Celiac Disease

Chapter
First Online:

Abstract

Celiac disease (CD) is a complex multifactorial disorder with autoimmune features occurring only in genetically predisposed individuals, carrying the human leukocyte antigen (HLA)-DQ2 and/or -DQ8 alleles, upon ingestion of gluten-containing dietary products. HLA predisposition explains only 35 % of the disease genetic susceptibility, while the remaining is due to numerous non-HLA genes that singularly contribute to a much lower extent to CD heritability. The prevalence of the disease is about 1 % of the general population; environmental factors in addition to gluten, such as dysbiosis, viral infection, and infancy feeding practices, may contribute to disease development. From a pathogenic standpoint, CD is characterized by a gluten-specific immune-mediated reaction arising in the small-intestinal mucosa that finally leads to tissue damage. The typical histological hallmarks of CD are an increased infiltration of intraepithelial lymphocytes, crypts hyperplasia, and villous atrophy. These microscopic features, together with the detection of CD-specific autoantibodies, allow the clinical diagnosis of CD. Its clinical presentation could widely vary from asymptomatic subjects to severe malabsorption leading to diarrhea and nutritional deficiencies. CD is often associated with other autoimmune condition (such as type-1 diabetes) and other congenital disorders (such as Down syndrome). The only currently available treatment is represented by a lifelong strict gluten-free diet, but many new potential therapies are under investigation and will be hopefully available in the nearest future.

Keywords

Celiac disease Gluten-dependent enteropathy Gluten intolerance Malabsorption Non-celiac gluten sensitivity Intestinal biopsy Tissue transglutaminase Anti-endomysium antibodies Deamidated gliadin peptides 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136–60.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Gee SJ. On the celiac affection. St Barth Hosp Rep. 1888;24:17–20.Google Scholar
  4. 4.
    van Berge-Henegouwen GP, Mulder CJ. Pioneer in the gluten free diet: Willem-Karel Dicke 1905–1962, over 50 years of gluten free diet. Gut. 1993;34(11):1473–5.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Shiner M. Coeliac disease: histopathological findings in the small intestinal mucosa studies by a peroral biopsy technique. Gut. 1960;1:48–54.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Groll A, Candy DC, Preece MA, Tanner JM, Harries JT. Short stature as the primary manifestation of coeliac disease. Lancet. 1980;2(8204):1097–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Cacciari E, Salardi S, Lazzari R, Cicognani A, Collina A, Pirazzoli P, et al. Short stature and celiac disease: a relationship to consider even in patients with no gastrointestinal tract symptoms. J Pediatr. 1983;103(5):708–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Jerosch J, Jantea C, Geske B. Osteomalacia and fatigue fractures in celiac disease. Z Rheumatol. 1990;49(2):100–2.PubMedGoogle Scholar
  9. 9.
    McFarlane XA, Bhalla AK, Reeves DE, Morgan LM, Robertson DA. Osteoporosis in treated adult coeliac disease. Gut. 1995;36(5):710–4.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clinical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases. Am J Gastroenterol. 1999;94(3):691–6.PubMedGoogle Scholar
  11. 11.
    Harper JW, Holleran SF, Ramakrishnan R, Bhagat G, Green PH. Anemia in celiac disease is multifactorial in etiology. Am J Hematol. 2007;82(11):996–1000.PubMedCrossRefGoogle Scholar
  12. 12.
    Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ. 1999;318(7177):164–7.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Bourne JT, Kumar P, Huskisson EC, Mageed R, Unsworth DJ, Wojtulewski JA. Arthritis and coeliac disease. Ann Rheum Dis. 1985;44(9):592–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Maki M, Hallstrom O, Verronen P, Reunala T, Lahdeaho ML, Holm K, et al. Reticulin antibody, arthritis, and coeliac disease in children. Lancet. 1988;1(8583):479–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Pinals RS. Arthritis associated with gluten-sensitive enteropathy. J Rheumatol. 1986;13(1):201–4.PubMedGoogle Scholar
  16. 16.
    Gabrielli M, Cremonini F, Fiore G, Addolorato G, Padalino C, Candelli M, et al. Association between migraine and Celiac disease: results from a preliminary case-control and therapeutic study. Am J Gastroenterol. 2003;98(3):625–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Lahat E, Broide E, Leshem M, Evans S, Scapa E. Prevalence of celiac antibodies in children with neurologic disorders. Pediatr Neurol. 2000;22(5):393–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Serratrice J, Disdier P, de Roux C, Christides C, Weiller PJ. Migraine and coeliac disease. Headache. 1998;38(8):627–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Altuntas B, Kansu A, Girgin N. Hepatic damage in gluten sensitive enteropathy. Acta Paediatr Jpn. 1998;40(6):597–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Vajro P, Fontanella A, Mayer M, De Vincenzo A, Terracciano LM, D’Armiento M, et al. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J Pediatr. 1993;122(3):416–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Bagnato GF, Quattrocchi E, Gulli S, Giacobbe O, Chirico G, Romano C, et al. Unusual polyarthritis as a unique clinical manifestation of coeliac disease. Rheumatol Int. 2000;20(1):29–30.PubMedCrossRefGoogle Scholar
  22. 22.
