Celiac Disease

Clinical Background

Celiac disease or gluten sensitive enteropathy (GSE) is a non-allergic immune-mediated sensitivity in genetically susceptible individuals to gluten in wheat or related proteins found in barley and rye.

Epidemiology

Incidence – 1/100 to 1/150 in the U.S.
Age – median is 20s
Ethnic – mainly affects Caucasians of North European ancestry

Risk Factors

HLA DQ2 allele (90-95%)
HLA DQ8 (5-10%)
75% concordance in monozygotic twins

Pathophysiology

Inappropriate immune response to gluten in wheat or related proteins in barley and rye
Celiac lesion may be characterized by increased intraepithelial lymphocytes (IEL) with crypt hyperplasia, partial, subtotal or total atrophy
tTG has been identified as the major target autoantigen of the endomysial antibody (EMA)
tTG is an enzyme that catalyzes the replacement by primary amines (cross-linking) as well as the hydrolysis (deamidation) of amide groups of protein and peptide-bound glutamine residues
Gliadin, a glutamine-rich protein, has been identified as a specific substrate for tTG
- Deamidation of gliadin has been reported to improve the overall diagnostic performance of the conventional antigliadin antibody assays

Clinical Presentation

Clinical manifestations are extremely varied and tend to differ by age group
General – anemia, fatigue, weight loss
Pediatrics – diarrhea, abdominal distention, or symptoms of malnutrition such as short stature, anemia, defects in dentition, failure to thrive, or developmental delay
Adults – abdominal pain, flatulence, diarrhea, and, in severe cases, steatorrhea
- Extraintestinal features among adults may include fatigue and malaise (may occur independently of anemia), neurologic or psychiatric disorders, neuromuscular abnormalities, infertility and mouth ulcers.
Associated conditions
- Dermatitis herpetiformis
- IgA deficiency
- Increased risk of lymphoma

Treatment

Gluten-free diet may control GSE and associated risks

Diagnosis

Indications for testing – chronic diarrhea without infectious etiology; family history of celiac disease
Laboratory testing
- Tissue transglutaminase (tTg) antibodies IgA by ELISA
  - Has been reported to have equivalent diagnostic utility as EMA IgA by IFA for celiac disease
  - Sensitivity and specificity about 98%
- Deaminated gliadin antibodies IgA by ELISA
  - Higher sensitivity/specificity than conventional antigliadin antibody tests
  - May be present without tTG IgA antibodies
- IgA deficiency
  - If IgA deficiency is suspected, determination of IgA levels prior to antibody testing is recommended
  - If patient is IgA deficient, all antibody testing will need to be performed using IgG tests to prevent underdiagnosis of celiac disease
- In some cases, tTg and/or deamidated gliadin IgG antibodies may be present despite detectable levels of IgA
  - If suspicion for celiac disease is strong and tTg IgA is negative, for the presence of tTG IgG and DPG (IgA and IgG) antibodies may be clinically relevant
- Celiac disease dual antigen screen may be clinically relevant in individuals with suboptimal or IgA deficiency
- HLA testing is not necessary for routine laboratory evaluation of celiac disease
  - May be indicated in individuals at risk for CD or individuals who are repeatedly seropositive but biopsy negative
  - The absence of HLA-DQ2 or DQ8 eliminates the risk for CD
- F-actin IgA – presence of anti-F actin antibodies in biopsy confirmed CD patients may indicate intestinal villus atrophy
  - Should be ordered only in patients with confirmed CD by biopsy
Tissue diagnosis
- Duodenal biopsy – gold standard for celiac disease diagnosis
  - Intestinal damage is assessed by a modified Marsh score which ranges from 0, 1, 2, 3a to 3c.
  - Only Marsh scores 2 and above are considered clinically significant
Criteria for diagnosis
- Positive EMA or tTG IgA serologic test
- Positive tissue biopsy
- Complete resolution of clinical symptoms and/or a seronegative response following a gluten-free diet (GFD)
  - Gluten rechallenge not necessary except in patients who had no initial biopsy or uncharacteristic biopsy

