Primary Motility  Disorders of the  Esophagus
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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Treatments
 

What are the effects of medical therapy on parietal cells? What are the consequences when medical treatment is stopped?

G. Tougas, R.H. Riddell, D.K. Driman (Hamilton)

Effects of acid suppression on gastrin secretion and gastric endocrine cells

The potent acid suppression resulting from the use of proton pump inhibitors (PPIs) has marked effects on gastric histology and physiology [1]. While most of the literature has been related to the effects of omeprazole therapy on gastric mucosal histology, there are reports confirming that the effects are likely observed with all PPIs and represent a class effect. Therefore for the purpose of the present discussion, all PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, etc.) will be considered as being from the same class.

By inhibiting H+, K+-ATPase activity ("the proton pump") within parietal cells, PPIs dramatically reduce gastric acid secretion. This in turn will induce a predictable elevation in gastrin secretion and endocrine cells (particularly G cell) [2]. However the elevation is generally modest and will reach a plateau 2-4 folds above basal levels after several months of treatment. Only in patients with already elevated gastrin levels does therapy with a PPI result in more sustained gastrin increases [3]. It is important to differentiate between gastric endocrine cell hyperplasia and the occurrence of carcinoid tumors. While the former is common after long-term acid suppression, endocrine cell neoplasia and carcinoid tumors do not result from long-term PPIs, whatever the dose used.

Therefore, the prolonged use of a PPI, through the nearly complete inhibition of acid secretion from parietal cells, predictably induces a moderate gastric endocrine hyperplasia.

There is however no evidence linking the long-term use of a PPI to carcinoid neoplasia or endocrine tumors in the absence of an auto-immune pernicious anemia or a gastrinoma.

Effects of acid suppression on gastric mucosa and parietal cell mass

The prolonged use of a PPI profoundly increases the prevalence and distribution of chronic atrophic gastritis [4]. However, this effect of PPIs is only seen in patients with chronic Helicobacter pylori infection and associated atrophic gastritis. More recent studies, particularly from Kuipers et al., have confirmed that in the absence of Helicobacter pylori, PPIs are not associated with an increased occurrence of atrophic gastritis than in control population.

On its own there is no evidence that acid suppression can increase the risk of gastric cancer, or that eradication of Helicobacter pylori, prior to the institution of long-term therapy with a PPI actually decreases the subsequent risk of developing gastric cancer.

More recent data have linked the chronic use of a PPI with an increased frequency of development of gastric polyps, particularly in the fundus [5]. Histologically, these polyps consist of poorly organized oxyntic mucosal cell clusters with scattered cysts found deep into the mucous neck cells. The increased risk of developing these relatively uncommon lesions appears to increase 10 fold in patients chronically receiving a proton pump (9/231 or 3.9%, versus 7/2072 or 0.3% in control subjects) [6]. There is anecdotal evidence to suggest that discontinuation of the PPI will lead to regression of the polyps although this has not been assessed prospectively. Thus far the neoplastic potential of these polyps has not been established but the evidence to date suggests that it is somewhat limited.

In patients without Helicobacter pylori, the prolonged use of PPIs actually produce parietal cell hypertrophy and hyperplasia, resulting in an effectively increased parietal cell mass [7]. In rats, omeprazole administration is associated with increased oxyntic mucosal thickness, a finding that has been attributed to sustained hypergastrinemia. A number of early reports have documented an increased parietal cell volume density and volume. Others have suggested that parietal cell hyperplasia also occurs. In a comprehensive study we have assessed the effects of long-term omeprazole therapy on gastric mucosal architecture and histology in Helicobacter pylori negative patients [7]. We compared the effects of omeprazole to the mucosal changes associated with ranitidine therapy as well. In this study, the use of a PPI was associated with marked and significant increases in parietal cell height, mass and number over control biopsies. Use of ranitidine increased parietal cell mass but had no discernible effect on the other parameters. For all parameters examined, the effect of omeprazole was greater than the effect of ranitidine. We were also able to establish a positive correlation between the duration of treatment (> 12 months versus < 12 months) and the magnitude of the changes in parietal cell height, mass and number.

It is likely that the parietal cell hyperplasia and hypertrophy we observe with omeprazole is due to a trophic effect resulting from the hypergastrinemia associated with the hypochlorhydria induced by a PPI. It also provides a physiological basis for the rebound hyperchlorhydria transiently associated with cessation of therapy with a PPI. There is evidence this effect is also observed with other PPIs as well, including lansoprazole.

The explanation for the apparent lack of effect of ranitidine is probably to be found in the much more modest acid secretory inhibition that can be achieved using a classical H2 receptor antagonist at a standard dose. It is likely that the histological effects of acid secretory inhibition are dose dependent, although there are presently no data to support this assertion.

Only one study has so far examined the consequence of stopping PPI therapy on the gastric mucosal effects of these compounds. In a long-term study of the effects of lansoprazole on parietal cells, Stolte et al. have confirmed our previous observations of hypertrophy and hyperplasia [8]. As their follow-up was much longer, they were also able to observe that the longer the treatment with a PPI, the higher the prevalence of parietal cell hyperplasia. More importantly, they have found that parietal cell hypertrophy is entirely reversible and that parietal cell architecture returns to normal within three months of discontinuing lansoprazole. It is very likely that this is the case for all PPIs although this has yet to be specifically examined for other PPIs.

In summary, therapy with PPIs has a number of effects on gastric mucosa. These include well characterized effects such as gastric endocrine cellular hyperplasia, which is reversible and is not associated with an increased incidence of carcinoid tumors. In addition, it will alter the pattern of atrophic gastritis observed in Helicobacter pylori infected patients, with an increased severity of the inflammation in the body and a proximal extension of the atrophic mucosal changes initially confined to the antrum. Again, from the presently available literature, there is little evidence that this effect of PPIs and of acid suppression on gastric atrophy has any neoplastic potential on its own. The issues regarding the occurrence of gastric cancer in Helicobacter pylori patients however remain of significant concern.

In Helicobacter pylori negative patients, therapy with PPIs will induce significant parietal cell hyperplasia and hypertrophy. These effects are a consequence of the increased gastrin levels that result from the potent suppression of acid secretion induced by PPIs. They probably account for the rebound acid secretion seen in many patients upon discontinuation of therapy with PPIs. However, this mucosal effect is reversible and mucosal architecture returns to normal within three months of cessation of the PPI.

References

1. Fitzgibbons PL, Jamidar PA. The effects of long-term acid suppression on gastric mucosal histology. Am J Clin Pathol 1998;110:569-571.

2. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective.Am J Gastroenterol 1997;92:51S-57S.

3. Klinkenberg-Knol EC, Festen HPM, Jansen JBMJ, et al. Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Intern Med 1994;121:161-167.

4. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996;334(16):1018-1022.

5. Graham JR. Omeprazole and gastric polyposis in humans. Gastroenterology 1993;104(5):1584.

6. Choudhry U, Boyce HW, Coppola D. Proton-pump inhibitor-associated gastric polyps. Am J Clin Pathol 1998;110:615621.

7. Driman DK, Wright C, Tougas G, Riddell RH. Omeprazole produces parietal cell hypertrophy and hyperplasia in humans. Dig Dis Sci 1996;41(10):2039-2047.

8. Stolte M, Meining A, Seifert E, Alexandridis T. Treatment with lansoprazole also induces hypertrophy of the parietal cells of the stomach. Pathol Res Pract 2000;196(1):9-13.


Publication date: August 2003 OESO©2015