    King TS, Anderson JR, Wraight EP, Hunter JO, Cox TM. Skeletal muscle weakness and dysphagia caused by acid maltase deficiency: nutritional consequences of coincident celiac sprue. JPEN J Parenter Enteral Nutr. 1997;21(1):46–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Freeman HJ. Reproductive changes associated with celiac disease. World J Gastroenterol. 2010;16(46):5810–4.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Tata LJ, Card TR, Logan RF, Hubbard RB, Smith CJ, West J. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology. 2005;128(4):849–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Choi JM, Lebwohl B, Wang J, Lee SK, Murray JA, Sauer MV, et al. Increased prevalence of celiac disease in patients with unexplained infertility in the United States. J Reprod Med. 2011;56(5–6):199–203.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Aine L, Maki M, Collin P, Keyrilainen O. Dental enamel defects in celiac disease. J Oral Pathol Med. 1990;19(6):241–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Rasmussen P, Espelid I. Coeliac disease and dental malformation. ASDC J Dent Child. 1980;47(3):190–2.PubMedGoogle Scholar
  28. 28.
    Shuster S, Watson AJ, Marks J. Coeliac syndrome in dermatitis herpetiformis. Lancet. 1968;1(7552):1101–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Walker-Smith JA, Talley NA. Coeliac disease and dermatitis herpetiformis. Med J Aust. 1973;1(1):10–2.PubMedGoogle Scholar
  30. 30.
    Hooft C, Roels H, Devos E. Diabetes and coeliac disease. Lancet. 1969;2(7631):1192.PubMedGoogle Scholar
  31. 31.
    Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK. Increased prevalence of coeliac disease in diabetes. Arch Dis Child. 1984;59(8):739–42.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Thain ME, Hamilton JR, Ehrlich RM. Coexistence of diabetes mellitus and celiac disease. J Pediatr. 1974;85(4):527–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, 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):1–19.PubMedCrossRefGoogle Scholar
  34. 34.
    Dydensborg S, Toftedal P, Biaggi M, Lillevang ST, Hansen DG, Husby S. Increasing prevalence of coeliac disease in Denmark: a linkage study combining national registries. Acta Paediatr. 2012;101(2):179–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Vilppula A, Kaukinen K, Luostarinen L, Krekela I, Patrikainen H, Valve R, et al. Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study. BMC Gastroenterol. 2009;9:49.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Lohi S, Mustalahti K, Kaukinen K, Laurila K, Collin P, Rissanen H, et al. Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther. 2007;26(9):1217–25.PubMedCrossRefGoogle Scholar
  37. 37.
    Mustalahti K, Catassi C, Reunanen A, Fabiani E, Heier M, McMillan S, et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann Med. 2010;42(8):587–95.PubMedCrossRefGoogle Scholar
  38. 38.
    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
  39. 39.
    Ludvigsson JF, Rubio-Tapia A, van Dyke CT, Melton LJ 3rd, Zinsmeister AR, Lahr BD, et al. Increasing incidence of celiac disease in a North American population. Am J Gastroenterol. 2013;108(5):818–24.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Lionetti E, Castellaneta S, Pulvirenti A, Tonutti E, Francavilla R, Fasano A, et al. Prevalence and natural history of potential celiac disease in at-family-risk infants prospectively investigated from birth. J Pediatr. 2012;161(5):908–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Walker MM, Murray JA, Ronkainen J, Aro P, Storskrubb T, D’Amato M, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology. 2010;139(1):112–9.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Decker E, Hornef M, Stockinger S. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Gut Microbes. 2011;2(2):91–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Marild K, Stephansson O, Montgomery S, Murray JA, Ludvigsson JF. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology. 2012;142(1):39–45, e3.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Myleus A, Hernell O, Gothefors L, Hammarstrom ML, Persson LA, Stenlund H, et al. Early infections are associated with increased risk for celiac disease: an incident case-referent study. BMC Pediatr. 2012;12:194.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Tjernberg AR, Ludvigsson JF. Children with celiac disease are more likely to have attended hospital for prior respiratory syncytial virus infection. Dig Dis Sci. 2014;59(7):1502–8.Google Scholar
  46. 46.
    Marild K, Ye W, Lebwohl B, Green PH, Blaser MJ, Card T, et al. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 2013;13:109.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Ivarsson A, Myleus A, Norstrom F, van der Pals M, Rosen A, Hogberg L, et al. Prevalence of childhood celiac disease and changes in infant feeding. Pediatrics. 2013;131(3):e687–94.CrossRefGoogle Scholar
  48. 48.
    Myleus A, Ivarsson A, Webb C, Danielsson L, Hernell O, Hogberg L, et al. Celiac disease revealed in 3 % of Swedish 12-year-olds born during an epidemic. J Pediatr Gastroenterol Nutr. 2009;49(2):170–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Whyte L, Kotecha S, Watkins W, Jenkins H. Coeliac disease is more common in children with high socio-economic status. Acta Paediatr. 2013;103(3):289–94Google Scholar
  50. 50.
    Kondrashova A, Mustalahti K, Kaukinen K, Viskari H, Volodicheva V, Haapala AM, et al. Lower economic status and inferior hygienic environment may protect against celiac disease. Ann Med. 2008;40(3):223–31.PubMedCrossRefGoogle Scholar
  51. 51.
    Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107(10):1538–44, quiz 7, 45.PubMedCrossRefGoogle Scholar
  52. 52.
    Rosen A, Sandstrom O, Carlsson A, Hogberg L, Olen O, Stenlund H, et al. Usefulness of symptoms to screen for celiac disease. Pediatrics. 2014;133(2):211–8Google Scholar
  53. 53.
