EVIDENCE-BASED ANSWER
Histological confirmation of infiltrative lesions via small bowel biopsy is the gold standard for diagnosing celiac disease. Four serum antibody assays may serve as a first-step diagnostic tool to identify biopsy candidates: immunoglobulin A tissue transglutaminase (IgA tTG), IgA endomysial antibody (IgA EMA), IgA antigliadin antibody (IgA AGA), and IgG antigliadin antibody (IgG AGA). IgA tTG and IgA EMA offer the best diagnostic accuracy. Patients with selective IgA deficiency may have falsely negative IgA assays (strength of recommendation [SOR]: B, based on a systematic review, multiple small cross-sectional studies, and expert opinion).
CLINICAL COMMENTARY
The most reliable testing option is also the most cost-effective
Belinda Fu, MD
University of Washington, Seattle
When faced with a cryptic array of available serologic tests for celiac disease, and often pressed for time to look up which one is best, we are often quite tempted to simply check “Celiac Panel” on the lab order sheet and just order them all. However, the authors present us with an evidence-based rationale for limiting our lab testing to just one of the available serologic tests.
What a delight to find that the most reliable testing option is also the most cost-effective. At our university hospital, the billable cost of each serologic marker for celiac disease is approximately $50, and the entire panel—which includes IgA tTG, IgG tTG, IgA EMA, and IgA/G AGA—is $250. Rather than ordering the redundant panel (why include anti-AGA at all?), it is far better to start with IgA tTG or IgA EMA, and follow-up with IgG levels if necessary.
When ordering these tests, it is worth noting that some physicians recommend patients be on a gluten-containing diet for 2 to 4 weeks before serologic testing, to minimize the possibility of insufficient antibody titers.
Evidence summary
Celiac disease (also called celiac sprue, nontropical sprue, or gluten-sensitive enteropathy) is an autoimmune disorder classified by intestinal inflammation and malabsorption in response to dietary gluten—a storage protein component of wheat gliadins. Celiac disease patients—0.5% to 1.0% of the US population1—are often sensitive to other closely related grain proteins found in oats, barley, and rye.
Celiac disease’s classic histological finding is an infiltrative small intestine lesion characterized by villous flattening, crypt hyperplasia, and lymphocyte accumulation in the lamina propria.2 The American Gastroenterological Association’s (AGA) diagnostic criteria include confirmation of this abnormal mucosa and unequivocal improvement on repeat biopsy following a gluten-free diet.3 However, either clinical improvement or biopsy of dermatitis herpetiformis skin lesions (common occurrences in celiac disease) are often considered adequate for diagnosis without repeat intestinal biopsies.
Its reversible nature makes prompt diagnosis of celiac disease important. Three antibodies commonly appear in celiac disease patients: antibodies to tTG, antiendomysial antibodies, and antigliadin antibodies.4-6 AGA binds dietary gluten and EMA binds the enzyme tTG, which is found in connective tissue surrounding the smooth muscle cells in the intestinal wall.
The gluten-autoantibody interaction in the small intestinal lumen has IgA as its major component; IgG represents a longer-term immune response. Serum assays of the IgA and IgG forms of AGA and tTG are enzyme-linked immunosorbent assays (ELISA); EMA is measured by indirect immunofluorescence.5,6
In 2 studies of the diagnostic accuracy of IgA tTG, 95% to 98% of biopsy-proven celiac disease patients had positive tests, while only 5% to 6% of controls were positive.4,5 In a systematic review, there was no statistically significant difference between IgA EMA and IgA tTG—both had sensitivities greater than 90% and specificities greater than 95%.7 IgA AGA did not perform as well (sensitivity 80%–90%, specificity 85%–95%). The TABLE summarizes the diagnostic accuracy of the various tests.
TABLE
Diagnostic accuracy of serologic tests for celiac disease patients with normal IgA levels
| SEROLOGIC TEST | SN | SP | LR+ | LR– |
|---|---|---|---|---|
| IgA tTG | 95%–98% .95 | 94%–95% .94 | 16 | 0.05 |
| IgA EMA | >90% .91 | >95% .90 | 23 | 0.09 |
| IgA AGA | 80%–90% .85 | 85%–95% .90 | 8.5 | 0.17 |
| IgG tTG | 40% | 95% | 8 | 0.63 |
| IgG EMA | 40% | 95% | 8 | 0.63 |
| IgG AGA | 80% | 80% | 4 | 0.25 |
| Sn, sensitivity; Sp, specificity; LR+, likelihood ratio of a positive test result; LR–, likelihood ratio of a negative test result. | ||||