Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

  Browse by Author
  Browse by Movies
Volume: Barrett's Esophagus
Chapter: Pathophysiology

Based on experimental findings of the protective effect of acid secretion against adenocarcinoma, how should the role of continuous acid suppression on the development of esophageal metaplasia and adenocarcinoma in patients with duodenogastric reflux be considered?

M. Fein, K.H. Fuchs (Würzburg)

Effect of acid suppression on the development of esophageal adenocarcinoma-epidemiologic studies

The results of epidemiologic studies may help to answer the question about the role of continuous acid suppression in patients with duodenogastric reflux. Two large studies on this issue have revealed similar results. In the first study of Chow et al. [1] the cancer risk was increased fourfold in patients who had received four or more prescriptions for H2 antagonists (95% confidence interval 1.3-12.4). The authors question the significance of this finding based on an analysis controlling for the effects of severity of reflux disease. In this subanalysis, the risk of adenocarcinoma was not related to the use of acid suppressant therapy, but it was linked instead to long-term gastroesophageal reflux disease (GERD). In the second study of Lagergren et al. [2] the cancer risk was increased threefold in patients who used medication for symptoms of reflux at least five years before the interview (95% confidence interval 2.0-4.6). Adjustment of these data for severity of symptoms did not alter the risk. The authors conclude that residual confounding by the severity of the reflux may have altered these estimates.

There are two possible explanations for the observed relation between acid suppression and cancer risk. One is that the reflux is treated insufficiently by the medication and that acid breakthrough especially when combined with duodenogastric reflux might be relevant for the development of cancer. The other explanation is that acid suppression may in fact contribute to adenocarcinoma especially in patients with duodenogastric reflux. This would be in accordance with the experimental finding of a protective effect of acid secretion against adenocarcinoma.

Protective effect of acid secretion against adenocarcinoma - animal studies

In the first study by Ireland et al. [3] Sprague-Dawley rats were operated to induce reflux of duodenal juice into the esophagus. The amount of acid was modulated by resecting parts of the stomach. All animals were treated with injections of nitrosamine and killed after 28 weeks. In this study, the admixture of gastric juice with duodenal juice modulated the tumorigenic effects. Specifically, the absence of gastric juice resulted in a threefold increase in the prevalence of adenocarcinoma. The protective effect of the stomach appeared to be related to the secretion of acid because there was a progressive increase in cancer prevalence as the amount of acid was reduced. While in this study exogenous carcinogens were used, the second study by Wetscher et al. [4] was done without applying carcinogens. Duodenogastric reflux was induced in Sprague-Dawley rats. Comparable to the clinical situation, acid suppression was done by administration of omeprazole in one group. After one year, 18 of 20 rats with duodenogastric reflux and acid suppression and 7 of 20 rats with duodenogastric reflux alone developed adenocarcinoma of the stomach. However, as no gastroesophageal reflux was induced, cancer in the esophagus was not observed. Both studies raise concern about continuous acid suppressant therapy, particularly in patients with duodenogastric reflux.

Mechanisms of carcinogenesis by duodenogastric reflux

One proposed mechanism of carcinogenesis relies on the reaction of physiologic bile acids with nitrite producing carcinogenic N-nitrosamides in the presence of bacterial overgrowth [5-7]. Endogenously formed N-nitroso bile acids would be an explanation how acid suppression may contribute to the development adenocarcinoma by duodenogastric reflux.

To test this hypothesis, the following experiments were performed [8]. Duodenal juice was analyzed for intestinal microflora, endogenously formed N-nitroso bile acids, and for genotoxicity in the animal model (n = 15). Intestinal microflora in the rat jejunum was analyzed before and two weeks after reflux inducing surgery. Evaluation of intestinal microflora showed Lactobacillus spp. and Bacteroides spp. as the jejunal flora that is regularly present in unoperated animals. Following surgery bacterial overgrowth with bacteria of the fecal flora occurred in all animals. E. coli, Proteus spp., and Enterococcus spp. were present in concentrations up to one million per ml. The bacteria that had been identified in the jejunum following surgery are capable of catalysing endogenous reactions to produce potential carcinogens and cocarcinogens [5, 9]. However, extensive HPLC-MS analysis clearly demonstrated the absence of any N-nitroso bile acid conjugate in the animal model. The primary constituents of duodenal juice, TCA and GCA, could be identified in any sample. Taking into consideration the only moderate mutagenic and carcinogenic potential of NO-TCA and NO-GCA [10, 11], it appears very unlikely that endogenous nitrosation of bile acids contributes to reflux induced carcinogenesis. Furthermore, neither the preoperative nor the postoperative samples were genotoxic in a micronucleus test. In this test the applied concentration of duodenal juice was sufficient to induce cytotoxic effects. Therefore, tumorigenesis of esophageal adenocarcinoma in the rodent model could not be linked to a specific carcinogen, especially not to nitroso bile acids. Consequently, the hypothesis that acid suppression contributes to the development adenocarcinoma by duodenogastric reflux could not be supported based on this specific mechanism of carcinogenesis.

