The race for the best serological marker for celiac disease is on
Vol. 24 • Issue 7 • Page 14
Celiac disease (CD) is an autoimmune inflammatory disorder of the small intestine, triggered by the ingestion of prolamins contained in wheat, barley, rye and, to a lesser extent, oats, in genetically susceptible individuals. Its incidence is 1% in western countries as compared to 6-10% for non-celiac gluten sensitivity.
The epidemiology and phenotype of CD is constantly changing. The classic intestinal clinical pictures of malnutrition, chronic diarrhea with protuberant abdomen are disappearing and extraintestinal manifestations are emerging. Skin, endocrine, skeletal, hepatic, hematological, thrombophylic, cardiac, gynecological, fertility, dental and behavioral abnormalities are often described.
Lately, we have witnessed an epidemiological shift in the disease phenotype toward more advanced age and increased prevalence of latent, hypo-symptomatic or asymptomatic behavior.1,2 The ratio between diagnosed and undiagnosed cases is 1:9. All these changes make the diagnosis of the disease more difficult and the reliance on symptomatology more remote.3 CD is a treatable disease and a gluten-free diet can prevent many of its complications; these are the main reasons why serological screening and diagnosis of CD are of prime importance.4
Multiple serological tests exist on the market, ranging from detection of anti-gliadin antibody to several autoimmune antibody tests. The first to be discovered (in the early 1980s) was IgA anti-endomysial antibody, followed by IgA/IgG anti-tissue transglutaminase (tTg), IgA/IgG anti-deaminated gliadin peptide (DGP) and, more recently, IgA/IgG anti neo-epitope tTg.4 This last antibody is induced when the endogenous enzyme tTg is crosslinked with gliadin-specific peptides, changing its electrical, structural and conformational
characteristics, creating neo-epitopes. These posttranslational modifications are crucial for changing the gliadin from a tolerant to auto-immunogenic form.
The antibodies against neo-epitopes of the tTg-DGP complex provide a new screening and diagnostic test in CD. Diagnostic sensitivities of 95% percent and specificities of 97 percent or more, when compared with the other traditional antibody assays, have been shown.5,6 It was suggested that these neo-epitope directed antibodies appear early during the development of CD, preceding the formation of anti-DGP and anti-tTg, through a mechanism of epitope spreading.7
A Closer Look at Neo-epitope Complex
Several very recent studies presented in international congresses (as yet unpublished) suggest that the autoantibodies generated against the neo-epitope complex represent the best means of screening populations and diagnosing high-risk groups for identification of silent or latent patients.8 A comparison of 12 different CD associated antibody isotypes revealed that anti-neo-epitope tTg antibodies stood out as the most reliable ones and best reflected intestinal damage.8 The anti-neo-epitope tTg antibody was found to be superior for diagnosing CD.9
In fact, several studies have shown the benefits of screening for CD using the tTg-DGPs complex strategy in the general population6,10 or in groups of at-risk subjects.11-16 Most recently, anti-neo-epitope tTg antibodies were shown to represent a new and sensitive serological marker of dermatitis herpetiformis, a disease closely related to CD.17
The Table summarizes the performance of serological markers in population screening and case finding of CD.
Based on the needs mentioned above and the performance of different serological markers, together with the urgency to improve the rate of CD diagnosis and implement a gluten-free diet as early as possible, it is suggested that anti-neo-epitope IgA/IgG antibodies should be preferably used to diagnose, monitor dietary restriction compliance and reflect the intestinal damage of CD. We suggest that the revised ESPGHAN criteria for pediatric CD diagnosis include anti-neo-epitope antibodies in the recently described diagnostic flow chart.
- Lerner A. Factors affecting the clinical presentation and time diagnosis of celiac disease: The Jerusalem and the West Bank-Gaza experience. Isr J Med Sci. 1994; 11:294-295.
- Lerner A, Agmon-Levin N, Shapira Y, Gilburd B, Reuter S, Lavi I, Shoenfeld Y. The thrombophilic network of autoantibodies in celiac disease. BMC Med. 2013; 11: 89.
