Celiac Disease: Diagnostic Advances, Differential Challenges, and Interface with Non-Celiac Gluten Sensitivity

Celiac disease (CeD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals, with a heterogeneous clinical spectrum spanning classical gastrointestinal symptoms, extraintestinal manifestations, and subclinical forms. We synthesize contemporary epidemiology, immunopathogenesis, and the updated 2025 European Society for the Study of Coeliac Disease diagnostic framework. Adaptive responses to deamidated gliadin peptides presented by human leukocyte antigen (HLA)-DQ2/DQ8, together with interleukin-15-driven activation of intraepithelial lymphocytes (IELs), culminate in villous atrophy, crypt hyperplasia, and increased IELs. Serology centered on tissue transglutaminase immunoglobulin A (tTG-IgA) with total immunoglobulin A assessment remains first-line, complemented by standardized duodenal sampling (≥4 distal + 2 bulb biopsies) and selective HLA typing. The guidelines conditionally endorse a no-biopsy pathway for adults <45 years with tTG-IgA ≥10× upper limit of normal confirmed on a second sample, emphasizing shared decision-making and exclusion of red flags. We delineate differential diagnoses (tropical sprue, Crohn’s disease, common variable immunodeficiency, small intestinal bacterial overgrowth) and contrast CeD with non-celiac gluten sensitivity, which lacks villous atrophy, disease-specific serology, and HLA association. Emerging tools (immunohistochemistry, CD3/CD8/γδ IELs, video capsule endoscopy, confocal laser endomicroscopy) and the limitations of salivary/fecal assays are reviewed. Early detection improves quality of life and reduces healthcare utilization. Future directions include artificial intelligence-assisted imaging, molecular immunophenotyping, and non-dietary therapeutics.