Primary Motility  Disorders of the  Esophagus
 The Esophageal
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Volume: Barrett's Esophagus
Chapter: Pathophysiology

H. pylori and intestinal metaplasia at the esophagogastric junction. European experience

M. Voutilainen, T. Rantanen, P. Sipponen (Jyväskylä, Tampere, Espoo)

Gastric cardia is a narrow isthmus of mucosa separating squamous esophageal and fundic mucosa. The glands of the gastric cardia mucosa are coiled and occasionally branched, and secrete mucus [1]. Gastric cardia is 1.0-4.0 mm in width, and its presence in childhood suggests that it is a normal and not metaplastic structure [2]. Chronic inflammation is often detected in the gastric cardia mucosa but its pathogenesis remains controversial: it may associate with H. pylori infection [3, 4] or gastroesophageal reflux disease (GERD) [5, 6].

Intestinal metaplasia (IM) is characterized by the presence of goblet cells and is subdivided into complete (type I) and incomplete (types II and III) IM. The histologic hallmark of Barrett's esophagus is the presence of incomplete IM in biopsy specimens obtained from columnar-lined distal esophagus. Incomplete IM is characterized by acid mucins on alcian blue or high iron diamine oxidase stains in goblet cells and adjacent columnar-appearing cells. IM is also observed in biopsy specimens obtained from normalappearing squamocolumnar junction [7, 8]. IM at the gastric cardia mucosa has been linked to both H. pylori infection and GERD [4, 5, 9, 10]. IM at this location is a topic of great interest, because IM associates with increased risk of cancer [11, 12] and the prevalences of esophageal and cardia carcinomas have been rising [13-17]. Barrett's esophagus is a risk factor for esophageal carcinoma [12], and adenocarcinomas of the esophagogastric junction (EGJ) may arise from short segments of Barrett-type metaplasia [18]. Barrett's esophagus and esophageal adocarcinoma are male-predominant diseases [12].

Chronic inflammation of the gastric cardia mucosa ("carditis")

We studied the prevalences of chronic cardia inflammation and IM and their associations in a consecutive series of 1,698 patients sent for upper gastrointestinal endoscopy during a four-month period in our hospital referral area, which serves approximately 250,000 inhabitants in Central Finland. Biopsy specimens were obtained from esophagus 2-3 cm orally from the Z-line, from junctional mucosa immediately distal to normal appearing squamocolumnar junction, from gastric antrum (> 3 cm from pyloric ring), and from gastric body (two biopsy specimens from each site). Biopsy specimens were transferred to laboratory formalin solution. In laboratory, the tissue samples were imbedded in paraffin blocks, sliced and stained with haematoxylin-eosin, alcian blue-periodic acid Schiff (pH 2.5) and modified Giemsa. The presence of H. pylori infection was determined only by histology. Clinical and endoscopic data were recorded on structured questionnaires. The final number of patients included in the subanalyses depended on the validity of biopsy specimens and the inclusion criteria.

gastric cardia mucosa by mononuclear cells - was detected in 790 (75%) patients, of whom 69% had chronic gastritis and 31% normal gastric histology. Of the patients with chronic gastritis, 70% were H. pylori positive. Mild chronic gastric cardiac inflammation was common (39%-63%) in all age groups and showed no correlation with increasing age, but the prevalence of moderate to severe carditis did rise with age (Figure 1). Of patients with normal gastric histology, 56% had carditis, whereas among the patients with chronic gastritis the prevalence of carditis was 80-93% (Table I).

We compared carditis patients with and without chronic gastritis to those without carditis (Table II). In patients with chronic gastritis, carditis was positively associated with age, the use of nonsteroidal anti-inflammatory drugs (NSAID), H. pylori infection, and microscopic esophagitis, as well as with complete and incomplete IM in the gastric cardia mucosa. In patients with histological normal gastric mucosa, carditis was associated with the use of NSAIDs, endoscopy-positive GERD, microscopic esophagitis and incomplete IM of the gastric cardia (Table II).

