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 more than 10 times the upper limit of normal. Duodenal biopsy shows villous atrophy and increased intraepithelial lymphocytes. Which of the following is the most likely diagnosis?
AChronic giardiasis
BWhipple's disease
CCeliac disease
DTropical sprue
ECrohn's disease
Reveal answer & full explanation
Correct answer: C — Celiac disease
AChronic giardiasis
BWhipple's disease
CCeliac disease✓
DTropical sprue
ECrohn's 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)
Chronic giardiasis — Giardia lamblia can blunt duodenal villi and cause steatorrhea, bloating, and weight loss, but it does not produce a markedly elevated anti-tTG IgA; stool antigen testing or trophozoites on duodenal biopsy make that diagnosis (confused-with-infectious-villous-blunting)
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?
ARepeat small bowel biopsy at 1 month
BObtain HLA-DQ2/DQ8 genotyping
CScreen for nutritional deficiencies
DEvaluate for intestinal lymphoma
EInitiate systemic corticosteroids
Reveal answer & full explanation
Correct answer: C — Screen for nutritional deficiencies
ARepeat small bowel biopsy at 1 month
BObtain HLA-DQ2/DQ8 genotyping
CScreen for nutritional deficiencies✓
DEvaluate for intestinal lymphoma
EInitiate systemic corticosteroids
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)
Evaluate for intestinal lymphoma — enteropathy-associated T-cell lymphoma is a recognized complication of celiac disease, and fatigue can raise concern for malignancy, but lymphoma is pursued when symptoms persist or alarm features such as new weight loss, fever, or abdominal pain develop despite strict gluten avoidance, not screened for routinely at diagnosis; his fatigue is far more likely to reflect iron deficiency (anchoring on a rare complication)
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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
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 2020): non-biopsy diagnosis allowed if tTG IgA ≥10× ULN (with normal total IgA) + positive EMA IgA on a second blood sample; HLA typing and symptoms are no longer required.
Total IgA — to identify IgA deficiency (~10-15× more common in celiac; present in 2-3% of patients); 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)
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
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
ALWAYS check total IgA when sending tTG IgA — IgA deficiency is ~10-15× more common in celiac (2-3% of patients) 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 on a second sample (ESPGHAN 2020; HLA typing not required).
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.
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