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Gastric cardia inflammation: role of helicobacter pylori infection and symptoms of gastroesophageal reflux disease
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 8, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02601-6
Gastric Cardia Inflammation: Role of Helicobacter pylori Infection and Symptoms of Gastroesophageal Reflux Disease Sergio Morini, M.D., Angelo Zullo, M.D., Cesare Hassan, M.D., Roberto Lorenzetti, M.D., Francesca Stella, M.D., and Maria Teresa Martini, M.D. Department of Gastroenterology and Digestive Endoscopy, “Nuovo Regina Margherita” Hospital; and Department of Pathological Anatomy, “San Giacomo” Hospital, Rome, Italy
OBJECTIVE: Although high prevalences of both chronic inflammation (carditis) and intestinal metaplasia at the gastric cardia have been reported, the pathogenesis is still unclear. This study assesses the role of Helicobacter pylori (H. pylori) infection and symptoms of gastroesophageal reflux disease (GERD) in these histological alterations. METHODS: Consecutive patients who underwent upper endoscopy were enrolled in the study, irrespective of their symptoms. Patients previously treated for H. pylori infection and those using proton pump inhibitors were excluded. Two biopsies were performed in the antrum, two in the gastric body, and two at the gastric cardia. All biopsies were used to look for H. pylori and for histological assessment. RESULTS: A total of 133 patients were enrolled. Carditis and intestinal metaplasia at the cardia were detected in 100 (75.2%) and in 18 (13.5%) patients, respectively. The H. pylori infection rate was significantly higher in patients with carditis than in those without it (87/100 vs 7/33; p ⬍ 0.0001), and was higher in those with intestinal metaplasia at the cardia than in those without it (17/94 vs 1/39; p ⫽ 0.03). Conversely, the prevalence of GERD symptoms was not significantly different between patients with and without carditis (34/100 vs 16/33; p ⫽ NS), and between those with and without intestinal metaplasia (5/50 vs 13/83; p ⫽ NS). Interestingly, the prevalence of both H. pylori (64/94 vs 39/94; p ⫽ 0.0005) and intestinal metaplasia (18/133 vs 4/133; p ⫽ 0.0042) in the gastric cardia was significantly higher than that in gastric body. CONCLUSION: According to our study data, the gastric cardia is frequently infected with H. pylori with consequent development of both carditis and intestinal metaplasia, whereas GERD does not seem to be involved in these histological changes. (Am J Gastroenterol 2001;96: 2337–2340. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Chronic inflammation is frequently detected in the mucosa of the gastric cardia (i.e., “carditis”) (1), and is associated
with intestinal metaplasia in 9 –23% of cases (2– 4). Moreover, the development of dysplasia in patients with intestinal metaplasia in the gastric cardia has also been reported at follow-up (5, 6). The significance of these histological changes is of current interest, as epidemiological studies have shown an increase in the incidence of gastric cardia adenocarcinoma over the last decades (7). The pathogenesis of the chronic damage of the cardia is still unclear (8, 9). Some authors assert a major role for gastroesophageal reflux disease (GERD), assuming that increased acid reflux may lead to chronic injury of the cardia, including the development of metaplasia, similarly to what occurs in the distal esophagus (10, 11). Conversely, other studies found an association between Helicobacter pylori (H. pylori) infection and the presence of both chronic inflammation and intestinal metaplasia in the cardia (4, 12). It has also been suggested that both H. pylori and GERD may independently cause chronic inflammation of the gastric cardia in different patients (13). On the other hand, according to other authors, neither H. pylori infection nor GERD play a role in the onset of carditis, with other factors such as age being associated with its development (14). Unraveling the pathogenic factors involved in carditis development could have a clinical impact on the management of such patients with respect to therapeutic approach and follow-up, and the conflicting results available suggest that further investigations are needed (9). The present study was performed to further evaluate the prevalence and the factors involved in the pathogenesis of chronic inflammation and intestinal metaplasia development at the gastric cardia.