Another mechanism for tumor development in this model is the process of chronic inflammation. This mechanism would support the hypothesis, that the observed relation between acid suppression and cancer risk is due to an insufficient acid suppressant therapy. Oxyradical overload disease develops in conditions involving chronic inflammation and may be chemically induced, e.g. by acid and duodenogastric reflux in Barrett esophagus [12]. Markers for oxidative stress have already been documented in human esophagitis [13-15] and in this rat model [16, 17]. The concept of mutagenesis driven by mitogenesis for the induction of this tumor entity is further supported by the mutation pattern of p53 in Barrett's carcinoma [18, 19]. The mutation pattern with a predominance of G-C to A-T transitions is similar to the mutations described for in vitro tests mimicking the situation of chronic inflammation [20]. Furthermore, a synergistic effect of acid reflux and duodenoesophageal reflux has been documented for the development of esophagitis, Barrett's esophagus and dysplasia in Barrett's esophagus in clinical studies [21-23]. These data support the hypothesis that the observed relation between acid suppression and cancer risk is due to an insufficient acid suppressant therapy and the synergism with duodenogastric reflux.

Long-term effects of acid suppressant therapy

The best way to address the question about the tumorigenic effect of acid suppressant therapy is to conduct a long-term follow-up study of patients with severe GERD. One group is treated with high dose acid suppression and the other group is treated medically on demand. If there is a protective effect of acid secretion against adenocarcinoma in the human situation, one would expect a higher cancer incidence in patients treated with high dose acid suppression. If the cancer risk is increased as a consequence of insufficient therapy, the cancer incidence should be higher in the group treated on demand.

Unfortunately, this issue has not been realized in a randomized, prospective study. Therefore, the results of two long-term studies applying these two therapeutic regimens are compared here. High dose acid suppressant therapy was realized in the study by Klinkenberg-Knol et al. [24]. In this study 230 patients had an endoscopy every year and dosage of proton pump inhibitors (PPI) was adjusted depending on the results of the endoscopy. The mean follow-up period was 6.5 years. Patients were treated with dosages of up to 120 mg omeprazole. Initially, 64 patients had a Barrett's esophagus. During the study period 20 of the remaining 166 patients developed a Barrett's esophagus. One cancer developed in the 230 patients, which was treated successfully with local therapy. This cancer risk is lower than the reported incidence of adenocarcinoma developing in Barrett's esophagus of about 1 per 200 patient years [25] indicating that a reduction of cancer risk may be possible by high dose acid suppressant therapy. In the second study by Spechler et al. [26] patients who had initially participated in a randomized study comparing medical versus surgical treatment were evaluated 11 to 15 years after completion of this protocol. Of the 166 patients who had been randomized to medical treatment, 75% reported the use PPI. As the dosage of medication was not controlled in any patient after completion of the study, this group is close to an on demand therapeutic regimen. The incidence of newly developed Barrett's esophagus was not reported, incidence of adenocarcinoma was 4 of 166 patients. This is more than four times higher than the figures in the other study. However, because of the low cancer incidence a higher number of patients would be necessary to show a significant difference. If this observed trend is correct, it would support the concept, that the main problem leading to cancer development in reflux disease is insufficient acid suppressant therapy.


So far, a protective effect of acid secretion against adenocarcinoma has only been demonstrated in two animal studies. Evaluation of the mechanisms of carcinogenesis, analysis of the esophageal exposure to duodenal juice and acid reflux, and clinical studies support the hypothesis, that the cancer risk in patients with duodenogastric reflux is mainly increased by an insufficient acid suppressant therapy. These data indicate that cancer risk may be reduced by an effective therapy. This can be attempted by a high dose therapy with PPI or ensured by successful antireflux surgery.


1. Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni JF Jr. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia. JAMA 1995;274:474-477.

2. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-831.

3. Ireland AP, Peters JH, Smyrk TC, DeMeester TR, Clark GW, Mirvish SS, Adrian TE. Gastric juice protects against the development of esophageal adenocarcinoma in the rat. Ann Surg 1996;224:358-371.

4. Wetscher GJ, Hinder RA, Smyrk T, Perdikis G, Adrian TE, Profanter C. Gastric acid blockade with omeprazole promotes gastric carcinogenesis induced by duodenogastric reflux. Dig Dis Sci 1999;44:1132-1135.

