Celiac disease built from mechanism through monitoring: modified gluten peptides bind HLA-DQ2/DQ8, drive T-cell inflammation, and trigger lymphocyte-mediated villous atrophy. The modern adult presents like IBS, iron deficiency, or an extraintestinal finding, so the threshold to test is broad. Diagnosis is serology-anchored and biopsy-confirmed while the patient still eats gluten, treated by a strict lifelong gluten-free diet with structured monitoring. Topics covered Pathogenesis and HLA-DQ2/DQ8 Extraintestinal and IBS-like presentations Silent, potential, and seronegative phenotypes Dermatitis herpetiformis tTG-IgA serology and total IgA Duodenal biopsy and Marsh classification Gluten-free diet and nutritional repletion Serologic and histologic monitoring Key decisions Order tTG-IgA plus a total IgA as first-line serology while the patient is still eating gluten; pivot to deamidated gliadin peptide IgG if IgA deficient. Use HLA-DQ2/DQ8 to exclude, never to confirm; it is not part of the initial algorithm. Confirm with at least four distal duodenal biopsies plus one or two bulb biopsies, since a minority have bulb-only atrophy. No-biopsy adult diagnosis needs tTG greater than 10x upper limit plus a positive endomysial antibody on a second sample, but biopsy remains the adult default. A persistently positive antibody after one year means ongoing gluten exposure and prompts a dietitian re-evaluation, not a refractory workup. Confirm mucosal healing with a repeat duodenal biopsy at about two years, because negative serology can dissociate from persistent atrophy. For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - Mechanism: gluten to villous atrophy (00:00) - Monitoring and confirming mucosal healing (01:22) - HLA as an exclusion tool (01:58) - Epidemiology and autoimmune comorbidity (02:42) - Modern presentations: IBS and iron deficiency (04:14) - Phenotypes and dermatitis herpetiformis (05:55) - Serology-anchored, biopsy-confirmed diagnosis (13:22) - Treatment: gluten-free diet and repletion

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