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Long term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett’s Esophagus in vivo
  1. Jolanta Obszynska (jolcia88{at}hotmail.co.uk)
  1. Leicester Royal Infirmary, United Kingdom
    1. Paul A Atherfold (paul.atherfold{at}clinpharm.ox.ac.uk)
    1. Leicester Royal Infirmary, United Kingdom
      1. Manoj Nanji (m.nanji{at}qmul.ac.uk)
      1. Oxford University, United Kingdom
        1. Deborah Glancy (deborah.glancy{at}uhl-tr.nhs.uk)
        1. Leicester Royal Infirmary, United Kingdom
          1. Sonia Santander (sonia.santander{at}clinpharm.ox.ac.uk)
          1. Oxford University, United Kingdom
            1. Trevor Graham (trevor.graham{at}cancer.org.uk)
            1. Cancer Research UK, United Kingdom
              1. William Otto (william.otto{at}cancer.org.uk)
              1. Cancer Research UK, United Kingdom
                1. Kevin West (kevin.west{at}uhl-tr.nhs.uk)
                1. University Hospitals of Leicester, United Kingdom
                  1. Rebecca Harrison (rebecca.harrison{at}uhl-tr.nhs.uk)
                  1. University Hospitals of Leicester, United Kingdom
                    1. Janusz A Jankowski (j.a.jankowski{at}qmul.ac.uk)
                    1. Leicester Royal Infirmary, United Kingdom

                      Abstract

                      Background: Barrett’s esophagus (BE) is a common premalignant lesion caused partly by acid reflux. The requisite therapy, proton pump inhibitors (PPI), have been implicated in the progression of BE. 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 then 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 CCK2 were expressed highest in the stomach, then next BE and least in squamous esophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in BE 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 to 103 pg/ml ± 94 (paired t-test, p<0.05)). In vitro gastrin also induced changes in OE33(E)cckr BE cells, but not OE21(E)cckr squamous cells, transfected with CCK2; migration was induced by 1ng/ml of gastrin but proliferation only arose with 100ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.

                      Conclusions: While the short term effects of gastrin enhance epithelial restitution in BE there is no clinical evidence that BE length expands over time. This large and long term randomised controlled trial of gastrin biology in BE is further proof of the clinical safety of PPI therapy.

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