{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T01:54:18Z","timestamp":1791078858045,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aliment Pharmacol Ther"],"abstract":"ABSTRACT<\/jats:title>\n \n Background and Aims<\/jats:title>\n Autoimmune gastritis (AIG) is characterized by chronic hypergastrinemia and is associated with an increased risk of gastric neuroendocrine neoplasms (gNENs). Because proton pump inhibitors (PPIs) further increase gastrin secretion, concerns have been raised regarding a potential additive effect on gastric neoplastic risk. This study aimed to evaluate the association between PPI exposure and gNEN occurrence in patients with AIG using a large real\u2010world database.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We conducted a retrospective propensity score\u2010matched cohort study using the TriNetX Global Collaborative Network. Patients with AIG were identified using diagnostic codes for chronic atrophic gastritis or pernicious anaemia, excluding\n \n Helicobacter pylori<\/jats:italic>\n <\/jats:styled-content>\n infection, gastric cancer, multiple endocrine neoplasia or other competing gastric conditions. Two cohorts were defined: patients with AIG receiving PPIs and patients without PPI exposure. The primary outcome was the overall occurrence of gNENs. A prespecified secondary analysis excluded patients with gNENs diagnosed before the index date to evaluate incident tumours. Secondary outcomes included hypergastrinemia, intestinal metaplasia and gastric polyps.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 153,687 patients with AIG were identified. After 1:1 propensity score matching, 40,489 patients were included in each cohort. After propensity score matching, gNENs were recorded in 241 patients (0.60%) without PPI exposure and 360 patients (0.89%) receiving PPIs. PPI exposure was associated with a significantly higher occurrence of gNENs (risk ratio [RR] 1.49, 95% CI 1.27\u20131.76), which was confirmed by time\u2010to\u2010event analysis (hazard ratio [HR] 1.44, 95% CI 1.22\u20131.70; log\u2010rank\n p<\/jats:italic>\n \u2009<\u20090.001). The association persisted after exclusion of patients with pre\u2010existing gNENs (RR 1.61, 95% CI 1.26\u20132.06; HR 1.52, 95% CI 1.19\u20131.95). PPI exposure was also associated with higher occurrences of hypergastrinemia (HR 1.17, 95% CI 1.00\u20131.37), intestinal metaplasia (HR 1.53, 95% CI 1.36\u20131.71) and gastric polyps (HR 2.48, 95% CI 2.25\u20132.73). No gastric adenocarcinomas were identified during follow\u2010up.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n In this large real\u2010world propensity score\u2010matched study, PPI exposure was associated with a greater occurrence of both overall and incident gNENs in patients with AIG. PPI use was also consistently associated with gastric mucosal alterations, including hypergastrinemia, intestinal metaplasia and gastric polyps. Although the absolute risk of gNENs remained low, these findings support judicious long\u2010term PPI prescribing in patients with AIG and reinforce the importance of appropriate endoscopic surveillance in this high\u2010risk population.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/apt.70954","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T15:24:03Z","timestamp":1788708243000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Association Between Proton Pump Inhibitor Use and Gastric Neuroendocrine Neoplasms in Autoimmune Gastritis: A Real\u2010World Propensity Score\u2010Matched Study From the Autoimmune gastRitis Italian netwOrk Study grOup"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3214-8192","authenticated-orcid":false,"given":"Sara","family":"Massironi","sequence":"first","affiliation":[{"name":"School of Medicine and Surgery, Vita\u2010Salute San Raffaele University Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6654-4911","authenticated-orcid":false,"given":"Marco Vincenzo","family":"Lenti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia Pavia Italy"},{"name":"First Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9503-8639","authenticated-orcid":false,"given":"Edith","family":"Lahner","sequence":"additional","affiliation":[{"name":"Department of Surgical\u2010Medical Sciences and Translational Medicine, Digestive and Liver Disease Unit, Sant'Andrea Hospital Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Galbiati","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, Vita\u2010Salute San Raffaele University Milan Italy"},{"name":"Gastroenterology and Endoscopy Unit IRCCS Ospedale San Raffaele Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Scatena","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, Vita\u2010Salute San Raffaele University Milan Italy"},{"name":"Gastroenterology and Endoscopy Unit IRCCS