Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 Esophagogastric  Junction
 Barrett's
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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Diagnosis
 

What is the rate of occurrence of esophageal columnar metaplasia after long-term proton pump inhibitor therapy?

G.N.J. Tytgat (Amsterdam)

There are essentially two aspects to the problem mentioned in the title:
- development of esophageal columnar metaplasia during long-term proton pump inhibitor (PPI) therapy and
- evolution of esophageal columnar metaplasia during long-term PPI therapy.

Development of esophageal columnar metaplasia during long-term proton pump inhibitor therapy

There are hardly any data in the literature on the development of esophageal columnar metaplasia during long-term PPI therapy. Neither do we know when and how esophageal columnar metaplasia develops in patients with gastroesophageal reflux disease (GERD). It is also largely an enigma whether columnar metaplasia gradually involves more of the esophagus or whether metaplasia rapidly develops to its full extent with little subsequent change. It is usually assumed that, at the time of diagnosis, columnar metaplasia is in principle a stable abnormality with little tendency to progress or to regress. Presumably severe damage of the squamous mucosa occurred sufficiently long ago as to go unnoticed.

Can acid suppressant therapy including PPI therapy prevent the development of esophageal columnar metaplasia? Again an unequivocal answer to this question cannot be given. It would appear however that acid suppressants, available and massively consumed for at least 20 years, have not led to abolition of development of columnar metaplasia. If anything, as far as we know, the prevalence of columnar metaplasia has increased and keeps increasing [1] (Figure 1).

It would be difficult to reconcile a rising prevalence of columnar metaplasia with a rising consumption of acid suppressants if acid reflux is the "only" driving force leading to damage of the squamous layer and ultimately to columnar metaplasia. This apparent discrepancy would indirectly support a role for a non-acid or biliary component in the refluxate in the generation of columnar metaplasia as suggested by many investigators.

Figure 1. Incidence of Barrett's esophagus in Tayside (Scotland).

Evolution of columnar metaplasia during acid suppression

Regression of the extent of columnar metaplasia during PPI therapy is in general a rarity if one disregards a few anecdotal observations. Medical therapy with acid suppressants usually does not cause neither full nor partial regression of intestinal metaplasia [2-5]. The results of Ortiz et al. [3] are illustrated in Figure 2. Even with a high dose omeprazole 40 mg BID for 3 months, the regression of columnar metaplasia was limited [6]. In the latter randomized double-blind trial of omeprazole 40 mg bid versus ranitidine 150 mg bid for 2 years, Peeters et al. [6] found a small but significant decrease in length and area of columnar metaplasia in the omeprazole treated group, but the surface area of columnar metaplasia was reduced by only 8%. In the omeprazole group 24-hour pH < 4 was reduced to 0.1%. In another follow-up study of 23 patients treated with omeprazole 40 mg daily for 5 years, there was no further decrease in the length of metaplasia over the last 3 years [7]. In a large multicenter Scandinavian study comparing surgical therapy to medical therapy,

Figure 2. Evolution of the columnar segment during medical therapy.

there was no change in the length of the columnar metaplastic segment in patients treated with PPI for up to 5 years (Lundell, personal communication).

Castell and Katzka [8] hypothesize that nocturnal acid breakthrough is a major factor responsible for ongoing nocturnal acid reflux, which continues to injure the esophageal mucosa, because of impaired motor clearing capacity which is especially common in patients with columnar metaplasia and large hiatal hernias. Whether interference with nocturnal acid reflux with H2-receptor antagonists sufficiently decreases nocturnal esophageal acidity to allow regression of the metaplastic change awaits further study. Absence of squirts of acid would allow the progenitor cells to differentiate back into the squamous phenotype.

Can acid suppressant therapy prevent the progression of columnar metaplasia to dysplasia and cancer?

According to Levine [9], during an average 3 years follow-up, approximately half the patients with columnar metaplasia tend to stay the same, a fourth have less severe morphologic abnormalities and a fourth experience progression to more severe histologic grades. When regression does occur, it is probably due to a false-positive reading of dysplasia secondary to inflammatory atypia.

