Esophagus to Small Intestine

Lancet Gastroenterol Hepatol. 2023;8(11):1005–14

Ciacci C, Bai JC, Holmes G, Al-Toma A, Biagi F, Carroccio A, Ciccocioppo R, Di Sabatino A, Gingold-Belfer R, Jinga M, Makharia G, Niveloni S, Norman GL, Rostami K, Sanders DS, Smecuol E, Villanacci V, Vivas S, Zingone F; Bi.A.CeD study group

Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected celiac disease without IgA deficiency (Bi.A.CeD): A multicenter, prospective cohort study

Background: Whether celiac disease in adults can be diagnosed with serology alone remains controversial. The authors aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of celiac disease.
Methods: In this multicenter, prospective cohort study, adult participants (aged ≥ 18 years) with suspected celiac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from February 27, 2018, to December 24, 2020, by 14 tertiary referral centers (10 from Europe, 2 from Asia, 1 from Oceania, and 1 from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test’s upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of celiac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver-operating characteristic curve (AUC) for categorical and continuous data.
Findings: 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 women [68%] and 140 men [32%]; mean age, 40 years [standard deviation 15]) were enrolled. Positive serum tTG-IgA was detected in 363 participants (83%) and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, 7 had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93.9% (95% confidence interval [CI]: 89.2–98.6), the negative predictive value was 90.4% (95% CI: 85.5–95.3), sensitivity was 98.0% (95% CI: 95.3–100.0), and specificity was 75.0% (95% CI: 66.6–83.4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and 7 false negative cases, resulting in a positive predictive value of 95.9% (95% CI: 92.0–99.8), a negative predictive value of 90.4% (95% CI: 85.5–95.3), a sensitivity of 98.0% (95% CI: 95.3–100.0), and a specificity of 81.5% (95% CI: 73.9–89.1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p < 0.0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0.87 (95% CI: 0.81–0.92) when applying the categorical definition of serum tTG-IgA (positive [> 1x ULN] vs. negative [≤ 1x ULN]), and 0.93 (95% CI: 0.89–0.96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (9 patients), autoimmune atrophic gastritis (3), reflux esophagitis (31), gastric or duodenal ulcer (3), and Barrett’s esophagus (1). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet.

Interpretation: These data showed that biopsy could be reasonably avoided in the diagnosis of celiac disease in adults with reliable suspicion of celiac disease and high serum anti-tissue transglutaminase IgA.

Prof. Dr. C. Ciacci, Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, Salerno, Italy, E-Mail:

DOI: 10.1016/s2468-1253(23)00205-4

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