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Volume: Barrett's Esophagus
Chapter: Pathophysiology

What is the role of Helicobacter pylori in intestinal metaplasia above, below, and at the gastroesophageal junction?

R.M. Genta (Geneva)

Until less than a decade ago few pathologists who detected goblet cells (or even gastric mucous cells with an irregular, globular shape) in a biopsy specimen labeled as "distal esophagus" would hesitate to make a diagnosis of Barrett's esophagus. In the last five years, the alarmingly increasing prevalence of adenocarcinoma of the gastroesophageal junction (GEJ) and a number of emerging issues regarding use and effects of acid suppression therapy have kindled a wave of interest in that rather neglected border zone known as cardia, previously the subject of sporadic, arcane studies [1].

The site of origin of adenocarcinomas arising from the GEJ can be determined when the entire resected specimen is available for examination, and when the tumor is small and still confined to an anatomically and pathologically circumscribed area, for example Barrett's mucosa in the lower esophagus. However, many if not most tumors are detected only after they have already invaded the adjacent structures of the lower esophagus, cardia, and proximal gastric corpus. In such cases it is virtually impossible to establish the epithelium from which the tumor originated; therefore, these "undetermined tumors" have been referred to junctional carcinomas. Since gastric adenocarcinomas generally arise from metaplastic epithelium, it is widely assumed that junctional adenocarcinomas have their precursor in intestinal metaplasia (IM) in the junctional area. Significant IM in the distal stomach is almost always associated with present or past Helicobacter pylori gastritis; however, some epidemiologists and clinical investigators have linked the recent increase in the incidence of junctional adenocarcinoma to the decreasing prevalence of H. pylori infection. In light of such apparently contrasting facts and hypotheses, one can legitimately ask the unifying question: "what is the role of H. pylori in the development of junctional intestinal metaplasia?" Here I will attempt to provide some answers by dissecting the question in three portions by considering separately the role of H. pylori infection in the genesis of IM above, at, and below the GEJ.

Intestinal metaplasia above the gastroesophageal junction

Barrett's esophagus is defined as the metaplastic conversion of normal esophageal squamous epithelium into columnar epithelium primarily of intestinal type with the development of goblet cells. Thus, the question can be phrased as "what is the role of H. pylori in the pathogenesis of Barrett's esophagus?" The answer is straightforward and virtually undisputed: none. In the first few years after H. pylori was discovered, several studies were deformed to investigate its possible role in the etiology of Barrett's esophagus. The findings were similar: either no association or a weak inverse association was detected [2, 3]. Not surprisingly, a significant inverse association was found between Barrett's esophagus and infection with cagA-positive H. pylori strains [4]. To develop Barrett's esophagus, one must have a normally functioning parietal cell mass with at least a normal acid production. Most subjects infected with cagA-positive H. pylori strains have severe corpus gastritis, a condition that reduces acid production even in the absence of detectable atrophy [5, 6]. Therefore, it seems fair to conclude that H. pylori plays no pathogenetic role in the development of Barrett's esophagus.

Intestinal metaplasia below the gastroesophageal junction

Even if there is little or no understanding of the steps that lead to the replacement of the mucous cells that line the normal gastric mucosa with an epithelium similar to that of the small intestine (IM), this change is incontrovertibly one of the long-term epiphenomena of H. pylori gastritis [7]. IM in the stomach of uninfected subjects is exceedingly rare; in contrast, as many as half of the patients with antral-predominant gastritis may have scattered foci of IM in the antrum, and virtually all those with atrophic pangastritis have extensive metaplastic areas in both antrum and corpus. The only other condition known to be associated with extensive IM is autoimmune atrophic gastritis, and there is emerging evidence that in some cases it may result by an autoimmune response to an earlier H. pylori infection.

Although few mapping studies designed to determine the prevalence of IM in the cardia in patients with extensive atrophic gastritis have been performed, our experience suggests that, while the cardia is not one of the most common locations for this lesion, it is involved as part of the most severe end of the spectrum of atrophic pangastritis [8]. Thus, if IM is found in the cardia, and it is associated with IM in other areas of the stomach, one can assume that H. pylori gastritis is the cause of that lesion.

Intestinal metaplasia at the gastroesophageal junction

Although it may be quite difficult to characterize precisely the location described by the locution "intestinal metaplasia at the gastroesophageal junction," for the sake of this discussion I shall use the following definition: the presence of goblet cells in the columnar cadiac-type mucosa in the immediate vicinity of the squamo-columnar junction, in the absence of significant intestinal metaplasia in the gastric corpus and antrum." Although this definition is restrictive, the exclusion of cases with simultaneous metaplastic atrophic gastritis is necessary, because such cases fall into the category discussed in the previous question.

Several published reports show that between 5% and 25% of patients with various upper gastrointestinal aliments, as well as some normal subjects, have collections of goblet cells at the GEJ [9-17]. In most of these studies, subjects with and without H. pylori infection were equally represented, and a significant relationship with reported gastroesophageal reflux disease symptoms or endoscopic esophagitis could not be demonstrated. Three hypotheses can be considered to explain this finding. In patients with reflux esophagitis, proinflammatory lymphokines from the eroded or inflamed distal esophagus may reach the adjacent portions of the cardia and elicit inflammation, in a fashion similar to the phenomenon known as backwash ileitis found in some patients with ulcerative colitis [18]. This distal diffusion of lymphokines (Figure 1) could cause a "forewash carditis", and the damaged columnar epithelium might undergo focal metaplastic intestinalization, as it happens in the gastric mucosa damaged by H. pylori-associated inflammation. The cardia is consistently affected and often severely inflamed in H. pylori gastritis [14, 19]. Thus, a second possibility is that, in rare patients with H. pylori the junctional region be the most severely affected area of the stomach, and the first one to undergo metaplastic changes. This may be due to individual susceptibility, to particular bacterial strains, or to yet unknown microenvironmental factors. Finally, one must consider that in many studies the histopathological characteristics of the esophagus and the distal stomach were not rigorously documented with extensive mapping protocols. Therefore, it is not inconceivable that if meticulous studies were performed, a majority of subjects with yet unexplained IM at the GEJ might eventually be proven to have either histological evidence of reflux esophagitis or H. pylori-associated metaplastic gastritis.

Clearly, as illustrated in Figure 2, more detailed studies are necessary before this third segment of the question can be answered satisfactorily [20].

Figure 1. In reflux esophagitis, proinflammatory lymphokines from the eroded or inflamed distal esophagus may reach the adjacent portions of the cardia and elicit inflammation, in a fashion similar to the phenomenon known as backwash ileitis found in some patients with ulcerative colitis. This distal diffusion of lymphokines could cause a "forewash carditis," and the damaged columnar epithelium might undergo focal metaplastic intestinalization (IM), as it happens in the gastric mucosa damaged by H. pylori-associated inflammation.

Figure 2. Intestinal metaplasia above the GEJ (A) is Barrett's esophagus and has no etiological relationship to H. pylori. Below the GEJ (B), intestinal metaplasia is usually part of metaplastic atrophic gastritis and is caused by H. pylori infection. The origin and significance of intestinal metaplasia strictly limited to the junctional zone (C) remain elusive.


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Publication date: August 2003 OESO©2015