Abstract
Objective: Studies of the etiology of intestinal metaplasia (IM) at a normal appearing gastroesophageal junction (GEJ) are conflicting as associations with both H. Pylori (HP) infection and gastroesophageal reflux has been reported. The aim of this study was to investigate whether IM at the GEJ is associated with gastroesophageal reflux or HP infection.
Material and methods: Fifty asymptomatic volunteers and 149 patients with reflux symptoms underwent endoscopy with biopsies obtained from the gastric antrum and the squamocolumnar junction (SCJ). All subjects underwent wireless 48 h pH monitoring with the electrode placed immediately above the SCJ and a fecal antigen test for HP infection. Clinical characteristics and the pattern of reflux were compared in subjects with and without IM.
Results: Three asymptomatic volunteers and 35 patients who had clearly irregular SCJs with short extensions of columnar mucosa were excluded from the study. In the remaining 47 asymptomatic volunteers and 114 patients, variables that reached a significance level of 0.1 or less on univariate analyses were used in a binomial regression analysis to assess their relative importance for the finding of IM. IM at the GEJ was significantly associated with abnormal distal esophageal acid exposure (5.5 (1.2–24.6), p = .026), the frequency of reflux episodes/hour (1.5 (1.1–2.2), p = .031), and an endoscopic appearance of the SCJ corresponding to ZAP grade I (4.6 (1.4–15.6), p = .013). There was no association with HP infection.
Conclusion: The finding of IM at an endoscopically normal-appearing GEJ is associated with gastroesophageal reflux but not with HP infection.
Introduction
IM within the columnar lined esophagus is strongly associated with gastroesophageal reflux and an increased risk of adenocarcinoma in the esophagus [Citation1–3], one of fastest increasing malignancies in the western world [Citation3]. IM in the stomach is also associated with adenocarcinoma, however, gastric cancer is usually secondary to HP infection [Citation4]. IM at the junction between the stomach and the esophagus in individuals with an endoscopically normal-appearing SCJ is a frequent finding [Citation5] but its clinical importance is unclear although it has been suggested to be associated with an increased risk of cancer [Citation6]. The etiology of IM at an endoscopically normal SCJ is controversial and has been debated since the 1990s. The results from available studies are conflicting as associations with both HP infection and gastroesophageal reflux has been reported [Citation7–18]. We believe that one of the reasons for the controversial conclusions in previous studies is a misapprehension concerning the anatomy and histology of the area of the GEJ and the proximal stomach. Furthermore, all but one of the existing studies [Citation7] are limited by the fact that they are based on patients’ symptoms and lack objective documentation of acid exposure. As it has been shown that the degree of acid exposure at the level of the GEJ is substantially underestimated by traditionally placed pH electrodes [Citation19], it is necessary to perform pH monitoring at the level of the SCJ in order to reliably study the association between minimal metaplastic changes at the GEJ and acid reflux.
The aim of this prospective study was to assess if IM found in cardiac-type mucosa at an endoscopically normal-appearing GEJ is associated with gastroesophageal reflux and/or HP infection. This was done by histologic evaluation of multiple biopsies obtained from endoscopically normal-appearing SCJs in large groups of asymptomatic volunteers and patients with symptoms suggestive of gastroesophageal reflux disease (GERD). Clinical characteristics, the pattern and degree of acid reflux immediately above the SCJ and the presence of HP infection were compared between individuals with and without IM.
Material and methods
Between October 2005 and April 2010, 50 asymptomatic volunteers and 149 patients with symptoms suggestive of GERD were recruited for this prospective study at the Endoscopy unit, Lund University Hospital. All participants underwent upper GI endoscopy and 48-hour wireless esophageal pH monitoring with a pH capsule positioned with the electrode immediately above the SCJ. The healthy volunteers were matched for gender and age and recruited as previously described [Citation20]. They were considered asymptomatic, as they reported no symptoms of GERD or short episodes of mild reflux symptoms less than once a month. The symptomatic patients were referred to the endoscopic unit, recruited through advertising within the hospital and in the local newspaper as described previously [Citation21]. The patients consisted of subjects with typical reflux symptoms such as heartburn and regurgitation (n = 94) and of subjects with atypical symptoms such as respiratory symptoms, chest pain and epigastric pain (n = 55).