- Katz KD, Rashtak S, Lahr BD et al. Screening for celiac disease in a North American population: Sequential serology and gastrointestinal symptoms. Amer J Gastroentrol 2011; 106:1333-1339.
- Lerner A. Editorial: Serological diagnosis of celiac disease-moving beyond the tip of the iceberg. Internat. J Celiac Dis. 2015.
- Bizzaro N, Tozzoli R, Villalta D, Fabris M, Tonutti E. Cutting-edge issues in celiac disease and in gluten intolerance. Clin Rev Allergy Immunol. 2012; 42:279-87.
- Tozzoli R, Kodermaz G, Tampoia M, Visentini D, Tonutti E, Bizzaro N. [detection of autoantibodies specific for transglutaminase-gliadin peptides complex: a new way to explore the celiac iceberg.] It J Lab Med. 2010; 6:28-35.
- Matthias T, Pfeiffer S, Selmi C, Gershwin M. Diagnostic challenges in celiac disease and the role of the tissue transglutaminase-neo-epitope. Clin Rev Allergy Immunol. 2010; 38:298-301.
- Matthias T, Jeremias P, Neidhöfer S, Lerner A. Antibodies against neo-epitope tTg complexed to gliadin are more reliable than anti-tTg for the diagnosis of pediatric celiac disease. 49th ESPGHAN congress, Amsterdam 6-9 th May, 2015.
- Matthias T, Jeremias P, Neidhöfer S, LernerA. Comparison of the reliability of celiac disease serology to reflect intestinal damage. 49th ESPGHAN congress, Amsterdam 6-9 th May, 2015.
- Remes-Troche JM, Ramírez-Iglesias MT, Rubio-Tapia A, Alonso-Ramos A, Velazquez A, Uscanga LF. Celiac disease could be a frequent disease in Mexico: Prevalence of tissue transglutaminase antibody in healthy blood donors. J Clin Gastroenterol. 2006; 40:697-700.
- Rozenberg O, Lerner A, Pacht A, Grinberg M, Reginashvili D, Henig C, Barak M. A novel algorithm for the diagnosis of celiac disease and a comprehensive review of celiac disease diagnostics. Clin Rev Allergy Immunol. 2012; 42:331-41.
- Rozenberg O, Lerner A, Pacht A, Grinberg M, Reginashvili D, Henig C, Barak M. A new algorithm for the diagnosis of celiac disease. Cell Mol Immunol. 2011; 8:146-9.
- Barak M, Rozenberg O, Froom P, Grinberg M, Reginashvili D, Henig C, Pacht A, Lerner A. Challenging our serological algorithm for celiac disease (CD) diagnosis by the ESPGHAN guidelines. Clin Chem Lab Med.2013;51;e257-259.
- Remes-Troche JM, Rios-Vaca A, Ramírez-Iglesias MT, Rubio-Tapia A, Andrade-Zarate V, Rodríguez-Vallejo F, López-Maldonado F, Gomez-Perez FJ, Uscanga LF. High prevalence of celiac disease in Mexican Mestizo adults with type 1 diabetes mellitus. J Clin Gastroenterol.2008; 42:460-5.
- Tozzoli R, Kodermaz G, Porcelli B et al. Clinical relevance and diagnostic accuracy of new ELISA method for the detection of autoantibodies to gliadin-transglutaminase complex. Proceedings of the 7th International Congress on autoimmunity, Ljubljana, 5-9 May, 2010.
- Tonutti E, Visentini D, Fabris M et al. Antibodies to the transglutaminase-deamidated gliadin complex: A new serological approach to the diagnosis of celiac disease.Proceedings of the 7th International Congress on autoimmunity, Ljubljana, 5-9 May, 2010.
- Lytton SD, Antiga E, Pfeiffer S, Matthias T, Szaflarska-Poplawska A, Ulaganathan VK, Placek W, Fabbri P, Hall R, Caproni M. Neo-epitope tissue transglutaminase autoantibodies as a biomarker of the gluten sensitive skin disease-dermatitis herpetiformis. Clin Chim Acta. 2013; 415:346-349.