Letters to the Editor
www.eurojgh.com
Acknowledgements Conflicts of interest
There are no conflicts of interest. References 1
2
3
4
Bornschein J, Dingwerth A, Selgrad M, Venerito M, Stuebs P, Frauenschlaeger K, et al. Adenocarcinomas at different positions at the gastro-oesophageal junction show distinct association with gastritis and gastric preneoplastic conditions. Eur J Gastroenterol Hepatol 2015; 27:492–500. McColl KE, Watabe H, Derakhshan MH. Role of gastric atrophy in mediating negative association between Helicobacter pylori infection and reflux oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 2008; 57:721–723. Anderson LA, Murphy SJ, Johnston BT, Watson RG, Ferguson HR, Bamford KB, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case–control study. Gut 2008; 57:734–739. Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin JK, Nyrén O. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 2004; 96:388–396.
DOI: 10.1097/MEG.0000000000000406
Response to: oesophageal adenocarcinoma and atrophic gastritis – different viewpoints on the junction Jan Bornscheina,b, aDepartment of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany and b MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge University, Biomedical Campus, Cambridge, UK Correspondence to Jan Bornschein, MD, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Street 44, D-39120 Magdeburg, Germany Tel: + 49 391 671 3100; fax: + 49 391 671 3105; e-mail: [email protected] Received 1 May 2015 Accepted 15 May 2015
We are very grateful for the constructive comments by C. Matuchansky [1] on our recently published data on the association of adenocarcinomas at the oesophagogastric junction with inflammatory and preneoplastic changes of the gastric mucosa [2]. Dr Matuchansky drew parallels to the Irish FINBAR cohort published by Anderson et al. [3], where serological surrogate parameters (Helicobacter pylori serology and pepsinogens in the serum) have been assessed for their association to reflux-induced changes at and proximal to the oesophagogastric junction. It has been pointed out that even without the presence of atrophy, as defined by a decreased pepsinogen 1 : 2 ratio, a positive H. pylori status shows an inverse association with the presence of Barrett’s oesophagus and oesophageal adenocarcinomas proximal to the junction (representing most likely Siewert type 1 tumours). This effect is consistent even when the cohort is adjusted for the presence of reflux
985
symptoms. Thus, there might be an ‘H. pylori-effect’ on Barrett’s associated cancers independent of gastric mucosal alterations as has been shown in our cohort. An inverse association of H. pylori with Barrett’s oesophagus has been shown repeatedly, and even a protective effect of the infection has been postulated [4,5]. This is based on the main hypothesis that because of atrophic changes of the gastric mucosa, the gastric acid output is reduced and therefore the burden of gastro-oesophageal reflux is lowered [6]. However, the data from our study as well as from previous cohorts indicate further atrophy-independent mechanisms. This could possibly be linked to an increase in interleukin 1β (IL-1β) secretion. IL-1β is the most powerful proinflammatory cytokine produced in response to H. pylori infection, and it is also known to act as a potent acid inhibitor [7]. Especially if H. pylori colonizes predominantly the gastric body, the antisecretory effect of IL-1β leads to hypochlorhydria and therefore less reflux. An additional impact of IL-1β is caused by its capability to modulate gastric motility and therefore delay gastric emptying [7]. In addition to these effects, constitutive overexpression of IL-1β in a mouse model led to upregulation of TFF2, CDX2 and NOTCH1 and consecutively development of Barrett’s oesophagus and oesophageal adenocarcinoma, interestingly, with the involvement of Lgr5-positive gastric progenitor cells [8]. This process was further accelerated by exposure to bile acids. It is still not entirely clear which components of the reflux have the main impact on the development of Barrett’s metaplasia and further dysplastic and neoplastic progression, but bile seems to be the more potent player compared with the gastric acid itself [9]. It is known that bile alone is capable of inducing the expression of both CDX1 and CDX2 and therefore the initiation of metaplastic transformation of the gastric mucosa as well as the formation of Barrett’s oesophagus [10,11]. Dixon et al. [12] reported in that patients with Barrett’s more often have bile-induced gastropathy than patients with erosive reflux disease or