Endoscopy
All participants received standardized oral and written study information from a research nurse. Medications with proton pump inhibitors were discontinued 10 days before the test but antacids were allowed until 24 hours before the endoscopy. All participants were offered local anesthetics and intravenous midazolam. Experienced endoscopists performed a complete examination (9 mm endoscope, OlympusTM, Sweden) including the esophagus, stomach and proximal duodenum, and the presence of hiatal hernia, erosive esophagitis and columnar lined esophagus was registered. The SCJ was defined as transition between pearly gray squamous epithelium and reddish gastric mucosa and the GEJ was defined by the proximal extent of the gastric rugal folds. During gentle insufflation and exsufflation, allowing for a dynamic assessment of the level of GEJ and shape of the SCJ, the geometry of SCJ was graded according to ZAP classification [Citation22].
Four biopsy specimens were obtained from the base of the SCJ for histological evaluation. In order to obtain biopsies of the true cardia, which is an extremely short (<0.4 mm) segment of cardiac-type mucosa in juxtaposition with the squamous epithelium at the SCJ [Citation23] an open pair of biopsy forceps was positioned with one jaw on each side of the base of the SCJ in order to obtain both squamous and cardiac mucosa. Subsequently, two biopsies were obtained from the gastric antrum for the histological analysis of HP and gastric IM. In addition, all participants had a fecal antigen test for analysis of the presence or absence of HP infection. Subjects were classified as positive for HP infection if at least one of the two tests were positive for the infection.
Esophageal pH monitoring
With the endoscope positioned within the esophagus, a delivery catheter carrying the pH capsule was introduced transorally and positioned in the stomach. The capsule was carefully withdrawn until the pH electrode was positioned immediately above the SCJ and attached to the esophageal mucosa as previously described [Citation24]. The position of the capsule was confirmed visually, making sure that the pH electrode was neither positioned too high nor dipping below the SCJ. Patients with the capsule inadvertently positioned with the electrode more than 5 mm above the SCJ were excluded. The distance between the pH electrode and the SCJ was assessed in relation to an open pair of biopsy forceps. For the purpose of other studies, a second pH capsule was subsequently positioned with the pH electrode 6 cm above the SCJ using an identical technique. All participants were encouraged to return to work and to engage in all normal activities during the pH study.
The pH recording was initiated after placement of the capsules and continued for 48 hours. The study subjects were asked to avoid acidic food products and alcohol, and to keep tobacco consumption to a minimum during the study period. All subjects were asked to keep a diary and record symptoms, meal times and times spent in the supine position. The data from the receivers were loaded into a computer and analyzed using the Polygram™ NET, (Medtronic, MN, USA) software. The software automatically calculated the characteristics of esophageal acid exposure. Based on previous studies, abnormal acid exposure was defined by a percentage of time with pH <4.0 that exceeded 5.7% [Citation25]. Recordings with duration of less than 36 hours were not considered successful and, therefore, not included in the analyses.
Biopsy specimen were fixed in formalin and stained with hematoxylin-eosin. Giemsa stain was used to assess HP colonization. The specimens were evaluated for the presence or absence of IM. Incomplete or specialized IM was defined as the presence of goblet cells containing Alcian-blue acidic Schiff positive mucins.
Statistical analysis
Analysis of normality was made using the Kolmogorov–Smirnov test. As the data were not normally distributed, comparisons were made using nonparametric tests and the results were reported as medians and interquartile ranges. The Mann–Whitney U-test was used to compare continuous data between individual groups and the chi-square test was used to compare proportions. The variables that reached a p-value of .1 or less in the univariate analyses were entered in a binary logistic regression analysis in order to assess their relative importance for the presence of IM at the GEJ. This analysis was made using a backward stepwise selection with removal testing based on the probability of the Wald statistic. The SPSS 22.0 (IBM, NY, USA) was used for all statistical analyses.
