Definition of Celiac Disease and Gluten Sensitivity

  • Karen M. Lammers
  • Brintha Vasagar
  • Alessio Fasano
Chapter
Part of the Clinical Gastroenterology book series (CG)

Abstract

As an important component of wheat, rye, and barley, gluten can be found in a large variety of foods consumed throughout the world (breads, pasta, pizza, etc.). However, the introduction of gluten-containing grains in the human diet about 10,000 years ago created the conditions for human diseases related to gluten exposure. These reactions to gluten represent a heterogeneous set of conditions, including celiac disease, non-celiac gluten sensitivity, and wheat allergy, which combined affect about 10 % of the general population. These three conditions represent distinct pathophysiological reactions to gluten ingestion, with differing clinical presentations, serological markers, and long-term treatments. Though current research strives to clarify the boundaries between these entities, their differences can be difficult to distinguish. This chapter provides an overview of the ever-evolving definitions of gluten-related disorders.

Keywords

Permeability Fatigue Lymphoma Osteoporosis Leukemia 

References

  1. 1.
    Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Auricchio S, De Ritis G, De Vincenzi M, Mancini E, Minetti M, Sapora O, et al. Agglutinating activity of gliadin-derived peptides from bread wheat: implications for coeliac disease pathogenesis. Biochem Biophys Res Commun. 1984;121(2):428–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Clemente MG, De Virgiliis S, Kang JS, Macatagney R, Musu MP, Di Pierro MR, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003;52(2):218–23.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Dolfini E, Elli L, Dasdia T, Bufardeci B, Colleoni MP, Costa B, et al. In vitro cytotoxic effect of bread wheat gliadin on the LoVo human adenocarcinoma cell line. Toxicol In Vitro. 2002;16(4):331–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Dolfini E, Elli L, Roncoroni L, Costa B, Colleoni MP, Lorusso V, et al. Damaging effects of gliadin on three-dimensional cell culture model. World J Gastroenterol. 2005;11(38):5973–7.PubMedGoogle Scholar
  6. 6.
    Maiuri L, Troncone R, Mayer M, Coletta S, Picarelli A, De Vincenzi M, et al. In vitro activities of A-gliadin-related synthetic peptides: damaging effect on the atrophic coeliac mucosa and activation of mucosal immune response in the treated coeliac mucosa. Scand J Gastroenterol. 1996;31(3):247–53.PubMedCrossRefGoogle Scholar
  7. 7.
    Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297(5590):2275–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Lammers KM, Khandelwal S, Chaudhry F, Kryszak D, Puppa EL, Casolaro V, et al. Identification of a novel immunomodulatory gliadin peptide that causes interleukin-8 release in a chemokine receptor CXCR3-dependent manner only in patients with coeliac disease. Immunology. 2011;132(3):432–40.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135(1):194–204. e193.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lionetti E, Catassi C. New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. Int Rev Immunol. 2011;30(4):219–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Dogan Y, Yildirmaz S, Ozercan IH. Prevalence of celiac disease among first-degree relatives of patients with celiac disease. J Pediatr Gastroenterol Nutr. 2012;55(2):205–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, 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):286–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Kneepkens CM, von Blomberg BM. Clinical practice: coeliac disease. Eur J Pediatr. 2012;171(7):1011–21.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Metso S, Hyytia-Ilmonen H, Kaukinen K, Huhtala H, Jaatinen P, Salmi J, et al. Gluten-free diet and autoimmune thyroiditis in patients with celiac disease. A prospective controlled study. Scand J Gastroenterol. 2012;47(1):43–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Volta U, Tovoli F, Caio G. Clinical and immunological features of celiac disease in patients with type 1 diabetes mellitus. Expert Rev Gastroenterol Hepatol. 2011;5(4):479–87.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, et al. Selective IgA deficiency in autoimmune diseases. Mol Med. 2011;17(11–12):1383–96.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Wouters J, Weijerman ME, van Furth AM, Schreurs MW, Crusius JB, von Blomberg BM, et al. Prospective human leukocyte antigen, endomysium immunoglobulin A antibodies, and transglutaminase antibodies testing for celiac disease in children with Down syndrome. J Pediatr. 2009;154(2):239–42.PubMedCrossRefGoogle Scholar