MATERIALS AND METHODS Patients referred to our endoscopic unit for diagnostic upper GI endoscopy were consecutively selected to be enrolled in the study. Patients included in the study had at least one of the following symptoms: epigastric pain, discomfort in the upper abdomen, delayed digestion, nausea/vomiting, belching, heartburn, or regurgitation. The presence of heartburn
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Table 1. Demographic and Clinical Characteristics of Patients Male/female Age, yr (mean ⫾ SD) Endoscopic finding Duodenal ulcer Gastric ulcer Normal Hiatal hernia Erosive esophagitis GERD symptoms
60/73 55 ⫾ 14 30 5 54 36 8 50
and/or regurgitation at least twice weekly for ⱖ6 months was considered to be suggestive of GERD (15). Patients previously treated for H. pylori infection, those who had taken proton pump inhibitors and/or antibiotics in the month before endoscopic examination, those with malignancy or previous gastric surgery, and those with any contraindication for biopsy at endoscopy were excluded from the study. During endoscopy, three biopsies were performed in the antrum, three in the gastric body, and two additional biopsy specimens were taken within 2 cm below a normal-looking squamocolumnar junction, as previously suggested (2, 16). All biopsy specimens were used for histological assessment with hematoxylin and eosin staining, and to look for H. pylori using Giemsa staining. Chronic inflammation and gastritis activity were graded according to the updated Sydney system in all gastric sites (17). Identification of H. pylori in any biopsy specimen from the cardia, corpus, or antrum was considered diagnostic of infection. Cardiac mucosa was identified by its tubular or coiled racemose glands composed of mucus secreting cells, and intestinal metaplasia was defined by the presence of goblet cells in glandular mucosa (18). Alcian blue (pH 2.5)/periodic acid-Schiff staining was used in selected cases in which there was uncertainty about the presence of intestinal metaplasia. Intestinal metaplasia was recorded as either absent or present. Slides were reviewed by a single pathologist who was unaware of the clinical and endoscopic findings. Hiatal hernia at endoscopy was defined as pouch of gastric mucosa ⬎2 cm long between the endoscopic squamocolumnar junction and the diaphragmatic hiatus, as suggested previously (19). Erosive esophagitis was defined according to the Savary-Miller classification (20). Statistical Analysis Statistical analysis was carried out using the t, Fisher’s exact, and 2 tests as appropriate. Values of p ⬍ 0.05 were considered to be statistically significant.
RESULTS A total of 140 patients were included in the study. Seven patients were excluded from the following analysis because the biopsy sampling at the cardia either was inadequate (two cases) or revealed oxintic (three cases) or esophageal (two cases) mucosa. Clinical and demographic characteristics of the remaining 133 patients are given in Table 1.
Table 2. Intestinal Metaplasia Distribution in All Gastric Sites Gastric Site
Number of Patients
Antrum Antrum ⫹ body Antrum ⫹ body ⫹ cardia Antrum ⫹ cardia Cardia
16 3 1 9 8
Histological assessment of the cardia showed chronic inflammation in 100 (75.2%) patients, with active inflammatory infiltrate in 57 of them, and a normal histological feature in the remaining 33 (24.8%) patients. There was no statistically significant difference between the two groups regarding age (56 ⫾ 12 vs 54 ⫾ 17 yr; respectively) and sex distribution (male/female ratio, 44/56 vs 16/17, respectively). The H. pylori infection rate was significantly higher in patients with carditis than in those without gastric cardia inflammation (87/100 vs 7/33; p ⬍ 0.0001), whereas the prevalence of both GERD symptoms (34/100 vs 16/33; p ⫽ NS) and hiatal hernia (25/100 vs 11/33; p ⫽ NS) were not significantly different between the groups. Specifically, of the 94 H. pylori–positive patients, bacteria were found only in the gastric cardia in three (3.2%) patients, in both the antrum and cardia (but not in the gastric body) in 27 (28.7%) patients, and in all the gastric sites (antrum, gastric body, and cardia) in 34 (36.2%) patients. In the remaining 30 patients, H. pylori was present only in the antrum in 18 (19.1%) patients and in both the antrum and the body in 12 (12.7%) patients. All 57 patients with H. pylori detected in the cardia showed chronic active inflammation at this site. Interestingly, the overall H. pylori prevalence in gastric cardia was significantly higher than that in the gastric body (64/94 vs 39/94; p ⫽ 0.0005) and was lower than that in the antrum (64/94 vs 91/94; p ⬍ 0.0001). As shown in Table 2, intestinal metaplasia in the gastric cardia was detected in 18 (13.5%) patients. The prevalence of intestinal metaplasia in the gastric cardia was higher than that in the gastric body (18/133 vs 4/133; p ⫽ 0.0042) and was similar to that in the antrum (18/133 vs 29/133; p ⫽ NS). In addition, a significant association between the presence of intestinal metaplasia in the gastric cardia and in the antrum was observed (p ⫽ 0.001). Intestinal metaplasia in the gastric cardia was found in 17 of 94 H. pylori–positive patients and in one of 39 H. pylori–negative patients (p ⫽ 0.03). It is noteworthy that among the H. pylori–positive patients with intestinal metaplasia in the gastric cardia, bacteria were found in this site in all cases. Conversely, the prevalence rate of intestinal metaplasia of the gastric cardia was similar between patients with and without GERD symptoms (5/50 vs 13/83; p ⫽ NS) as well as between those with and without hiatal hernia (8/36 vs 10/87; p ⫽ NS). No case of dysplasia in the gastric cardia was observed in our study. In the 39 H. pylori–negative patients, histological features of carditis were detected in 13 (33.3%) cases, and only one case of intestinal metaplasia was noted. Finally, the preva-
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lence of GERD symptoms was not statistically different between patients with and without carditis (6/13 vs 13/26; p ⫽ NS).
