Celiac disease - Webs
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 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.
Prevalence
• Celiac disease was previously believed to be more common in western 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 is 5.5%.
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 |
| |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 |
Pathogenesis
Gluten
• 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 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 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, 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 |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 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 type has an expansion of phenotypically normal intraepithelial lymphocytes( 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 CD3ε 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, |Primary biliary cirrhosis. |
|Addison’s disease. |Autoimmune hepatitis. |
|Dermatitis herpetiformis. |PSC. |
|Down syndrome. |Cryptogenic liver disease. |
|Mild asymptomatic ↑ AST, ALT. |NAFLD. |
|Turner’s syndrome |Ulcerative colitis & CD. |
|Later menarche and infertility. |IgA nephropathy. |
|Occipital calcifications and ataxia. |Idiopathic epilepsy. |
Complications
• 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.
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 (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 severity.
• 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%.
• AGA IgA
o Measured by ELISA.
o Sensitivity 85%-90%, specificity 90%.
• IgG EMA and IgG tTG (sensitivity ................
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