Molecular Diagnosis & Therapy

, Volume 12, Issue 5, pp 289–298 | Cite as

Celiac Disease

Risk Assessment, Diagnosis, and Monitoring
  • Mala Setty
  • Leonardo Hormaza
  • Stefano GuandaliniEmail author
Gastrointestinal Disorders


Celiac disease is an autoimmune disorder occurring in genetically susceptible individuals, triggered by gluten and related prolamins. Well identified haplotypes in the human leukocyte antigen (HLA) class II region (either DQ2 [DQA*0501-DQB*0201] or DQ8 [DQA*0301 -DQB1*0302]) confer a large part of the genetic susceptibility to celiac disease.

Celiac disease originates as a result of a combined action involving both adaptive and innate immunity. The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrating HLA-DQ2 or -DQ8 restrictive binding motifs across various gluten proteins. As for innate immunity, through specific natural killer receptors expressed on their surface, intra-epithelial lymphocytes recognize nonclassical major histocompatibility complex (MHC)-I molecules such as MICA, which are induced on the surface of enterocytes by stress and inflammation, and this interaction leads to their activation to become lymphokine-activated killing cells.

Four possible presentations of celiac disease are recognized: (i) typical, characterized mostly by gastrointestinal signs and symptoms; (ii) atypical or extraintestinal, where gastrointestinal signs/symptoms are minimal or absent and a number of other manifestations are present; (iii) silent, where the small intestinal mucosa is damaged and celiac disease autoimmunity can be detected by serology, but there are no symptoms; and, finally, (iv) latent, where individuals possess genetic compatibility with celiac disease and may also show positive autoimmune serology, that have a normal mucosa morphology and may or may not be symptomatic.

The diagnosis of celiac disease still rests on the demonstration of changes in the histology of the small intestinal mucosa. The classic celiac lesion occurs in the proximal small intestine with histologic changes of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytosis. Currently, serological screening tests are utilized primarily to identify those individuals in need of a diagnostic endoscopic biopsy. The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98%) and specificity (around 96%). Anti-endomysium antibodies-IgA (EMA), on the other hand, have close to 100% specificity and a sensitivity of greater than 90%. The interplay between gliadin peptides and TG2 is responsible for the generation of novel antigenic epitopes, the TG2-generated deamidated gliadin peptides. Such peptides represent much more celiac disease-specific epitopes than native peptides, and deamidated gliadin antibodies (DGP) have shown promising results as serological markers for celiac disease. Serology has also been employed in monitoring the response to a gluten-free diet.

Despite the gluten-free diet being so effective, there is a growing demand for alternative treatment options. In the future, new forms of treatment may include the use of gluten-degrading enzymes to be ingested with meals, the development of alternative, gluten-free grains by genetic modification, the use of substrates regulating intestinal permeability to prevent gluten entry across the epithelium, and, finally, the availability of different forms of immunotherapy.