nonulcer dyspepsia controls. Furthermore, bile reflux was an independent risk factor for intestinal metaplasia at the cardia, whereas H. pylori infection was not [13]. Independent of the H. pylori infection status, bile reflux can induce intestinal metaplasia of the gastric mucosa and even lead to further progression of these lesions [14–16]. The prevalence of intestinal metaplasia in the stomach, however, is highest when both factors are present: H. pylori and bile reflux [17,18]. This is in line with previously published data showing the highest upregulation of CDX2 in antrum and cardia of patients with both positive H. pylori status and gastro-oesophageal reflux disease [19]. In these cases, the induction of CDX2 as the main driver of intestinal metaplasia seems to be mediated by distinct mechanisms as in the presence of H. pylori infection, the CDX2 expression correlates positively with the degree of the mucosal infiltration with immune cells, whereas the reflux-induced expression of CDX2 is independent of the mucosal inflammation [19]. This is supported by the fact that bile-related gastropathy is characterized more by macroscopic signs of inflammation, that is, mucosal erythema, whereas H. pylori gastritis is
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
986
August 2015 • Volume 27 • Number 8
European Journal of Gastroenterology & Hepatology
characterized by infiltration of the mucosa with inflammatory cells [20]. Thus, in view of the metaplastic and neoplastic changes at the oesophagogastric junction, there seems to be a complex interplay of the influences that affect both the stomach as well as the distal oesophagus. Although atrophy of the gastric mucosa is related to H. pylori infection, intestinal metaplasia can be considered in association with both the infection and exposure to duodenogastric bile reflux. Therefore, patients with Barrett’s oesophagus can also show an increased prevalence of gastric intestinal metaplasia because of exposure of the gastric mucosa to bile. It is also of importance that duodenogastric bile reflux is associated with a reduced H. pylori density in the gastric mucosa as certain bile acids can decrease the bacterium’s capability for mucosal adherence [17,21]. This could be responsible for the reduced prevalence of H. pylori infection in patients with Barrett’s oesophagus and Siewert type 1 cancers, rather than H. pylori infection having an actual ‘protective’ effect. There is some hope that with the increased use of high-throughput techniques, we will be able to shed more light on the distinct pathogenetic pathways that are involved in carcinogenesis at the oesophagogastric junction.
6 7 8
9
10
11
12
13 14
15
Acknowledgements 16
Conflicts of interest
There are no conflicts of interest. 17
References 1 Matuchansky C. Oesophageal adenocarcinoma and atrophic gastritis. Eur J Gastroenterol Hepatol 2015; 27:984–985. 2 Bornschein J, Dingwerth A, Selgrad M, Venerito M, Stuebs P, Frauenschlaeger K, et al. Adenocarcinomas at different positions at the gastrooesophageal junction show distinct association with gastritis and gastric preneoplastic conditions. Eur J Gastroenterol Hepatol 2015; 27:492–500. 3 Anderson LA, Murphy SJ, Johnston BT, Watson RG, Ferguson HR, Bamford KB, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR casecontrol study. Gut 2008; 57:734–739. 4 Rubenstein JH, Inadomi JM, Scheiman J, Schoenfeld P, Appelman H, Zhang M, et al. Association between Helicobacter pylori and Barrett’s esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 2014; 12:239–245. 5 Vicari JJ, Peek RM, Falk GW, Goldblum JR, Easley KA, Schnell J, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the
18
19
20
21
spectrum of gastroesophageal reflux disease. Gastroenterology 1998; 115:50–57. Blaser MJ. Helicobacter pylori and esophageal disease: wake-up call? Gastroenterology 2010; 139:1819–1822. El-Omar EM. The importance of interleukin 1beta in Helicobacter pylori associated disease. Gut 2001; 48:743–747. Quante M, Bhagat G, Abrams JA, Marache F, Good P, Lee MD, et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 2012; 21:36–51. McQuaid KR, Laine L, Fennerty MB, Souza R, Spechler SJ. Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment Pharmacol Ther 2011; 34:146–165. Park MJ, Kim KH, Kim HY, Kim K, Cheong J. Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells. Carcinogenesis 2008; 29:2385–2393. Xu Y, Watanabe T, Tanigawa T, Machida H, Okazaki H, Yamagami H, et al. Bile acids induce Cdx2 expression through the farnesoid X receptor in gastric epithelial cells. J Clin Biochem Nutr 2010; 46:81–86. Dixon MF, Neville PM, Mapstone NP, Moayyedi P, Axon AT. Bile reflux gastritis and Barrett’s oesophagus: further evidence of a role for duodenogastro-oesophageal reflux? Gut 2001; 49:359–363. Dixon MF, Mapstone NP, Neville PM, Moayyedi P, Axon AT. Bile reflux gastritis and intestinal metaplasia at the cardia. Gut 2002; 51:351–355. Matsuhisa T, Arakawa T, Watanabe T, Tokutomi T, Sakurai K, Okamura S, et al. Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia: a multicenter study of 2283 cases. Dig Endosc 2013; 25:519–525. Matsuhisa T, Tsukui T. Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens. J Clin Biochem Nutr 2012; 50:217–221. Johannesson KA, Hammar E, Staël von Holstein C. Mucosal changes in the gastric remnant: long-term effects of bile reflux diversion and Helicobacter pylori infection. Eur J Gastroenterol Hepatol 2003; 15:35–40. Sobala GM, O’Connor HJ, Dewar EP, King RF, Axon AT, Dixon MF. Bile reflux and intestinal metaplasia in gastric mucosa. J Clin Pathol 1993; 46:235–240. Zullo A, Rinaldi V, Hassan C, Lauria V, Attili AF. Gastric pathology in cholecystectomy patients: role of Helicobacter pylori and bile reflux. J Clin Gastroenterol 1998; 27:335–338. Bornschein J, Wex T, Peitz U, Kuester D, Roessner A, Malfertheiner P. The combined presence of H. pylori infection and gastro-oesophageal reflux disease leads to an up-regulation of CDX2 gene expression in antrum and cardia. J Clin Pathol 2009; 62:254–259. Lee Y, Tokunaga A, Tajiri T, Masuda G, Okuda T, Fujita I, et al. Inflammation of the gastric remnant after gastrectomy: mucosal erythema is associated with bile reflux and inflammatory cellular infiltration is associated with Helicobacter pylori infection. J Gastroenterol 2004; 39:520–526. Mathai E, Arora A, Cafferkey M, Keane CT, O’Morain C. The effect of bile acids on the growth and adherence of Helicobacter pylori. Aliment Pharmacol Ther 1991; 5:653–658.
DOI: 10.1097/MEG.0000000000000416
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.eurojgh.com
Acknowledgements Conflicts of interest
There are no conflicts of interest. References 1
2
3
4
Bornschein J, Dingwerth A, Selgrad M, Venerito M, Stuebs P, Frauenschlaeger K, et al. Adenocarcinomas at different positions at the gastro-oesophageal junction show distinct association with gastritis and gastric preneoplastic conditions. Eur J Gastroenterol Hepatol 2015; 27:492–500. McColl KE, Watabe H, Derakhshan MH. Role of gastric atrophy in mediating negative association between Helicobacter pylori infection and reflux oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 2008; 57:721–723. Anderson LA, Murphy SJ, Johnston BT, Watson RG, Ferguson HR, Bamford KB, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case–control study. Gut 2008; 57:734–739. Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin JK, Nyrén O. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 2004; 96:388–396.
DOI: 10.1097/MEG.0000000000000406
Response to: oesophageal adenocarcinoma and atrophic gastritis – different viewpoints on the junction Jan Bornscheina,b, aDepartment of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany and b MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge University, Biomedical Campus, Cambridge, UK Correspondence to Jan Bornschein, MD, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Street 44, D-39120 Magdeburg, Germany Tel: + 49 391 671 3100; fax: + 49 391 671 3105; e-mail: [email protected] Received 1 May 2015 Accepted 15 May 2015
We are very grateful for the constructive comments by C. Matuchansky [1] on our recently published data on the association of adenocarcinomas at the oesophagogastric junction with inflammatory and preneoplastic changes of the gastric mucosa [2]. Dr Matuchansky drew parallels to the Irish FINBAR cohort published by Anderson et al. [3], where serological surrogate parameters (Helicobacter pylori serology and pepsinogens in the serum) have been assessed for their association to reflux-induced changes at and proximal to the oesophagogastric junction. It has been pointed out that even without the presence of atrophy, as defined by a decreased pepsinogen 1 : 2 ratio, a positive H. pylori status shows an inverse association with the presence of Barrett’s oesophagus and oesophageal adenocarcinomas proximal to the junction (representing most likely Siewert type 1 tumours). This effect is consistent even when the cohort is adjusted for the presence of reflux
985