Ospedale San Raffaele Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Miceli","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2565-6220","authenticated-orcid":false,"given":"Chiara Della","family":"Bella","sequence":"additional","affiliation":[{"name":"Department of Molecular and Developmental Medicine University of Siena Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2541-9428","authenticated-orcid":false,"given":"Federica","family":"Facciotti","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences University of Milan\u2010Bicocca Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario M.","family":"D'Elios","sequence":"additional","affiliation":[{"name":"Department of Molecular and Developmental Medicine University of Siena Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-8645","authenticated-orcid":false,"given":"Antonio","family":"Di Sabatino","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia Pavia Italy"},{"name":"First Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7341-1351","authenticated-orcid":false,"given":"Silvio","family":"Danese","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, Vita\u2010Salute San Raffaele University Milan Italy"},{"name":"Gastroenterology and Endoscopy Unit IRCCS Ospedale San Raffaele Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41575-026-01200-0","article-title":"Autoimmune Gastritis: Emerging Insights and Clinical Management","volume":"23","author":"Lenti M. V.","year":"2026","journal-title":"Nature Reviews. Gastroenterology & Hepatology"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102025\u2010337458"},{"issue":"3","key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.autrev.2018.08.011","article-title":"The Changing Face of Chronic Autoimmune Atrophic Gastritis: An Updated Comprehensive Perspective","volume":"18","author":"Massironi S.","year":"2019","journal-title":"Autoimmunity Reviews"},{"issue":"8","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.4251\/wjgo.v15.i8.1451","article-title":"Incidence and Prevalence of Gastric Neuroendocrine Tumors in Patients With Chronic Atrophic Autoimmune Gastritis","volume":"15","author":"Massironi S.","year":"2023","journal-title":"World Journal of Gastrointestinal Oncology"},{"issue":"1","key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00428-025-04340-x","article-title":"Neuroendocrine Neoplasms of the Stomach. Update on Diagnostic Criteria, Classification, and Prognostic Markers","volume":"488","author":"Uccella S.","year":"2026","journal-title":"Virchows Archiv"},{"issue":"5","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.14309\/ajg.0000000000003235","article-title":"Serum Gastrin Levels Are Associated With Prevalent Neuroendocrine Tumors in Autoimmune Metaplastic Atrophic Gastritis","volume":"120","author":"Jove A.","year":"2025","journal-title":"American Journal of Gastroenterology"},{"issue":"20","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.3390\/cells14201576","article-title":"The Autoimmune Gastritis Puzzle: Emerging Cellular Crosstalk and Molecular Pathways Driving Parietal Cell Loss and ECL Cell Hyperplasia","volume":"14","author":"Massironi S.","year":"2025","journal-title":"Cells"},{"issue":"10","key":"e_1_2_11_9_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20102444","article-title":"The Enterochromaffin\u2010Like [ECL] Cell\u2010Central in Gastric Physiology and Pathology","volume":"20","author":"Waldum H. L.","year":"2019","journal-title":"International Journal of Molecular Sciences"},{"issue":"3","key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1530\/eje.1.01862","article-title":"Plasma Chromogranin A in Patients With Autoimmune Chronic Atrophic Gastritis, Enterochromaffin\u2010Like Cell Lesions and Gastric Carcinoids","volume":"152","author":"Peracchi M.","year":"2005","journal-title":"European Journal of Endocrinology"},{"issue":"1","key":"e_1_2_11_11_1","article-title":"Spurious Elevations of Chromogranin A in the Setting of Autoimmune Metaplastic Atrophic Gastritis","volume":"18","author":"Jose E.","year":"2026","journal-title":"Cureus"},{"issue":"6","key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/apt.13324","article-title":"Systematic Review: The Effects of Long\u2010Term Proton Pump Inhibitor Use on Serum Gastrin Levels and Gastric Histology","volume":"42","author":"Lundell L.","year":"2015","journal-title":"Alimentary Pharmacology & Therapeutics"},{"issue":"2","key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.5056\/jnm18001","article-title":"Advantages and Disadvantages of Long\u2010Term Proton Pump Inhibitor Use","volume":"24","author":"Kinoshita Y.","year":"2018","journal-title":"Journal of Neurogastroenterology and Motility"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","DOI":"10.1177\/1756284819834511","article-title":"Long\u2010Term Use of Proton\u2010Pump Inhibitors and Risk of Gastric Cancer: A Review of the Current Evidence","volume":"12","author":"Cheung K. 