Celiac Disease Human Leukocyte Antigen Coeliac Disease Villous Atrophy Celiac Disease Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Guandalini S. Celiac disease. In: Guandalini S, editor. Essential pediatric gastroenterology, hepatology and nutrition. New York: McGraw-Hill Publishers, 2005: 221–30Google Scholar
  2. 2.
    Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003; 163(3): 286–92PubMedCrossRefGoogle Scholar
  3. 3.
    Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA 2005; 293(19): 2343–51PubMedCrossRefGoogle Scholar
  4. 4.
    Ivarsson A, Hernell O, et al. Breast-feeding protects against celiac disease. Am J Clin Nutr 2002; 75(5): 914–21PubMedGoogle Scholar
  5. 5.
    Akobeng AK, Ramanan AV, Buchan I, et al. Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch Dis Child 2006; 91(1): 39–43PubMedCrossRefGoogle Scholar
  6. 6.
    Stene LC, Honeyman MC, Hoffenberg EJ, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 2006; 101(10): 2333–40PubMedCrossRefGoogle Scholar
  7. 7.
    Tollefsen S, Arentz-Hansen H, Fleckenstein B, et al. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest 2006; 116(8): 2226–36PubMedCrossRefGoogle Scholar
  8. 8.
    Arentz-Hansen H, Korner R, Molberg O, et al. The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 2000; 191(4): 603–12PubMedCrossRefGoogle Scholar
  9. 9.
    Arentz-Hansen H, McAdam SN, Molberg O, et al. Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 2002; 123(3): 803–9PubMedCrossRefGoogle Scholar
  10. 10.
    Acalovschi M, Jayanthi V, Probert CS, et al. Management of coeliac disease: a changing diagnostic approach but what value in follow up? Qual Health Care 1992; 1(1): 26–8PubMedCrossRefGoogle Scholar
  11. 11.
    Jabri B, Sollid LM. Mechanisms of disease: immunopathogenesis of celiac disease. Nat Clin Pract Gastroenterol Hepatol 2006; 3(9): 516–25PubMedCrossRefGoogle Scholar
  12. 12.
    Ciccocioppo R, Di Sabatino A, Corazza GR. The immune recognition of gluten in coeliac disease. Clin Exp Immunol 2005; 140(3): 408–16PubMedCrossRefGoogle Scholar
  13. 13.
    Molberg O, McAdam SN, Korner R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998; 4(6): 713–7PubMedCrossRefGoogle Scholar
  14. 14.
    Kaukinen K, Peraaho M, Collin P, et al. Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: a prospective and randomized clinical study. Scand J Gastroenterol 2005; 40(5): 564–72PubMedCrossRefGoogle Scholar
  15. 15.
    Meresse B, Curran SA, Ciszewski C, et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med 2006; 203(5): 1343–55PubMedCrossRefGoogle Scholar
  16. 16.
    Meresse B, Chen Z, Ciszewski C, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004; 21(3): 357–66PubMedCrossRefGoogle Scholar
  17. 17.
    Dickey W, Hughes DF, McMillan SA. Patients with serum IgA endomysial antibodies and intact duodenal villi: clinical characteristics and management options. Scand J Gastroenterol 2005; 40(10): 1240–3PubMedCrossRefGoogle Scholar
  18. 18.
    Guandalini S. Celiac disease. In: Guandalini S, editor. Textbook of pediatric gastroenterology and nutrition. London: Taylor & Francis Books Ltd, 2004: 435–50Google Scholar
  19. 19.
    Marsh MN. Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology1992; 102(1): 330–54PubMedGoogle Scholar
  20. 20.
    Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40(1): 1–19PubMedCrossRefGoogle Scholar
  21. 21.
    Berger E, Buergin-Wolff A, Freudenberg E. Diagnostic value of the demonstration of gliadin antibodies in celiac disease [in German]. Klin Wochenschr 1964; 42: 788–90PubMedCrossRefGoogle Scholar
  22. 22.
    Chorzelski TP, Beutner EH, Sulej J, et al. IgA anti-endomysium antibody: a new immunological marker of dermatitis herpetiformis and coeliac disease. Br J Dermatol 1984; 111(4): 395–402PubMedCrossRefGoogle Scholar
  23. 23.
    Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997; 3(7): 797–801PubMedCrossRefGoogle Scholar
  24. 24.
    Rostami K, Kerckhaert J, Tiemessen R, et al. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999; 94(4): 888–94PubMedCrossRefGoogle Scholar
  25. 25.
    Tursi A, Brandimarte G, Giorgetti G, et al. Low prevalence of antigliadin and antiendomysium antibodies in subclinical/silent celiac disease. Am J Gastroenterol 2001; 96(5): 1507–10PubMedCrossRefGoogle Scholar
  26. 26.
    Villalta D, Alessio MG, Tampoia M, et al. Diagnostic accuracy of IgA anti-tissue transglutaminase antibody assays in celiac disease patients with selective IgA deficiency. Ann NY Acad Sci 2007; 1109: 212–20PubMedCrossRefGoogle Scholar
  27. 27.
    Rostom A, Dube C, Cranney A, et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology 2005; 128(4 Suppl. 1): S38–46PubMedCrossRefGoogle Scholar
  28. 28.
    Villalta D, Alessio MG, Tampoia M, et al. Testing for IgG class antibodies in celiac disease patients with selective IgA deficiency: a comparison of the diagnostic accuracy of 9 IgG anti-tissue transglutaminase, 1 IgG anti-gliadin and 1 IgG anti-deaminated gliadin peptide antibody assays. Clin Chim Acta 2007; 382(1–2): 95–9PubMedCrossRefGoogle Scholar
  29. 29.
