To outline current concepts regarding etiology, diagnosis, and treatment of intestinal metaplasia of the esophagus and cardia.
Summary Background Data
Previously, endoscopic visualization of columnar mucosa extending a minimum of 3 cm into the esophagus was sufficient for the diagnosis of Barrett’s esophagus, but subsequently the importance of intestinal metaplasia and the premalignant nature of Barrett’s have been recognized. It is now apparent that shorter lengths of intestinal metaplasia are common, and share many features of traditional 3-cm Barrett’s esophagus.
Originally the term “Barrett’s esophagus” was used to describe an esophagus in which a portion of the normal squamous mucosa was replaced by columnar epithelium. Since the 1950s, when the term became popularized, much has been learned about this condition, and new concepts continue to emerge that force reevaluation of this disorder. In fact, the meaning of the term Barrett’s esophagus is perhaps more ambiguous now than ever before.
Stomach Versus Esophagus
Since the early 1900s, the presence of ulcers within a columnar epithelial-lined, tubular structure of the foregut have been described. In the mid-1900s, the debate raged over whether these ulcers were located in a tubularized portion of stomach or in the esophagus. Using criteria “relevant to the physiologist, surgeon, and physician,” Dr. Norman Barrett, an influential British surgeon, wrote in 1950 that sections of the gastrointestinal tract are defined by their mucosa, and therefore the esophagus is “that part of the foregut distal to the cricopharyngeal sphincter which is lined by squamous epithelium.” 1 He went on to state that when ulcers are found below the squamocolumnar junction, they represent gastric ulcers within “a pouch of stomach … drawn up by scar tissue into the mediastinum” or more likely represent “examples of a congenital short esophagus.”
In 1953, Allison and Johnstone demonstrated that the tubularized portion of the foregut declared by Dr. Barrett to be stomach had no peritoneal covering, normal esophageal musculature, and typical esophageal mucous glands. They concluded that “it appears better to refer to that congenital abnormality which from the outside looks like esophagus and from the inside looks like stomach as ‘esophagus lined with gastric mucous membrane.’ ” 2 Although they called the mucosa “gastric,” they recognized that oxyntic cells were not present.
In 1957, Dr. Barrett accepted the viewpoint that in some patients the columnar epithelium extended further proximally into the esophagus than could be accounted for by a hiatal hernia. Further, he concurred with Allison and Johnstone that the columnar mucosa, despite its “gastric” appearance, did not contain oxyntic cells and did not function like gastric mucosa. He agreed to the term “columnar-lined lower esophagus,” and subsequently his name became synonymous with the condition.
Congenital Versus Acquired
In their 1953 report, Allison and Johnstone had noted that the presence of a columnar-lined esophagus was usually associated with a hiatal hernia, and that all of the patients had reflux esophagitis. Still, like Dr. Barrett, they considered it to be of congenital origin. Later Dr. Barrett, while still favoring a congenital etiology, conceded that “if the cardiac valve of a normal person were to become incompetent and if the lower esophagus were, as a result, to be bathed for a long time by digestive gastric juice, the squamous epithelium could be eaten away and totally replaced by columnar cells.” 3
In 1959, Moersch et al 4 reviewed the specimens from 36 patients who had undergone esophageal resections at the Mayo Clinic for esophagitis. They noted that “cells resembling young columnar cells were seen occasionally, and thus the question of inflammatory metaplasia had to be considered.” This was the first convincing evidence that the columnar epithelium of Barrett’s esophagus was acquired, and that it was
caused by repetitive exposure of the distal esophagus to refluxed gastric juice. Subsequently several studies, including the 1970 landmark experimental report by Bremner et al, 5 confirmed the association between a columnar-lined esophagus and gastroesophageal reflux disease (GERD), and the congenital theory was discarded.
In the late 1950s, the term Barrett’s esophagus was understood to mean a columnar-lined esophagus, and this rather vague definition persisted until the 1980s. Refinements in the definition came about as a result of two issues. The first was that as endoscopy became more common, it was recognized that many patients had hiatal hernias and esophagitis, and that it was difficult and error-prone for an endoscopist to determine precisely where the esophagus ended and the stomach began. In addition, Hayward in 1961 6 had written that the “normal” esophagus could have 1 to 2 cm of columnar mucosa at the distal end. Therefore, to avoid an overdiagnosis of Barrett’s resulting either from failure to recognize a tubularized portion of herniated stomach on endoscopy, or from failure to allow for the “normal” 2 cm of columnar mucosa in the distal esophagus, a 3-cm rule was introduced in the early 1980s. This rule stipulated that a diagnosis of Barrett’s esophagus required a minimum of 3 cm of columnar mucosa to be present above the perceived gastroesophageal junction. Although various authors used between 2 and 5 cm of columnar mucosa, some minimum length requirement was adopted by most physicians and persists in the minds of many people to this day.
The prevalence of Barrett’s esophagus is unknown, but any estimate depends significantly on the definition one uses for Barrett’s. Using the traditional definition of at least 3 cm of columnar mucosa above the gastroesophageal junction, Barrett’s has been reported in 0.45% to 2.2% of all patients undergoing upper endoscopy and in up to 12% of patients undergoing endoscopy for symptoms of reflux. 14 If all patients with a biopsy showing intestinal metaplasia, regardless of length, were included in the definition, then the incidence increases to 9% to 32% of unselected patients undergoing upper endoscopy. 15 Based on an autopsy series, Cameron et al 16 estimated the prevalence of traditional Barrett’s in the general population to be 376 cases per 100,000 population. Consequently, they suggested that for every known patient with Barrett’s, there might be 20 or more unrecognized ones in the general population. It is likely that the prevalence of any length of intestinal metaplasia within the esophagus is even greater.
In addition to an increased amount and exposure time of refluxed gastric juice, the composition of the refluxed juice likely contributes to the pathogenesis of Barrett’s esophagus. The observations that gastric hypersecretion can be associated with Barrett’s and that Barrett’s has developed after total gastrectomy suggest that acid gastric juice is not the sole factor responsible for this disease. 21 Recent reports are focusing on the importance of refluxed duodenal secretions in the development of intestinal metaplasia. Patients who reflux both gastric and duodenal juice have been found to have a higher prevalence of esophagitis and Barrett’s esophagus than do patients who reflux gastric juice alone. 18 Analysis of the composition of reflux in 281 patients with GERD demonstrated that the patients with the greatest degree of mucosal injury were more likely to have both gastroduodenal and acid reflux as opposed to pure gastric reflux ( Table 1 ). 22 In addition, patients with Barrett’s had a significantly higher prevalence and duration of abnormal esophageal bilirubin exposure, which is a tag for duodenal juice, compared with patients with only esophagitis. 23 Among patients with Barrett’s, significantly greater esophageal bilirubin exposure has been demonstrated in those in whom dysplasia develops ( Fig. 1 ).