    Dixit R, Lebwohl B, Ludvigsson JF, Lewis SK, Rizkalla-Reilly N, Green PH. Celiac disease is diagnosed less frequently in young adult males. Dig Dis Sci. 2014;59(7):1509–12.Google Scholar
  54. 54.
    Pinkhasov RM, Wong J, Kashanian J, Lee M, Samadi DB, Pinkhasov MM, et al. Are men shortchanged on health? Perspective on health care utilization and health risk behavior in men and women in the United States. Intl J Clin Pract. 2010;64(4):475–87.CrossRefGoogle Scholar
  55. 55.
    Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol. 2001;96(1):126–31.PubMedCrossRefGoogle Scholar
  56. 56.
    Megiorni F, Mora B, Bonamico M, Barbato M, Montuori M, Viola F, et al. HLA-DQ and susceptibility to celiac disease: evidence for gender differences and parent-of-origin effects. Am J Gastroenterol. 2008;103(4):997–1003.PubMedCrossRefGoogle Scholar
  57. 57.
    Ploski R, Ek J, Thorsby E, Sollid LM. On the HLA-DQ (alpha 1*0501, beta 1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201. Tissue Antigens. 1993;41(4):173–7.PubMedCrossRefGoogle Scholar
  58. 58.
    van Belzen MJ, Koeleman BP, Crusius JB, Meijer JW, Bardoel AF, Pearson PL, et al. Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients. Genes Immun. 2004;5(3):215–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Molberg O, Kett K, Scott H, Thorsby E, Sollid LM, Lundin KE. Gliadin specific, HLA DQ2-restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand J Immunol. 1997;46(3):103–9.CrossRefGoogle Scholar
  60. 60.
    Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998;4(6):713–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Mearin ML, Biemond I, Pena AS, Polanco I, Vazquez C, Schreuder GT, et al. HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease. Gut. 1983;24(6):532–7.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Megiorni F, Mora B, Bonamico M, Barbato M, Nenna R, Maiella G, et al. HLA-DQ and risk gradient for celiac disease. Hum Immunol. 2009;70(1):55–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Zubillaga P, Vidales MC, Zubillaga I, Ormaechea V, Garcia-Urkia N, Vitoria JC. HLA-DQA1 and HLA-DQB1 genetic markers and clinical presentation in celiac disease. J Pediatr Gastroenterol Nutr. 2002;34(5):548–54.PubMedCrossRefGoogle Scholar
  64. 64.
    Congia M, Cucca F, Frau F, Lampis R, Melis L, Clemente MG, et al. A gene dosage effect of the DQA1*0501/DQB1*0201 allelic combination influences the clinical heterogeneity of celiac disease. Hum Immunol. 1994;40(2):138–42.PubMedCrossRefGoogle Scholar
  65. 65.
    Al-Toma A, Goerres MS, Meijer JW, Pena AS, Crusius JB, Mulder CJ. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol. 2006;4(3):315–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci U S A. 2003;100(21):12390–5.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Louka AS, Moodie SJ, Karell K, Bolognesi E, Ascher H, Greco L, et al. A collaborative European search for non-DQA1*05-DQB1*02 celiac disease loci on HLA-DR3 haplotypes: analysis of transmission from homozygous parents. Hum Immunol. 2003;64(3):350–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Pietzak MM, Schofield TC, McGinniss MJ, Nakamura RM. Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles. Clin Gastroenterol Hepatol. 2009;7(9):966–71.PubMedCrossRefGoogle Scholar
  69. 69.
    Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, 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):469–77.PubMedCrossRefGoogle Scholar
  70. 70.
    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
  71. 71.
    Zhernakova A, Withoff S, Wijmenga C. Clinical implications of shared genetics and pathogenesis in autoimmune diseases. Nat Rev Endocrinol. 2013;9(11):646–59.PubMedCrossRefGoogle Scholar
  72. 72.
    Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Ann Rev Immunol. 2011;29:493–525.CrossRefGoogle Scholar
  73. 73.
    Decker E, Engelmann G, Findeisen A, Gerner P, Laass M, Ney D, et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics. 2010;125(6):e1433–40.PubMedCrossRefGoogle Scholar
  74. 74.
    Ivarsson A. The Swedish epidemic of coeliac disease explored using an epidemiological approach—some lessons to be learnt. Best Pract Res Clin Gastroenterol. 2005;19(3):425–40.PubMedCrossRefGoogle Scholar
  75. 75.
    Ivarsson A, Persson LA, Nystrom L, Hernell O. The Swedish coeliac disease epidemic with a prevailing twofold higher risk in girls compared to boys may reflect gender specific risk factors. Eur J Epidemiol. 2003;18(7):677–84.PubMedCrossRefGoogle Scholar
  76. 76.
    Ivarsson A, Persson LA, Nystrom L, Ascher H, Cavell B, Danielsson L, et al. Epidemic of coeliac disease in Swedish children. Acta Paediatrica. 2000;89(2):165–71.PubMedCrossRefGoogle Scholar
  77. 77.
    Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. Am J Clin Nutr. 2002;75(5):914–21.PubMedGoogle Scholar
  78. 78.