DISCUSSION In recent last decades, epidemiological studies have shown an increased incidence of adenocarcinoma at the gastroesophageal junction (7). This observation has triggered several studies aimed at evaluating mucosal damage of the gastric cardia, and a high prevalence (9 –23%) of both chronic inflammation and intestinal metaplasia has been reported in different populations of patients undergoing upper endoscopy (2–16). To date, the pathogenesis of such histological alterations is still debated. At least two different pathogenic factors have been suggested to play a role— namely, GERD and H. pylori infection (8, 9). The conflicting results observed may depend on different methodological strategies used in the various studies. For example, some studies enrolled patients without a sufficient washout period after proton pump inhibitor therapy (11), whereas others included in the H. pylori–positive group those patients tested only with serology (2, 4). It is known that both of these procedures could affect the true prevalence of infection (21). Moreover, other studies enrolled only patients who were H. pylori positive, without an adequate control group (3). In another study, an unexpectedly low prevalence of H. pylori infection was observed in symptomatic patients who underwent upper endoscopy (12). The present study included patients with and without H. pylori infection and/or GERD symptoms to assess the importance of both factors in the pathogenesis of mucosal damage at the gastric cardia. Our data have shown a very high prevalence of chronic inflammation at this site, confirming previous reports (2–16, 22). Carditis was found to be strongly associated with H. pylori infection, whereas symptoms of GERD did not seem to play an important role in carditis development. Moreover, the presence of intestinal metaplasia in the gastric cardia was fairly high, being found in about 15% of our patients, in agreement with another recent study (23). As previously reported (2– 4, 6), our data suggest that intestinal metaplasia is strongly associated with H. pylori infection but not with GERD symptoms. Interestingly, bacteria were detected in cardia specimens from all but one patient with intestinal metaplasia. These results were not unexpected, as the cardiac glands are greatly similar to those of the antrum (18), where bacteria are assumed to be the main cause of both gastritis and intestinal metaplasia (24). Moreover, the degree of inflammatory response to H. pylori in the cardiac mucosa has previously been found to be similar to that in the antral mucosa (25). It is noteworthy that, in our study, intestinal metaplasia at the gastric cardia was observed in 26.6% of the 64 patients with H. pylori infection involving this gastric site, a rate very similar to that previously reported in the antrum of H. pylori– positive patients (26). Intestinal metaplasia in the gastric
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antrum is regarded as a risk factor for cancer in the distal stomach (27); it is not clear whether the development of such metaplasia in the gastric cardia has the same pathogenic implications, although it may be possible (28). Indeed, the development of dysplasia in patients with intestinal metaplasia in the gastric cardia has been reported in two recent prospective studies (5, 6). Therefore, the strong association between H. pylori infection and intestinal metaplasia in the gastric cardia that was found in several histological studies (2– 4, 6, 12, 23, 29) and that was clearly confirmed by our data is intriguing, although the association between serological detection of H. pylori infection and gastric cardia cancer has been regarded as weak by some (30). Thus, further investigations are warranted in this field. Another relevant finding of our study is the observation that the overall prevalence of infection in the gastric cardia is significantly higher than that in the gastric body. Moreover, our data showed that the presence of H. pylori can be confined to the gastric cardia, as reported in another recent study (31). Indeed, H. pylori was detected exclusively in the gastric cardia specimens (but not in other gastric sites) in three (3.2%) patients, all of whom harbored chronic active inflammation and intestinal metaplasia. Such features would have been missed if biopsies had not been performed at the gastric cardia, and therefore the infection in these patients would not have been identified or treated. Moreover, it has been reported that after eradication therapy, H. pylori may persist in the cardia alone, while disappearing from the antrum and gastric body (31). In these cases, the bacterium— erroneously considered to be eradicated— continues to cause chronic and potentially increasing damage (5, 6). Therefore, cardia biopsy may be useful for obtaining a more complete histological sampling (31), especially considering that, in our study, biopsies performed routinely in the gastric body demonstrated a prevalence of both infection and metaplasia that was significantly lower than that seen in the cardia. Contrary to a previous report (11), carditis was infrequently (⬍35%) found in our H. pylori–negative patient group, and intestinal metaplasia was very rare in this group. Moreover, GERD symptoms did not seem to be involved in the development of chronic inflammation. The significance of carditis in this group remains controversial, and other factors could be advocated to explain its pathogenesis (9). In conclusion, our data showed that the gastric cardia is frequently infected by H. pylori, with the consequent development of both chronic inflammation and intestinal metaplasia, whereas GERD does not seem to be involved in these histological changes. Reprint requests and correspondence: Sergio Morini, M.D., Ospedale Nuovo Regina Margherita, U.O. Gastroenterologia ed Endoscopia Digestiva, Via E. Morosini, 30, 00153 Roma, Italy. Received Sep. 19, 2000; accepted Apr. 2, 2001.
