Celiac disease

Definition:

  • A food intolerance and autoimmune disorder characterized by permanent intolerance to proteins from wheat, rye and barley chronic inflammation of the proximal small intestinal mucosa that heals when foods containinggluten are excluded from diet.
  • Functional changes include:
  • Decreased digestion of food.
  • Decreased absorption of macronutrients and micronutrients.
  • Increased net secretion of water and solute.
  • Less frequently ulceration or stricturing.
  • Extraintestinal manifestations.

Prevalence

  • Celiac disease was previously believed to be more common inwestern European countries.
  • It is now apparent that celiac disease is also common in the United States, Eastern Europe, and many other countries with the exception of Japan.
  • The prevalence of celiac disease in first-degree relatives of patients with celiac disease is5.5%.

Pathology

  • The site of maximum impact is the proximal small intestine, where dietary gluten first encounters the mucosal immune system.

Table 1.Histologic Grading in Celiac Disease
Marsh 0 / Normal mucosal and villous architecture
Marsh I / Infiltrative
  • Normal mucosal and villous architecture
  • Increased numbers of intraepithelial lymphocytes

Marsh II / Hyperplastic Similar to above, but with
  • Enlarged crypts
  • Increased crypt cell division

Marsh III / a-Partial villous atrophy
  • Shortened blunt villi
  • Mild lymphocyte infiltration
  • Enlarged hyperplastic crypts
b-Subtotal villous atrophy
  • Clearly atrophic villi, but still recognizable
  • Enlarged crypts whose immature epithelial cells
  • Influx of inflammatory cells
c-Total villous atrophy
  • Complete loss of villi
  • Severe crypt hyperplastic
  • Infiltrativeinflammatory lesion

Marsh IV / Hypoplastic
  • Total villous atrophy
  • Normal crypt depth, but hypoplasia
  • Normal intraepithelial lymphocyte count
  • Many feel this does not exist and represents severe malnutrition

Pathogenesis

Gluten

  • Celiac disease is activated by the dietary ingestion of gluten (inwheat, barley, and rye).
  • These proteins are enriched in glutamines and prolines and undergo incomplete digestion in the upper gastrointestinal tract wide variety ofpeptide derivatives.
  • The specific peptide sequences include a 33-amino acid peptide from an α-gliadin that survives intestinal digestion, and is highlyimmunogenic pass through the epithelial barrier and reach antigen-presenting cells in the lamina propria triggering immune response.

Mucosal Immune Response

  • Immunogenic peptides rich in glutamine and proline chronic immune response mediatedby:
  1. Innateimmune response.
  2. Adaptiveimmuneresponse.
  1. Adaptive response
  • Mediated by gluten-reactive CD4+T cells in the lamina propria that recognizes certain gluten-derived peptides when they are presented by the HLA class II molecules DQ2 or DQ8.
  • T cells activated by gluten produce interferon gamma andother proinflammatory cytokines release of metalloproteinases and other tissue damaging mediators  villous injury and crypt hyperplasia.
  1. Innate response
  • Marked byincreased expression of interleukin-15 by enterocytesactivation of populations of intraepithelial lymphocytes that express the NK marker (NKG2D) recognize and kill enterocytes that express stressmolecules (MICA) on their surface.
  • There is activation of dendritic cells that influence the adaptive response.

Role of tTG (enzyme found both within outside of cells)

  • A target of an autoimmune humoral response  secreted and circulating antibodies predominantly of the immunoglobulin (Ig) A isotype.
  • Enzymatic deamidationof glutamine residues in gluten peptides that make deamidated gluten peptides more antigenic.
  • Important also in the destructive effect of CD8+ cytotoxic cells on the epithelium.

Clinical manifestations

  • Age of onset: early childhood (9-24 mo)or in the third or fourth decade of life.
  • Female: male is 2:1.

Table 3.Celiac disease phenotypes
Classic /
  • Most commonly described.
  • Features of intestinal malabsorption (diarrhoea, steatorrhoea,weight loss, fatigue and anaemia).
  • Gluten-induced villous atrophy and other classic histologic features.
  • Patients present because of gastrointestinal symptoms.

Atypical /
  • Most common form.
  • Little to no gastrointestinal symptoms (abdominal discomfort, bloating, indigestion).
  • Come to medical attention because of other reasons such as iron deficiency, osteoporosis, short stature, or infertility.
  • Gluten-induced villous atrophy.
  • Large numbers go undiagnosed.

Silent /
  • Refersto asymptomatic patients who are discovered to have gluten-induced villous atrophy.
  • Discovered after serologic screening or perhaps during endoscopy and biopsy for another reason.

Latent /
  • Patients with a previous diagnosis of celiac disease that responded to a GFD
  • Have a normal mucosal histology or only an increase in intraepithelial lymphocytes.
  • Can also represent patients with normal intestinal mucosa on a gluten-containing diet who will subsequently develop celiac disease.

Refractory /
  • Patients with severe villous atrophy associated with severe malabsorption who does not or no longer respond to a GFD.
  • Other treatable forms of enteropathy must be excluded.
  • Some develop complications such as ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.
  • Two types:
  • First typehas an expansion of phenotypically normal intraepithelial lymphocytes respond to corticosteroids and/or immunosuppression.
  • Second typeis associated with a clonal expansion of intraepithelial lymphocytes. These intraepithelial lymphocytes bear an unusual phenotype (express the CD3εbut lack the expression of CD4, CD8) derived by interleukin 15 are independent of gluten stimulation.