Written informed consent was obtained from all participants. The patients received no remuneration for participating in the study. Lund University Ethics committee approved the study (LU 719-03).
Results
Three of the asymptomatic volunteers (6%) and 35 of the symptomatic patients (23.5%, p = .006) had irregular SCJs with projections of metaplastic columnar mucosa that extended 5 mm or more above the base of the SCJ, corresponding to ZAP grade II. As the aim of this study was to evaluate the etiology of IM in individuals with endoscopically normal-appearing GEJs, these subjects were excluded from the analysis. Consequently, the study population consisted of 47 asymptomatic volunteers and 114 patients with symptoms suggestive of GERD. Symptomatic patients had a significantly higher BMI compared with the asymptomatic volunteers but there was no difference in age or gender distribution (). Hiatal hernia, erosive esophagitis, ASA-treatment and a history of HP eradication therapy were significantly more prevalent in patients compared with asymptomatic volunteers (). Fourteen percent of symptomatic patients and 8.5% of asymptomatic volunteers had a positive test for HP or a history of HP eradication therapy. Forty-five of the 161 participants (28%) were found to have IM at the GEJ. There was no significant difference in the prevalence of IM at the GEJ between asymptomatic volunteers and patients. The gender distribution, median age and BMI were similar in subjects with and without IM (). The clinical characteristics of subjects with and without IM at the GEJ are shown in . IM was significantly associated with an endoscopic appearance of the SCJ corresponding to ZAP grade I but there was no association with HP infection. demonstrates the characteristics of acid reflux in subjects with and without IM at the GEJ. IM was significantly associated with increasing frequency of reflux episodes and with abnormal esophageal acid exposure measured immediately above the SCJ.
Table 1. Demographic data of healthy volunteers and symptomatic patients.
Table 2. Clinical characteristics of healthy volunteers and symptomatic patients.
Table 3. Demographic characteristics of subjects with and without IM at the GEJ.
Table 4. Clinical characteristics of subjects with and without IM at the GEJ.
Table 5. Characteristics of acid reflux measured immediately above the SCJ in subjects with and without IM on biopsies of a normal appearing GEJ.
The factors that reached a p-value of .1 or less in the univariate analyses were entered in a binomial logistic regression analysis to assess their independent importance for the presence of IM at the GEJ (). IM at the GEJ was significantly associated with increasing number of reflux episodes per hour, abnormal acid exposure in the most distal esophagus and with an endoscopic appearance of the SCJ corresponding to ZAP grade I. Further, there was a small but significant negative association between IM at the GEJ and increasing percentage time with pH below 4.0 measured immediately above the SCJ.
Table 6. Binary logistic regression showing the relative risk for IM at an endoscopically normal-appearing GEJ.
Discussion
We have studied the etiology of IM at the GEJ by histologic examination of biopsies obtained from the exact level of the SCJ, by targeted registration of acid reflux immediately above the SCJ and by assessment of HP infection in asymptomatic volunteers and symptomatic patients. Our results suggest that IM at an endoscopically normal-appearing SCJ develops as a consequence of gastroesophageal reflux and is not associated with HP infection.
Over the last several decades, there has been a dramatic rise in the incidence of adenocarcinoma in the area of the GEJ [Citation3]. This has led to an increasing interest regarding the etiology and pathogenesis of pathologic processes that occur in this area. It is generally accepted that reflux disease leads to inflammation and IM within the esophagus and that HP infection often leads to inflammation and subsequently atrophy and IM within the stomach [Citation4]. However, IM at the junction between these organs in the absence of endoscopically apparent metaplastic columnar mucosa is controversial. The results of available studies are conflicting with reported associations with both HP infection and with gastroesophageal reflux [Citation7–18]. However, in previous studies, the conclusions are merely based on endoscopy and patients’ symptoms, and suffer from the limitation that they lack objective documentation of acid reflux and control groups with healthy asymptomatic volunteers.