The variables with a significant correlation to carditis (except microscopic esophagitis and cardia IM, Table II) were included in multiple logistic regression analyses. These

Figure 1. The prevalences of chronic gastric cardia inflammation ("carditis" or "junctitis"), complete intestinal metaplasia (IM), and incomplete intestinal IM (specialized columnar epithelium) in patients with histologically normal stomach.

Table I. The prevalences of carditis in different types of gastritis. Each gastritis subtype was compared with the normal gastric histology group (from [19] with permission).

Table II. The comparison of carditis patients with or without chronic gastritis with the subjects with normal gastric cardia histology (from [19] with permission).

multivariate analyses revealed that in patients with chronic gastritis, H. pylori infection was the only independent risk factor for carditis, the odds ratio (OR) being 2.9 (95% confidence interval CI 1.6-5.0). In patients with normal stomach (i.e. without chronic gastritis), endoscopic erosive esophagitis was the only risk factor for carditis (OR 1.8, 95% CI 1.1-3.1).

Intestinal metaplasia at the gastric cardia

We investigated the prevalence and associations of incomplete and complete IM with chronic H. pylori gastritis and endoscopy-positive or erosive GERD [20, 21]. In a consecutive series of 1,058 patients who underwent upper gastrointestinal endoscopy, the prevalence of gastric cardia complete IM was 19% and that of incomplete IM 10%; 62 patients (6%) harboured both types of IM simultaneously. In univariate analysis, complete cardia IM associated positively with age, H. pylori infection and chronic carditis, whereas incomplete cardia IM associated with age, endoscopic erosive esophagitis and carditis, as well as H. pylori infection of the gastric mucosa (Table III). Neither IM subtype associated with male sex.

Complete type IM associated positively with multifocal atrophic gastritis and chronic gastritis of any type, whereas incomplete junctional IM did not associate with any type of gastritis (Table IV). Moreover, of patients with histological normal gastric mucosa (n = 426), 6% had complete and 7% incomplete IM in gastric cardia mucosa [21].

Multivariate analyses revealed that independent risk factors for complete junctional IM were age (OR 1.2 per decade, 95% CI 1.0-1.4), antral predominant non-atrophic gastritis

Table III. Demographic, endoscopic and histological characteristics of patients with junctional complete or incomplete intestinal metaplasia (IM) compared with those of the control group without these lesions (from [21] with permission).

Table IV. The prevalences of esophagogastric junctional complete and incomplete intestinal metaplasia (IM) in different types of gastritis (from [21] with permission).

(OR 2.6, 95% CI 1.3-5.2), antral predominant atrophic gastritis (OR 2.1, 95% CI 1.1-5.2), and multifocal atrophic gastritis (OR 7.1, 95% CI 2.5-19.8), whereas carditis (OR 1.2, 95% CI 0.6-2.2), cardia H. pylori infection (OR 1.8, 95% CI 0.9-3.8) or gastric H. pylori infection (OR 0.7, 95% CI 0.3-1.4) were not independent risk factors. Independent risk factors for incomplete IM of the gastric cardia were age (OR 1.3 per decade, 95% CI 1.21.6), endoscopic erosive esophagitis (OR 1.9, 95% CI 1.1-3.2), and carditis (OR 2.9, 95% CI 1.3-62), whereas antral predominant atrophic gastritis (OR 1.4, 95% CI 0.9-2.4) and gastric H. pylori infection (OR 1.0, 95% CI 0.6-1.7) were not independent risk factors for cardia incomplete IM [21].

When comparing junctional incomplete IM at normal-appearing squamocolumnar junction (N = 99) with classical Barrett's esophagus (n = 25), we observed that unlike Barrett's esophagus, junctional incomplete IM was not a male-predominant lesion: the male to female ratio for Barrett's esophagus was 2.4:1 and for cardia incomplete IM 1:1.3 (p = 0.01) [22]. Both junctional specialized columnar epithelium and Barrett's esophagus associated with endoscopy-positive GERD, and the mean age of these patient groups was equal (63 years [95% CI 58-69] for Barrett's esophagus patients and 64 years [95% CI 6267] for junctional specialized columnar epithelium patients). Compared with Barrett's esophagus, dysplasia in junctional metaplastic mucosa was significantly less common (24% versus 0%, p < 0.001).


