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Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo
  1. Jolanta A Obszynska1,
  2. Paul A Atherfold1,
  3. Manoj Nanji2,3,
  4. Deborah Glancy1,
  5. Sonia Santander3,4,
  6. Trevor A Graham5,
  7. William R Otto5,
  8. Kevin West6,
  9. Rebecca F Harrison1,6,
  10. Janusz AZ Jankowski1,2,3,6
  1. 1Digestive Diseases Centre, Leicester Royal Infirmary, UK
  2. 2Department of Gastroenterology, Institute for Cell and Molecular Sciences, Queen Mary, University of London, UK
  3. 3GI Prevention Group, Radcliffe Infirmary, University of Oxford, UK
  4. 4Instituto Aragonés de Ciencias de la Salud, CIBERehd, Zaragoza, Spain
  5. 5Histopathology Laboratory, Cancer Research, UK
  6. 6Department of Pathology, University Hospitals of Leicester, UK
  1. Correspondence to Professor Janusz Jankowski, Digestive Diseases Centre, Level 4 Windsor Building, Leicester Royal, Leicester, LE1 5WW, UK; j.a.jankowski{at}qmul.ac.uk

Abstract

Background Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man.

Methods We undertook detailed serological and tissue assessment of gastrin and CCK2 receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa.

Results Gastrin and its cognate receptor CCK2R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml±57 pg/ml to 103 pg/ml±94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)cckr Barrett's oesophagus cells, but not OE21(E)cckr squamous cells, transfected with CCK2R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.

Conclusion While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.

  • Barrett's metaplasia
  • oesophagus
  • gastrin
  • CCK2 receptor
  • GORD
  • migration
  • proliferation
  • anchorage-independent growth

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Footnotes

  • See Editorial, p148

  • JAO and PAA contributed equally to this study.

  • Funding Cancer Research UK, James Black Foundation and University Hospitals of Leicester.

  • Competing interests Declared (the declaration can be viewed on the Gut website at http://gut.bmj.com/content/vol59/issue2)

  • Ethics approval This study was conducted with the approval of the UHL Trust, Leicester and QMUL London.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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