  18. 18.
    Catassi C, Anderson RP, Hill ID, Koletzko S, Lionetti E, Mouane N, et al. World perspective on celiac disease. J Pediatr Gastroenterol Nutr. 2012;55(5):494–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Catassi C, Kryszak D, Bhatti B, Sturgeon C, Helzlsouer K, Clipp SL, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010;42(7):530–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Ahn R, Ding YC, Murray J, Fasano A, Green PH, Neuhausen SL, et al. Association analysis of the extended MHC region in celiac disease implicates multiple independent susceptibility loci. PLoS One. 2012;7(5):e36926.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet. 2011;43(12):1193–201.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med. 2012;367(25):2419–26.PubMedCrossRefGoogle Scholar
  23. 23.
    Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013;62(1):43–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Sellitto M, Bai G, Serena G, Fricke WF, Sturgeon C, Gajer P, et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS One. 2012;7(3):e33387.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Kaukinen K, Collin P, Maki M. Latent coeliac disease or coeliac disease beyond villous atrophy? Gut. 2007;56(10):1339–40.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Catassi C, Fasano A. Celiac disease diagnosis: simple rules are better than complicated algorithms. Am J Med. 2010;123(8):691–3.PubMedCrossRefGoogle Scholar
  27. 27.
    Hollon JR, Cureton PA, Martin ML, Puppa EL, Fasano A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013;13(1):40.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Catassi C, Fabiani E, Iacono G, D’Agate C, Francavilla R, Biagi F, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007;85(1):160–6.PubMedGoogle Scholar
  29. 29.
    Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB. 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):757–66.PubMedCrossRefGoogle Scholar
  30. 30.
    Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, Drijfhout JW, Jonker H, van Soest L, et al. Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology. 2005;129(3):797–806.PubMedCrossRefGoogle Scholar
  31. 31.
    Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011;9:23.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):508–14. quiz 515.PubMedCrossRefGoogle Scholar
  33. 33.
    Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012;107(12):1898–906. quiz 1907.PubMedCrossRefGoogle Scholar
  34. 34.
    Lundin KE, Alaedini A. Non-celiac gluten sensitivity. Gastrointest Endosc Clin N Am. 2012;22(4):723–34.PubMedCrossRefGoogle Scholar
  35. 35.
    Sanders DS, Aziz I. Non-celiac wheat sensitivity: separating the wheat from the chat! Am J Gastroenterol. 2012;107(12):1908–12.PubMedCrossRefGoogle Scholar
  36. 36.
    Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull. 2011;37(1):94–100.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Armstrong D, Don-Wauchope AC, Verdu EF. Testing for gluten-related disorders in clinical practice: the role of serology in managing the spectrum of gluten sensitivity. Can J Gastroenterol. 2011;25(4):193–7.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Ford AC, Chey WD, Talley NJ, Malhotra A, Spiegel BM, Moayyedi P. Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis. Arch Intern Med. 2009;169(7):651–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Cash BD, Rubenstein JH, Young PE, Gentry A, Nojkov B, Lee D, et al. The prevalence of celiac disease among patients with nonconstipated irritable bowel syndrome is similar to controls. Gastroenterology. 2011;141(4):1187–93.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Clin Gastroenterol Hepatol. 2011;9(11):965–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Vazquez-Roque MI, Camilleri M, Smyrk T, Murray JA, Marietta E, O’Neill J, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013;144(5):903–11. e903.PubMedCrossRefGoogle Scholar
  42. 42.
    Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006;55(10):1512–20.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Rodgers LS, Beam MT, Anderson JM, Fanning AS. Epithelial barrier assembly requires coordinated activity of multiple domains of the tight junction protein ZO-1. J Cell Sci. 2013;126:1565–75.PubMedCrossRefGoogle Scholar
  44. 44.
    Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and −2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141(7):1539–50.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Madara JL, Pappenheimer JR. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J Membr Biol. 1987;100(2):149–64.PubMedCrossRefGoogle Scholar
  46. 46.