    Akobeng AK, Ramanan AV, Buchan I, Heller RF. Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch Dis Child. 2006;91(1):39–43.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Akobeng AK, Heller RF. Assessing the population impact of low rates of breast feeding on asthma, coeliac disease and obesity: the use of a new statistical method. Arch Dis Child. 2007;92(6):483–5.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Guandalini S. The influence of gluten: weaning recommendations for healthy children and children at risk for celiac disease. Nestle Nutr Workshop Ser Paediatr Programme. 2007;60:139–51, discussion 51–5.CrossRefGoogle Scholar
  81. 81.
    Szajewska H, Chmielewska A, Piescik-Lech M, Ivarsson A, Kolacek S, Koletzko S, et al. Systematic review: early infant feeding and the prevention of coeliac disease. Aliment Pharmacol Ther. 2012;36(7):607–18.PubMedCrossRefGoogle Scholar
  82. 82.
    Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Tonutti E, Amarri S, Barbato M, Barbera C, Barera G, Bellantoni A, Castellano E, Guariso G, Limongelli MG, Pellegrino S, Polloni C, Ughi C, Zuin G, Fasano A, Catassi C. Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med. 2014;371:1295–303.Google Scholar
  83. 83.
    Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A, Crespo Escobar P, Kolaček S, Koletzko S, Korponay-Szabo IR, Mummert E, Polanco I, Putter H, Ribes-Koninckx C, Shamir R, Szajewska H, Werkstetter K, Greco L, Gyimesi J, Hartman C, Hogen Esch C, Hopman E, Ivarsson A, Koltai T, Koning F, Martinez-Ojinaga E, te Marvelde C, Pavic A, Romanos J, Stoopman E, Villanacci V, Wijmenga C, Troncone R, Mearin ML. Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014;371:1304–15.Google Scholar
  84. 84.
    Kagnoff MF, Austin RK, Hubert JJ, Bernardin JE, Kasarda DD. Possible role for a human adenovirus in the pathogenesis of celiac disease. J Exp Med. 1984;160(5):1544–57.PubMedCrossRefGoogle Scholar
  85. 85.
    Kagnoff MF, Paterson YJ, Kumar PJ, Kasarda DD, Carbone FR, Unsworth DJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut. 1987;28(8):995–1001.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol. 2006;101(10):2333–40.PubMedCrossRefGoogle Scholar
  87. 87.
    Atkinson MA, Chervonsky A. Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease. Diabetologia. 2012;55(11):2868–77.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Mathis D, Benoist C. Microbiota and autoimmune disease: the hosted self. Cell Host Microbe. 2011;10(4):297–301.PubMedCrossRefGoogle Scholar
  89. 89.
    Forsberg G, Fahlgren A, Horstedt P, Hammarstrom S, Hernell O, Hammarstrom ML. Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease. Am J Gastroenterol. 2004;99(5):894–904.PubMedCrossRefGoogle Scholar
  90. 90.
    Sanz Y, Sanchez E, Marzotto M, Calabuig M, Torriani S, Dellaglio F. Differences in faecal bacterial communities in coeliac and healthy children as detected by PCR and denaturing gradient gel electrophoresis. FEMS Immunol Med Microbiol. 2007;51(3):562–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Di Cagno R, De Angelis M, De Pasquale I, Ndagijimana M, Vernocchi P, Ricciuti P, et al. Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol. 2011;11:219.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Nistal E, Caminero A, Herran AR, Arias L, Vivas S, de Morales JM, et al. Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflamm Bowel Dis. 2012;18(4):649–56.PubMedCrossRefGoogle Scholar
  93. 93.
    Nadal I, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J Medical Microbiol. 2007;56(Pt 12):1669–74.CrossRefGoogle Scholar
  94. 94.
    Sanchez E, Nadal I, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Reduced diversity and increased virulence-gene carriage in intestinal enterobacteria of coeliac children. BMC Gastroenterol. 2008;8:50.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    De Palma G, Nadal I, Medina M, Donat E, Ribes-Koninckx C, Calabuig M, et al. Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol. 2010;10:63.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol. 2009;62(3):264–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Jabri B, Sollid LM. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol. 2009;9(12):858–70.PubMedCrossRefGoogle Scholar
  98. 98.
    Abadie V, Discepolo V, Jabri B. Intraepithelial lymphocytes in celiac disease immunopathology. Seminars Immunopathol. 2012;34(4):551–66.CrossRefGoogle Scholar
  99. 99.
    Shewry PR, Halford NG. Cereal seed storage proteins: structures, properties and role in grain utilization. J Exp Bot. 2002;53(370):947–58.PubMedCrossRefGoogle Scholar
  100. 100.
    Shewry PR, Tatham AS. The prolamin storage proteins of cereal seeds: structure and evolution. Biochem J. 1990;267(1):1–12.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    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
  102. 102.
    Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, Lebreton C, Menard S, Candalh C, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. 2008;205(1):143–54.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Pinkas DM, Strop P, Brunger AT, Khosla C. Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol. 2007;5(12):e327.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Sollid LM, Jabri B. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr Opin Immunol. 2011;23(6):732–8.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    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 U S A. 2004;101(12):4175–9.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Sollid LM, Molberg O, McAdam S, Lundin KE. Autoantibodies in coeliac disease: tissue transglutaminase–guilt by association? Gut. 1997;41(6):851–2.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Sperandeo MP, Tosco A, Izzo V, Tucci F, Troncone R, Auricchio R, et al. Potential celiac patients: a model of celiac disease pathogenesis. PloS One. 2011;6(7):e21281.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, et al. Synergy of IL-21 and IL-15 in regulating CD8 + T cell expansion and function. J Exp Med. 2005;201(1):139–48.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. 2003;362(9377):30–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Barone MV, Gimigliano A, Castoria G, Paolella G, Maurano F, Paparo F, et al. Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut. 2007;56(4):480–8.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Nanayakkara M, Kosova R, Lania G, Sarno M, Gaito A, Galatola M, et al. A celiac cellular phenotype, with altered LPP sub-cellular distribution, is inducible in controls by the toxic gliadin peptide P31–43. PloS One. 2013;8(11):e79763.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity. 2004;21(3):367–77.PubMedCrossRefGoogle Scholar
  113. 113.