The acid environment of the area of the GEJ is of particular interest as this is the region were complications such as esophagitis, metaplasia and adenocarcinoma most commonly occur [Citation12]. However, information of the acid milieu in the area of the GEJ has until recently been sparse as the pH electrode of traditional catheter-based techniques for esophageal pH monitoring is positioned 6–7 cm above the SCJ in order to avoid gastric pH tracings [Citation26,Citation27]. With the capsule-based technique, the pH electrode can be attached to the esophageal mucosa at any level and maintain a consistent position within the esophagus throughout the test, allowing for a reliable assessment of the acid environment in the area of the SCJ [Citation28]. Studies using simultaneous dual pH monitoring with one capsule positioned with the pH electrode at the traditional level and one immediately above the SCJ, has demonstrated that the degree of acid exposure at the level of the GEJ is substantially underestimated by traditionally placed pH electrodes and that only approximately 25% of reflux events detected at the level of the SCJ extend to the level of conventionally placed pH sensors [Citation19]. Thus, in order to reliably study the association between metaplastic changes at the GEJ and acid reflux, targeted pH monitoring of the area of the SCJ is necessary.
We found a relatively high prevalence of IM at the GEJ, but the frequency of IM was similar to that of several earlier reports [Citation13,Citation29–33]. The large difference in the reported prevalence of IM at the GEJ is possibly explained by a true difference in the prevalence of IM in different study populations, but could also be a result of different biopsy protocols. It has been demonstrated that the number and location of the biopsies have a large impact on the frequency of IM of this area [Citation30]. The prevalence of HP infection of patients, including those that had a history of HP eradication therapy, in the present study population was 14%, which was considerably lower than that of similar studies [Citation7–18]. Although we found a relatively low frequency of HP infection, we believe that the reported prevalence of the infection is accurate as all subjects had a fecal antigen test as well as biopsies of the gastric antrum that were analyzed for the presence of HP infection. Furthermore, the withdrawal time for PPIs was sufficient to allow for a reliable detection of the infection [Citation34]. The relatively low prevalence of HP may be explained by a generally low HP prevalence in Sweden compared to other parts of the world, but also by differences in HP infection in the different study populations due to selection bias. Current studies have shown that the prevalence of HP is decreasing globally [Citation35] and according to a recent report, the prevalence of HP infection in Sweden is as low as 15.8% [Citation36]. As the prevalence of HP infection in our patient population was similar to the reported national prevalence, we believe that our study population was unselected and unbiased and representative of the Swedish population in terms of HP infection. In contrast to several previous studies [Citation11–18], we found no association between IM at the GEJ and HP infection.
We believe that one of the reasons for the contradictory results of previous studies is a misapprehension concerning the anatomy and histology of the area of the GEJ and the proximal stomach. Generally, the cardia is referred to as the proximal part of the stomach. However, cardia is not an organ, and metaplastic changes and adenocarcinoma in the area of the GEJ originate from either the distal esophagus or the proximal stomach. Similarly, differences in definitions and usage of the term cardia have led to a misconception regarding the meaning of the commonly used terms cardia IM, IM at the SCJ and IM at the GEJ. The true gastric cardia is an extremely short segment (<0.4 mm) of mucosa that is typically composed of pure mucous glands or sometimes mixed mucous/oxyntic glands that is juxtaposed with the squamous epithelium at the SCJ [Citation23]. Originally, the terms cardia IM and IM at the GEJ was referred to as IM within cardiac-type mucosa at the junction between the esophagus and stomach in subjects without endoscopically visible metaplasia. Due to confusion secondary to inadequate standardization of methods, definitions and terminology, investigators have provided data without knowledge of the precise origin of the biopsies upon which the studies are based on. This has led to that the terms cardia IM, IM at the GEJ and IM at the SCJ have frequently been used to describe IM in the in biopsies of the proximal stomach. We obtained the biopsies from the base of the SCJ with the jaws of the biopsy forceps on either side of the SCJ in order to obtain cardiac-type mucosa, but in many studies biopsies have been obtained below a normal SCJ, which means that that the specimens are gastric in origin and composed of a mucosa that is resistant to the noxious effects of gastric acid. It is therefore not surprising that inflammation and IM in such biopsies are associated with HP infection and not with the hallmarks of GERD. However, it is theoretically possible that IM in biopsies of cardiac-type mucosa, which appears to be affected by the injurious effects of both gastric acid and HP infection, may have two distinct etiologies. As suggested by the results of our study, IM can be a consequence of acid reflux but it is also conceivable that an association between IM in the true cardia and HP infection in a population with an extraordinarily high prevalence of pangastritis secondary to the infection could be found.