Additional Information

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Celiac Disease Reflexive Panel 0051065 Method: Nephelometry/Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay	Preferred panel for celiac disease diagnosis (panel includes IgA, tissue transglutaminase antibodies and deamidated gliadin peptide antibodies)	Test results alone are not diagnostic, biopsy is currently recommended for a diagnosis of celiac disease/gluten sensitive enteropathy Panel not recommended for follow-up testing in confirmed celiac disease patients
Celiac Disease Dual Antigen Screen with Reflex 2002026 Method: Nephelometry/Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay	May be indicated for patients with IgA deficiency or suboptimal IgA levels, especially in pediatric patients Panel includes celiac disease dual-antigen screen; tissue transglutaminase antibodies IgA and IgG; and gliadin peptide antibodies IgA and IgG
Tissue Transglutaminase Antibody, IgA 0097709 Method: Enzyme-Linked Immunosorbent Assay	Preferred screening assay for suspected celiac disease patients who are not IgA deficient	Certain individuals, particularly children <3 years old may test negative for tTG IgA antibodies Not recommended for individuals with suboptimal IgA or IgA deficiency Test results alone are not diagnostic; biopsy is currently recommended for a diagnosis of celiac disease/gluten sensitive enteropathy	If positive and celiac disease confirmed, test may be useful in monitoring compliance to gluten-free diet
Deamidated Gliadin Peptide (DGP) Antibody, IgA 0051357 Method: Enzyme-Linked Immunosorbent Assay	Certain individuals, particularly children <3 years old who test negative for tTG and/or EMA antibodies, may be positive for gliadin IgA and/or IgG antibodies	Test results alone are not diagnostic, biopsy is currently recommended for a diagnosis of celiac disease/gluten sensitive enteropathy	If positive and celiac disease confirmed, test may be useful in monitoring compliance to gluten-free diet
Tissue Transglutaminase Antibody, IgG 0056009 Method: Enzyme-Linked Immunosorbent Assay	Screen for celiac disease in patient who is IgA deficient or has suboptimal IgA levels	Test results alone are not diagnostic; biopsy is currently recommended for a diagnosis of celiac disease/gluten sensitive enteropathy Certain individuals, particularly children <3 years old who test negative for tTG and/or EMA antibodies, may be positive for gliadin IgA and/or IgG antibodies	If positive and celiac disease confirmed, test may be useful in monitoring compliance to gluten-free diet
Deamidated Gliadin Peptide (DGP) Antibody, IgG 0051359 Method: Enzyme-Linked Immunosorbent Assay	Screen for celiac disease in patient who is IgA deficient or has suboptimal IgA levels	Test results alone are not diagnostic, biopsy is currently recommended for a diagnosis of celiac disease/gluten sensitive enteropathy Certain individuals, particularly children <3 years old who test negative for tTG and/or EMA antibodies, may be positive for gliadin IgA and/or IgG antibodies	If positive and celiac disease confirmed, test may be useful in monitoring compliance to gluten-free diet
Celiac Disease Dual Antigen Screen 0051689 Method: Enzyme Linked Immunosorbent Assay	Screen for at risk individuals with deficient or suboptimal IgA levels	If positive, individual tTG and gliadin peptide antibody assays must be performed
F-Actin (Smooth Muscle) Antibody, IgA 0051724 Method: Enzyme-Linked Immunosorbent Assay	Identify a subset of celiac disease patients with more severe intestinal mucosa damage Monitor disease activity and adherence to gluten-free diet in patients with biopsy-proven celiac disease	Should not be used in screening for celiac disease Does not replace intestinal biopsy for confirming celiac disease	If positive and celiac disease confirmed, test may be useful in monitoring compliance to gluten-free diet

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Reticulin Antibody, IgA with Reflex to Titer 0050698 Method: Indirect Fluorescent Antibody	Not recommended for celiac disease testing Use tissue transglutaminase testing
Reticulin Antibody, IgG 0098878 Method: Indirect Fluorescent Antibody	Not recommended for celiac disease testing
Immunoglobulin A, Serum 0050340 Method: Nephelometry	First step in celiac diagnostic algorithm; IgA results determine whether to use IgA or IgG tTg and DGP assays
Tissue Transglutaminase Antibody, IgA with Reflex to Endomysial Antibody, IgA Titer by IFA 0050734 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody	Screen for celiac disease in patients who are not IgA deficient Certain individuals, particularly children <3 years old who test negative for tTG and/or EMA antibodies, may be positive for gliadin IgA and/or IgG antibodies tTG IgA and EMA IgA have equivalent diagnostic utility for celiac disease
Deamidated Gliadin Peptide (DGP) Antibodies, IgA & IgG 0051358 Method: Enzyme-Linked Immunosorbent Assay	Certain individuals, particularly children <3 years old who test negative for tTG and/or EMA antibodies, may be positive for gliadin IgA and/or IgG antibodies Test results alone are not diagnostic; biopsy is currently recommended for a diagnosis of celiac disease/gluten sensitive enteropathy