    Nanayakkara M, Lania G, Maglio M, Discepolo V, Sarno M, Gaito A, et al. An undigested gliadin peptide activates innate immunity and proliferative signaling in enterocytes: the role in celiac disease. AmJ Clin Nutr. 2013;98(4):1123–35.CrossRefGoogle Scholar
  114. 114.
    Nanayakkara M, Lania G, Maglio M, Kosova R, Sarno M, Gaito A, et al. Enterocyte proliferation and signaling are constitutively altered in celiac disease. PloS One. 2013;8(10):e76006.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Ben Ahmed M, Belhadj Hmida N, Moes N, Buyse S, Abdeladhim M, Louzir H, et al. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol. 2009;182(11):6763–70.PubMedCrossRefGoogle Scholar
  116. 116.
    Zanzi D, Stefanile R, Santagata S, Iaffaldano L, Iaquinto G, Giardullo N, et al. IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in celiac disease. Am J Gastroenterol. 2011;106(7):1308–17.PubMedCrossRefGoogle Scholar
  117. 117.
    Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992;102(1):330–54.PubMedGoogle Scholar
  118. 118.
    Garampazzi A, Rapa A, Mura S, Capelli A, Valori A, Boldorini R, et al. Clinical pattern of celiac disease is still changing. J Pediatr Gastroenterol Nutr. 2007;45(5):611–4.PubMedCrossRefGoogle Scholar
  119. 119.
    Lebenthal E, Shteyer E, Branski D. The changing clinical presentation of celiac disease. In: Fasano A, Troncone R, Branski D, editors. Frontiers in celiac disease. Basel: Karger; 2008. p. 18–22.CrossRefGoogle Scholar
  120. 120.
    Maki M, Kallonen K, Lahdeaho ML, Visakorpi JK. Changing pattern of childhood coeliac disease in Finland. Acta Paediatr Scand. 1988;77(3):408–12.PubMedCrossRefGoogle Scholar
  121. 121.
    Roma E, Panayiotou J, Karantana H, Constantinidou C, Siakavellas SI, Krini M, et al. Changing pattern in the clinical presentation of pediatric celiac disease: a 30-year study. Digestion. 2009;80(3):185–91.PubMedCrossRefGoogle Scholar
  122. 122.
    Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac disease. Dig Dis Sci. 2003;48(2):395–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Rostami Nejad M, Rostami K, Pourhoseingholi MA, Nazemalhosseini Mojarad E, Habibi M, Dabiri H, et al. Atypical presentation is dominant and typical for coeliac disease. J Gastrointestin Liver Dis. 2009;18(3):285–91.PubMedGoogle Scholar
  124. 124.
    Rashid M, Cranney A, Zarkadas M, Graham ID, Switzer C, Case S, et al. Celiac disease: evaluation of the diagnosis and dietary compliance in Canadian children. Pediatrics. 2005;116(6):e754–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Ehsani-Ardakani MJ, Rostami Nejad M, Villanacci V, Volta U, Manenti S, Caio G, et al. Gastrointestinal and non-gastrointestinal presentation in patients with celiac disease. Arch Iran Med. 2013;16(2):78–82.PubMedGoogle Scholar
  126. 126.
    Bai JC, Maurino E, Martinez C, Vazquez H, Niveloni S, Soifer G, et al. Abnormal colonic transit time in untreated celiac sprue. Acta Gastroenterol Latinoam. 1995;25(5):277–84.PubMedGoogle Scholar
  127. 127.
    Sadik R, Abrahamsson H, Kilander A, Stotzer PO. Gut transit in celiac disease: delay of small bowel transit and acceleration after dietary treatment. Am J Gastroenterol. 2004;99(12):2429–36.PubMedCrossRefGoogle Scholar
  128. 128.
    Cucchiara S, Bassotti G, Castellucci G, Minella R, Betti C, Fusaro C, et al. Upper gastrointestinal motor abnormalities in children with active celiac disease. J Pediatr Gastroenterol Nutr. 1995;21(4):435–42.PubMedCrossRefGoogle Scholar
  129. 129.
    Diamanti A, Capriati T, Basso MS, Panetta F, Di Ciommo Laurora VM, Bellucci F, et al. Celiac disease and overweight in children: an update. Nutrients. 2014;6(1):207–20.PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Aad G, Abajyan T, Abbott B, Abdallah J, Abdel Khalek S, Abdelalim AA, et al. Search for magnetic monopoles in sqrt[s]=7 TeV pp collisions with the ATLAS detector. Phys Rev Lett. 2012;109(26):261803.PubMedCrossRefGoogle Scholar
  131. 131.
