Celiac disease

DEFINITION & EPIDEMIOLOGY

• Definition: T-cell-mediated chronic inflammatory enteropathy with autoimmune component. Triggered by ingestion of gluten in genetically susceptible individuals.
• Prevalence: Approximately 1% in US and Europe. Higher seroprevalence in symptomatic pediatric populations.
• Demographics: Female predominance (2-3:1). Can present at any age following gluten introduction.

PATHOPHYSIOLOGY

• Environmental Trigger: Gluten (found in wheat, rye, barley). Composed of gliadins and glutenins.
• Peptide Resistance: High glutamine and proline content prevents complete enzymatic digestion in gastrointestinal tract.
• Permeability: Gliadin enhances paracellular permeability (zonulin-mediated pathway), crossing intestinal epithelium into lamina propria.
• Deamidation: Tissue transglutaminase 2 (tTG) deamidates gliadin peptides.
• Antigen Presentation: Deamidated peptides exhibit high affinity for HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting dendritic cells.
• Immune Activation: Presentation to CD4+ T-cells drives TH1-predominant cytokine response (Interferon-ɣ, IL-15, IL-21).
• Mucosal Damage: Cascade results in intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy.
• Autoantibody Production: B-cells produce celiac-specific antibodies: anti-tTG, anti-endomysial (EMA), and anti-deamidated gliadin peptide (DGP).

GENETICS & ASSOCIATIONS

• Genetic Susceptibility: >95% possess HLA-DQ2 allele (HLA-DQA105/DQB102); remainder possess HLA-DQ8.
• Heritability: 75% concordance in monozygotic twins; 10% prevalence among first-degree relatives.

High-Risk Associated Conditions

Screening recommended for asymptomatic children with:

• Type 1 Diabetes Mellitus (10% prevalence)
• Autoimmune thyroid disease (Hashimoto, Graves)
• Selective IgA deficiency
• Down syndrome, Turner syndrome, Williams-Beuren syndrome
• Autoimmune liver disease
• Juvenile idiopathic arthritis

CLINICAL PRESENTATION (OSLO DEFINITIONS)

Spectrum ranges from severe malabsorption to asymptomatic.

Celiac Crisis

• Rare, acute, life-threatening presentation.
• Explosive diarrhea, profound hypoproteinemia, metabolic acidosis, severe dehydration, lethargy.

DIAGNOSTIC EVALUATION

Testing mandates concurrent gluten-containing diet.

1. Serological Testing

• First-line Screen: Tissue transglutaminase (tTG) IgA + Total Serum IgA.

• IgA Deficient Patients: Evaluate using IgG-based assays (IgG tTG, IgG DGP, or IgG EMA).
• Anti-Endomysial Antibody (EMA) IgA: High specificity; observer-dependent immunofluorescence assay. Used as confirmatory test.
• Deamidated Gliadin Peptide (DGP): Useful adjunct, especially IgG DGP in IgA-deficient patients or children <2 years old.

2. ESPGHAN 2020 No-Biopsy Algorithm

Diagnosis confirmed without duodenal biopsy if ALL criteria met:

• Symptomatic or asymptomatic child.
• Initial tTG-IgA titer $\ge$ 10x Upper Limit of Normal (ULN).
• Positive EMA-IgA drawn on a second, separate blood sample.
• Note: HLA typing no longer mandatory for no-biopsy pathway.

3. Endoscopy & Histology

Gold standard when no-biopsy criteria unmet (tTG-IgA <10x ULN).

• Endoscopic Markers: Scalloping of duodenal folds, mosaic pattern, nodularity, loss of circular folds, visible submucosal vessels. (50% sensitivity; normal appearance does not exclude disease).
• Biopsy Protocol: Minimum 4 biopsies from distal duodenum + 1-2 biopsies from duodenal bulb (disease may be patchy or isolated to bulb).

Modified Marsh-Oberhuber Histological Classification

4. Genetic Testing (HLA DQ2/DQ8)

• High negative predictive value.
• Absence of DQ2/DQ8 makes celiac disease highly unlikely.
• Useful for excluding disease in diagnostically uncertain cases or screening at-risk groups (Down syndrome, T1DM) to eliminate need for future serologic screening.

DIFFERENTIAL DIAGNOSIS

MANAGEMENT

Strict, lifelong elimination of gluten remains the sole medical therapy.

1. Dietary Intervention

• Gluten-Free Diet (GFD): Absolute avoidance of wheat, rye, barley, and derivatives (triticale, kamut, spelt, malt).
• Threshold: Daily gluten intake must remain <10-50 mg to prevent histological damage.
• Oats: Pure, uncontaminated oats are safe and tolerated by majority; add sequentially after disease remission.

2. Nutritional Rehabilitation

• Screen for and treat micronutrient deficiencies: Iron, Folate, Vitamin D, Calcium, Vitamin B12.

• Assess bone health (DEXA scan) if classical severe malabsorptive symptoms present.

3. NIH "CELIAC" Mnemonic for Management

• C: Consultation with skilled dietitian.
• E: Education about disease.
• L: Lifelong adherence to GFD.
• I: Identification/treatment of nutritional deficiencies.
• A: Access to advocacy group.
• C: Continuous long-term follow-up.

4. Long-Term Monitoring

• Assess dietary compliance, growth (BMI, height velocity), and symptom resolution.
• Serial tTG-IgA testing at 6 months, then annually. Titers should decline/normalize within 12 months on strict GFD.
• Follow-up intestinal biopsy not routinely indicated if clinical and serological response achieved.

COMPLICATIONS & PROGNOSIS

• Nonresponsive Celiac Disease: Persistent symptoms/serology. Most common cause: intentional or inadvertent ongoing gluten ingestion.
• Growth Failure: Untreated disease results in permanent short stature. Excellent catch-up growth typically observed if treated before puberty.
• Malignancy Risk: Enteropathy-associated T-cell lymphoma (EATL) or small bowel adenocarcinoma. Increased risk in adulthood if untreated; minimized to baseline population risk with strict GFD compliance.
• Autoimmune Propagation: Continued gluten exposure hypothesized to increase risk of concurrent autoimmune diseases (T1DM, thyroiditis).