Celiac Disease
Immune-mediated small bowel injury triggered by dietary gluten in genetically susceptible (HLA-DQ2/DQ8) individuals.
Also known as: celiac disease, celiac sprue, gluten-sensitive enteropathy
Overview
Chronic, immune-mediated enteropathy of the small intestine triggered by dietary gluten (wheat, rye, barley) in genetically susceptible individuals (HLA-DQ2 or HLA-DQ8). Characterized by villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis, with resolution on a gluten-free diet.
Epidemiology
Prevalence ~1% in Western populations; female predominance (~2:1). Often underdiagnosed. Bimodal age distribution — childhood and 4th-6th decades.
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Risk factors
- HLA-DQ2 (95%) or HLA-DQ8 — necessary but not sufficient
- First-degree relative with celiac (10-15% risk)
- Type 1 diabetes (~5% prevalence)
- Autoimmune thyroid disease
- Down syndrome, Turner syndrome, Williams syndrome
- Selective IgA deficiency
- Microscopic colitis
- Autoimmune liver disease (PBC, AIH)
- Dermatitis herpetiformis
Pathophysiology
Gluten peptides (particularly gliadin) are deamidated by tissue transglutaminase (tTG) in the lamina propria. Modified peptides bind HLA-DQ2/DQ8 on antigen-presenting cells, activating CD4+ T cells and triggering Th1-driven inflammation. Intraepithelial CD8+ lymphocytes mediate enterocyte injury, leading to villous atrophy. B-cell response produces anti-tTG, anti-endomysial, and anti-deamidated gliadin antibodies.
Clinical presentation
Symptoms
- Classic/GI: chronic diarrhea, steatorrhea, abdominal pain, bloating, flatulence, weight loss
- Non-classic/atypical: iron-deficiency anemia (most common adult presentation), osteoporosis, infertility, recurrent miscarriage, neurologic symptoms (peripheral neuropathy, ataxia), elevated transaminases, depression
- Silent: detected on screening (family member with celiac, type 1 diabetes); minimal/no symptoms
- Dermatitis herpetiformis — intensely pruritic vesicular rash on extensor surfaces (elbows, knees, buttocks); pathognomonic skin manifestation
- Children: failure to thrive, short stature, delayed puberty, dental enamel defects, irritability
Signs / physical exam
- Pallor (iron-deficiency anemia)
- Glossitis, angular stomatitis
- Dermatitis herpetiformis (papulovesicular eruption on extensor surfaces)
- Aphthous ulcers
- Abdominal distension
- Signs of malabsorption: bruising (vitamin K), osteomalacia (vitamin D), edema (hypoalbuminemia)
- Cerebellar ataxia, peripheral neuropathy
- Failure to thrive in children
Classic findings
Iron-deficiency anemia or osteoporosis in an adult without obvious cause — test for celiac disease.
Differential diagnosis
- Non-celiac gluten sensitivity — Symptoms with gluten but negative serology and normal biopsy on gluten-containing diet
- Wheat allergy — IgE-mediated; positive skin prick or specific IgE; rapid symptom onset
- Irritable bowel syndrome — Bloating, pain, altered bowel habits without serology positivity or villous atrophy
- Tropical sprue — Tropical residence, B12 and folate deficiency, responds to antibiotics
- Common variable immunodeficiency — Recurrent infections, low immunoglobulins, lymphoid hyperplasia of small bowel
- Autoimmune enteropathy — Refractory diarrhea in adults; anti-enterocyte antibodies
- Eosinophilic gastroenteritis — Eosinophilic infiltrate on biopsy; peripheral eosinophilia common
- Microscopic colitis — Chronic watery diarrhea; biopsy of normal-appearing colon
- Whipple disease — Tropheryma whipplei; PAS-positive macrophages; arthralgias, weight loss, lymphadenopathy
- Lactose intolerance — Symptoms with dairy; positive breath test; normal serology
- Refractory celiac disease (type I/II) — Persistent villous atrophy despite strict GFD; type II precedes enteropathy-associated T-cell lymphoma
Diagnostic workup
Diagnostic criteria
Adults: positive serology (tTG IgA with normal total IgA, or EMA, or DGP) + duodenal biopsy showing Marsh II-IV changes on a gluten-containing diet + clinical response to GFD. Children: ESPGHAN allows non-biopsy diagnosis if tTG IgA >10× ULN + positive EMA on separate sample + HLA-DQ2/DQ8.