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REFERENCES 1. Riddell RH. The biopsy diagnosis of gastroesophageal reflux disease, “carditis,” and Barrett’s esophagus, and sequelae of therapy. Am J Surg Pathol 1996;20(suppl 1):S31–50. 2. Morales GT, Sampliner RE, Bhattacharyya A. Intestinal metaplasia of gastric cardia. Am J Gastroenterol 1997;92:414 – 8. 3. Hackelsberger A, Gunther T, Schultze V, et al. Prevalence and pattern of Helicobacter pylori gastritis in the gastric cardia. Am J Gastroenterol 1997;92:2220 – 4. 4. Golblum JR, Vicari JJ, Falk GW, et al. Inflammation and intestinal metaplasia of the gastric cardia: The role of gastroesophageal reflux and H. pylori infection. Gastroenterology 1998;114:633–9. 5. Sharma P, Weston AP, Morales T, et al. Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia. Gut 2000;46:9 –13. 6. Morales TG, Camargo E, Bhattacharyya A, et al. Long-term follow-up of intestinal metaplasia of the gastric cardia. Am J Gastroenterol 2000:95:1677– 80. 7. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104:510 –3. 8. Genta RM. Giving carditis back to the heart. Gut 1999;43: 793–7. 9. O’Connor HJ. Gastro-oesophageal reflux disease, Helicobacter pylori and gastric cardia: A tale of two pathologies? Digest Liver Dis 2000;32:573– 6. 10. Voutilainen M, Farkkila M, Juhola M, et al. Specialized columnar epithelium of the esophagogastric junction: Prevalence and association: The Central Finland Endoscopy Study Group. Am J Gastroenterol 1999;94:913– 8. 11. Bowrey DJ, Clark GWB, Williams GT. Patterns of gastritis in patients with gastro-oesophageal reflux disease. Gut 1999;45: 789 – 803. 12. El-Serag HB, Sonnemberg A, Jamal MM, et al. Characteristics of intestinal metaplasia in the gastric cardia. Am J Gastroenterol 1999;94:622–7. 13. Hackelsberger A, Gunther T, Schultze V, et al. Intestinal metaplasia at the gastro-oesophageal junction: Helicobacter pylori gastritis or gastro-oesophageal reflux disease? Gut 1998;43:17–21. 14. Trudgill NJ, Suvarna SK, Kapur KC, Riley SA. Intestinal metaplasia at the squamocolumnar junction in patients attending for diagnostic gastroscopy. Gut 1997;41:585–9. 15. Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990;335:205– 8.
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16. Wu JCY, Sung JJY, Ng EKW, et al. Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: A study form the east. Am J Gastroenterol 1999;94:1790 – 4. 17. Dixon FM, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. Am J Surg Pathol 1996;20:1161– 81. 18. Owen DA. Normal histology of the stomach. Am J Surg Pathol 1986;10:48 – 61. 19. Mittal RK, Lange RC, McCallum RW. Identification and mechanism of delayed esophageal acid clearance in subjects with hiatus hernia. Gastroenterology 1987;92:130 –5. 20. Savary M, Miller G. The oesophagus. Handbook and atlas of endoscopy. Solothurn: Verlag Gassmann, 1978:119 –205. 21. European Helicobacter pylori Study Group. Technical annex: Tests used to assess Helicobacter pylori infection. Gut 1997; 41(suppl 2):S10 – 8. 22. Peck-Radosavljevic M, Puspok A, Potzi R, Oberhuber G. Histological findings after routine biospy at the gastro-oesophageal junction. Eur J Gastroenterol Hepatol 1999;11:1265–70. 23. Pieramico O, Zanetti MV. Relationship between intestinal metaplasia of the gastro-oesophageal junction, Helicobacter pylori infection and gastro-oesophageal reflux disease: A prospective study. Digest Liver Dis 2000;32:567–72. 24. Fontham ETH, Ruiz B, Perez A, et al. Determinants of Helicobacter pylori infection and chronic gastritis. Am J Gastroenterol 1995;90:1094 –101. 25. Genta RM, Huberman RM, Graham DY. The gastric cardia in Helicobacter pylori infection. Hum Pathol 1994;25:915–9. 26. Craanen ME, Dekker W, Block P, et al. Intestinal metaplasia and Helicobacter pylori: An endoscopic bioptic study of the gastric antrum. Gut 1992;33:16 –20. 27. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process–first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res 1992;52:6735– 40. 28. MacDonald WC, MacDonald JB. Adenocarcinoma of the esophagus and/or gastric cardia. Cancer 1987;60:1094 – 8. 29. Hirota WK, Loughney TM, Lazas DJ, et al. Specialized intestinal metaplasia, dysplasia, and cancer of the esophagus and esophagogastric junction: Prevalence and clinical data. Gastroenterology 1999;116:277– 85. 30. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114:1169 –79. 31. Sheu BS, Lin XZ, Yang HB, Chien CH. Cardiac biopsy of stomach may improve the detection of H. pylori after dual therapy. Hepatogastroenterol 1999;46:543– 8.
