Clinical and Molecular Signatures of Gallbladder Lesions: Insights into Metabolic and Inflammatory Pathways

Background: Gallbladder carcinoma (GBC) represents one of the most aggressive malignancies of the hepatobiliary system, evolving along a continuum from chronic inflammation to preneoplastic lesions and invasive cancer. This progression is frequently associated with gallstones and chronic cholecystitis and shares common pathogenic mechanisms with systemic inflammatory and metabolic disorders. Despite its relatively low incidence, GBC is characterized by poor prognosis, largely due to late-stage diagnosis and limited understanding of its molecular underpinnings. Methods: We conducted an observational study including 60 adult patients with radiologically suspected gallbladder cancer (GBC). Patients with disseminated disease, ongoing oncologic treatment, or synchronous malignancies were excluded. Fasting venous blood samples were collected to evaluate tumor markers and biochemical parameters, including carcinoembryonic antigen (CEA) and carbohydrate antigen CA 19-9. Surgical specimens were analyzed histopathologically and staged according to the European Society for Medical Oncology TNM classification system. Statistical analysis was performed using SPSS software (version 26.0), with appropriate parametric or non-parametric tests applied based on data distribution, and a p-value < 0.05 considered statistically significant. Results: Based on histological findings, patients were stratified into benign gallbladder disease (GBD) and GBC groups. CA 19-9 demonstrated higher mean serum levels with lower variability compared to CEA, suggesting superior sensitivity and diagnostic stability for gallbladder adenocarcinoma. In contrast, CEA levels exhibited greater fluctuation, limiting its reliability as a standalone biomarker. Importantly, the combined use of CA 19-9 and CEA improved diagnostic accuracy, supporting a multimarker approach for better clinical stratification. Our findings highlight the diagnostic value of CA 19-9 as a robust biomarker in GBC and support the integration of combined biomarker panels. Beyond tumor markers, the study identified a strong interplay between systemic inflammation and metabolic comorbidities, with obesity and hypertension significantly associated with chronic gallbladder pathology, and diabetes mellitus contributing to increased risk of acute inflammatory episodes. Elevated inflammatory markers, leukocytosis, and cholestatic enzyme alterations further supported the presence of a systemic inflammatory milieu. Multivariate analysis revealed that C-reactive protein (CRP), as a marker of systemic inflammation, was significantly influenced by a combination of clinical and biochemical variables, including age, hemoglobin, hypertension, amylase, CA 19-9, and CEA, explaining over 50% of its variability and up to 85% in advanced fibrotic changes. Additionally, platelet counts were significantly reduced in adenocarcinoma and correlated specifically with CA 19-9 levels, suggesting a potential link between tumor burden, inflammation, and platelet dynamics. Conclusions: Therefore, the observed associations between chronic inflammation, metabolic dysregulation, and tumor marker expression suggest a potential link between gallbladder carcinogenesis and systemic cardiometabolic pathways, opening new perspectives for early detection and targeted therapeutic strategies.