Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

  Browse by Author
  Browse by Movies
OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Pathophysiology
 

What are the indications for esophageal pH monitoring in children with Barrett's disease?

S.R. Orenstein (Pittsburgh)

Barrett's intestinal metaplasia (IM) of the esophageal epithelium is considered to be acquired as a sequel of chronic reflux of acid (and perhaps other materials) into the esophagus, and to be a precursor of esophageal cancer. To the extent that the transformation from IM to esophageal malignancy may be slowed, halted, or reversed by elimination of the acid reflux, it would be beneficial to eliminate acid gastroesophageal reflux with certainty.

As an acquired lesion that apparently requires prolonged acid exposure, Barrett's esophagus is not common in children, but it does occur [1-3]. Its frequency in the adult population has been cited as 0.02% of the living population (acknowledging a considerable number of additional undiagnosed, silent cases), 0.3% of unselected autopsied adults, 0.64.5% of adults undergoing endoscopy, 11-36% of adults with endoscopic esophagitis, and 25-44% of adults with strictures [4, 5]. These figures compare with its prevalence in 6.213% of children with endoscopic esophagitis in three studies [6-8], one of which also calculated Barrett's as occurring in 2.7% of all children undergoing endoscopy [8].

Barrett's epithelium may arise abruptly in the child or adult, but its histopathologic concentration of goblet cells seems to increase exponentially with age between 5 and 29 years, both on a population basis and in individual patients sampled sequentially, thereafter remaining at a stable plateau between 40 and 80 years of age [6]. (This increase in goblet cell prevalence and concentration is in contrast to a relatively stable presence of intestinal mucin cells and Paneth's cells.) Thus Barrett's epithelium, and the presence and concentration of goblet cells, increases with age, which might be because of increasing chronicity of acid exposure. Similarly, the risk of Barrett's epithelium increases with duration of reflux symptoms, yielding an odds ratio of 3.0 for adults with reflux symptoms lasting 1-5 years, and 6.4 for those with symptoms longer than 10 years, compared with a group whose symptoms had been present less than a year [9]. In a parallel observation, duration of reflux symptoms affected the risk of esophageal adenocarcinoma in adults, such that reflux symptoms 12-20 years had an odds ratio of 5.2 (95% Cl, 3.1-8.6), compared to an odds ratio of 16.4 (95% Cl, 8.3-28.4) for those whose symptoms had lasted longer than 20 years [10]. Adenocarcinoma has rarely been reported in children; a review of the literature cites 10 cases between ages 11 and 25 years [11].

The chronicity of acid exposure, discussed above, is necessarily limited in children, but children who develop Barrett's have a high incidence of co-morbidities (neurologic impairment, chronic lung disease, repaired esophageal atresia, chemotherapy, and hiatal hernia) which promote Barrett's despite the more limited chronicity. These co-morbidities may be viewed as representing increasing severity of acid exposure, either in terms of degree of acidity or in terms of daily duration of exposure. The mechanisms by which these co-morbidities exacerbate severity of acid exposure are nicely summarized by Hassall [5, 12]. Although daily duration of esophageal exposure to acid has been disputed as a factor promoting Barrett's esophagus in one study which found similar daily duration in adults with severe esophagitis as in those with Barretts [13], the pH probe scores utilized can document only the daily duration of acid exposure, ignoring the potential roles of the degree of acidity (which is addressed by measures such as the "area under the curve" not used in that study) or of chronicity.

Despite the convincing evidence that chronicity, daily duration, and degree of acidity play a role in the generation of Barrett's esophagus, evidence that elimination of acid reflux may reverse metaplasia or reduce the malignant potential of Barrett's esophagus is more limited and ambiguous. Antireflux surgery in children [14, 15] and pH-probe-titrated pharmacotherapy in adults [16] have both been reported to be unsuccessful, but may not have been optimally performed and titrated. Indeed, there have been reports of regression of metaplasia in children [17, 18] as well as in adults [19 ,20], and this hope underlies the current practice of managing Barrett's epithelium by fundoplication or aggressive pharmacotherapy incorporating proton pump inhibitors.

It has recently been strongly recommended that pH monitoring be utilized in adults with Barrett's epithelium to assure complete control of acid reflux [21]. This recommendation is based on several observations. First, patients with Barrett's epithelium seem to have a decreased sensitivity to esophageal acid exposure, making control of symptoms a poor representation of control of acid reflux [22, 23]. Second, components and dosages of optimal acid-suppressive pharmacotherapy vary considerably, even among adults of similar size [24, 25], because of genetic polymorphism [26] as well as other factors. Third, pH-probe directed aggressive pharmacotherapy has produced preliminary reports of less proliferation, more differentiation, and more regression of Barrett's epithelium in adults [19, 20, 27].

