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Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet
  1. Tarcisio Not1,2,
  2. Fabiana Ziberna1,2,
  3. Serena Vatta1,2,
  4. Sara Quaglia1,2,
  5. Stefano Martelossi1,2,
  6. Vincenzo Villanacci3,
  7. Roberto Marzari4,
  8. Fiorella Florian4,
  9. Monica Vecchiet4,
  10. Ana-Marija Sulic4,
  11. Fortunato Ferrara1,2,
  12. Andrew Bradbury5,
  13. Daniele Sblattero6,
  14. Alessandro Ventura1,2
  1. 1Department of Reproductive, Developmental and Public Health Sciences, University of Trieste, Trieste, Italy
  2. 2Institute of Child Health IRCCS ‘Burlo Garofolo’, Trieste, Italy
  3. 3Department of Pathology, Spedali Civili, University of Brescia, Brescia, Italy
  4. 4Department of Life Science, University of Trieste, Trieste, Italy
  5. 5Biosciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
  6. 6Department of Medical Sciences, and IRCAD, University of Eastern Piedmont, Novara, Italy
  1. Correspondence to Tarcisio Not, Istituto per l'Infanzia ‘Burlo Garofolo’, Via dell'Istria 65/1, Trieste 34100, Italy; not{at}


Background and objective Antitransglutaminase (anti-TG2) antibodies are synthesised in the intestine and their presence seems predictive of future coeliac disease (CD). This study investigates whether mucosal antibodies represent an early stage of gluten intolerance even in the absence of intestinal damage and serum anti-TG2 antibodies.

Methods This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities. Fifteen subjects were symptomatic and seven were asymptomatic. The presence of immunoglobulin A anti-TG2 antibodies in the intestine was studied by creating phage-antibody libraries against TG-2. The presence of intestinal anti-TG2 antibodies was compared with the serum concentration of the intestinal fatty acid-binding protein (I-FABP), a marker for early intestinal mucosal damage. The effects of a 12-month gluten-free diet on anti-TG2 antibody production and the subjects' clinical condition was monitored. Twelve subjects entered the study as controls.

Results The intestinal mucosa appeared normal in 18/22; 4 had a slight increase in intraepithelial lymphocytes. Mucosal anti-TG2 antibodies were isolated in 15/22 subjects (68%); in particular symptomatic subjects were positive in 13/15 cases and asymptomatic subjects in 2/7 cases (p=0.01). No mucosal antibodies were selected from the controls' biopsies. There was significant correlation between the presence of intestinal anti-TG2 antibodies and positive concentrations of I-FABP (p=0.0008). After a gluten-free diet, 19/22 subjects underwent a second intestinal biopsy, which showed that anti-TG2 antibodies had disappeared in 12/15 (p=0.002), while I-FABP decreased significantly (p<0.0001). The diet resolved both extraintestinal and intestinal symptoms.

Conclusions A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms.

Clinical trial number NCT00677495.

  • Genetic gluten intolerance
  • intestinal antitransglutaminase antibodies
  • intestinal fatty acid-binding protein
  • phage-antibody libraries
  • gluten-free diet
  • gluten-sensitive enteropathy
  • mucosal immunity

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  • Funding This study was supported by the following grants: grant 35/07RF from the Institute of Child Health IRCCS ‘Burlo Garofolo’ to TN, Compagnia SanPaolo to DS and EC Marie Curie Research Training Network (MRTN-CT-2006-036032) to RM.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Independent Ethical Committee of the Institute of Child Health IRCCS ‘Burlo Garofolo’ (CE/V-75 2007).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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