Test code: 36336

Clinical use

• Diagnose celiac disease (CD) in children and adults

Clinical background

CD is an autoimmune disorder caused by an inappropriate immune response to dietary gluten in genetically susceptible individuals. The inflammatory response to ingested gluten leads to defects in the mucosa of the small intestine (eg, villous blunting due to crypt hyperplasia), which can inhibit the absorption of nutrients.^1–4 CD affects approximately 1% of people in the United States,^2,5,6 but the prevalence is higher in people with type 1 diabetes; autoimmune thyroiditis; Down, Turner, or Williams syndromes; selective IgA deficiency; or a first-degree relative with CD.^1,6 The incidence and prevalence of CD have increased considerably over the last 50 years.^2,4,7 

Although CD primarily affects the small intestine, symptoms can be both gastrointestinal (eg, diarrhea, constipation, abdominal pain) and extraintestinal (eg, dermatitis herpetiformis, anemia, osteoporosis, headaches, fatigue) or be absent.^2,5,6 Young children with CD may also experience abdominal distension as well as short stature and delayed puberty due to malabsorption of nutrients.^2,6,7 

Early diagnosis of CD and adoption of a gluten-free diet are necessary for mucosal healing.^6–8 Diagnosis begins with clinical assessment and serologic testing, and may need to be confirmed by biopsy of the small intestine.^1,5,7,9 Levels of CD-related antibodies decrease after starting a gluten-free diet, so patients undergoing serologic testing for CD should be on a gluten-containing diet (ie, a normal diet), according to guidelines from the American College of Gastroenterology (ACG) and the World Gastroenterology Organisation.^1,7,9 Tests for the following antibodies are used in the diagnosis of CD in adults and children:

• Tissue transglutaminase (tTG) IgA: tTG IgA is highly sensitive and specific for CD⁶ (Table 1 ^6,7,9–11) and is recommended as a first-line marker for CD.^7,9
• Endomysial (EMA) IgA: EMA IgA has a lower sensitivity but higher specificity for CD than does tTG IgA⁶ and can be used to confirm positive tTG IgA test results (>10x upper limit of normal); testing is recommended in adults who are unwilling or unable to undergo upper gastrointestinal endoscopy and in children only if family agrees with a no-biopsy strategy.⁹ 
• tTG IgG and deamidated gliadin peptide (DGP) IgG antibodies: Although tTG IgG and DGP IgG are less sensitive than tTG IgA for CD, they are highly specific⁶; testing is recommended for adults and children who are IgA-deficient.⁹
• Total IgA: Total IgA is measured to identify selective IgA deficiency relative to age-specific reference ranges. IgA deficiency is more common among CD patients (2% to 3%)¹² than the general population (<0.45%)¹³ and can affect interpretation of serologic test results. Patients with IgA deficiency may have negative results on IgA antibody tests (tTG IgA and EMA IgA) but positive results on IgG antibody tests (tTG IgG and DGP IgG).^5,9 

Table 1. Sensitivity and Specificity of Serologic Markers of CD

The Celiac Disease Comprehensive Panel With Gliadin Antibody (IgG) (test code 36336) begins by testing for tTG IgA (test code 8821) and total IgA (test code 539, Table 2) consistent with 2023 ACG guidelines.⁹ A tTG IgA result above the reference range prompts reflex to an EMA IgA test cascade (test code 15064), with a positive result reflexing to EMA titer for quantification. Total IgA below the lower limit of the age-specific reference range (or <47 mg/dL if no age is specified) prompts reflex to tTG IgG (test code 11070) and DGP IgG (test code 11212). Reflex tests are performed at additional charge and are associated with an additional CPT code(s). Panel components may be ordered separately (Table 2). The Celiac Disease Comprehensive Panel (test code 19955) reflexes to EMA IgA and titer, but not tTG and DGP IgGs.

Table 2. Individual Tests Included in the Celiac Disease Comprehensive Panel With Gliadin Antibody (IgG)

The Celiac Disease Comprehensive Panel With Gliadin Antibodies (Age 5 and Under) (test code 36331) begins by testing for 4 analytes: tTG IgA (test code 8821), DGP IgA (test code 11228), DGP IgG (test code 11212), and total IgA (test code 539, Table 2) consistent with legacy 2013 ACG guidelines for children younger than 2 years.⁷ This test option involves reflex testing to EMA titer (if EMA IgA positive) and tTG IgG testing if IgA-deficient based on age-specific reference ranges. Panel components may be ordered separately (Table 2). The Celiac Disease Comprehensive Panel, Infant (test code 15981) is similar but does not include DGP IgG.

Interpretive information

Positive results from any CD-specific antibody test (tTG IgA, tTG IgG, DGP IgA or IgG) are consistent with a diagnosis of CD. Following a positive tTG IgA result, a positive EMA screen increases the specificity of the diagnosis. Guidelines indicate that a serologic diagnosis of CD should be confirmed with biopsy of the small intestine, but patients may be diagnosed without a biopsy in certain situations, ie, in adults who are unwilling or unable to undergo upper GI endoscopy and in children only if family agrees with a no-biopsy strategy.⁹

Among patients with normal IgA levels, a negative tTG IgA result indicates that CD is unlikely. Patients with IgA levels below the lower limit of the reference range, based on age, may be IgA-deficient. Among IgA-deficient patients, negative tTG IgA results may reflect a lack of IgA antibodies, but negative DGP IgG and tTG IgG results indicate that CD is unlikely. However, negative serology does not rule out CD; some patients with CD may be seronegative, and some may have false-negative results if they started a gluten-free diet before testing.

If results of serologic tests are negative but clinical suspicion of CD remains high, biopsy of the small intestine may be appropriate.^7,9 Testing for HLA-DQ2 and HLA-DQ8 (HLA Typing for Celiac Disease; test code 17135), which are present in almost all people with CD, can help rule out CD when clinical and laboratory findings are equivocal.^1,5,7,9