Celiac disease

Definitions

Symptomatic

• Frank malabsorption symptoms and signs
• extraintestinal symptoms
• positive CD-specific antibodies
• small intestinal biopsy with mucosal damage

Silent CD

• asymptomatic CD with positive CD-specific antibodies and small intestinal biopsy with severe mucosal damage consistent with CD

Potential CD

• Potential CD is defined when patients have positive CD-specific antibodies, but with out documented small bowel damage

Etiopathogenesis

• immune mediated systemic disorder
• due to gluten in wheat and related protamines from rye and barley in genetically susceptible individuals
• environmental factors play a role in the timing of presentation
  • large amount of gluten in early age ⟶ earlier development of autoimmune disease
  • lower amount of gluten in first 2 years ⟶ lower risk of CD
• Other risk factors
  • mode of delivery
  • socioeconomic class
  • season of birth
  • use of drugs

Diagnosis of Celiac Disease / Serological testing

• anti TG2 IgA antibodies and total IgA
  • if anti TG2 IgA and total IgA are both normal ⟶ CD unlikely
  • if anti TG2 IgA - positive ⟶ refer to pediatric gastroenterologist for further workup
    • if anti TG2 IgA is 1x to 10x of normal ⟶ patient to undergo multiple biopsy
    • if anti TG2 IgA is >10x of normal ⟶ obtain EMA titers - positive⟶ Celiac is confirmed - start on lifelong anti gluten diet
    • if anti TG2 IgA is >10x of normal ⟶ obtain EMA titers - negative ⟶ Obtain duodenal biopsy
  • If ↓ anti TG2 IgA ⟶ anti TG2 IgG testing
• While doing biopsy at least four fragments should be obtained from the descending part of duodenum
• HLA testing can be done in cases of uncertainty
  

Genetics

• genetic predisposition in monozygous twins approach 100%
• Strongest HLA association
  • HLA DQ2.5 (encoded by one or two molecules of HLA DQA1*05 and HLA DQB1*02)
  • HLA DQ2.2
  • HLA DQ8 (DQA1*0301/DQB1*0302)

Pathogenesis

• T cell mediated chronic inflammatory disorder with an autoimmune component
• Initial triggers
  • Altered processing by intraluminal enzymes.
  • Increased intestinal permeability.
  • Activation of innate immunity mechanisms.
• Gliadin ingestion
  • resistant to digestion
  • incomplete digestion enhances the immunomodulatory and toxic effects
  • tTG2 converts glutamine to glutamic acid in gliadin peptides
  • Enhances peptide binding affinity to HLA-DQ2/DQ8
  • stimulate innate immunity - notably IL15 and IL21
• IL15
  • activation of lamina propria T cells
  • Expression of NK receptors CD94 and NKG2D.
• IL-21
  • Intraepithelial lymphocyte (IEL) homeostasis is severely impaired.
  • Dominated by interferon-γ (Th1 skewed).
• Enhanced cytotoxicity, apoptosis, and villous atrophy (flat mucosa on histology).
• Other features
  • TG2 can present in other tissues like liver, lymph nodes, and muscle

Clinical features

• in the first two years
  • failure to thrive
  • chronic diarrhea
  • vomiting
  • muscle wasting
  • anorexia
  • irritability
  • abdominal distension
• Extraintestinal manifestation
  • Iron Deficiency Anemia unresponsive to iron therapy
  • osteoporosis
  • short stature
  • delayed puberty
  • osteoporosis
  • aphthous stomatitis
  • pancytopenia
  • peripheral neuropathy
  • enamel hypoplasia
• Other disease associations
  • Type 1 DM
  • Addison's
  • Autoimmune thyroid
  • Sjogren
  • Rheumatic Arthritis
  • autoimmune cholangitis
  • autoimmune hepatitis
  • primary biliary cholangitis
  • JIA

Management

Gluten-Free Diet (GFD)

• Only effective treatment: Lifelong, strict adherence to a gluten-free diet.
• Requires elimination of:
  • Wheat
  • Barley
  • Rye
• Use only rice, corn, maize, buckwheat, millet, amaranth, quinoa, sorghum, potato or potato starch, soybean, tapioca, and teff, bean, and nut flours.
• Oats:
  • Generally safe for most CD patients.
  • Risk of gluten contamination during harvesting, milling, and shipping.

Gluten Thresholds

• Codex Alimentarius Guidelines:
  • Gluten-free defined as <20 ppm (20 mg/kg).
• Tolerable daily gluten intake:
  • Suggested threshold: <50 mg/day.

Risks of Untreated CD

• Silent CD (no symptoms but positive serology):
  • Risks include osteopenia, autoimmune disorders, and intestinal lymphoma.
• Potential CD:
  • TG2 antibodies present without histologic damage.
  • Requires:
    • Confirmation of adequate gluten intake.
    • Proper biopsy orientation.
    • Monitoring at a tertiary medical center.

Dietary Counseling and Monitoring

• Education by an experienced dietitian is essential.
• Adolescents may struggle with compliance:
  • Monitor for depression.
  • Refer to psychology/adolescent medicine if needed.
• Regular follow-up:
  • Assess symptoms, growth, physical exam, and diet adherence.
  • Recommended blood tests at diagnosis:
    • CBC, liver panel, thyroid function, calcium, vitamin D, iron, ferritin.
  • Follow abnormal values until normalized.
• TG2 antibody levels:
  • Used to monitor adherence to GFD.
  • May take 2–3 years to normalize.
  • Check every 1–2 years after normalization or sooner if symptoms arise.
• Commercial tests:
  • Detect gluten peptides in urine/stool.
  • Under investigation for validation.

Emerging Therapies

• Clinical trials underway for treatments targeting:
  • IL-15
  • IL-21
  • Gluten degradation

Refractory or Nonresponsive CD

• persistent of symptoms of atrophy of intestinal villi after ≥ 12 months of strict gluten free diet
• rare in children compared to older patients
• Types
  • type 1
    • less severe
    • endoscopic and histological features similar to those in uncomplicated active celiac disease
  • type 2
    • severe malnutrition with wasting
    • protein losing enteropathy
    • ulcerative jejunitis
• Requires a systematic diagnostic approach:
  • Confirm diagnosis.
  • Rule out alternate diagnosis
    • malabsorption syndromes
    • autoimmune enteropathy
    • small bowel intestinal overgrowth
    • milk protein allergy
    • pancreatic insufficiency
  • Assess dietary compliance
  • look for gluten contamination
  • Explore therapeutic options.
• Consider open-capsule budesonide or prednisolone as first line therapy