Beyond metaplasia: unraveling the complex pathogenesis of autoimmune atrophic gastritis and its implications for gastric cancer risk.

Abstract

Autoimmune gastritis (AIG) is a chronic inflammatory condition characterized by immune-mediated destruction of gastric parietal cells, leading to oxyntic atrophy, achlorhydria and hypergastrinemia. While AIG was historically linked to gastric adenocarcinoma and type I neuroendocrine tumors (NETs), recent evidence suggests the risk of adenocarcinoma in AIG is lower than previously believed, particularly in Helicobacter pylori (H. pylori)-negative patients. The increased cancer risk in AIG is mainly attributed to concurrent or past H. pylori infection. The incidence of gastric adenocarcinoma in AIG ranges from 0.12% to 0.5% per year, with cumulative risks over 10 years reported at 1-3%. In contrast, type I NETs are more commonly associated with AIG, with an annual incidence of 0.68-2.8% and cumulative rates as high as 15.3% over 5 years. Adenomatous polyps, which can progress to malignancy, have been reported in 4.6-13.6% of AIG patients. This review examines the immune and molecular mechanisms underlying AIG's pathogenesis, positioning it as a model of immune-mediated epithelial injury with limited carcinogenic potential. AIG is associated with reparative metaplastic phenotypes, such as pseudopyloric and complete intestinal metaplasia, which contrast with the more aggressive incomplete intestinal metaplasia observed in H. pylori-induced gastritis. The reduced risk of adenocarcinoma in AIG is attributed to the absence of H. pylori, a T cell-dominated microenvironment, minimal macrophage infiltration and protective factors such as altered gastric microbiota, epigenetic modifications, increased CD3+ intraepithelial cytotoxic T lymphocytes and reduced interleukin-33/interleukin-13 signaling. Although AIG is linked to preneoplastic changes, its primary neoplastic risks include the development of type I NETs and adenomatous polyps, which carry a potential for malignant transformation, necessitating long-term surveillance in patients with hypergastrinemia, extensive atrophy and associated gastric lesions. Challenges persist in distinguishing AIG from other atrophic gastritis types due to limitations in serological and histological markers, but emerging diagnostic tools, such as lymphocyte profiling and molecular assays, promise improved accuracy. This review underscores the importance of tailored surveillance and management strategies to address the distinct neoplastic risks associated with AIG, while advocating for further research into its immune landscape and molecular pathways.