This recommendation can be made even more strongly for pediatric patients with Barrett's epithelium. First, the decreased sensitivity to acid and the unreliability of "heartburn" as a clue to inadequate acid suppression is present in children [8], despite the suggestion in one adult study that it was due to age as a confounding variable [28]. Indeed, the unreliability of symptoms is magnified greatly in many children with Barrett's epithelium because normal children are poorer historians than adults, and the comorbidities (including neurologic disabilities) found in children with Barrett's epithelium make them less sensitive to the symptoms of acid reflux, and less effective at communicating the symptoms even when they are perceived [5].

Second, optimal dosing of antireflux medications are far less well established in children than in adults, because of the dearth of pharmacodynamic studies, and far more variable in children than in adults, because of the huge variability in size and metabolism during childhood development. My own perception has been that current recommendations for dosing such pharmacotherapy is often too low in children. A multicenter study of 65 children from 16 centers in 6 countries which titrated omeprazole by distal esophageal pH probe to pH < 4 for = 6% of 24-hour found the required dose to range from 0.7-3.5 mg/kg/d, and from less than 10 mg to as high as 80 mg daily [29]. The maximal doses of 3.5 mg/kg/d and 80 mg daily were reached by 4% and 7% of the children, respectively. Additionally, the fact of growth means that even once established, a dose is likely to be outgrown multiple times by a child during a lifetime of management of Barrett's. Fundoplication, similarly, is likely to fail over a period of years [30], making pH probe assessment of continuing competence of the wrap a rational procedure, particularly if there is endoscopic evidence of non-regression or progression of the IM following such surgery. In fact, one study of 152 patients following antireflux surgery (22 Nissen fundoplication, 130 posterior gastropexy with calibration of the cardia) accompanied by highly selective vagotomy examined pH probe studies 6-12 months following the surgery in 52 of the patients, finding 30 of the studies abnormal, with daily duration of pH < 4 ranging from 560%, the abnormal studies occurring particularly in those with Barrett's esophagus complicated by stricture or ulcer.

Third, the importance of promoting and maintaining regression in a 10-year-old with Barrett's esophagus is clearly even more pressing than in an 80-year-old adult, because of the large number of lifetime years at risk for adenocarcinoma.

Given that pH probe titration and monitoring of therapy is rational, with what frequency should it be performed? There are really no data with which to answer this question. Certainly an initial titration to adequacy of pharmacotherapy would be useful, and it is likely that repeat evaluations at intervals during growth might disclose the need for dose adjustment. Progression or lack of regression of the metaplastic epithelium histologically should also prompt reevaluation of adequacy of acid suppression. Whether this should be done annually or at some other interval is a subject worthy of investigation.

The optimal placement of the probe (intragastric versus distal esophagus) is also undetermined, but it might be argued that the intragastric location, more sensitively detecting breakthrough acid secretion, would be optimal. If the probe is placed in the esophagus, the thresholds prompting adjustment of therapy should also be considered. It may not be optimal to make the duration of esophageal acid exposure "normal" but rather to eliminate such exposure completely, but that has not been shown with certainty. Similarly, it is unknown what the threshold of acid detection should be. Is a pH above 4 optimal, or should the goal be to maintain the esophageal pH higher than that?

There are many unanswered questions related to the utilization of esophageal pH monitoring in children with Barrett's esophagus, but the stakes for this disease in children are even higher than those in adults.

References

1. Hassall E, Weinstein WM, Ament ME. Barrett's esophagus in childhood. Gastroenterology 1985;89:1331-1337.

2. Othersen H, Ocampo R, Parker E, Smith C, Tagge E. Barrett's esophagus in children: diagnosis and management. Ann Surg 1993;217:676-681.

3. Cooper JE, Spitz L, Wilkins BM. Barrett's esophagus in children: a histologic and histochemical study of 11 cases. J Pediatr Surg 1987;22:191-196.

4. Hassall E. Barrett's esophagus: new definitions and approaches in children. J Pediatr Gastroenterol Nutr 1993;16:345364.

5. Hassall E. Co-morbidities in childhood Barrett's esophagus. J Pediatr Gastroenterol Nutr 1997;25:255-260.

6. Qualman S, Murray R, McClung J, Lucas J. Intestinal metaplasia is age related in Barrett's esophagus. Arch Pathol Lab Med 1990;114:1236-1240.

7. Dahms BB, Rothstein FC. Barrett's esophagus in children: a consequence of chronic gastroesophageal reflux. Gastroenterology 1984;86:318-323.