Our results suggest that IM at a normal appearing SCJ is a consequence of gastroesophageal reflux. The strongest predictor for IM at the GEJ in the binary logistic regression analysis was the presence of abnormal acid exposure monitored immediately above the SCJ, with a relative risk that was 5.5 times higher than for subjects with normal acid exposure. The number of reflux episodes per hour was also associated with an independent and statistically significant increase in relative risk, a risk that increased 1.5 times with every single reflux episode/hour. The finding of IM in subjects with distal esophageal reflux within normal limits is intriguing. This observation may possibly be explained by an individual variation in the propensity to develop IM in response to injury. It is possible that IM at an endoscopically normal GEJ may be a consequence of physiological reflux or moderate reflux at the level of the SCJ in subjects prone for metaplasia development. Subjects with such a predisposition and a higher degree of reflux that extends further into the esophagus would most likely develop endoscopically visible segments of columnar metaplasia. These hypotheses are supported by studies suggesting that there may be an individual predisposition for the development of metaplasia and that the extent of esophageal metaplasia correlates with the degree of esophageal acid exposure [Citation37,Citation38]
Most previous studies on the etiology of IM at the GEJ include patients with endoscopically normal-appearing SCJs, but clear definitions of normality or distinct descriptions of the endoscopic appearance of the SCJs of included patients are lacking. It is often believed, without confirmation in the literature, that the normal SCJ may be serrated or irregular with short projections of columnar mucosa that extend into the esophagus [Citation39–44]. We have recently suggested that the normal SCJ is even with no serrations and also minimal irregularities is a consequence of acid reflux [Citation25]. Therefore, we made an effort to characterize the geometry of the SCJ in a standardized fashion in order to exclude subjects with clearly irregular SCJs (ZAP grade II and III) and to study the importance of ZAP grades 0 and I on the prevalence of IM at the GEJ. Although biopsies were obtained at the base of SCJ of patients with ZAP grade I, IM at the GEJ was significantly more frequent in subject with ZAP grade I compared with those with an entirely even SCJ. This observation confirms our previous suggestion that also small irregularities of the SCJ are small areas of metaplastic columnar mucosa and manifestations of acid reflux. It also elucidates the importance of a distinct classification of the SCJ in this type of studies. Unfortunately, patients with ZAP grade 0 were rare which made further analysis of this group difficult. In a sub-analysis of subjects with a SCJ corresponding to ZAP grade 0, no significant association between IM and acid reflux or HP infection could be found.
IM limited to the GEJ is probably associated with an increased risk of developing adenocarcinoma in this area [Citation6]. However, IM is a frequent observation and as the risk of developing adenocarcinoma in BE is associated with the extent of metaplasia [Citation45], the risk of cancer development in IM of a normal appearing GEJ is most likely negligible for the individual patient. Consequently, routine biopsies of the GEJ or surveillance protocols for patients with IM at the GEJ at an endoscopically normal-appearing SCJ cannot be recommended.
This is the first study that explores the relationship between HP infection and the acid environment at the level of an endoscopically normal-appearing GEJ with the histologic finding of IM at the SCJ in patients and asymptomatic volunteers. Our study has shown that IM at the GEJ is a consequence of gastroesophageal reflux and not associated with HP infection. The clinical importance of this entity is unclear and warrants further studies.
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References
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