Gastrointestinal · PANCE / PANRE

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

Modified Marsh classification of duodenal histology in celiac disease.

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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