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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