The conflicting results of the studies on the pathogenesis of gastric carditis and IM may result from different prevalence of H. pylori infection and GERD in different populations. Further, patient selection may be a source of bias in some studies. To avoid the lastmentioned bias, we collected data from a large and consecutive series of patients referred for upper gastrointestinal endoscopy. Third, the use of both hematoxylin-eosin and alcian blue stains is essential to differentiate complete and incomplete IM types, as well as enhancing the probability of detecting IM [23]. Because gastric cardia is only a few millimetres in width, failure to obtain the biopsy specimen from directly across the EGJ may cause biopsy sampling error.

It emerges from the present series of studies that chronic inflammation in the gastric cardia mucosa is a common lesion in patients with normal-appearing EGJ at endoscopy. That the prevalence of moderate to severe carditis increased with age suggests that it is an acquired lesion. Our data indicate that chronic inflammation may result from two different pathogenic mechanisms. The majority of patients with carditis have chronic gastritis, for which H. pylori infection is the major etiologic factor. Our results suggest that in most cases carditis is a manifestation of pangastritis. They further indicate, however, that carditis also exists in otherwise histologically normal stomach mucosa. This is concordant with Bowrey et al., who recently reported the existence of isolated non-H. pylori carditis [24]. Öberg et al. have shown that carditis associates with deteriorated lower esophageal sphincter tone and increased esophageal acid exposure [5]. These studies suggest that independent carditis in otherwise normal stomach may be regarded as an objective marker of GERD. Chronic inflammation at the GEJ is, however, very common and may in some cases be due to physiological reflux [25]. Our finding that mild carditis was equally common in all age groups suggests that only moderate to severe carditis may be an objective marker for GERD.

Our studies indicate that both complete and incomplete IM in the gastric cardia are common lesions, which accords with earlier findings [7, 8, 23]. The fact that the prevalences of both complete and incomplete IM increased with age suggests they are acquired lesions. Both IM subtypes occurred in men and women at similar frequencies, contrasting with Barrett's esophagus and junctional carcinomas, which are malepredominant diseases.

The present findings help clarify the conflicting data on the role of H. pylori infection and GERD in the pathogenesis of junctional IM. Although both IM subtypes may occur simultaneously, the complete type associates strongly with chronic gastritis and particularly with multifocal atrophic gastritis. This suggests that junctional complete IM results from multifocal atrophic gastritis, i.e. is a sequel to H. pylori infection. H. pylori infection was determined only by histology and the true H. pylori prevalence was probably higher than we observed. Both types of cardia IM were observed, however, even in patients with histologically normal stomach. This finding indicates that these histopathological lesions can occur independently of H. pylori infection, which implies that cardia IM may also result from other pathogenic factors, for example GERD.

Compared with complete cardia IM, multivariate analysis showed a different risk factor profile for junctional incomplete IM. Endoscopy-positive GERD, but not H. pylori infection, was an independent risk factor for junctional incomplete IM. This suggests that junctional incomplete IM is an objective marker for GERD. Although cardia incomplete IM and Barrett's esophagus are histologically indistinguishable, the former harboured dysplasia significantly less frequently than the latter. Short-term follow-up studies have revealed that the risk of cardia IM developing dysplasia is lower compared with short segments of Barrett's esophagus [26]. The size of the metaplastic mucosa may contribute to the prevalence of dysplasia [12]. Thus junctional incomplete IM does not seem to be such a high-risk adenocarcinoma lesion as Barrett's esophagus is for esophageal adenocarcinoma, and endoscopic biopsy surveillance of patients with cardia IM but without dysplasia is not advocated.


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Publication date: August 2003 OESO©2015