Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 The
 Esophagogastric  Junction
 Barrett's
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OESO©2015
 
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.

Conclusion

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.

References

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Publication date: August 2003 OESO©2015