Celiac Disease Study Notes

Celiac Disease Overview

  • Celiac disease is a common cause of chronic diarrhea and other gastrointestinal symptoms.

  • Defined as an immunologically mediated disorder of the small intestine.

  • Caused by dietary exposure to triggering proteins found in wheat, barley, and rye.

  • Hallmark: Villous atrophy, which generally resolves or improves with the removal of offending proteins.

Normal vs. Celiac-Affected Small Bowel

  • Normal small bowel: Prominent villi.

  • Celiac disease: Flattening of the villi; increased inflammatory cell infiltrate.

  • Symptoms can be gastrointestinal and systemic.

Etiology of Celiac Disease

  • Genetic Predisposition: Clearer than in inflammatory bowel disease; multifactorial influences including:

    • Environmental factors (gluten-containing proteins).

    • Immunological factors.

Immunogenic Proteins in Gluten

  • Wheat: Gliadins.

  • Barley: Hordines.

  • Rye: Seculins.

  • Collectively referred to as gluten, rich in glutamines and prolines.

  • These proteins are incompletely digested by gastric, pancreatic and brushborder proteases, leading to large peptides that can induce an immune response in susceptible individuals.

Genetics of Celiac Disease

  • First Degree Relatives Risk: 5-10%.

  • HLA Identical Siblings Risk: ~30%.

  • True Identical Twins Risk: >75%.

  • HLA haplotypes:

    • HLA DQ2 and HLA DQ8 are necessary but not sufficient for Celiac disease development.

    • A mutation in these requires additional factors for disease manifestation.

  • Testing Implications:

    • HLA DQ2/DQ8 cannot diagnose celiac disease but a negative test can exclude it.

Environmental Influences on Celiac Disease

  • No clear relationship identified involving:

    • Age of gluten introduction.

    • Breastfeeding.

    • Other factors (smoking, antibiotic use, PPIs, infant infection) are inconclusive in relation to disease predisposition.

Role of Tissue Transglutaminase

  • Central to immune response:

    • Found in gut mucosa; a repair enzyme.

    • Cross-links extracellular matrix proteins.

    • Deamidates glutamine in gliadin to glutamate, increasing gliadin's affinity to HLA DQ2/DQ8.

    • Promotes T cell activation leading to immune response and tissue damage.

Biochemical Sequence of Immune Response

  • Ingestion of gluten → Incomplete digestion → Gliadins cross epithelium (transcellularly or paracellularly) → Deamidation by transglutaminase → Complex formation with DQ2/DQ8 → Presentation to CD4 T cells → Immune response, tissue damage, and villous atrophy.

Prevalence and Demographics

  • Prevalence: Approximately 1% of the population, primarily in Caucasians of Northern European descent.

  • Rarely diagnosed in ethnic Chinese and certain other groups due to lack of HLA haplotypes.

  • Currently more common in adults than in children due to nonspecific and variable mild symptoms, often resulting in a diagnosis delay of 5-10 years.

  • Phenomenon of silent celiac disease leads to undiagnosed cases. Estimates suggest about 8 undiagnosed adults for every diagnosed case.

Clinical Spectrum of Celiac Disease

  • Potential Celiac Disease: Positive serology but normal intestinal biopsies.

  • Asymptomatic Patients: Positive serology, histologic changes, absence of symptoms.

  • Mild Symptoms: Can be intestinal or extraintestinal.

  • Classic Celiac Disease: Diarrhea, malabsorption symptoms, anemia, osteoporosis.

  • Refractory Celiac Disease: Persistent symptoms and villous atrophy despite adhering to a gluten-free diet.

Co-associated Conditions and Manifestations

  • Increased frequency of autoimmune diseases, including:

    • Autoimmune thyroiditis.

    • Atrophic gastritis.

    • Type 1 diabetes.

    • Primary biliary cholangitis.

    • Autoimmune hepatitis.

    • Dermatitis herpetiformis: An itchy rash presenting on upper limbs.

    • IgA deficiency common in celiac patients.

    • Osteoporosis: 20-40% of untreated celiac patients are osteopenic, connected to malabsorption and silent bone loss. Bone mineral density (BMD) improves on a gluten-free diet but remains reduced compared to healthy controls.

Diagnosis of Celiac Disease

  • Methods: Combination of antibody testing and small bowel biopsy; adjunctive HLA testing.

  • Must be consuming gluten during diagnosis for antibody tests and biopsy to identify histologic changes.

Antibody Tests

  • Tests include:

    • Anti-gliadin Antibodies (especially deamidated).

    • Anti-endomysial Antibodies.

    • Anti-transglutaminase Antibodies: Most commonly used now.

    • Requires both IgA and IgG testing due to co-occurrence of IgA deficiency in celiac disease.

Endoscopic Findings

  • Normal duodenum appearance includes lots of villi and folds.

  • Celiac disease indicates loss of features, blunting of folds, and denudation of mucosa.

  • Histological changes include villous atrophy and intraepithelial lymphocytosis.

HLA Testing

  • Essential for confirming the risk but not diagnostic due to the need for binding gliadin to tissue transglutaminase complex.

  • Positive results are less useful; negative results can help exclude the condition.

  • HLA testing may clarify uncertain diagnoses or in patients on gluten-free diets seeking diagnosis confirmation.

Treatment and Management

  • Primary treatment: Strict lifelong gluten-free diet (no wheat, barley, or rye; Oats are controversial but can be pure).

  • Importance of compliance to prevent surreptitious gluten ingestion from sauces, processed foods, etc.

Reasons for Treating Asymptomatic Patients

  • Asymptomatic patients may have underlying conditions or deficiencies that are not recognized until dietary changes lead to improvements.

  • Address malabsorption-related nutritional deficiencies (e.g., iron deficiency due to compromised duodenal absorption).

  • Reducing risks of malignancies associated with untreated celiac (e.g., enteropathy-associated T-cell lymphoma, small bowel adenocarcinoma).

Monitoring and Follow-Up

  • Important to monitor improvement after initiating a gluten-free diet:

    • Blood tests after 6 months to check antibody levels.

    • Clinical evaluation and repeat gastroscopy 6-12 months later to assess mucosal recovery via histology.

    • Check nutritional markers and bone mineral density.

Nonresponsive Cases

  • Commonly due to diet non-adherence (deliberate or inadvertent exposure).

  • Other reasons include ulcerative jejunoileitis and refractory sprue.

  • Rare cases may progress to enteropathy-associated T-cell lymphomas.

Summary

  • High suspicion for celiac disease is necessary given its prevalence.

  • Antibody testing is crucial but not definitive—small bowel biopsy is essential for diagnosis.

  • HLA DQ2/DQA testing provides useful exclusionary value but is not diagnostic.

  • Lifelong adherence to a gluten-free diet is the primary treatment.