Vol. 96, No. 8, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02601-6
Gastric Cardia Inflammation: Role of Helicobacter pylori Infection and Symptoms of Gastroesophageal Reflux Disease Sergio Morini, M.D., Angelo Zullo, M.D., Cesare Hassan, M.D., Roberto Lorenzetti, M.D., Francesca Stella, M.D., and Maria Teresa Martini, M.D. Department of Gastroenterology and Digestive Endoscopy, “Nuovo Regina Margherita” Hospital; and Department of Pathological Anatomy, “San Giacomo” Hospital, Rome, Italy
OBJECTIVE: Although high prevalences of both chronic inflammation (carditis) and intestinal metaplasia at the gastric cardia have been reported, the pathogenesis is still unclear. This study assesses the role of Helicobacter pylori (H. pylori) infection and symptoms of gastroesophageal reflux disease (GERD) in these histological alterations. METHODS: Consecutive patients who underwent upper endoscopy were enrolled in the study, irrespective of their symptoms. Patients previously treated for H. pylori infection and those using proton pump inhibitors were excluded. Two biopsies were performed in the antrum, two in the gastric body, and two at the gastric cardia. All biopsies were used to look for H. pylori and for histological assessment. RESULTS: A total of 133 patients were enrolled. Carditis and intestinal metaplasia at the cardia were detected in 100 (75.2%) and in 18 (13.5%) patients, respectively. The H. pylori infection rate was significantly higher in patients with carditis than in those without it (87/100 vs 7/33; p ⬍ 0.0001), and was higher in those with intestinal metaplasia at the cardia than in those without it (17/94 vs 1/39; p ⫽ 0.03). Conversely, the prevalence of GERD symptoms was not significantly different between patients with and without carditis (34/100 vs 16/33; p ⫽ NS), and between those with and without intestinal metaplasia (5/50 vs 13/83; p ⫽ NS). Interestingly, the prevalence of both H. pylori (64/94 vs 39/94; p ⫽ 0.0005) and intestinal metaplasia (18/133 vs 4/133; p ⫽ 0.0042) in the gastric cardia was significantly higher than that in gastric body. CONCLUSION: According to our study data, the gastric cardia is frequently infected with H. pylori with consequent development of both carditis and intestinal metaplasia, whereas GERD does not seem to be involved in these histological changes. (Am J Gastroenterol 2001;96: 2337–2340. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Chronic inflammation is frequently detected in the mucosa of the gastric cardia (i.e., “carditis”) (1), and is associated
with intestinal metaplasia in 9 –23% of cases (2– 4). Moreover, the development of dysplasia in patients with intestinal metaplasia in the gastric cardia has also been reported at follow-up (5, 6). The significance of these histological changes is of current interest, as epidemiological studies have shown an increase in the incidence of gastric cardia adenocarcinoma over the last decades (7). The pathogenesis of the chronic damage of the cardia is still unclear (8, 9). Some authors assert a major role for gastroesophageal reflux disease (GERD), assuming that increased acid reflux may lead to chronic injury of the cardia, including the development of metaplasia, similarly to what occurs in the distal esophagus (10, 11). Conversely, other studies found an association between Helicobacter pylori (H. pylori) infection and the presence of both chronic inflammation and intestinal metaplasia in the cardia (4, 12). It has also been suggested that both H. pylori and GERD may independently cause chronic inflammation of the gastric cardia in different patients (13). On the other hand, according to other authors, neither H. pylori infection nor GERD play a role in the onset of carditis, with other factors such as age being associated with its development (14). Unraveling the pathogenic factors involved in carditis development could have a clinical impact on the management of such patients with respect to therapeutic approach and follow-up, and the conflicting results available suggest that further investigations are needed (9). The present study was performed to further evaluate the prevalence and the factors involved in the pathogenesis of chronic inflammation and intestinal metaplasia development at the gastric cardia.
