Celiac disease by nuhman10


									                                  Celiac disease
 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 containing gluten are
   excluded from diet.
 Functional changes include:
       o Decreased digestion of food.
       o Decreased absorption of macronutrients and micronutrients.
       o Increased net secretion of water and solute.
       o Less frequently ulceration or stricturing.
       o Extraintestinal manifestations.

 Celiac disease was previously believed to be more common in western European
 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 is 5.5%.

 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

                Infiltrative inflammatory 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


 Celiac disease is activated by the dietary ingestion of gluten (in wheat, barley,
   and rye).
 These proteins are enriched in glutamines and prolines and undergo incomplete
   digestion in the upper gastrointestinal tract  wide variety of peptide derivatives.
 The specific peptide sequences include a 33-amino acid peptide from an α-
   gliadin that survives intestinal digestion, and is highly immunogenic  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
   mediated by:
       1. Innate immune response.
       2. Adaptive immune response.
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 and other proinflammatory
   cytokines  release of metalloproteinases and other tissue damaging mediators
    villous injury and crypt hyperplasia.
2. Innate response
 Marked by increased expression of interleukin-15 by enterocytes  activation of
   populations of intraepithelial lymphocytes that express the NK marker (NKG2D)
    recognize and kill enterocytes that express stress molecules (MICA) on their
 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 deamidation of 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,
              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        Refers to 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
              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 type has an expansion of phenotypically normal intraepithelial lym-
                 phocytes respond to corticosteroids and/or immunosuppression.
              Second type is associated with a clonal expansion of intraepithelial
                 lymphocytes. These intraepithelial lymphocytes bear an unusual phenotype
                 (express the CD3 ε but lack the expression of CD4, CD8) derived by
                 interleukin 15 are independent of gluten stimulation.

Associated Disorders
    DM1                                             Chronic liver disorders such as
    Autoimmune thyroid disease,                         o Primary biliary cirrhosis.
    Addison’s disease.                                  o Autoimmune hepatitis.
    Dermatitis herpetiformis.                           o PSC.
                                                         o Cryptogenic liver disease.

      Down syndrome.                                     o NAFLD.
      Mild asymptomatic ↑ AST, ALT.                 Ulcerative colitis & CD.
      Turner’s syndrome                             IgA nephropathy.
      Later menarche and infertility.               Idiopathic epilepsy.
      Occipital calcifications and ataxia.

   Complications related to malabsorption.
        o Anaemia.
        o Osteoporosis and fracture of ulna, radius, hip and spine (screened using
            DEXA scanning).
   Ulcerative jejunoileitis.
   Intestinal T-cell lymphoma.
   Other types of intestinal and extraintestinal B-cell NHL.
   Cancer esophagus, stomach, pancreas, liver, small bowel and pleura.
   Melanoma and leukemia.


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 (not routine).
 A 4-week challenge with sufficient gluten to reproduce the symptoms is adequate
  before biopsy specimens.

Serologic Tests
 Serologic test results will revert to normal over a period of 6 months to 1 year and
   symptoms will improve on a GFD.
 Sensitivity of the serologic tests decreases with lower Marsh grades of histologic
 Antigliadin antibodies (AGA).
 Endomysial antibodies (EMA).
 Tissue transglutaminase antibody (tTGA).
 Endomysial antibodies IgA
      o Measured using an immunofluorescence technique.
      o Sensitivity 97.4%, specificity 99.6%.
 tTGA IgA
      o Most efficient single serologic test for the detection of celiac disease.
      o Measured by quantitative ELISA.
      o Sensitivity is 90%, specificity 95.1%.
      o Measured by ELISA.
      o Sensitivity 85%-90%, specificity 90%.

   IgG EMA and IgG tTG (sensitivity <70%, specificity 100%).

Serologic Tests in Selective IgA-Deficient Patients
 Common in patients with celiac disease.
           o IgG AGA (sensitivity and specificity 80%-90%).
           o 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 the disease.


       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
      significantly after 12 months of GFD.
   Improvement in nutritional and biochemical status, including improvements in
   Improvement in bone mineral density.

Monitoring Adherence to a GFD
 Symptom improvement
 Repeat serologic testing after 6 months.
      o Serologic test results tend to become negative as the histologic findings

Causes of Relapsing Symptoms in Treated Celiac Disease
 Incompletely healed celiac disease.
      o No strict gluten restriction (persistent positive serologic test results).
 An associated condition.
 A complication.
 A second unrelated diagnosis
      o Microscopic colitis.
      o Irritable bowel syndrome.
      o Pancreatic exocrine insufficiency.
      o Bacterial overgrowth.
      o Disaccharidase deficiency.
      o Autoimmune enteropathy.
      o Common variable immunodeficiency syndrome.
      o Tropical sprue.
      o 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 in corticosteroids nonresponders.
   Combination therapy.
   Anti–interleukin-15 monoclonal antibodies (HuMax-IL-15).

Novel therapeutic possibilities
       1. Oral proteases
 Bacterial prolyl-endopeptidases (PEPs) (F. meningosepticum PEP)  able to digest
   ingested gluten  degrade the 33mer T cell stimulatory peptide  reduce the amount
   of immunostimulatory gliadin peptides.
 Lactobacillus helveticus has a zinc-dependent PEP that can also cleave long
 Cysteine endoprotease EPB derived from barley is a glutamine-specific enzyme that
   rapidly hydrolyzes intact gliadin polypeptides.
       2. 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.
       3. Generation of wheat (and other cereals) with absent or reduced
           immunogenicity by genetic modification.
       4. Potential therapeutic targets
 Tissue transglutaminase inhibitors  inhibit deamidated peptides
       o Monodansyl cadaverine
       o Suicide inhibitor which inhibits human TG2.
 Zonulin receptor antagonist (AT-1001)  prevents gluten-induced disruption of the
   epithelial barrier.
 HLA-DQ2 peptide 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  bisphosphonates or hormone replacement therapy.
 Multivitamins.


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