Kauer et al. [10] speculate that prolonged acid suppression may promote the development of metaplasia and neoplasia. According to Lagergren et al. [11] the risk of esophageal carcinoma is three times higher among patients using acid suppressants compared to those who do not. According to Hameeteman et al. [12] esophageal intestinal metaplasia rose from 34 to 37 out of 50 patients during a 5 year acid suppressant study period. In addition low-grade dysplasia rose from 6 to 10, high-grade from 1 to 3 and cancer from 0 to 5 out of 50 patients. Similarly Sharma et al. [13] followed 32 patients during acid suppressant therapy and found a 5.7% annual incidence of progression to dysplasia. Highgrade dysplasia developed in 2 patients of whom one progressed to cancer. Katz et al. [14] followed 102 patients with columnar metaplasia for a mean of 4.8 years. By 3 years dysplasia had developed in 8% of the medically treated patients. The results of Ortiz et al. [3] are summarized in Table I.

Table I. Endoscopic and histological findings before and after treatment.

In the earlier mentioned Scandinavian study, no patient with esophageal columnar metaplasia developed dysplasia during acid suppressant therapy (Lundell, personal communication).

From the above studies it would appear that development of dysplasia is possible during acid suppressant therapy. DeMeester and DeMeester [15] hypothesize that the usual acid suppressant therapy is inadequate because the pH range of the refluxate during standard acid suppression is often substantially below pH 7, allowing bile salts to become protonated, liposoluble and capable of ready diffusion into columnar cells. For bile salts to remain completely ionized and innocuous, a permanent gastric pH of 7 must be maintained.

References

1. Prach AT, MacDonald TA, Hopwood DA, Johnston DA. Increasing incidence of Barrett's oesophagus: education, enthusiasm, or epidemiology? Lancet 1997;350:933.

2. Shaffer R, Francis J, Carrougher J, Kadakia S. Effect of omeprazole on Barrett's epithelium after

3. years of therapy. Gastroenterology 1996;110:A255. 3. Ortiz A, Martinez de Haro LF, Parrilla P, et al. Conservative treatment versus antireflux surgery in Barrett's oesophagus: long-term results of a prospective study. Br J Surg 1996;83:274-278.

4. Sampliner RE, Garewal HS, Fennerty MB, Aickin M. Lack of impact of therapy on extent of Barrett's esophagus in 67 patients. Dig Dis Sci 1990;35:93-96.

5. Weston AP, Krmpotich PT, Cherian R, Dixon A, Topalovski M. Prospective long-term endoscopic and histological follow-up of short-segment Barrett's esophagus: comparison with traditional long-segment Barrett's esophagus. Am J Gastroenterol 1997;92:407-413.

6. Peeters FTM, Ganesh S, Kuipers EJ, Sluiter WJ, Klinkenberg-Knol EC, Lamers CBHW, Kleisbeuker JH. Endoscopic regression of Barrett's oesophagus during omeprazole treatment: a randomized double blind study. Gut 1999;45:489494.

7. Wilkinson SP, Biddlestone L, Gore S, Shepherd NA. Regression of columnar-lined (Barrett's) oesophagus with omeprazole 40 mg daily: results of 5 years of continuous therapy. Aliment Pharmacol Ther 1999;13:1205-1209.

8. Castell DO, Katzka DA. Importance of adequate acid suppression in the management of Barrett's esophagus. Gastroenterology 1999;117:1509-1510.

9. Levin DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus. Gastroenterology 1993;105:40-50.

10. Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone. The need for surgical therapy re-emphasized. Ann Surg 1995;222:525-533.

11. 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.

12. Hameeteman W, Tytgat GN, Houthoff HJ, Van den Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-1256.

13. Sharma P, Morales TG, Bhattacharyya A, Garewal HS, Sampliner RE. Dysplasia in short-segment Barrett's esophagus: a prospective 3-year follow-up. Am J Gastroenterol 1997;92:2012-2016.

14. Katz D, Rothstein R, Schwed A, Dunn J, Seaur K, Antonioli DA. The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett's esophagus. Am J Gastroenterol 1998;13:536-541.

15. DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus. Ann Surg 2000;231:303321.


Publication date: August 2003 OESO©2015