Associated Disorders

  • DM1
  • Autoimmune thyroid disease,
  • Addison’s disease.
  • Dermatitis herpetiformis.
  • Down syndrome.
  • Mild asymptomatic ↑AST, ALT.
  • Turner’s syndrome
  • Later menarche and infertility.
  • Occipital calcifications and ataxia.
/
  • Chronic liver disorders such as
  • Primary biliary cirrhosis.
  • Autoimmune hepatitis.
  • PSC.
  • Cryptogenic liver disease.
  • NAFLD.
  • Ulcerative colitisCD.
  • IgA nephropathy.
  • Idiopathic epilepsy.

Complications

  • Complications related to malabsorption.
  • Anaemia.
  • Osteoporosisand fracture of ulna, radius, hip and spine (screened using DEXAscanning).
  • Ulcerative jejunoileitis.
  • Intestinal T-cell lymphoma.
  • Other types of intestinal and extraintestinalB-cell NHL.
  • Cancer esophagus, stomach, pancreas, liver, small bowel and pleura.
  • Melanoma and leukemia.

Diagnosis

Upper intestinal endoscopy and small bowel biopsy

  • Small intestinal mucosal biopsy remains the gold standard for diagnosis.
  • Multiple biopsies(4–6) are required as mucosal changes can be patchy.
  • Histologic changes are scored based on Marsh system.
  • Staining for CD3 to detect the intraepithelial lymphocyte population (notroutine).
  • A 4-week challenge with sufficient gluten to reproduce the symptoms is adequate before biopsy specimens.

Serologic Tests

  • Serologictest results will revert to normal over a period of 6 months to1 year and symptoms will improve on a GFD.
  • Sensitivity of the serologic tests decreases with lower Marshgrades of histologic severity.
  • Antigliadin antibodies (AGA).
  • Endomysial antibodies(EMA).
  • Tissue transglutaminase antibody(tTGA).
  • Endomysial antibodies IgA
  • Measured using an immunofluorescence technique.
  • Sensitivity97.4%,specificity99.6%.
  • tTGA IgA
  • Most efficient single serologic test for the detection of celiac disease.
  • Measured by quantitative ELISA.
  • Sensitivity is 90%, specificity 95.1%.
  • AGA IgA
  • Measured by ELISA.
  • Sensitivity 85%-90%, specificity 90%.
  • IgG EMA and IgG tTG (sensitivity70%,specificity 100%).

Serologic Tests in SelectiveIgA-Deficient Patients

  • Common in patients with celiac disease.
  • IgG AGA (sensitivity and specificity 80%-90%).
  • IgG EMA and IgG tTG (sensitivity 100%,specificity 100%).

Testing for the presence of specific HLA class II DQ alleles (DQ2 or DQ8) can help exclude thedisease.

Treatment

  • Strict gluten free diet.

Benefits of a strict GFD

  • Significant reduction in risk of NHL.
  • Body weight, BMI, bone mass, and triceps skin fold thickness increased significantlyafter 12 months of GFD.
  • Improvement in nutritional and biochemical status, including improvements in IDA.
  • Improvement in bone mineral density.

Monitoring Adherence to a GFD

  • Symptom improvement
  • Repeat serologic testing after 6 months.
  • Serologic test resultstend to become negative as the histologic findings improve.

Causes of Relapsing Symptoms in Treated Celiac Disease

  • Incompletely healed celiac disease.
  • No strict gluten restriction (persistent positive serologic test results).
  • An associated condition.
  • A complication.
  • Asecond unrelated diagnosis
  • Microscopic colitis.
  • Irritable bowel syndrome.
  • Pancreatic exocrine insufficiency.
  • Bacterial overgrowth.
  • Disaccharidasedeficiency.
  • Autoimmune enteropathy.
  • Common variable immunodeficiency syndrome.
  • Tropical sprue.
  • Eosinophilic gastroenteritis.

Treatment of Refractory Celiac Disease

  • Nutritional support with total parenteral nutrition.
  • Occasionally, patients respond to removal of food proteins other than gluten.
  • Corticosteroids, including oral budesonide will suppress inflammation.
  • Azathioprine may be beneficial incorticosteroids nonresponders.
  • Combination therapy.
  • Anti–interleukin-15 monoclonal antibodies (HuMax-IL-15).

Novel therapeutic possibilities

  1. Oral proteases
  • Bacterial prolyl-endopeptidases(PEPs) (F. meningosepticum PEP)ableto digest ingested gluten  degrade the 33mer T cell stimulatory peptide reduce the amount of immunostimulatorygliadin peptides.
  • Lactobacillus helveticus has a zinc-dependent PEP that can also cleave long substrates.
  • Cysteine endoprotease EPB derived from barley is a glutamine-specific enzyme that rapidly hydrolyzes intact gliadin polypeptides.
  • Silencing of gluten-reactive T cells(immune tolerance)
  • Anti-CD3 antibodies(targeted against the T cell receptor).
  • Soluble dimers of HLA–peptide complexes.
  • Intranasal administration of gluten or gluten T-cell epitopes.
  • Generation of wheat (and othercereals) with absent or reduced immunogenicity by genetic modification.
  • Potential therapeutic targets
  • Tissue transglutaminase inhibitors inhibit deamidated peptides
  • Monodansyl cadaverine
  • Suicide inhibitor which inhibits human TG2.
  • Zonulin receptor antagonist (AT-1001)prevents gluten-induced disruption of the epithelial barrier.
  • HLA-DQ2peptide blockers.
  • Anti-IFN- (Fontolizumab)Interferon- is the dominant cytokine produced by gluten-reactive T cells.
  • Integrin -4 antagonist (Natalizumab)selective inhibition of leukocyte adhesion.
  • NKG2D antagonists.

Treatment of complications

  • Osteoporosis bisphosphonatesor hormone replacement therapy.
  • Multivitamins.

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