Gluten Sensitivity Antibodies Cascade

This test is intended to aid in the differential diagnosis of gluten-related disorders in patients with symptoms associated with gluten ingestions. Gluten is a key structural protein found in wheat, rye and barley. Gliadin, the alcohol-soluble fraction of gluten, contains most of the toxic components and is resistant to degradation in the upper human gastrointestinal tract. Reactions to ingested gluten occur in three forms: autoimmune (celiac disease (CD), allergic), wheat allergy (WA) and non-celiac gluten sensitivity (NCGS). This screening profile is designed to aid in the differential diagnosis of these gluten-related disorders. 

Celiac disease (CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically susceptible individuals. It affects about 1% of the population worldwide and is characterized by chronic diarrhea, weight loss, abdominal distention/pain, iron deficiency anemia, chronic fatigue and dermatitis herpetiformis. Autoimmune damage causes villous atrophy and crypt hyperplasia on small intestinal biopsy, which is diagnostic, while serology, especially antibodies to tissue transglutaminase (anti-tTG IgA) or deamidated gliadin peptide (anti-DGP IgG) in cases of IgA deficiency, are very specific to CD and can support diagnosis. 

Wheat allergy is an adverse IgE-mediated immunologic reaction to wheat proteins and represents a classic food allergy that can affect the skin, gastrointestinal tract and respiratory system. Clinical manifestations include baker's asthma, rhinitis, contact urticaria, and, in severe cases, anaphylaxis. The condition is relatively uncommon, with an estimated prevalence of <1% to 4%. Various wheat grain proteins have been identified as allergens, and testing for wheat-specific IgE and to components such as w-5 gliadin (Tri a 19), lipid transfer  protein (Tri a 14), gliadin, Phl p 12 (Timothy grass profilin) and/or cross-reactive carbohydrate determinant (CCD) is used to support diagnosis. 

Non-celiac gluten sensitivity (NCGS) is a food sensitivity that does not involve allergic or autoimmune mechanisms. It is characterized by both intestinal and extraintestinal symptoms, often resembling irritable bowel syndrome (IBS), including abdominal pain, bloating, gas, and irregular bowel movements. Extraintestinal manifestations can include headache or migraine, "foggy mind," chronic fatigue, joint and muscle pain, tingling or numbness in the extremities, eczema, anemia and depression. NCGS currently lacks specific serological biomarkers; diagnosis is made by exclusion of celiac disease and wheat allergy and confirmed by correlating symptoms with gluten ingestion and elimination. Its prevalence is not clearly defined; some reports indicate prevalence between ~0.5% and 10% with much higher prevalence in symptomatic patients (up to 40% in symptomatic children). It may overlap with irritable bowel syndrome (IBS). Anti-gliadin (native) antibodies, especially IgG, can partially support NCGS diagnosis with reported positive predictive value of more than 50% in patients diagnosed with NCGS, especially in the absence of celiac markers, tTG and DGP antibodies. 

Step 1: The screening starts with testing for tTG IgA and DGP IgG. When either or both of the results are positive, testing stops and the interpretive comment on the report is: "Suggestive of celiac disease or other gluten-sensitive enteropathies. Subsequent testing for Endomysial Antibody, IgA [164996] may be indicated." When the result is negative, testing reflexes to the second step. 

Step 2: In the second step, the test for wheat allergen-specific IgE is performed. If positive, the interpretive comment is: "Suggestive of wheat allergy. The patient may benefit from a gluten-free diet." When the result is negative, testing reflexes to the third step. 

Step 3: In the last step, the test for IgG antibodies to native gliadin (AGA) is performed. When the result is positive, the interpretive comment is: "Suggestive of non-celiac gluten sensitivity." When the result is negative, the comment is: "Not suggestive of gluten sensitivity."