8. Oderda G, Dell'olio D, Ansaldi N. Barrett's esophagus. Gastroenterology 1988;94(1):252.

9. Lieberman DA, Oehlke M, Helfand M, GORGE consortium. Risk factors for Barrett's esophagus in community-based practice. Am J Gastroenterol 1997;92(8):1293-1297.

10. Lagergren J, Bergstrom R, Lindgren A, Nyren 0. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N EngI J Med 1999;340:825-831.

11. Hassall E, Dimmick JE, Magee JF. Adenocarcinoma in childhood Barrett's esophagus: case documentation and the need for surveillance in children. Am J Gastroenterol 1993;88:282-288.

12. Hassall E, Israel D, Davidson A, Wong L. Barrett's esophagus in children with cystic fibrosis: not a coincidental association. Am J Gastroenterol 1993;88:1934-1938.

13. Coenraad M, Masclee AMM, Straathof JWA, Ganesh S, Griffioen G, Lamers CBHW. Is Barrett's esophagus characterized by more pronounced acid reflux than severe esophagitis? Am J Gastroenterol 1998;93(7):1068-1072.

14. Cheu HW, Grosfeld JL, Heifetz SA, Fitzgerald J, Rescoria F, West K. Persistence of Barrett's esophagus in children after antireflux surgery: influence on follow-up care. J Pediatr Surg 1992;27:260-266.

15. Rofail M, Friedman M, Mendelsohn G, Schoenfield L, Dahms B, Rothstein F. Pediatric Barrett's esophagus: long-term follow-up. Am J Gastroenterol 1991;86(9):1302.

16. Sharma P, Sampliner RE, Camargo E. Normalization of esophageal pH with high-dose proton pump inhibitor therapy does not result in regression of Barrett's esophagus. Am J Gastroenterol 1997;92(4):582-585.

17. Hassall E, Weinstein WM. Partial regression of childhood Barrett's esophagus after fundoplication. Am J Gastroenterol 1992;87:1506-1512.

18. Conti Nibali S, Barresi G, Tuccari G, Rivosecchi M, Magazzu G. Barrett's esophagus in an infant: a long standing history with final postsurgical regression. J Pediatr Gastroenterol Nutr 1988;7:602-607.

19. Srinivasan R, Ramakrishnan A, Katzka D, et al. Effect of maximal acid reflux control on Barrett's esophagus (BE). Am J Gastroenterol 1999;94:2600.

20. Peters F, Ganesh S, Kuipers E, et al. Endoscopic regression of Barrett's oesophagus during omeprazole treatment: a randomised double blind study. Gut 1999;45:489-494.

21. Castell D. Acid suppression therapy in Barrett's esophagus: the importance of pH monitoring. Curr Gastroenterol Rep 2000;2:173-174.

22. Johnson D, Winters C, Spurling T, et al. Esophageal acid sensitivity in Barrett's esophagus. J Clin Gastroenterol 1987;9:23-27.

23. Katzka D, Castell D. Successful elimination of reflux symptoms does not insure adequate control of acid reflux in patients with Barrett's esophagus. Am J Gastroenterol 1994;89:989-991.

24. Peghini P, Katz P, Castell D. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole:a controlled study in normal subjects. Gastroenterology 1998;115:1335-1339.

25. Peghini P, Katz P, Castell D. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763-767.

26. Sagar M, Tybring G, DahI ML, Bertilsson L, Seensalu R. Effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C1 9 polymorphism. Gastroenterology 2000;119:670-676.

27. Ouatu-Lascar R, Fitzgerald R, Triadafilopoulos G. Differentiation and proliferation in Barrett's esophagus and the effects of acid suppression. Gastroenterology 1999;117:327-335.

28. Grade A, Pulliam G, Johnson C, Garewal H, Sampliner RE, Fass R. Reduced chemoreceptor sensitivity in patients with Barrett's esophagus may be related to age and not to the presence of Barrett's epithelium. Am J Gastroenterol 1997;92(11):2040-2043.

29. Hassall E, Israel D, Shepherd R, Radke M, Dalvag A, Junghard 0, Lundborg P, The International Pediatric Omeprazole Study Group. Omeprazole for treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and dose requirements. J Pediatr 2000;137:800-807.

30. Csendes A, Braghetto I, Burdiles P, Puente G, Korn 0, Diaz JC, Maluenda F. Long-term results of classic antireflux surgery in 152 patients with Barrett's esophagus: clinical, radiologic, endoscopic, manometric, and acid reflux test analysis before and late after operation. Surgery 1998;123:645-657.


Publication date: August 2003 OESO©2015