PPIs Do Not Reduce the Risk of Esophageal Adenocarcinoma Associated With Barrett’s Esophagus

Post on February 14, 2017 by André Broussard, D.C.

February 07, 2017

PloS One

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  • No association between the use of proton pump inhibitors (PPIs) and reduced risk for esophageal adenocarcinoma and high-grade dysplasia in patients with Barrett’s esophagus was found in an analysis of nine observational studies. Nor was a duration–response relationship noted.
  • PPIs were not found to provide any significant protection against esophageal adenocarcinoma and high-grade dysplasia in patients with Barrett’s esophagus.

Written by  David Rakel MD, FAAFP

PPI use does NOT prevent cancer in people with Barrett’s esophagus

As the research for potential harm of long-term acid suppression has grown (see table below), using PPIs to prevent the progression from Barrett’s esophagus to high-grade metaplasia and esophageal adenocarcinoma has been a common practice despite these risks. Our intention has been to lower acid to reduce its harm on sensitized esophageal epithelium. This study suggests that this practice is not helpful.

This systematic review and meta-analysis evaluated 5712 patients with Barrett’s esophagus from 9 studies. The authors compared patients on PPIs for <2–3 years and >2–3 years with nonusers and found no statistical association with risk of high-grade dysplasia or adenocarcinoma (unadjusted OR, 0.43; 95% CI, 0.17–1.08).

The authors propose that the potential beneficial protective effect that PPIs may have on the esophageal epithelium may be offset by the elevated gastrin levels seen with chronic acid suppression. In vitro studies have shown that gastrin has a pro-proliferative effect on Barrett’s epithelium.

This study is in line with the national guidelines that recommend PPIs for symptom management alone and not for prevention of esophageal adenocarcinoma.

Possible mechanisms of harm for chronic acid suppression with PPIs

  • Sensing low acid, the body thinks it needs to make more and so increases gastrin production, which may stimulate proliferation of Barrett’s epithelium (current study).
  • Acid is needed to stimulate pancreatic digestive enzyme production and is needed to convert pepsin to activated protease enzymes. Lack of the body’s ability to break down food proteins can increase autoimmune potential and food protein intolerance (eosinophilic esophagitis).1
  • Acid is needed to absorb key nutrients. (iron, B vitamins, magnesium, calcium).
  • Acid is needed to keep bacteria from growing in the small intestine, and thus chronic suppression result in small bowel bacterial overgrowth and dysbiosis (C. diff, SBBO, community-acquired pneumonia, and gastroenteritis).
  • Chronic acid suppression has been associated with more amyloid plaque development (dementia).
  • Acid is needed for function of lysosomes, which clear waste from the endothelium. Poor lysosome function results in more plaque buildup and endothelial dysfunction. (heart disease, kidney disease, stroke).2

Potential Harm of Chronic Acid Suppression Chart R

Nature gave us acid for a reason. If we simply shut it off with our technology, we are learning study by study that there are long-term consequences.

First do no harm.

References

  1. Molina-Infante J, Zamorano J. Acid-suppressive therapy and eosinophilic esophagitis: friends or foes? Am J Gastroenterol. 2010;105(3):699-700. http://www.nature.com/ajg/journal/v105/n3/full/ajg2009590a.html
  2. Yepuri G, Sukhovershin R, Nazari-Shafti TZ, et al. Proton Pump Inhibitors Accelerate Endothelial Senescence. Circ Res. 2016;118(12):e36-e42. http://circres.ahajournals.org/content/118/12/e36.long
  3. Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol. 2013;6(4):443-451. http://www.tandfonline.com/doi/abs/10.1586/17512433.2013.811206?journalCode=ierj20
  4. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292(16):1955-1960. http://jamanetwork.com/journals/jama/fullarticle/199672
  5. Canani RB, Cirillo P, Roggero P, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117(5):e817-e820. http://pediatrics.aappublications.org/content/117/5/e817.long
  6. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294(23):2989-2995. http://jamanetwork.com/journals/jama/fullarticle/202048
  7. Hegar B, Hutapea EI, Advani N, Vandenplas Y. A double-blind placebo-controlled randomized trial on probiotics in small bowel bacterial overgrowth in children treated with omeprazole. Jornal de pediatria. 2013;89(4):381-387. http://www.sciencedirect.com/science/article/pii/S0021755713000922
  8. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology. 2010;139(1):93-101. http://www.gastrojournal.org/article/S0016-5085(10)00488-9/abstract
  9. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442. https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2013.280490
  10. Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption. Gastroenterology. 1981;81(6):1068-1071. http://www.gastrojournal.org/article/S0016-5085(81)80013-3/abstract
  11. Gau JT, Yang YX, Chen R, Kao TC. Uses of proton pump inhibitors and hypomagnesemia. Pharmacoepidemiol Drug Saf. 2012;21(5):553-559. http://onlinelibrary.wiley.com/wol1/doi/10.1002/pds.3224/full
  12. Shah NH, LePendu P, Bauer-Mehren A, et al. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PLoS One. 2015;10(6):e0124653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462578/
  13. Lazarus B, Chen Y, Wilson FP, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med. 2016;176(2):238-246. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2481157
  14. Gomm W, von Holt K, Thome F, et al. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol. 2016;73(4):410-416. http://jamanetwork.com/journals/jamaneurology/article-abstract/2487379
  15. Sehested TS, Fosbol EL, Hansen PW, et al. Proton pump inhibitor use increases the associated risk of first-time ischemic stroke. A nationwide cohort study. 2016 American Heart Association Scientific Sessions; 2016; New Orleans, LA. http://circ.ahajournals.org/content/134/Suppl_1/A18462
  16. Tsai CF, Chen MH, Wang YP, et al. Proton Pump Inhibitors Increase Risk for Hepatic Encephalopathy in Patients With Cirrhosis in A Population Study. Gastroenterology. 2017;152(1):134-141. http://www.gastrojournal.org/article/S0016-5085(16)35032-6/fulltext

Abstract

OBJECTIVES

Proton pump inhibitors (PPIs) have been used for treatment of Barrett’s esophagus (BE) for many years. However, the connection between PPIs and esophageal adenocarcinoma (EAC) in patients with BE has still been controversial. The current systematic review and meta-analysis was designed to evaluate the association between PPIs and the risk of EAC or high-grade dysplasia (HGD) in patients with BE.

METHODS

A systematic literature search of studies reporting the association between PPIs and the risk of EAC and/or HGD in patients with BE was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Next, literature was screened using previously established criteria and relevant data were extracted from included studies. Finally, the software program Review Manage 5.2 was applied to aggregate data and analyze the results.

RESULTS

Nine observational studies, comprising five cohort and four case-control studies (including a total of 5712 patients with BE), were identified. Upon meta-analysis, PPIs were found to have no association with the risk of EAC and/or HGD in patients with BE (unadjusted OR 0.43, 95% CI 0.17-1.08). Analysis for duration response relationship revealed no significant trend toward protection against EAC or HGD with PPIs usage for >2~3 years (one study using 7-year cutoff) when compared to usage for shorter time periods (PPIs usage >2~3 years vs. <2~3 years: OR 0.91 (95% CI 0.25-3.31) vs. 0.91 (0.40-2.07)).There also was considerable heterogeneity between studies.

CONCLUSION

No dysplasia- or cancer-protective effects of PPIs usage in patients with BE were identified by our analysis. Therefore, we conclude that clinicians who discuss the potential chemopreventive effects of PPIs with their patients, should be aware that such an effect, if exists, has not been proven with statistical significance.

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