Clin Chem. 2023 Oct 3;69(10):1114-1131. doi: 10.1093/clinchem/hvad082.
Figure 1. Pathophysiology of serum biomarkers in AAG. Under normal conditions, the parietal cells of the corpus oxyntic mucosa produce chlorhydric acid and intrinsic factors, while the chief cells of the corpus mucosa produce pepsinogen I, and those of the antral mucosa produce pepsinogen I and II. Among others, the antrum also harbors specialized endocrine G cells that regulate gastric acid secretion. Autoantibodies are usually not produced. In AAG, the specialized cells of the gastric corpus mucosa are heavily damaged due to autoimmune destruction with the production of autoantibodies against parietal cells and intrinsic factors. Atrophy of the parietal cells leads to hypochlorhydria and reduced secretion of intrinsic factors with consequent iron and cobalamin deficiency and gastric dysbiosis. Atrophy of the corpus mucosa chief cells leads to low pepsinogen I levels and a low PGI/II ratio. By contrast, reduced gastric acid secretion acts as a stimulator for antral G cells, resulting in hypergastrinemia.
Table 1. Serum preendoscopic assessment of AAG by autoantibodies against parietal cells (PCA): diagnostic assays, types of analytical method, and performance.
Table 2. Serum preendoscopic assessment of AAG by autoantibodies against intrinsic factor (IFA): diagnostic assays, types of analytical method, and performance.
Table 3. Serum preendoscopic assessment of AAG by biomarkers of corpus atrophy: gastrin and pepsinogen: diagnostic assays, types of analytical method, and performance.
Figure 2. Proposal for a diagnostic algorithm in patients with clinical suspicion for AAG. In patients with a high level of clinical suspicion of AAG, such as those presenting with cobalamin deficiency with or without anemia, not-otherwise explained iron-deficiency anemia, long-standing dyspepsia, or family history of gastric cancer, gastroscopy with antral and corporal biopsies for histopathological assessment is indicated, and serum assessment may be performed to complete diagnosis. In patients with a lower level of clinical suspicion for autoimmune atrophic gastritis, such as patients presenting with recent or intermittent dyspepsia, autoimmune comorbidities (autoimmune thyroid disease, type 1 diabetes, vitiligo) or family history for AAG, serum preendoscopic assessment by using biomarkers of gastric autoimmunity, such as parietal cell autoantibodies, and, when available, intrinsic factor autoantibodies should be performed. The diagnostic performance of these autoantibodies can be improved by using biomarkers of corpus atrophy, such as gastrin or pepsinogen I, II, and their ratio, when patients are on PPIs or are positive for Helicobacter pylori infection. Patients who are positive for one of these biomarkers should be sent to gastroscopy with biopsies to confirm the presence of AAG
Figure 3. Model for possible changes of biomarkers of gastric autoimmunity and gastric corpus atrophy over time. Biomarkers of gastric autoimmunity might be viewed as complementary to those of gastric atrophic damage. The first ones, autoantibodies against parietal cells and intrinsic factor, initially increase in parallel with the increase in gastric oxyntic mucosa damage and presentation of the autoantigen identified as H+-K+-ATPase and intrinsic factor, but at a certain point of the natural history, they start to decrease, likely due to the exhaustion of the autoantigen as a consequence of the progression of gastric corpus atrophy. In contrast, due to impaired gastric acid secretion and the loss of corpus zymogenic cells, gastrin levels increase and pepsinogen levels decrease over time with increasing severity of atrophic damage.
BACKGROUND: Autoimmune atrophic gastritis (AAG) is a persistent, corpus-restricted immune-mediated destruction of the gastric corpus oxyntic mucosa with reduced gastric acid and intrinsic factor secretion, leading to iron deficiency and pernicious anemia as a consequence of iron and cobalamin malabsorption. Positivity toward parietal cell (PCA) and intrinsic factor (IFA) autoantibodies is very common. AAG may remain asymptomatic for many years, thus making its diagnosis complex and often delayed. Due to the increased risk of gastric neoplasms, a timely diagnosis of AAG is clinically important.
CONTENT: The gold standard for AAG diagnosis is histopathological assessment of gastric biopsies obtained during gastroscopy, but noninvasive, preendoscopic serological screening may be useful in some clinical scenarios. Serum biomarkers for AAG may be divided into 2 groups: gastric autoimmunity-related biomarkers, such as PCA and IFA, and gastric corpus atrophy/reduced gastric acid secretion-related biomarkers, such as serum gastrin and pepsinogens. The present review focuses on the clinical significance and pitfalls of serum biomarkers related to gastric autoimmunity and gastric corpus atrophy, including some discussion of analytical methods.
SUMMARY: Serum assays for PCA, IFA, gastrin, and pepsinogen I show good diagnostic accuracy for noninvasive diagnostic work-up of AAG. Diagnostic performance may increase by combining >1 of these tests, overcoming the problem of seronegative AAG. However, appropriately designed, comparative studies with well-characterized patient cohorts are needed to better define the reliability of these biomarkers in the diagnosis of patients with AAG. Currently, positive serum tests should always be followed by the state-of-art diagnostic test, that is, histopathological assessment of gastric biopsies obtained during gastroscopy to definitively confirm or rule out AAG and eventually neoplastic complications.
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