Celiac disease

Etiology

• Genetic predisposition with association to HLA antigens
  • HLA-DQ2 in 90–95% of patients
  • HLA-DQ8 in 5–10% of patients
• Consuming gliadin from grains such as wheat, rye, and barley leads to an autoimmune reaction within the small intestinal wall.

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Pathophysiology

• Trigger: Ingestion of gluten (protein in wheat, barley, rye). Its component, gliadin, is the primary immunogenic particle.
• Key Immune Steps:
  1. tTG Activity: Gliadin peptides are deamidated by tissue transglutaminase (tTG) in the lamina propria.
  2. Antigen Presentation: APCs (Antigen Presenting Cells) present deamidated gliadin to CD4⁺ T-cells via HLA-DQ2/DQ8.
  3. Inflammation: Activated T-cells release inflammatory cytokines (e.g., IFN-γ), leading to tissue damage.
  4. Antibody Production: B-cells are stimulated to produce characteristic autoantibodies: Anti-tTG (IgA), Anti-endomysial (IgA), and Anti-DGP.
• Histologic Damage: Chronic inflammation causes classic findings in the small bowel (duodenum/jejunum).
  • Villous atrophy: Blunting of villi leads to malabsorption.
  • Crypt hyperplasia: Compensatory lengthening of crypts.
  • Intraepithelial lymphocytosis: Increased lymphocytes in the epithelial layer.

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Clinical features

Gastrointestinal symptoms

• Chronic or recurring diarrhea: steatorrhea
• Flatulence, abdominal bloating, and pain

Extraintestinal symptoms and associations

• Malabsorption symptoms: fatigue, weight loss, vitamin deficiency, iron deficiency anemia, osteoporosis, hypocalcemia
• In children: failure to thrive, growth failure, delayed puberty, secondary hyperparathyroidism
• Dermatologic associations: dermatitis herpetiformis
  • Transglutaminases play a role in forming extensively cross-linked proteins (e.g., elastin, coagulation by factor XIII).
• Neuropsychiatric symptoms: peripheral neuropathies (numbness, burning and tingling of the hands and feet) , headache, ataxia, depression, irritability
• Commonly associated with autoimmune diseases

Diagnostics

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Laboratory studies

• IgA tissue transglutaminase antibody (tTG IgA): initial test
• Total IgA
  • Indicated for all patients because of the high prevalence of IgA deficiency in patients with celiac disease (approx. 2–3%)
    • Both celiac disease and selective IgA deficiency have strong associations with specific HLA genes, particularly HLA-DQ2 and HLA-DQ8.
  • If patients have low IgA, perform further IgG-based testing.
• Deamidated gliadin peptide
  • IgG-based testing: indicated in IgA deficiency or discordant biopsy and serology
    • IgG-tissue transglutaminase (tTG IgG)
    • IgG deamidated gliadin peptide (DGP IgG)
  • IgA-based testing: IgA deamidated gliadin peptide (DGP IgA)
• Anti-endomysial antibody (EMA): Potential second-line confirmatory test (high-specificity)
• Celiac disease is not associated with elevated systemic inflammatory markers (eg, C-reactive protein, erythrocyte sedimentation rate), since it’s limited.

Endoscopy

• EGD with small intestine biopsy (confirmatory test)
  • Intraepithelial lymphocytic infiltration
  • Crypt hyperplasia
  • Villous atrophy

Differential diagnostics

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Comparison of Common GI Disorders

Feature	Celiac Disease	Crohn Disease	Tropical Sprue	Lactose Intolerance	Irritable Bowel Syndrome (IBS)
Patho	Autoimmune vs. Gliadin (HLA-DQ2/8)	Transmural inflammation (Th1 mediated)	Post-infectious; affects entire small bowel	Lactase enzyme deficiency	Gut-brain axis d/o; visceral hypersensitivity
Location	Proximal Small Bowel (Duodenum)	Anywhere (“mouth to anus”); Terminal Ileum common	Entire Small Bowel	Small Intestine Brush Border	Colon (Function, not structure)
Biopsy	Villous atrophy, crypt hyperplasia	Non-caseating granulomas, transmural inflammation	Villous atrophy (less severe)	Normal	Normal
KeyDx	↑ Anti-tTG Ab; Dermatitis herpetiformis	Skip lesions, “cobblestoning”, fistulas	Hx of travel to tropics; Folate/B12 def.	H₂ breath test; symptoms with dairy	Pain relieved by defecation; Dx of exclusion
Tx	Gluten-free diet	Anti-TNF, Corticosteroids, 5-ASA	Antibiotics, Folic Acid	Avoid dairy; lactase pills	Low FODMAP diet, fiber, symptom control

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Tropical sprue

• Definition: A disease characterized by chronic diarrhea with subsequent malabsorption in association with a stay in the tropics or subtropics.
• Epidemiology: occurs in residents of the tropics and subtropics or in travelers returning from these areas (after trips lasting several weeks)
• Etiology: exact cause not known; most likely due to bacterial infection that leads to structural damage of the intestinal mucosa
• Clinical features: similar to Celiac disease
• Diagnostics
  • Endoscopy of the small bowel and biopsy: villous atrophy, elongated crypts, presence of inflammatory cells (plasma cells, lymphocytes, eosinophils)
• Treatment: tetracycline in combination with folic acid for 3–6 months

Treatment

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• Strict, lifelong gluten-free diet
  • Abstain from products containing wheat, rye, barley, or spelt.
  • Symptoms usually improve quickly