MATERIALS AND METHODS Patients referred to our endoscopic unit for diagnostic upper GI endoscopy were consecutively selected to be enrolled in the study. Patients included in the study had at least one of the following symptoms: epigastric pain, discomfort in the upper abdomen, delayed digestion, nausea/vomiting, belching, heartburn, or regurgitation. The presence of heartburn
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Table 1. Demographic and Clinical Characteristics of Patients Male/female Age, yr (mean ⫾ SD) Endoscopic finding Duodenal ulcer Gastric ulcer Normal Hiatal hernia Erosive esophagitis GERD symptoms
60/73 55 ⫾ 14 30 5 54 36 8 50
and/or regurgitation at least twice weekly for ⱖ6 months was considered to be suggestive of GERD (15). Patients previously treated for H. pylori infection, those who had taken proton pump inhibitors and/or antibiotics in the month before endoscopic examination, those with malignancy or previous gastric surgery, and those with any contraindication for biopsy at endoscopy were excluded from the study. During endoscopy, three biopsies were performed in the antrum, three in the gastric body, and two additional biopsy specimens were taken within 2 cm below a normal-looking squamocolumnar junction, as previously suggested (2, 16). All biopsy specimens were used for histological assessment with hematoxylin and eosin staining, and to look for H. pylori using Giemsa staining. Chronic inflammation and gastritis activity were graded according to the updated Sydney system in all gastric sites (17). Identification of H. pylori in any biopsy specimen from the cardia, corpus, or antrum was considered diagnostic of infection. Cardiac mucosa was identified by its tubular or coiled racemose glands composed of mucus secreting cells, and intestinal metaplasia was defined by the presence of goblet cells in glandular mucosa (18). Alcian blue (pH 2.5)/periodic acid-Schiff staining was used in selected cases in which there was uncertainty about the presence of intestinal metaplasia. Intestinal metaplasia was recorded as either absent or present. Slides were reviewed by a single pathologist who was unaware of the clinical and endoscopic findings. Hiatal hernia at endoscopy was defined as pouch of gastric mucosa ⬎2 cm long between the endoscopic squamocolumnar junction and the diaphragmatic hiatus, as suggested previously (19). Erosive esophagitis was defined according to the Savary-Miller classification (20). Statistical Analysis Statistical analysis was carried out using the t, Fisher’s exact, and 2 tests as appropriate. Values of p ⬍ 0.05 were considered to be statistically significant.
RESULTS A total of 140 patients were included in the study. Seven patients were excluded from the following analysis because the biopsy sampling at the cardia either was inadequate (two cases) or revealed oxintic (three cases) or esophageal (two cases) mucosa. Clinical and demographic characteristics of the remaining 133 patients are given in Table 1.
Table 2. Intestinal Metaplasia Distribution in All Gastric Sites Gastric Site
Number of Patients
Antrum Antrum ⫹ body Antrum ⫹ body ⫹ cardia Antrum ⫹ cardia Cardia
16 3 1 9 8
Histological assessment of the cardia showed chronic inflammation in 100 (75.2%) patients, with active inflammatory infiltrate in 57 of them, and a normal histological feature in the remaining 33 (24.8%) patients. There was no statistically significant difference between the two groups regarding age (56 ⫾ 12 vs 54 ⫾ 17 yr; respectively) and sex distribution (male/female ratio, 44/56 vs 16/17, respectively). The H. pylori infection rate was significantly higher in patients with carditis than in those without gastric cardia inflammation (87/100 vs 7/33; p ⬍ 0.0001), whereas the prevalence of both GERD symptoms (34/100 vs 16/33; p ⫽ NS) and hiatal hernia (25/100 vs 11/33; p ⫽ NS) were not significantly different between the groups. Specifically, of the 94 H. pylori–positive patients, bacteria were found only in the gastric cardia in three (3.2%) patients, in both the antrum and cardia (but not in the gastric body) in 27 (28.7%) patients, and in all the gastric sites (antrum, gastric body, and cardia) in 34 (36.2%) patients. In the remaining 30 patients, H. pylori was present only in the antrum in 18 (19.1%) patients and in both the antrum and the body in 12 (12.7%) patients. All 57 patients with H. pylori detected in the cardia showed chronic active inflammation at this site. Interestingly, the overall H. pylori prevalence in gastric cardia was significantly higher than that in the gastric body (64/94 vs 39/94; p ⫽ 0.0005) and was lower than that in the antrum (64/94 vs 91/94; p ⬍ 0.0001). As shown in Table 2, intestinal metaplasia in the gastric cardia was detected in 18 (13.5%) patients. The prevalence of intestinal metaplasia in the gastric cardia was higher than that in the gastric body (18/133 vs 4/133; p ⫽ 0.0042) and was similar to that in the antrum (18/133 vs 29/133; p ⫽ NS). In addition, a significant association between the presence of intestinal metaplasia in the gastric cardia and in the antrum was observed (p ⫽ 0.001). Intestinal metaplasia in the gastric cardia was found in 17 of 94 H. pylori–positive patients and in one of 39 H. pylori–negative patients (p ⫽ 0.03). It is noteworthy that among the H. pylori–positive patients with intestinal metaplasia in the gastric cardia, bacteria were found in this site in all cases. Conversely, the prevalence rate of intestinal metaplasia of the gastric cardia was similar between patients with and without GERD symptoms (5/50 vs 13/83; p ⫽ NS) as well as between those with and without hiatal hernia (8/36 vs 10/87; p ⫽ NS). No case of dysplasia in the gastric cardia was observed in our study. In the 39 H. pylori–negative patients, histological features of carditis were detected in 13 (33.3%) cases, and only one case of intestinal metaplasia was noted. Finally, the preva-
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lence of GERD symptoms was not statistically different between patients with and without carditis (6/13 vs 13/26; p ⫽ NS).
