Gastrointestinal · PANCE / PANRE

Celiac Disease

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

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.

Try two board-style Celiac Disease questions

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Question 1GastrointestinalMedium
A 35-year-old woman has chronic diarrhea, steatorrhea, bloating, and weight loss. Anti-tissue transglutaminase (anti-tTG) IgA is markedly elevated at 1:1280. Duodenal biopsy shows villous atrophy and increased intraepithelial lymphocytes. Which of the following is the most likely diagnosis?
  • AWhipple's disease
  • BCrohn's disease
  • CTropical sprue
  • DCeliac disease
Reveal answer & full explanation
Correct answer: D — Celiac disease
  • AWhipple's disease
  • BCrohn's disease
  • CTropical sprue
  • DCeliac disease✓

Why Celiac disease is correct

  • A strongly positive anti-tissue transglutaminase (anti-tTG) IgA is the most sensitive and specific serology for celiac disease, an immune reaction to gluten in genetically predisposed (HLA-DQ2/DQ8) individuals
  • Duodenal biopsy showing villous atrophy with increased intraepithelial lymphocytes (Marsh III) confirms the diagnosis
  • The malabsorptive picture (chronic diarrhea, steatorrhea, and weight loss) fits, and treatment is a strict lifelong gluten-free diet

Why the others are wrong

  • Whipple's disease — causes malabsorption but with arthralgias and PAS-positive macrophages on biopsy, not villous atrophy with a positive anti-tTG (confused-with-malabsorption)
  • Crohn's disease — produces transmural, patchy inflammation rather than diffuse villous atrophy and is not associated with anti-tTG positivity (buzzword-matching on chronic diarrhea)
  • Tropical sprue — can cause villous atrophy and steatorrhea after travel to an endemic region, but it is anti-tTG negative and responds to antibiotics and folate (confused-with-villous-atrophy)
Question 2GastrointestinalMedium
A 40-year-old man with newly biopsy-confirmed celiac disease is started on a gluten-free diet. He reports several months of fatigue. Which of the following is the most important additional step to take at the time of diagnosis?
  • AObtain HLA-DQ2/DQ8 genotyping
  • BScreen for nutritional deficiencies
  • CInitiate systemic corticosteroids
  • DRepeat small bowel biopsy at 1 month
Reveal answer & full explanation
Correct answer: B — Screen for nutritional deficiencies
  • AObtain HLA-DQ2/DQ8 genotyping
  • BScreen for nutritional deficiencies✓
  • CInitiate systemic corticosteroids
  • DRepeat small bowel biopsy at 1 month

Why Screen for nutritional deficiencies is correct

  • Celiac disease damages the proximal small bowel, where iron, folate, calcium, and fat-soluble vitamins are absorbed, so newly diagnosed patients should be screened for deficiencies at diagnosis
  • Iron-deficiency anemia is the most common finding and explains this patient's fatigue; folate, vitamin B12, vitamin D, zinc, and copper should also be checked, and a baseline DEXA scan is recommended because malabsorption predisposes to osteoporosis
  • Screening for and replacing deficiencies at diagnosis, alongside the gluten-free diet, is consistent with current ACG guidance and is what reverses the systemic consequences of malabsorption

Why the others are wrong

  • Obtain HLA-DQ2/DQ8 genotyping — HLA typing is used to exclude celiac disease when the diagnosis is uncertain or when a patient is already gluten-free; it adds nothing once biopsy has confirmed disease and does nothing for his malabsorption (buzzword-matching celiac to its genetic marker)
  • Initiate systemic corticosteroids — Steroids are reserved for refractory celiac disease or celiac crisis, not initial management, which is dietary gluten withdrawal (right-disease-wrong-treatment)
  • Repeat small bowel biopsy at 1 month — Mucosal healing takes months to years; response is monitored with anti-tissue transglutaminase IgA at 6-12 months, so a 1-month rebiopsy is premature and low-yield (premature closure on early re-testing)
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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 StageHistologic FindingSignificance
0NormalPre-infiltrative; HLA-positive may be at risk
IIntraepithelial lymphocytosis (>25 IELs per 100 enterocytes)Infiltrative; supports celiac with positive serology
IIIEL + crypt hyperplasia, normal villiHyperplastic; supports celiac
IIIVillous atrophy + IEL + crypt hyperplasia (a: partial, b: subtotal, c: total)Destructive; classic celiac
IVTotal atrophy + crypt hypoplasiaHypoplastic; 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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Commonly confused with

vs Irritable Bowel Syndrome

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