    Germann R, Kuch M, Prinz K, Ebbing A, Schindera F. Celiac disease: an uncommon cause of recurrent intussusception. J Pediatr Gastroenterol Nutr. 1997;25(4):415–6.PubMedCrossRefGoogle Scholar
  132. 132.
    Reilly NR, Aguilar KM, Green PH. Should intussusception in children prompt screening for celiac disease? J Pediatr Gastroenterol Nutr. 2013;56(1):56–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Vajro P, Paolella G, Maggiore G, Giordano G. Meta-analysis: pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2013; 56(6):663–70.Google Scholar
  134. 134.
    Kolho KL, Farkkila MA, Savilahti E. Undiagnosed coeliac disease is common in Finnish adults. Scand J Gastroenterol. 1998;33(12):1280–3.PubMedCrossRefGoogle Scholar
  135. 135.
    Zanini B, Caselani F, Magni A, Turini D, Ferraresi A, Lanzarotto F, et al. Celiac disease with mild enteropathy is not mild disease. Clin Gastroenterol Hepatol. 2013;11(3):253–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation. J Am Acad Dermatol. 2011;64(6):1017–24, quiz 25–6.PubMedCrossRefGoogle Scholar
  137. 137.
    Nicolas ME, Krause PK, Gibson LE, Murray JA. Dermatitis herpetiformis. Intl J Dermatol. 2003;42(8):588–600.CrossRefGoogle Scholar
  138. 138.
    Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part II. Diagnosis, management, and prognosis. J Am Acad Dermatol. 2011;64(6):1027–33, quiz 33–4.PubMedCrossRefGoogle Scholar
  139. 139.
    Caproni M, Antiga E, Melani L, Fabbri P, Italian Group for Cutaneous I. Guidelines for the diagnosis and treatment of dermatitis herpetiformis. J Eur Acad Dermatol Venereol. 2009;23(6):633–8.PubMedCrossRefGoogle Scholar
  140. 140.
    Margoni D, Chouliaras G, Duscas G, Voskaki I, Voutsas N, Papadopoulou A, et al. Bone health in children with celiac disease assessed by dual x-ray absorptiometry: effect of gluten-free diet and predictive value of serum biochemical indices. J Pediatr Gastroenterol Nutr. 2012;54(5):680–4.PubMedCrossRefGoogle Scholar
  141. 141.
    Krupa-Kozak U. Pathologic bone alterations in celiac disease: etiology, epidemiology, and treatment. Nutrition. 2014;30(1):16–24.PubMedCrossRefGoogle Scholar
  142. 142.
    Ghozzi M, Sakly W, Mankai A, Bouajina E, Bahri F, Nouira R, et al. Screening for celiac disease, by endomysial antibodies, in patients with unexplained articular manifestations. Rheumatol Int. 2013; 34(5):637–42.Google Scholar
  143. 143.
    Dimitrova AK, Ungaro RC, Lebwohl B, Lewis SK, Tennyson CA, Green MW, et al. Prevalence of migraine in patients with celiac disease and inflammatory bowel disease. Headache. 2013;53(2):344–55.PubMedCrossRefGoogle Scholar
  144. 144.
    Chin RL, Sander HW, Brannagan TH, Green PH, Hays AP, Alaedini A, et al. Celiac neuropathy. Neurology. 2003;60(10):1581–5.PubMedCrossRefGoogle Scholar
  145. 145.
    Ruggieri M, Incorpora G, Polizzi A, Parano E, Spina M, Pavone P. Low prevalence of neurologic and psychiatric manifestations in children with gluten sensitivity. J Pediatr. 2008;152(2):244–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Pengiran Tengah DS, Holmes GK, Wills AJ. The prevalence of epilepsy in patients with celiac disease. Epilepsia. 2004;45(10):1291–3.PubMedCrossRefGoogle Scholar
  147. 147.
    Fois A, Vascotto M, Di Bartolo RM, Di Marco V. Celiac disease and epilepsy in pediatric patients. Child’s Nerv Sys. 1994;10(7):450–4.CrossRefGoogle Scholar
  148. 148.
    Ludvigsson JF, Zingone F, Tomson T, Ekbom A, Ciacci C. Increased risk of epilepsy in biopsy-verified celiac disease: a population-based cohort study. Neurology. 2012;78(18):1401–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Canales P, Mery VP, Larrondo FJ, Bravo FL, Godoy J. Epilepsy and celiac disease: favorable outcome with a gluten-free diet in a patient refractory to antiepileptic drugs. Neurologist. 2006;12(6):318–21.PubMedCrossRefGoogle Scholar
  150. 150.
    Pascotto A, Coppola G, Ecuba P, Liguori G, Guandalini S. Epilepsy and occipital calcifications with or without celiac disease: report of four cases. J Epilepsy. 1994;7:130–6.CrossRefGoogle Scholar
  151. 151.
    Ludvigsson JF, Inghammar M, Ekberg M, Egesten A. A nationwide cohort study of the risk of chronic obstructive pulmonary disease in coeliac disease. J Intern Med. 2012;271(5):481–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Emilsson L, Carlsson R, Holmqvist M, James S, Ludvigsson JF. The characterisation and risk factors of ischaemic heart disease in patients with coeliac disease. Aliment Pharmacol Ther. 2013;37(9):905–14.PubMedCrossRefGoogle Scholar
  153. 153.
    Ludvigsson JF, Lindelof B, Rashtak S, Rubio-Tapia A, Murray JA. Does urticaria risk increase in patients with celiac disease? A large population-based cohort study. Eur J Dermatol. 2013;23(5):681–7.PubMedCentralPubMedGoogle Scholar
  154. 154.
