Celiac disease is an autoimmune condition in which dietary gluten (the storage protein in wheat, barley, and rye) triggers an immune response in genetically susceptible individuals that damages the small intestinal lining. Unlike food allergy (IgE-mediated, immediate) or non-celiac gluten sensitivity (mechanism unclear, no intestinal damage), celiac disease has a specific and reproducible mechanism: gliadin peptides (a gluten component) that are resistant to digestive proteolysis cross the intestinal epithelium, are deamidated by tissue transglutaminase 2 (tTG2), and bind to HLA-DQ2 or DQ8 molecules on antigen-presenting cells, activating CD4+ T cells that drive both the adaptive immune response and the production of the anti-tTG2 antibodies used for diagnosis.
The result is progressive villous atrophy — flattening of the finger-like villi of the small intestinal lining that are responsible for the vast majority of nutrient absorption. A healthy small intestine with normal villi has the absorptive surface area of a tennis court (~250m²); in untreated celiac with complete villous atrophy, this is reduced to the area of a table (~2m²). This explains why celiac produces malabsorption of virtually everything — iron, calcium, folate, vitamin D, B12, zinc, fat-soluble vitamins — and why presentations can include anemia, osteoporosis, peripheral neuropathy, infertility, and dermatitis herpetiformis rather than obvious diarrhea.
| Condition | Mechanism | Diagnosis | Intestinal Damage | Treatment |
|---|---|---|---|---|
| Celiac disease | Autoimmune — T-cell mediated, anti-tTG2 antibodies, HLA-DQ2/DQ8 required | tTG-IgA serology + duodenal biopsy (Marsh ≥2) | Yes — villous atrophy (Marsh 3) | Strict lifelong gluten-free diet; even trace amounts cause ongoing damage |
| Non-celiac gluten sensitivity (NCGS) | Unclear — possible innate immune activation; no tTG2 antibodies; no HLA requirement; possible FODMAP overlap (fructans in wheat) | Diagnosis of exclusion: negative celiac serology + normal biopsy + symptom response to GFD | No villous atrophy; possible mild intraepithelial lymphocytosis | Gluten-free or low-gluten diet; tolerance varies; cross-contamination threshold higher than celiac |
| Wheat allergy | IgE-mediated — immediate hypersensitivity to wheat proteins (not specifically gluten) | Skin prick test, specific IgE (ImmunoCAP), oral food challenge | No villous atrophy; mucosal mast cell activation | Wheat avoidance; some can tolerate barley/rye; may be outgrown in childhood; EpiPen for anaphylaxis risk |
Step 1 — Serology: Anti-tissue transglutaminase IgA (tTG-IgA) is the first-line screening test with sensitivity ~95% and specificity ~98% for celiac disease. Total IgA must also be measured — approximately 2–3% of celiac patients have IgA deficiency, in which case tTG-IgA is falsely negative and IgG-based tests (tTG-IgG or deamidated gliadin peptide IgG, DGP-IgG) must be used instead.
Critical requirement: do not go gluten-free before testing. The tTG-IgA will normalize on a gluten-free diet within weeks to months, producing false-negative results. Many people self-diagnose, start a GFD, feel better, then present for testing with negative serology — making diagnosis impossible without a gluten challenge (6–8 weeks of gluten reintroduction). If you suspect celiac, get tested first.
Step 2 — Duodenal biopsy: Positive serology must be confirmed by endoscopy with multiple duodenal biopsies (≥4 from the second/third duodenum). The Marsh classification grades the degree of damage: Marsh 1 (increased intraepithelial lymphocytes only), Marsh 2 (crypt hyperplasia added), Marsh 3a/b/c (partial to total villous atrophy). A diagnosis of celiac disease requires at least Marsh 2 on biopsy. Marsh 3 with positive serology is the classic presentation.
HLA testing: HLA-DQ2/DQ8 testing has a very high negative predictive value — if negative, celiac disease is effectively ruled out. Useful for: screening first-degree relatives, resolving diagnostic uncertainty in patients already on GFD, or testing asymptomatic at-risk individuals.
For celiac disease, the GFD is not a dietary preference — it is medical treatment. The threshold for gluten that triggers intestinal damage in celiac is approximately 10mg/day (about 1/70th of a slice of bread). Cross-contamination from shared cooking surfaces, toasters, fryers, pasta water, and serving utensils is sufficient to cause ongoing mucosal damage — even in the absence of symptoms. Asymptomatic celiac patients (a significant minority) can have ongoing villous atrophy despite feeling well; symptoms are not a reliable guide to mucosal healing.
Healing timeline: on a strict GFD, tTG-IgA antibodies typically normalize within 6–12 months. Duodenal villous architecture normalizes within 1–2 years in most patients (slower in adults than children). Follow-up biopsy at 12–24 months confirms mucosal healing. Persistent villous atrophy despite strict GFD = non-responsive celiac — requires evaluation for refractory celiac disease (RCD), inadvertent gluten exposure, or alternative diagnoses.
Oats: Pure, uncontaminated oats are tolerated by approximately 95% of celiac patients — the oat protein (avenin) is not a significant trigger for most; the problem is cross-contamination during growing and processing. "Certified gluten-free oats" are grown and processed to avoid contamination and are safe for most celiac patients. Regular oats (even from oat-only facilities) carry cross-contamination risk and should be avoided initially.
Nutritional deficiency screening: At diagnosis, check iron (CBC + ferritin), folate, vitamin B12, vitamin D, calcium, zinc, and copper. Villous atrophy selectively impairs absorption of all of these. Correct identified deficiencies with supplements — the GFD will improve absorption over time, but deficiencies often require direct repletion.
Bone density: DEXA scan at diagnosis — celiac-related calcium and vitamin D malabsorption often produces osteopenia or osteoporosis even in young adults. Vitamin D + calcium supplementation is typically required during the healing phase.
Dietitian referral: Essential at diagnosis. A celiac-experienced dietitian provides GFD education, cross-contamination guidance, label reading (gluten hides in many unexpected foods: soy sauce, malt vinegar, modified food starch, communion wafers, medications), and ongoing support.
First-degree relative screening: Siblings and parents of celiac patients have a 10% risk of celiac disease (vs 1% general population). All first-degree relatives should be tested with tTG-IgA + total IgA, and HLA testing if negative serology but ongoing concern.
Annual follow-up: Annual tTG-IgA to confirm adherence and monitor healing. Annual nutritional panel (same deficiency screen as at diagnosis). Symptoms alone are insufficient to monitor — many patients have ongoing damage without symptoms.
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