symptoms. Thus, there might be an ‘H. pylori-effect’ on Barrett’s associated cancers independent of gastric mucosal alterations as has been shown in our cohort. An inverse association of H. pylori with Barrett’s oesophagus has been shown repeatedly, and even a protective effect of the infection has been postulated [4,5]. This is based on the main hypothesis that because of atrophic changes of the gastric mucosa, the gastric acid output is reduced and therefore the burden of gastro-oesophageal reflux is lowered [6]. However, the data from our study as well as from previous cohorts indicate further atrophy-independent mechanisms. This could possibly be linked to an increase in interleukin 1β (IL-1β) secretion. IL-1β is the most powerful proinflammatory cytokine produced in response to H. pylori infection, and it is also known to act as a potent acid inhibitor [7]. Especially if H. pylori colonizes predominantly the gastric body, the antisecretory effect of IL-1β leads to hypochlorhydria and therefore less reflux. An additional impact of IL-1β is caused by its capability to modulate gastric motility and therefore delay gastric emptying [7]. In addition to these effects, constitutive overexpression of IL-1β in a mouse model led to upregulation of TFF2, CDX2 and NOTCH1 and consecutively development of Barrett’s oesophagus and oesophageal adenocarcinoma, interestingly, with the involvement of Lgr5-positive gastric progenitor cells [8]. This process was further accelerated by exposure to bile acids. It is still not entirely clear which components of the reflux have the main impact on the development of Barrett’s metaplasia and further dysplastic and neoplastic progression, but bile seems to be the more potent player compared with the gastric acid itself [9]. It is known that bile alone is capable of inducing the expression of both CDX1 and CDX2 and therefore the initiation of metaplastic transformation of the gastric mucosa as well as the formation of Barrett’s oesophagus [10,11]. Dixon et al. [12] reported in that patients with Barrett’s more often have bile-induced gastropathy than patients with erosive reflux disease or nonulcer dyspepsia controls. Furthermore, bile reflux was an independent risk factor for intestinal metaplasia at the cardia, whereas H. pylori infection was not [13]. Independent of the H. pylori infection status, bile reflux can induce intestinal metaplasia of the gastric mucosa and even lead to further progression of these lesions [14–16]. The prevalence of intestinal metaplasia in the stomach, however, is highest when both factors are present: H. pylori and bile reflux [17,18]. This is in line with previously published data showing the highest upregulation of CDX2 in antrum and cardia of patients with both positive H. pylori status and gastro-oesophageal reflux disease [19]. In these cases, the induction of CDX2 as the main driver of intestinal metaplasia seems to be mediated by distinct mechanisms as in the presence of H. pylori infection, the CDX2 expression correlates positively with the degree of the mucosal infiltration with immune cells, whereas the reflux-induced expression of CDX2 is independent of the mucosal inflammation [19]. This is supported by the fact that bile-related gastropathy is characterized more by macroscopic signs of inflammation, that is, mucosal erythema, whereas H. pylori gastritis is
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
986
August 2015 • Volume 27 • Number 8
European Journal of Gastroenterology & Hepatology
characterized by infiltration of the mucosa with inflammatory cells [20]. Thus, in view of the metaplastic and neoplastic changes at the oesophagogastric junction, there seems to be a complex interplay of the influences that affect both the stomach as well as the distal oesophagus. Although atrophy of the gastric mucosa is related to H. pylori infection, intestinal metaplasia can be considered in association with both the infection and exposure to duodenogastric bile reflux. Therefore, patients with Barrett’s oesophagus can also show an increased prevalence of gastric intestinal metaplasia because of exposure of the gastric mucosa to bile. It is also of importance that duodenogastric bile reflux is associated with a reduced H. pylori density in the gastric mucosa as certain bile acids can decrease the bacterium’s capability for mucosal adherence [17,21]. This could be responsible for the reduced prevalence of H. pylori infection in patients with Barrett’s oesophagus and Siewert type 1 cancers, rather than H. pylori infection having an actual ‘protective’ effect. There is some hope that with the increased use of high-throughput techniques, we will be able to shed more light on the distinct pathogenetic pathways that are involved in carcinogenesis at the oesophagogastric junction.