5. Mirvish SS. The etiology of gastric cancer. Intragastric nitrosamide formation and other theories. J Natl Cancer Inst 1983;71:629-647.

6. Miwa K, Hattori T, Miyazaki I. Duodenogastric reflux and foregut carcinogenesis. Cancer 1995;75:1426-1432.

7. Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett 1995;93:17-48.

8. Fein M, Fuchs KH, Stopper H, Diem S, Herderich M. Duodenogastric reflux and foregut carcinogenesis: analysis of the duodenal juice in the rodent cancer model. Carcinogenesis 2000;21:2079-2084.

9. Calmels S, Bereziat JC, Ohshima H, Bartsch H. Bacterial formation of N-nitroso compounds from administered precursors in the rat stomach after omeprazole-induced achlorhydria. Carcinogenesis 1991;12:435-439.

10. Puju S, Shuker DEG, Bishop WW, Falchuk KR, Tannenbaum SR, Thilly WG. Mutagenecity of N-nitroso bile acid conjugates in Salmonella typhimurium and diploid human lymphoblasts. Cancer Res 1982;42:2601-2604.

11. Busby WF, Shuker DEG, Charnley G, Newberne PM, Tannenbaum SR, Wogan GN. Carcinogenicity in rats of the nitrosated bile acid conjugates N-nitrosoglycocholic acid and N-nitrosotaurocholic acid. Cancer Res 1985;45:1367-1371.

12. Ambs S, Hussain SP, Marrogi AJ, Harris CC. Cancer-prone oxyradical overload disease. IARC Sci Publ 1999;295-302.

13. Olyaee M, Sontag S, Salman W, Schnell T, Mobarhan S, Eiznhamer D, Keshavarzian A. Mucosal reactive oxygen species production in oesophagitis and Barrett's oesophagus. Gut 1995;37:168-173.

14. Peters WH, Roelofs HM, Hectors MP, Nagengast FM, Jansen JB. Glutathione and glutathione S-transferases in Barrett's epithelium. Br J Cancer 1993;67:1413-1417.

15. Wetscher GJ, Hinder RA, Bagchi D, Hinder PR, Bagchi M, Perdikis G, McGinn T. Reflux esophagitis in humans is mediated by oxygen-derived free radicals. Am J Surg 1995;170:552-556.

16. Wetscher GJ, Perdikis G, Kretchmar DH, Stinson RG, Bagchi D, Redmond EJ, Adrian TE, Hinder RA. Esophagitis in Sprague-Dawley rats is mediated by free radicals. Dig Dis Sci 1995;40:1297-1305.

17. Chen X, Ding YW, Yang G, Bondoc F, Lee MJ, Yang CS. Oxidative damage in an esophageal adenocarcinoma model with rats. Carcinogenesis 2000;21:257-263.

18. Gleeson CM, Sloan JM, McGuigan JA, Ritchie AJ, Russell SE. Base transitions at CpG dinucleotides in the p53 gene are common in esophageal adenocarcinoma. Cancer Res 1995;55:3406-3411.

19. Schneider PM, Casson AG, Levin B, Garewal HS, Hoelscher AH, Becker K, Dittler HJ, Cleary KR, Troster M, Siewert JR, Roth JA. Mutations of p53 in Barrett's esophagus and Barrett's cancer: a prospective study of ninety-eight cases. J Thorac Cardiovasc Surg 1996;111:323-331.

20. Routledge MN, Wink DA, Keefer LK, Dipple A. Mutations induced by saturated aqueous nitric oxide in the pSP189 supF gene in human Ad293 and E. coli MBM7070 cells. Carcinogenesis 1993;14:1251-1254.

21. Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease. Gastroenterology 1996;111:1192-1199.

22. Fein M, Ireland AP, Ritter MP, Peters JH, Hagen JA, Bremner CG, DeMeester TR. Duodenogastric reflux potentiates the injurious effects of gastroesophageal reflux. J Gastrointest Surg 1997;1:27-33.

23. Vaezi MF, Richter JE. Synergism of acid and duodenogastroesophageal reflux in complicated Barrett's esophagus. Surgery 1995;117:699-704.

24. Klinkenberg-Knol EC, Nelis F, Dent J, Snel P, Mitchell B, Prichard P, Lloyd D, Havu N, Frame MH, Roman J, Walan A, Group LT. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000;118:661-669.

25. O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry. Am J Gastroenterol 1999;94:2037-2042.

26. Spechler SJ, Lee EY, Ahnen D, Goyal RK, Sampliner RE, Raufman J, et al. Long-term outcome of medical and surgical therapies for GERD: effects on survival. Gastroenterology 2000;118:A193.

Publication date: August 2003 OESO©2015