    Tripathi A, Lammers KM, Goldblum S, Shea-Donohue T, Netzel-Arnett S, Buzza MS, et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci USA. 2009;106(39):16799–804.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000;113(Pt 24):4435–40.PubMedGoogle Scholar
  48. 48.
    El Asmar R, Panigrahi P, Bamford P, Berti I, Not T, Coppa GV, et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002;123(5):1607–15.PubMedCrossRefGoogle Scholar
  49. 49.
    Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005;2(9):416–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, et al. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408–19.PubMedCrossRefGoogle Scholar
  52. 52.
    Diosdado B, van Bakel H, Strengman E, Franke L, van Oort E, Mulder CJ, et al. Neutrophil recruitment and barrier impairment in celiac disease: a genomic study. Clin Gastroenterol Hepatol. 2007;5(5):574–81.PubMedCrossRefGoogle Scholar
  53. 53.
    Monsuur AJ, de Bakker PI, Alizadeh BZ, Zhernakova A, Bevova MR, Strengman E, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet. 2005;37(12):1341–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Wapenaar MC, Monsuur AJ, van Bodegraven AA, Weersma RK, Bevova MR, Linskens RK, et al. Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis. Gut. 2008;57(4):463–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Sollid LM, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998;115(3):551–63.PubMedCrossRefGoogle Scholar
  56. 56.
    Nilsen EM, Lundin KE, Krajci P, Scott H, Sollid LM, Brandtzaeg P. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut. 1995;37(6):766–76.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci USA. 2004;101(12):4175–9.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821–52.PubMedCrossRefGoogle Scholar
  59. 59.
    Castellanos-Rubio A, Santin I, Irastorza I, Castano L, Carlos Vitoria J, Ramon Bilbao J. TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity. 2009;42(1):69–73.PubMedCrossRefGoogle Scholar
  60. 60.
    Harris KM, Fasano A, Mann DL. Cutting edge: IL-1 controls the IL-23 response induced by gliadin, the etiologic agent in celiac disease. J Immunol. 2008;181(7):4457–60.PubMedGoogle Scholar
  61. 61.
    Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Carteni M, Casolaro V, et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2010;152(1):75–80.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, 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):357–66.PubMedCrossRefGoogle Scholar
  63. 63.
    Granzotto M, dal Bo S, Quaglia S, Tommasini A, Piscianz E, Valencic E, et al. Regulatory T-cell function is impaired in celiac disease. Dig Dis Sci. 2009;54(7):1513–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Hmida NB, Ben Ahmed M, Moussa A, Rejeb MB, Said Y, Kourda N, et al. Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease? Am J Gastroenterol. 2012;107(4):604–11.PubMedCrossRefGoogle Scholar
  65. 65.
    Keet CA, Matsui EC, Dhillon G, Lenehan P, Paterakis M, Wood RA. The natural history of wheat allergy. Ann Allergy Asthma Immunol. 2009;102(5):410–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Zuidmeer L, Goldhahn K, Rona RJ, Gislason D, Madsen C, Summers C, et al. The prevalence of plant food allergies: a systematic review. J Allergy Clin Immunol. 2008;121(5):1210–8. e1214.PubMedCrossRefGoogle Scholar
  67. 67.
    Matricardi PM, Bockelbrink A, Beyer K, Keil T, Niggemann B, Gruber C, et al. Primary versus secondary immunoglobulin E sensitization to soy and wheat in the Multi-Centre Allergy Study cohort. Clin Exp Allergy. 2008;38(3):493–500.PubMedCrossRefGoogle Scholar
  68. 68.
    Ostblom E, Lilja G, Pershagen G, van Hage M, Wickman M. Phenotypes of food hypersensitivity and development of allergic diseases during the first 8 years of life. Clin Exp Allergy. 2008;38(8):1325–32.PubMedCrossRefGoogle Scholar
  69. 69.
    Inomata N. Wheat allergy. Curr Opin Allergy Clin Immunol. 2009;9(3):238–43.PubMedCrossRefGoogle Scholar
  70. 70.
    Nakamura A, Tanabe S, Watanabe J, Makino T. Primary screening of relatively less allergenic wheat varieties. J Nutr Sci Vitaminol (Tokyo). 2005;51(3):204–6.CrossRefGoogle Scholar
  71. 71.
    Tatham AS, Shewry PR. Allergens to wheat and related cereals. Clin Exp Allergy. 2008;38(11):1712–26.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Karen M. Lammers
    • 1
  • Brintha Vasagar
    • 1
  • Alessio Fasano
    • 2
  1. 1.Department of PediatricsMassachusetts General Hospital for Children, Massachusetts General Hospital EastCharlestown, BostonUSA
  2. 2.Department of PediatricsMassachusetts General Hospital for Children, Massachusetts General Hospital EastCharlestown, BostonUSA

Personalised recommendations