    Ludvigsson JF, Aro P, Walker MM, Vieth M, Agreus L, Talley NJ, et al. Celiac disease, eosinophilic esophagitis and gastroesophageal reflux disease, an adult population-based study. Scand J Gastroenterol. 2013;48(7):808–14.PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Sadr-Azodi O, Sanders DS, Murray JA, Ludvigsson JF. Patients with celiac disease have an increased risk for pancreatitis. Clin Gastroenterol Hepatol. 2012;10(10):1136–42, e3.PubMedCentralPubMedCrossRefGoogle Scholar
  156. 156.
    Ludvigsson JF, Murray JA, Adams PC, Elmberg M. Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients. Scand J Gastroenterol. 2013;48(2):176–82.PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Mollazadegan K, Kugelberg M, Lindblad BE, Ludvigsson JF. Increased risk of cataract among 28,000 patients with celiac disease. Am J Epidemiol. 2011;174(2):195–202.PubMedCrossRefGoogle Scholar
  158. 158.
    Mollazadegan K, Kugelberg M, Tallstedt L, Ludvigsson JF. Increased risk of uveitis in coeliac disease: a nationwide cohort study. Br J Ophthalmol. 2012;96(6):857–61.PubMedCrossRefGoogle Scholar
  159. 159.
    Emilsson L, Andersson B, Elfstrom P, Green PH, Ludvigsson JF. Risk of idiopathic dilated cardiomyopathy in 29,000 patients with celiac disease. J Am Heart Assoc. 2012;1(3):e001594.PubMedCentralPubMedCrossRefGoogle Scholar
  160. 160.
    Ludvigsson JF, Zingone F, Fored M, Ciacci C, Cirillo M. Moderately increased risk of urinary stone disease in patients with biopsy-verified coeliac disease. Aliment Pharmacol Ther. 2012;35(4):477–84.PubMedCrossRefGoogle Scholar
  161. 161.
    Welander A, Prutz KG, Fored M, Ludvigsson JF. Increased risk of end-stage renal disease in individuals with coeliac disease. Gut. 2012;61(1):64–8.PubMedCrossRefGoogle Scholar
  162. 162.
    Passananti V, Siniscalchi M, Zingone F, Bucci C, Tortora R, Iovino P, et al. Prevalence of eating disorders in adults with celiac disease. Gastroenterol Res Pract. 2013;2013:491657.PubMedCentralPubMedCrossRefGoogle Scholar
  163. 163.
    Ludvigsson JF, Rubio-Tapia A, Chowdhary V, Murray JA, Simard JF. Increased risk of systemic lupus erythematosus in 29,000 patients with biopsy-verified celiac disease. J Rheumatol. 2012;39(10):1964–70.PubMedCentralPubMedCrossRefGoogle Scholar
  164. 164.
    Zugna D, Richiardi L, Stephansson O, Pasternak B, Ekbom A, Cnattingius S, et al. Risk of congenital malformations among offspring of mothers and fathers with celiac disease: a nationwide cohort study. Clin Gastroenterol Hepatol. 2013;12(7):1108–1116.e6.Google Scholar
  165. 165.
    Ludvigsson JF, West J, Ekbom A, Stephansson O. Reduced risk of breast, endometrial and ovarian cancer in women with celiac disease. Int J Cancer. 2012;131(3):E244–50.CrossRefGoogle Scholar
  166. 166.
    Meini A, Pillan NM, Villanacci V, Monafo V, Ugazio AG, Plebani A. Prevalence and diagnosis of celiac disease in IgA-deficient children. Ann Allergy Asthma Immunol. 1996;77(4):333–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Cataldo F, Marino V, Bottaro G, Greco P, Ventura A. Celiac disease and selective immunoglobulin A deficiency. J Pediatr. 1997;131(2):306–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Bybrant MC, Ortqvist E, Lantz S, Grahnquist L. High prevalence of celiac disease in Swedish children and adolescents with type 1 diabetes and the relation to the Swedish epidemic of celiac disease: a cohort study. Scand J Gastroenterol. 2014;49(1):52–8.PubMedCrossRefGoogle Scholar
  169. 169.
    Barera G, Bonfanti R, Viscardi M, Bazzigaluppi E, Calori G, Meschi F, et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics. 2002;109(5):833–8.PubMedCrossRefGoogle Scholar
  170. 170.
    Tiberti C, Panimolle F, Bonamico M, Filardi T, Pallotta L, Nenna R, et al. Long-standing type 1 diabetes: patients with adult-onset develop celiac-specific immunoreactivity more frequently than patients with childhood-onset diabetes, in a disease duration-dependent manner. Acta Diabetol. 2014;51(4):675–8.Google Scholar
  171. 171.
    Scaramuzza AE, Mantegazza C, Bosetti A, Zuccotti GV. Type 1 diabetes and celiac disease: the effects of gluten free diet on metabolic control. World J Diab. 2013;4(4):130–4.CrossRefGoogle Scholar
  172. 172.
    Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP study group for autoimmune disorders in celiac disease. Gastroenterology. 1999;117(2):297–303.PubMedCrossRefGoogle Scholar
  173. 173.
