with acid suppression therapy, antireflux surgery restores lower esophageal sphincter function and abolishes reflux of gastric contents into the esophagus. Consequently, an antireflux operation ends the repetitive injury to both the metaplastic and normal esophageal mucosa. Randomized clinical studies have confirmed superior control of reflux following antireflux surgery compared to medical therapy, and antireflux surgery has been proven safe, effective, and durable[82,89]. In addition, many patients are candidates for a minimally invasive laparoscopic approach associated with a short hospital stay and rapid recovery. We therefore favor the performance of an antireflux procedure in patients with Barrett’s esophagus.

There have been conflicting reports about whether intestinal metaplasia regresses following antireflux surgery. Brand, in 1980, described complete regression in four of 10 patients with Barrett’s esophagus who underwent fundoplication[90]. Subsequently, most reports have demonstrated that while some regression of the length of Barrett’s esophagus is common, complete regression occurs only rarely, particularly with long-segment disease. In contrast, intestinal metaplasia of the cardia and short segments of Barrett’s esophagus much more commonly regress to no intestinal metaplasia after fundoplication[91-93]. Furthermore, during prospective follow-up of patients with a columnar-lined esophagus without intestinal metaplasia treated either medically or with antireflux surgery, Oberg et al[94] showed that significantly fewer patients developed intestinal metaplasia after antireflux surgery.

Perhaps of greater importance is the issue of progression of Barrett’s esophagus to dysplasia or cancer after surgical treatment of reflux disease. Compared to medical therapy, antireflux surgery is associated with a reduced incidence of dysplasia and adenocarcinoma. McCallum et al[95] have prospectively followed 181 patients with Barrett’s esophagus. Twenty-nine had antireflux surgery while the remaining 152 patients were treated medically. After a mean follow-up of 62 mo in the surgical group and 49 mo in the medical group, there was a significant difference in the incidence of dysplasia and adenocarcinoma. Dysplasia was found in 3.4% of the surgical group compared with 19.7% in the medically treated group. No patient in the surgically treated group developed adenocarcinoma of the esophagus compared with two medically treated patients. They concluded that compared with medical therapy, an antireflux operation in patients with Barrett’s esophagus was significantly associated with the prevention of dysplasia and cancer. Similarly, Katz et al[96] have followed 102 patients with Barrett’s esophagus for a mean of 4.8 years. By 3 years, approximately 8% of the medically treated patients had developed dysplasia. In contrast, patients treated by antireflux surgery had a significantly reduced risk of developing dysplasia (P = 0.03)[96]. In the only randomized controlled trial that has compared medical therapy with antireflux surgery for Barrett’s esophagus, Parrilla et al[97] showed that patients with functioning fundoplication had a significantly reduced incidence of developing dysplasia compared to patients on medical therapy. Evidence at the molecular level has shown that antireflux surgery reduces the expression of genes potentially involved in the progression of Barrett’s esophagus to cancer down to the level of control subjects without reflux[98,99]. These studies provide an insight into how antireflux surgery might be protective against progression of Barrett’s esophagus to cancer.

Opposing these studies are two Swedish database studies that have suggested that antireflux surgery does not protect against progression to cancer. However, the serious flaw in both these studies is that the prevalence of Barrett’s esophagus was not known in either population, and it is quite likely that far more patients in the antireflux surgery group had Barrett’s esophagus than the comparison groups[100,101]. The presence of Barrett’s esophagus is the leading known risk factor for subsequent development of esophageal adenocarcinoma, therefore, both studies only add to the controversy rather than provide any reliable answer to this important issue. Another factor that complicates any analysis of progression of Barrett’s esophagus after antireflux surgery is that the cellular and genetic alterations that lead to the development of dysplasia and adenocarcinoma might have already occurred before the antireflux procedure. It has been estimated to take up to 6 years for adenocarcinoma to develop within Barrett’s esophagus with low-grade dysplasia, and thus some cancers, particularly those that present during the first few postoperative years, probably do not represent progression of disease after surgery. McDonald et al[102] have made this point in a study from the Mayo Clinic. They found invasive adenocarcinoma in two patients and carcinoma in situ in one patient during surveillance after antireflux surgery, but they noted that no patient developed carcinoma after 39 mo, despite a median follow-up of 6.5 years, and a maximum follow-up of 18.2 years.


There is increasing evidence that at the normal gastroesophageal junction, esophageal squamous mucosa abuts oxyntic fundic mucosa of the stomach. With exposure to gastric juice, the squamous mucosa is injured, and over time becomes replaced by columnar cardiac mucosa. Deterioration of the lower esophageal sphincter allows reflux to extend up into the esophagus, and the squamocolumnar junction migrates proximally. Although it is likely that acidic gastric juice drives the transformation of squamous mucosa to cardiac mucosa, there is substantial evidence that other components of gastric juice, particularly bilirubin, are essential for subsequent intestinalization of the cardiac mucosa.

Barrett’s esophagus is a premalignant mucosa, and the risk of malignant transformation is approximately 0.5% per patient-year. The finding of dysplasia is currently the most commonly used indicator of increased malignant risk, but it has high inter-observer variability. It is expected that ultimately molecular markers will prove more helpful than histology in Barrett’s esophagus, and there are ongoing efforts to determine biomarkers that will better delineate an individual’s risk for progression to cancer. Surveillance endoscopy in patients with Barrett’s esophagus has proven efficacy, but is time-consuming and haphazardly applied. Currently, screening endoscopy is not recommended for Barrett’s esophagus, but given the dramatic increase in the incidence of esophageal adenocarcinoma, new technologies that permit widespread and cost-effective screening are needed. Patients with Barrett’s esophagus are commonly treated with acid-suppressive medication, but there are few data that this therapy alters the natural history of the disease, and thus current medical guidelines are to treat for symptomatic relief rather than for documented pH control. Antireflux surgery abolishes reflux and has been shown to normalize gene expression in patients with Barrett’s esophagus, but controversy persists regarding the impact of an antireflux procedure on the risk of Barrett’s esophagus progression.


Peer reviewer: Marco Giuseppe Patti, MD, Professor of Surgery, Director, Center for Esophageal Diseases, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, MC 5095, Room G 201, Chicago, IL 60637, United States

S- Editor Wang YR L- Editor Kerr C E- Editor Lin YP

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