DISCUSSION In recent last decades, epidemiological studies have shown an increased incidence of adenocarcinoma at the gastroesophageal junction (7). This observation has triggered several studies aimed at evaluating mucosal damage of the gastric cardia, and a high prevalence (9 –23%) of both chronic inflammation and intestinal metaplasia has been reported in different populations of patients undergoing upper endoscopy (2–16). To date, the pathogenesis of such histological alterations is still debated. At least two different pathogenic factors have been suggested to play a role— namely, GERD and H. pylori infection (8, 9). The conflicting results observed may depend on different methodological strategies used in the various studies. For example, some studies enrolled patients without a sufficient washout period after proton pump inhibitor therapy (11), whereas others included in the H. pylori–positive group those patients tested only with serology (2, 4). It is known that both of these procedures could affect the true prevalence of infection (21). Moreover, other studies enrolled only patients who were H. pylori positive, without an adequate control group (3). In another study, an unexpectedly low prevalence of H. pylori infection was observed in symptomatic patients who underwent upper endoscopy (12). The present study included patients with and without H. pylori infection and/or GERD symptoms to assess the importance of both factors in the pathogenesis of mucosal damage at the gastric cardia. Our data have shown a very high prevalence of chronic inflammation at this site, confirming previous reports (2–16, 22). Carditis was found to be strongly associated with H. pylori infection, whereas symptoms of GERD did not seem to play an important role in carditis development. Moreover, the presence of intestinal metaplasia in the gastric cardia was fairly high, being found in about 15% of our patients, in agreement with another recent study (23). As previously reported (2– 4, 6), our data suggest that intestinal metaplasia is strongly associated with H. pylori infection but not with GERD symptoms. Interestingly, bacteria were detected in cardia specimens from all but one patient with intestinal metaplasia. These results were not unexpected, as the cardiac glands are greatly similar to those of the antrum (18), where bacteria are assumed to be the main cause of both gastritis and intestinal metaplasia (24). Moreover, the degree of inflammatory response to H. pylori in the cardiac mucosa has previously been found to be similar to that in the antral mucosa (25). It is noteworthy that, in our study, intestinal metaplasia at the gastric cardia was observed in 26.6% of the 64 patients with H. pylori infection involving this gastric site, a rate very similar to that previously reported in the antrum of H. pylori– positive patients (26). Intestinal metaplasia in the gastric
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antrum is regarded as a risk factor for cancer in the distal stomach (27); it is not clear whether the development of such metaplasia in the gastric cardia has the same pathogenic implications, although it may be possible (28). Indeed, the development of dysplasia in patients with intestinal metaplasia in the gastric cardia has been reported in two recent prospective studies (5, 6). Therefore, the strong association between H. pylori infection and intestinal metaplasia in the gastric cardia that was found in several histological studies (2– 4, 6, 12, 23, 29) and that was clearly confirmed by our data is intriguing, although the association between serological detection of H. pylori infection and gastric cardia cancer has been regarded as weak by some (30). Thus, further investigations are warranted in this field. Another relevant finding of our study is the observation that the overall prevalence of infection in the gastric cardia is significantly higher than that in the gastric body. Moreover, our data showed that the presence of H. pylori can be confined to the gastric cardia, as reported in another recent study (31). Indeed, H. pylori was detected exclusively in the gastric cardia specimens (but not in other gastric sites) in three (3.2%) patients, all of whom harbored chronic active inflammation and intestinal metaplasia. Such features would have been missed if biopsies had not been performed at the gastric cardia, and therefore the infection in these patients would not have been identified or treated. Moreover, it has been reported that after eradication therapy, H. pylori may persist in the cardia alone, while disappearing from the antrum and gastric body (31). In these cases, the bacterium— erroneously considered to be eradicated— continues to cause chronic and potentially increasing damage (5, 6). Therefore, cardia biopsy may be useful for obtaining a more complete histological sampling (31), especially considering that, in our study, biopsies performed routinely in the gastric body demonstrated a prevalence of both infection and metaplasia that was significantly lower than that seen in the cardia. Contrary to a previous report (11), carditis was infrequently (⬍35%) found in our H. pylori–negative patient group, and intestinal metaplasia was very rare in this group. Moreover, GERD symptoms did not seem to be involved in the development of chronic inflammation. The significance of carditis in this group remains controversial, and other factors could be advocated to explain its pathogenesis (9). In conclusion, our data showed that the gastric cardia is frequently infected by H. pylori, with the consequent development of both chronic inflammation and intestinal metaplasia, whereas GERD does not seem to be involved in these histological changes. Reprint requests and correspondence: Sergio Morini, M.D., Ospedale Nuovo Regina Margherita, U.O. Gastroenterologia ed Endoscopia Digestiva, Via E. Morosini, 30, 00153 Roma, Italy. Received Sep. 19, 2000; accepted Apr. 2, 2001.