6 7 8
9
10
11
12
13 14
15
Acknowledgements 16
Conflicts of interest
There are no conflicts of interest. 17
References 1 Matuchansky C. Oesophageal adenocarcinoma and atrophic gastritis. Eur J Gastroenterol Hepatol 2015; 27:984–985. 2 Bornschein J, Dingwerth A, Selgrad M, Venerito M, Stuebs P, Frauenschlaeger K, et al. Adenocarcinomas at different positions at the gastrooesophageal junction show distinct association with gastritis and gastric preneoplastic conditions. Eur J Gastroenterol Hepatol 2015; 27:492–500. 3 Anderson LA, Murphy SJ, Johnston BT, Watson RG, Ferguson HR, Bamford KB, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR casecontrol study. Gut 2008; 57:734–739. 4 Rubenstein JH, Inadomi JM, Scheiman J, Schoenfeld P, Appelman H, Zhang M, et al. Association between Helicobacter pylori and Barrett’s esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. Clin Gastroenterol Hepatol 2014; 12:239–245. 5 Vicari JJ, Peek RM, Falk GW, Goldblum JR, Easley KA, Schnell J, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the
18
19
20
21
spectrum of gastroesophageal reflux disease. Gastroenterology 1998; 115:50–57. Blaser MJ. Helicobacter pylori and esophageal disease: wake-up call? Gastroenterology 2010; 139:1819–1822. El-Omar EM. The importance of interleukin 1beta in Helicobacter pylori associated disease. Gut 2001; 48:743–747. Quante M, Bhagat G, Abrams JA, Marache F, Good P, Lee MD, et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 2012; 21:36–51. McQuaid KR, Laine L, Fennerty MB, Souza R, Spechler SJ. Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment Pharmacol Ther 2011; 34:146–165. Park MJ, Kim KH, Kim HY, Kim K, Cheong J. Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells. Carcinogenesis 2008; 29:2385–2393. Xu Y, Watanabe T, Tanigawa T, Machida H, Okazaki H, Yamagami H, et al. Bile acids induce Cdx2 expression through the farnesoid X receptor in gastric epithelial cells. J Clin Biochem Nutr 2010; 46:81–86. Dixon MF, Neville PM, Mapstone NP, Moayyedi P, Axon AT. Bile reflux gastritis and Barrett’s oesophagus: further evidence of a role for duodenogastro-oesophageal reflux? Gut 2001; 49:359–363. Dixon MF, Mapstone NP, Neville PM, Moayyedi P, Axon AT. Bile reflux gastritis and intestinal metaplasia at the cardia. Gut 2002; 51:351–355. Matsuhisa T, Arakawa T, Watanabe T, Tokutomi T, Sakurai K, Okamura S, et al. Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia: a multicenter study of 2283 cases. Dig Endosc 2013; 25:519–525. Matsuhisa T, Tsukui T. Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens. J Clin Biochem Nutr 2012; 50:217–221. Johannesson KA, Hammar E, Staël von Holstein C. Mucosal changes in the gastric remnant: long-term effects of bile reflux diversion and Helicobacter pylori infection. Eur J Gastroenterol Hepatol 2003; 15:35–40. Sobala GM, O’Connor HJ, Dewar EP, King RF, Axon AT, Dixon MF. Bile reflux and intestinal metaplasia in gastric mucosa. J Clin Pathol 1993; 46:235–240. Zullo A, Rinaldi V, Hassan C, Lauria V, Attili AF. Gastric pathology in cholecystectomy patients: role of Helicobacter pylori and bile reflux. J Clin Gastroenterol 1998; 27:335–338. Bornschein J, Wex T, Peitz U, Kuester D, Roessner A, Malfertheiner P. The combined presence of H. pylori infection and gastro-oesophageal reflux disease leads to an up-regulation of CDX2 gene expression in antrum and cardia. J Clin Pathol 2009; 62:254–259. Lee Y, Tokunaga A, Tajiri T, Masuda G, Okuda T, Fujita I, et al. Inflammation of the gastric remnant after gastrectomy: mucosal erythema is associated with bile reflux and inflammatory cellular infiltration is associated with Helicobacter pylori infection. J Gastroenterol 2004; 39:520–526. Mathai E, Arora A, Cafferkey M, Keane CT, O’Morain C. The effect of bile acids on the growth and adherence of Helicobacter pylori. Aliment Pharmacol Ther 1991; 5:653–658.
DOI: 10.1097/MEG.0000000000000416
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
