title: Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology.
abstract: BACKGROUND
  Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy.
  
  
  OBJECTIVE
  To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology.
  
  
  METHODS
  A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology.
  
  
  RESULTS
  A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found.
  
  
  CONCLUSIONS
  Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.
authors.affiliation: Gastrocentrum, Department of Clinical Sciences, Intervention and Technology (CLINTEC), Centre for Digestive Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Lundell
authors.affiliation: Institut für Pathologie, Klinikum Bayreuth GmbH, Bayreuth, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Vieth
authors.affiliation: PharmaGenesis London, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Gibson
authors.affiliation: Global Medicines Development, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kahrilas
mesh_terms: D004334:Drug Administration Schedule; D019861:Enterochromaffin-like Cells / Q000473:pathology*; D005755:Gastrins / Q000096:biosynthesis / Q000097:blood*; D016481:Helicobacter Infections / Q000188:drug therapy; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced*; D018358:Neuroendocrine Tumors / Q000139:chemically induced / Q000473:pathology; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000473:pathology
chemical_list: D005755:Gastrins; D054328:Proton Pump Inhibitors