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T.","year":"2006","journal-title":"Basic & Clinical Pharmacology & Toxicology"},{"issue":"10","key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1136\/gut.33.10.1303","article-title":"Trophic Effect of Gastrin on the Enterochromaffin Like Cells of the Rat Stomach: Establishment of a Dose Response Relationship","volume":"33","author":"Brenna E.","year":"1992","journal-title":"Gut"},{"issue":"38","key":"e_1_2_11_29_1","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000035062","article-title":"Whether Long\u2010Term Use of Proton Pump Inhibitor Increases the Risk of Precancerous Lesions in the Stomach: A Systematic Review and Meta\u2010Analysis of Randomized Controlled Trials","volume":"102","author":"Lv F.","year":"2023","journal-title":"Medicine (Baltimore)"},{"issue":"15","key":"e_1_2_11_30_1","doi-asserted-by":"crossref","first-page":"4599","DOI":"10.3748\/wjg.v21.i15.4599","article-title":"Influence of Proton Pump Inhibitors on Gastritis Diagnosis and Pathologic Gastric Changes","volume":"21","author":"Nasser S. C.","year":"2015","journal-title":"World Journal of Gastroenterology"},{"key":"e_1_2_11_31_1","article-title":"Long\u2010Term Proton Pump Inhibitor (PPI) Use and the Development of Gastric Pre\u2010Malignant Lesions","volume":"12","author":"Song H.","year":"2014","journal-title":"Cochrane Database of Systematic Reviews"},{"issue":"4","key":"e_1_2_11_32_1","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/qjmed\/hcaf028","article-title":"Beyond Metaplasia: Unraveling the Complex Pathogenesis of Autoimmune Atrophic Gastritis and Its Implications for Gastric Cancer Risk","volume":"118","author":"Zhang T.","year":"2025","journal-title":"QJM"},{"issue":"4","key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.cgh.2026.01.007","article-title":"AGA Clinical Practice Update on Management of Gastric Polyps: Expert Review","volume":"24","author":"Buchner A. M.","year":"2026","journal-title":"Clinical Gastroenterology and Hepatology"},{"issue":"6","key":"e_1_2_11_34_1","article-title":"Gastric Polyps in Long\u2010Term Proton Pump Inhibitor Use: Identification of Risks and Characteristics","volume":"16","author":"Bouhairie M. M.","year":"2024","journal-title":"Cureus"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.dld.2024.07.024","article-title":"Occurrence and Characteristics of Endoscopic Gastric Polyps in Patients With Autoimmune Gastritis (AGAPE Study): A Multicentric Cross\u2010Sectional Study","volume":"57","author":"Massironi S.","year":"2024","journal-title":"Digestive and Liver Disease"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/j.dld.2023.02.008","article-title":"Exploring the Spectrum of Incidental Gastric Polyps in Autoimmune Gastritis","volume":"55","author":"Massironi S.","year":"2023","journal-title":"Digestive and Liver Disease"},{"key":"e_1_2_11_37_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1244400","article-title":"Long\u2010Term Proton Pump Inhibitors Use and Its Association With Premalignant Gastric Lesions: A Systematic Review and Meta\u2010Analysis","volume":"14","author":"Zheng Z.","year":"2023","journal-title":"Frontiers in Pharmacology"},{"issue":"1","key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3748\/wjg.15.1","article-title":"Importance of Gastrin in the Pathogenesis and Treatment of Gastric Tumors","volume":"15","author":"Burkitt M. D.","year":"2009","journal-title":"World Journal of Gastroenterology"},{"key":"e_1_2_11_39_1","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2020.00112","article-title":"Gastrin, Cholecystokinin, Signaling, and Biological Activities in Cellular Processes","volume":"11","author":"Zeng Q.","year":"2020","journal-title":"Frontiers in Endocrinology"},{"issue":"48","key":"e_1_2_11_40_1","article-title":"Unmasking the High\u2010Risk Phenotype in Autoimmune Gastritis: A Pathologist's Roadmap for the Clinician","volume":"31","author":"Wang C. L.","year":"2025","journal-title":"World Journal of Gastroenterology"},{"issue":"1","key":"e_1_2_11_41_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jcmgh.2017.03.004","article-title":"Gastrin and Gastric Cancer","volume":"4","author":"Smith J. P.","year":"2017","journal-title":"Cellular and Molecular Gastroenterology and Hepatology"},{"issue":"12","key":"e_1_2_11_42_1","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.2174\/156802607780960519","article-title":"Role of CCK\/Gastrin Receptors in Gastrointestinal\/Metabolic Diseases and Results of Human Studies Using Gastrin\/CCK Receptor Agonists\/Antagonists in These Diseases","volume":"7","author":"Berna M. 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