Scientific Background and Rationale Chronic atrophic gastritis (CAG) represents a critical precancerous lesion in the Correa cascade (chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → gastric adenocarcinoma). Despite its clinical importance, the relationship between histopathologically confirmed CAG and dyspeptic symptom profiles remains poorly characterized. Current clinical practice faces a diagnostic challenge: endoscopic features suggestive of atrophic gastritis correlate imperfectly with histopathological confirmation, and substantial symptom overlap exists between CAG and functional dyspepsia (FD), which accounts for over 80% of dyspeptic presentations.
Previous studies examining symptom profiles in CAG patients have yielded inconsistent results, with limited data using standardized pathological criteria (Updated Sydney System, OLGA staging) combined with validated symptom assessment tools. Additionally, the independent contributions of H. pylori infection, psychological comorbidities, sleep disturbances, and dietary patterns to dyspeptic symptoms in CAG remain incompletely understood.
This prospective observational study addresses these knowledge gaps by comparing symptom burden between pathologically confirmed CAG and non-CAG patients, while systematically evaluating multifactorial influences on symptom generation.
Study Design and Methodology
Patient Identification and Recruitment:
Patients will be recruited from the gastroenterology outpatient clinic and endoscopy unit at the Third Affiliated Hospital of Zhejiang Chinese Medical University. Potential participants include those with recent (≤1 year) endoscopic findings suggestive of atrophic gastritis, those undergoing CAG surveillance, and those presenting with new-onset dyspepsia requiring endoscopic evaluation. Based on estimated prevalence (approximately 25-30% of endoscopically suspected CAG cases show no atrophy histologically), screening 258-315 patients is projected to yield at least 80 pathologically confirmed non-CAG controls, providing \>80% power to detect a 15% between-group difference in FD symptom prevalence (α=0.05, two-sided).
Histopathological Classification:
All participants undergo standardized 5-point gastric mucosal biopsy following the Updated Sydney System: lesser curvature of antrum (2-3 cm from pylorus), greater curvature of antrum, lesser curvature of corpus, greater curvature of corpus, and incisura angularis. Specimens are evaluated by experienced gastrointestinal pathologists blinded to clinical and symptom data. Atrophy is graded using the Operative Link for Gastritis Assessment (OLGA) staging system. Patients are classified as CAG group (confirmed glandular atrophy in any biopsy site) or non-CAG group (no atrophic changes despite endoscopic suspicion).
Comprehensive Assessment Protocol:
Following informed consent, participants complete a single baseline assessment without longitudinal follow-up:
Symptom Quantification: The Gastrointestinal Symptom Scale (GOSS) measures dyspeptic symptoms on a 7-point Likert scale (0=absent, 6=very severe) over the preceding two weeks. Cardinal FD symptoms (epigastric pain, burning, early satiety, postprandial fullness) are analyzed individually and compositely. A score ≥4 on any cardinal symptom defines clinically significant FD symptoms.
Multifactorial Covariate Assessment:
H. pylori status: Serological testing (anti-H. pylori IgG); documentation of recent eradication therapy if applicable Dietary habits: Structured questionnaire assessing meal regularity, spicy/fried/cold food consumption, alcohol, smoking, tea/coffee intake Sleep quality: Pittsburgh Sleep Quality Index (PSQI; 19 items across 7 components; global score \>5 indicates poor sleep) Psychological status: Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS); 20 items each; index scores ≥50 indicate clinically significant symptoms Perceived stress: Visual analog scale (0-10)
Exploratory Metabolomics Substudy:
A subset of 60-80 participants (balanced across CAG/non-CAG and symptom presence/absence) provide fasting blood samples for serum metabolomics. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) in dual ionization modes enables non-targeted metabolite profiling. Metabolite identification utilizes HMDB, METLIN, and KEGG databases. Multivariate analyses (PCA, OPLS-DA) identify differentially abundant metabolites; pathway enrichment analysis explores biological mechanisms potentially linking metabolic alterations to symptom generation. Target metabolite classes include amino acids and derivatives (tryptophan, tyrosine, glutamate), organic acids, lipid species, bile acids, and neurotransmitter precursors implicated in brain-gut axis dysfunction.
Analytical Approach
Primary Analysis:
Between-group comparisons (CAG vs. non-CAG) for symptom prevalence (chi-square/Fisher's exact test) and severity scores (independent t-test/Mann-Whitney U test based on distribution). Effect sizes reported as odds ratios or mean differences with 95% confidence intervals.
Secondary Analyses:
Multivariable logistic regression identifying independent predictors of clinically significant FD symptoms, adjusting for age, sex, H. pylori status, BMI, psychological factors, sleep quality, and dietary habits Development of a symptom-based predictive model for pathological CAG using logistic regression with backward stepwise selection; model performance evaluated via AUC-ROC, calibration plots, and bootstrap internal validation Metabolomics analysis with false discovery rate correction for multiple comparisons; metabolites with VIP scores \>1.0 and adjusted p\<0.05 considered significant; correlation analyses between differential metabolites and symptom severity Data Management and Quality Assurance Data entry into secure electronic case report forms with built-in validation checks ensures accuracy. Quality control measures include: standardized staff training, regular monitoring of completeness/consistency, double data entry for critical variables, and periodic audits. Patient identifiers are replaced with unique study codes; only authorized personnel access the database.
Clinical and Scientific Significance This investigation will provide evidence-based insights into whether pathologically confirmed CAG associates with distinct symptom profiles compared to endoscopically suspected but histologically non-atrophic gastritis. Results may inform clinical decision-making regarding surveillance strategies, symptom management approaches, and patient counseling. The symptom-based predictive model may assist clinicians in estimating CAG probability using readily available clinical variables.
The exploratory metabolomics component may identify novel biomarkers and metabolic pathways underlying symptom generation, generating hypotheses for future mechanistic studies and potentially supporting development of non-invasive diagnostic tools or targeted therapeutic interventions.
Study duration: 24 months encompassing preparation, recruitment/data collection, and analysis/reporting phases.