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REFERENCES 1. Riddell RH. The biopsy diagnosis of gastroesophageal reflux disease, “carditis,” and Barrett’s esophagus, and sequelae of therapy. Am J Surg Pathol 1996;20(suppl 1):S31–50. 2. Morales GT, Sampliner RE, Bhattacharyya A. Intestinal metaplasia of gastric cardia. Am J Gastroenterol 1997;92:414 – 8. 3. Hackelsberger A, Gunther T, Schultze V, et al. Prevalence and pattern of Helicobacter pylori gastritis in the gastric cardia. Am J Gastroenterol 1997;92:2220 – 4. 4. Golblum JR, Vicari JJ, Falk GW, et al. Inflammation and intestinal metaplasia of the gastric cardia: The role of gastroesophageal reflux and H. pylori infection. Gastroenterology 1998;114:633–9. 5. Sharma P, Weston AP, Morales T, et al. Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia. Gut 2000;46:9 –13. 6. Morales TG, Camargo E, Bhattacharyya A, et al. Long-term follow-up of intestinal metaplasia of the gastric cardia. Am J Gastroenterol 2000:95:1677– 80. 7. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104:510 –3. 8. Genta RM. Giving carditis back to the heart. Gut 1999;43: 793–7. 9. O’Connor HJ. Gastro-oesophageal reflux disease, Helicobacter pylori and gastric cardia: A tale of two pathologies? Digest Liver Dis 2000;32:573– 6. 10. Voutilainen M, Farkkila M, Juhola M, et al. Specialized columnar epithelium of the esophagogastric junction: Prevalence and association: The Central Finland Endoscopy Study Group. Am J Gastroenterol 1999;94:913– 8. 11. Bowrey DJ, Clark GWB, Williams GT. Patterns of gastritis in patients with gastro-oesophageal reflux disease. Gut 1999;45: 789 – 803. 12. El-Serag HB, Sonnemberg A, Jamal MM, et al. Characteristics of intestinal metaplasia in the gastric cardia. Am J Gastroenterol 1999;94:622–7. 13. Hackelsberger A, Gunther T, Schultze V, et al. Intestinal metaplasia at the gastro-oesophageal junction: Helicobacter pylori gastritis or gastro-oesophageal reflux disease? Gut 1998;43:17–21. 14. Trudgill NJ, Suvarna SK, Kapur KC, Riley SA. Intestinal metaplasia at the squamocolumnar junction in patients attending for diagnostic gastroscopy. Gut 1997;41:585–9. 15. Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990;335:205– 8.
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16. Wu JCY, Sung JJY, Ng EKW, et al. Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: A study form the east. Am J Gastroenterol 1999;94:1790 – 4. 17. Dixon FM, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. Am J Surg Pathol 1996;20:1161– 81. 18. Owen DA. Normal histology of the stomach. Am J Surg Pathol 1986;10:48 – 61. 19. Mittal RK, Lange RC, McCallum RW. Identification and mechanism of delayed esophageal acid clearance in subjects with hiatus hernia. Gastroenterology 1987;92:130 –5. 20. Savary M, Miller G. The oesophagus. Handbook and atlas of endoscopy. Solothurn: Verlag Gassmann, 1978:119 –205. 21. European Helicobacter pylori Study Group. Technical annex: Tests used to assess Helicobacter pylori infection. Gut 1997; 41(suppl 2):S10 – 8. 22. Peck-Radosavljevic M, Puspok A, Potzi R, Oberhuber G. Histological findings after routine biospy at the gastro-oesophageal junction. Eur J Gastroenterol Hepatol 1999;11:1265–70. 23. Pieramico O, Zanetti MV. Relationship between intestinal metaplasia of the gastro-oesophageal junction, Helicobacter pylori infection and gastro-oesophageal reflux disease: A prospective study. Digest Liver Dis 2000;32:567–72. 24. Fontham ETH, Ruiz B, Perez A, et al. Determinants of Helicobacter pylori infection and chronic gastritis. Am J Gastroenterol 1995;90:1094 –101. 25. Genta RM, Huberman RM, Graham DY. The gastric cardia in Helicobacter pylori infection. Hum Pathol 1994;25:915–9. 26. Craanen ME, Dekker W, Block P, et al. Intestinal metaplasia and Helicobacter pylori: An endoscopic bioptic study of the gastric antrum. Gut 1992;33:16 –20. 27. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process–first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res 1992;52:6735– 40. 28. MacDonald WC, MacDonald JB. Adenocarcinoma of the esophagus and/or gastric cardia. Cancer 1987;60:1094 – 8. 29. Hirota WK, Loughney TM, Lazas DJ, et al. Specialized intestinal metaplasia, dysplasia, and cancer of the esophagus and esophagogastric junction: Prevalence and clinical data. Gastroenterology 1999;116:277– 85. 30. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114:1169 –79. 31. Sheu BS, Lin XZ, Yang HB, Chien CH. Cardiac biopsy of stomach may improve the detection of H. pylori after dual therapy. Hepatogastroenterol 1999;46:543– 8.