    Volta U, Granito A, Fiorini E, et al. Usefulness of antibodies to deamidated gliadin peptides in celiac disease diagnosis and follow-up. Dig Dis Sci 2008 Jun; 53(6): 1582–8PubMedCrossRefGoogle Scholar
  30. 30.
    Kaukinen K, Collin P, Laurila K, et al. Resurrection of gliadin antibodies in coeliac disease: deamidated gliadin peptide antibody test provides additional diagnostic benefit. Scand J Gastroenterol 2007; 42(12): 1428–33PubMedCrossRefGoogle Scholar
  31. 31.
    Greco L, Romino R, Cote I, et al. The first large population based twin study of coeliac disease. Gut 2002; 50(5): 624–8PubMedCrossRefGoogle Scholar
  32. 32.
    Sollid LM, Lie BA. Celiac disease genetics: current concepts and practical applications. Clin Gastroenterol Hepatol 2005; 3(9): 843–51PubMedCrossRefGoogle Scholar
  33. 33.
    Amundsen SS, Adamovic S, Hellqvist A, et al. A comprehensive screen for SNP associations on chromosome region 5q31-33 in Swedish/Norwegian celiac disease families. Eur J Hum Genet 2007; 15(9): 980–7PubMedCrossRefGoogle Scholar
  34. 34.
    Holopainen P, Naluai AT, Moodie S, et al. Candidate gene region 2q33 in European families with coeliac disease. Tissue Antigens 2004; 63(3): 212–22PubMedCrossRefGoogle Scholar
  35. 35.
    Naluai AT, Nilsson S, Samuelsson L, et al. The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders. Tissue Antigens 2000; 56(4): 350–5PubMedCrossRefGoogle Scholar
  36. 36.
    Liu Y, Helms C, Liao W, et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease Loci. PLoS Genet 2008; 4(3): e1000041PubMedCrossRefGoogle Scholar
  37. 37.
    Karell K, Louka AS, Moodie SJ, et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003; 64(4): 469–77PubMedCrossRefGoogle Scholar
  38. 38.
    Margaritte-Jeannin P, Babron MC, Bourgey M, et al. HLA-DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on Coeliac Disease. Tissue Antigens 2004; 63(6): 562–7PubMedCrossRefGoogle Scholar
  39. 39.
    Hunt KA, Zhernakova A, Turner G, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 2008; 40(4): 395–402PubMedCrossRefGoogle Scholar
  40. 40.
    Akobeng AK, Thomas AG. Systematic review: tolerable amount of gluten for people with coeliac disease. Aliment Pharmacol Ther 2008; 27(11): 1044–52PubMedCrossRefGoogle Scholar
  41. 41.
    Casellas F, Rodrigo L, Vivancos JL, et al. Factors that impact health-related quality of life in adults with celiac disease: a multicenter study. World J Gastroenterol 2008; 14(1): 46–52PubMedCrossRefGoogle Scholar
  42. 42.
    Garsed K, Scott BB. Can oats be taken in a gluten-free diet? A systematic review. Scand J Gastroenterol 2007; 42(2): 171–8CrossRefGoogle Scholar
  43. 43.
    Vargas Perez ML, Melero Ruiz J, Fernandez de Mera J, et al. Serological and genetic markers in the diagnosis and follow-up of co eliac disease [in Spanish]. An Pediatr (Barc) 2005; 62(5): 412–9CrossRefGoogle Scholar
  44. 44.
    Dickey W, Hughes DF, McMillan SA. Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery. Am J Gastroenterol 2000; 95(3): 712–4PubMedCrossRefGoogle Scholar
  45. 45.
    Bardella MT, Velio P, Cesana BM, et al. Coeliac disease: a histological follow-up study. Histopathology 2007; 50(4): 465–71PubMedCrossRefGoogle Scholar
  46. 46.
    Khosla C, Gray GM, Sollid LM. Putative efficacy and dosage of prolyl endopeptidase for digesting and detoxifying gliadin peptides. Gastroenterology 2005; 129(4): 1362–3; author reply 1363PubMedCrossRefGoogle Scholar
  47. 47.
    Hernando A, Mujico JR, Mena MC, et al. Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States and Canada by Sandwich R5 ELISA. Eur J Gastroenterol Hepatol 2008; 20(6): 545–54PubMedCrossRefGoogle Scholar
  48. 48.
    Watts T, Berti I, Sapone A, et al. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci U S A 2005; 102(8): 2916–21PubMedCrossRefGoogle Scholar
  49. 49.
    Paterson BM, Lammers KM, Arrieta MC, et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007; 26(5): 757–66PubMedCrossRefGoogle Scholar
  50. 50.
    Bayry J, Lacroix-Desmazes S, Kazatchkine MD, et al. Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action. Nat Clin Pract Rheumatol 2007; 3(5): 262–72PubMedCrossRefGoogle Scholar
  51. 51.
    Ferrari-Lacraz S, Zanelli E, Neuberg M, et al. Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J Immunol 2004; 173(9): 5818–26PubMedGoogle Scholar
  52. 52.
    Morris JC, Janik JE, White JD, et al. Preclinical and phase I clinical trial of blockade of IL-15 using Mikbetal monoclonal antibody in T cell large granular lymphocyte leukemia. Proc Natl Acad Sci U S A 2006; 103(2): 401–6PubMedCrossRefGoogle Scholar
  53. 53.
    Vivas S, Ruiz de Morales JM, Ramos F, et al. Alemtuzumab for refractory celiac disease in a patient at risk for enteropathy-associated T-cell lymphoma. N Engl J Med 2006; 354(23): 2514–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Mala Setty
    • 1
  • Leonardo Hormaza
    • 1
  • Stefano Guandalini
    • 1
    Email author
  1. 1.Section of Gastroenterology, Hepatology and Nutrition, Department of PediatricsUniversity of ChicagoChicagoUSA

Personalised recommendations