Labs
- Anti-tissue transglutaminase IgA (tTG IgA) — first-line; sensitivity 95%, specificity 95%
- Total IgA — to identify IgA deficiency (3-5× more common in celiac); if low, use IgG-based assays (tTG IgG or deamidated gliadin peptide IgG)
- Anti-endomysial IgA (EMA) — high specificity (~100%); confirmatory
- Anti-deamidated gliadin peptide (DGP) IgG — useful in IgA deficiency or children <2 yr
- MUST be on gluten-containing diet for accurate serology (≥3 g gluten/day × 6+ weeks)
- HLA-DQ2/DQ8 — high NPV; negative result essentially rules out celiac; positive does not confirm (30% of population carries)
- CBC, iron studies, ferritin, B12, folate, vitamin D, calcium, alk phos
- LFTs (transaminitis in ~30%)
- TSH (autoimmune thyroid screen)
- DEXA scan for osteoporosis
Imaging
- Upper endoscopy with multiple duodenal biopsies — REQUIRED for diagnosis in adults: 1-2 from bulb + ≥4 from second/third portion; findings: scalloping of folds, mosaic pattern, decreased folds
- Histology: increased intraepithelial lymphocytes (>25 per 100 enterocytes), crypt hyperplasia, villous atrophy (Marsh classification 0-IV)
- Video capsule endoscopy or small bowel imaging — assess complications (refractory disease, lymphoma, ulcerative jejunitis)
Diagnostic algorithm
| Marsh Stage | Histologic Finding | Significance |
|---|---|---|
| 0 | Normal | Pre-infiltrative; HLA-positive may be at risk |
| I | Intraepithelial lymphocytosis (>25 IELs per 100 enterocytes) | Infiltrative; supports celiac with positive serology |
| II | IEL + crypt hyperplasia, normal villi | Hyperplastic; supports celiac |
| III | Villous atrophy + IEL + crypt hyperplasia (a: partial, b: subtotal, c: total) | Destructive; classic celiac |
| IV | Total atrophy + crypt hypoplasia | Hypoplastic; refractory disease, may herald lymphoma |
Treatment
First-line
- STRICT LIFELONG GLUTEN-FREE DIET — only proven treatment
- Avoid wheat, rye, barley, malt; oats often tolerated (must be uncontaminated)
- Referral to registered dietitian experienced in celiac disease
- Treat nutritional deficiencies: iron, B12, folate, vitamin D, calcium, zinc
- DEXA scan at diagnosis; supplement vitamin D and calcium
- Vaccinate against pneumococcal disease (functional hyposplenism risk)
- Family screening — first-degree relatives via tTG IgA
- Monitor: tTG IgA every 6-12 months (should normalize within 1-2 yr on GFD); repeat biopsy at 1-2 yr if symptoms persist or serology remains positive
- Treat dermatitis herpetiformis with dapsone (rapid symptom relief) + strict GFD (treats underlying disease)
Second-line / adjunct
- Refractory celiac disease type I (persistent symptoms and atrophy without aberrant lymphocyte clone): rule out gluten contamination, address comorbidities (microscopic colitis, lactose intolerance, IBS overlap); consider budesonide or immunosuppression
- Refractory celiac disease type II (clonal expansion of aberrant intraepithelial lymphocytes): risk of enteropathy-associated T-cell lymphoma; specialty center management; consider cladribine, autologous stem cell transplant
- Emerging therapies in trials: gluten-degrading enzymes (latiglutenase), zonulin antagonists (larazotide), tTG inhibitors, immune-modulating peptides (Nexvax2 — discontinued)
Complications
- Iron-deficiency anemia, megaloblastic anemia (B12, folate)
- Osteoporosis, osteomalacia, fractures
- Infertility, recurrent miscarriage
- Short stature in children
- Hyposplenism (functional)
- Neurologic: peripheral neuropathy, gluten ataxia
- Enteropathy-associated T-cell lymphoma (EATL) — rare; risk in refractory disease type II
- Small bowel adenocarcinoma
- Refractory celiac disease
- Increased risk of autoimmune conditions (type 1 diabetes, thyroid disease, Addison, autoimmune hepatitis)
- Dermatitis herpetiformis
PANCE pearls
- ALWAYS check total IgA when sending tTG IgA — IgA deficiency is 3-5× more common in celiac and causes false-negative serology.
- Patients must be on a gluten-containing diet (≥3 g/day × 6+ weeks) for accurate serology and biopsy — discourage empiric GFD before testing.
- Adult diagnosis requires duodenal biopsy in addition to serology — children may avoid biopsy if tTG IgA >10× ULN + positive EMA + HLA-DQ2/DQ8 (ESPGHAN criteria).
- Take 4-6 biopsies including duodenal bulb — patchy disease may be missed otherwise.
- HLA-DQ2/DQ8 negative essentially rules out celiac disease (high NPV).
- Iron-deficiency anemia in an adult without obvious source — screen for celiac.
- Dermatitis herpetiformis is pathognomonic — pruritic vesicles on extensor surfaces; biopsy shows granular IgA deposits.
- Strict lifelong gluten-free diet is the ONLY proven treatment — cross-contamination matters; even small amounts can perpetuate disease.
- Pneumococcal vaccination recommended due to functional hyposplenism in celiac.
- Persistent symptoms on GFD: ongoing gluten exposure (most common), refractory disease, lactose intolerance, microscopic colitis, IBS overlap, complications.
- Refractory celiac type II — clonal IEL expansion — high lymphoma risk; refer to specialty center.
- Non-celiac gluten sensitivity is real but serologically and histologically negative.
References
- ACG 2023 — Rubio-Tapia A et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol 2023;118:59-76
- AGA 2019 — Husby S et al. AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease. Gastroenterology 2019;156:885-889
- ESPGHAN 2020 — Husby S et al. ESPGHAN Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr 2020;70:141-156
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