    Elli L, Bonura A, Garavaglia D, Rulli E, Floriani I, Tagliabue G, et al. Immunological comorbity in coeliac disease: associations, risk factors and clinical implications. J Clin Immunol. 2012;32(5):984–90.PubMedCrossRefGoogle Scholar
  174. 174.
    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
  175. 175.
    Elli L, Discepolo V, Bardella MT, Guandalini S. Does gluten intake influence the development of celiac disease-associated complications? J Clin Gastroenterol. 2014;48(1):13–20.PubMedCrossRefGoogle Scholar
  176. 176.
    Marild K, Stephansson O, Grahnquist L, Cnattingius S, Soderman G, Ludvigsson JF. Down syndrome is associated with elevated risk of celiac disease: a nationwide case-control study. J Pediatr. 2013;163(1):237–42.Google Scholar
  177. 177.
    Bonamico M, Bottaro G, Pasquino AM, Caruso-Nicoletti M, Mariani P, Gemme G, et al. Celiac disease and turner syndrome. J Pediatr Gastroenterol Nutr. 1998;26(5):496–9.PubMedCrossRefGoogle Scholar
  178. 178.
    Santer R, Pankau R, Schaub J, Burgin-Wolff A. Williams–Beuren syndrome and celiac disease. J Pediatr Gastroenterol Nutr. 1996;23(3):339–40.PubMedCrossRefGoogle Scholar
  179. 179.
    Giersiepen K, Lelgemann M, Stuhldreher N, Ronfani L, Husby S, Koletzko S, et al. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J Pediatr Gastroenterol Nutr. 2012;54(2):229–41.PubMedCrossRefGoogle Scholar
  180. 180.
    Amarri S, Alvisi P, De Giorgio R, Gelli MC, Cicola R, Tovoli F, et al. Antibodies to Deamidated gliadin peptides: an accurate predictor of coeliac disease in infancy. J Clin Immunol. 2013; 33(5):1027–30.Google Scholar
  181. 181.
    Barbato M, Maiella G, Di Camillo C, Guida S, Valitutti F, Lastrucci G, et al. The anti-deamidated gliadin peptide antibodies unmask celiac disease in small children with chronic diarrhoea. Dig Liver Dis. 2011;43(6):465–9.PubMedCrossRefGoogle Scholar
  182. 182.
    Aleanzi M, Demonte AM, Esper C, Garcilazo S, Waggener M. Celiac disease: antibody recognition against native and selectively deamidated gliadin peptides. Clin Chem. 2001;47(11):2023–8.PubMedGoogle Scholar
  183. 183.
    Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656–76.PubMedCentralPubMedCrossRefGoogle Scholar
  184. 184.
    Dahlbom I, Olsson M, Forooz NK, Sjoholm AG, Truedsson L, Hansson T. Immunoglobulin G (IgG) anti-tissue transglutaminase antibodies used as markers for IgA-deficient celiac disease patients. Clin Diagn Lab Immunol. 2005;12(2):254–8.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Korponay-Szabo IR, Dahlbom I, Laurila K, Koskinen S, Woolley N, Partanen J, et al. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut. 2003;52(11):1567–71.PubMedCentralPubMedCrossRefGoogle Scholar
  186. 186.
    Villalta D, Alessio MG, Tampoia M, Tonutti E, Brusca I, Bagnasco 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):95–9.PubMedCrossRefGoogle Scholar
  187. 187.
    Villalta D, Tonutti E, Prause C, Koletzko S, Uhlig HH, Vermeersch P, et al. IgG antibodies against deamidated gliadin peptides for diagnosis of celiac disease in patients with IgA deficiency. Clin Chem. 2010;56(3):464–8.PubMedCrossRefGoogle Scholar
  188. 188.
    Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Report of a Working Group of ESPGAN. Arch Dis Child. 1990;65:909–11.CrossRefGoogle Scholar
  189. 189.
    Bai JC, Fried M, Corazza GR, Schuppan D, Farthing M, Catassi C, et al. World gastroenterology organisation global guidelines on celiac disease. J Clin Gastroenterol. 2013;47(2):121–6.PubMedCrossRefGoogle Scholar
  190. 190.
    Aziz I, Evans KE, Hopper AD, Smillie DM, Sanders DS. A prospective study into the aetiology of lymphocytic duodenosis. Aliment Pharmacol Ther. 2010;32(11–12):1392–7.PubMedCrossRefGoogle Scholar
  191. 191.
    Santolaria S, Dominguez M, Alcedo J, Abascal M, Garcia-Prats MD, Marigil M, et al. Lymphocytic duodenosis: etiological study and clinical presentations. Gastroenterol Hepatol. 2013;36(9):565–73.PubMedCrossRefGoogle Scholar
  192. 192.
    Waisbourd-Zinman O, Hojsak I, Rosenbach Y, Mozer-Glassberg Y, Shalitin S, Phillip M, et al. Spontaneous normalization of anti-tissue transglutaminase antibody levels is common in children with type 1 diabetes mellitus. Dig Dis Sci. 2012;57(5):1314–20.PubMedCrossRefGoogle Scholar
  193. 193.
    Biagi F, Trotta L, Alfano C, Balduzzi D, Staffieri V, Bianchi PI, et al. Prevalence and natural history of potential celiac disease in adult patients. Scand J Gastroenterol. 2013;48(5):537–42.PubMedCrossRefGoogle Scholar
  194. 194.
    Kurppa K, Ashorn M, Iltanen S, Koskinen LL, Saavalainen P, Koskinen O, et al. Celiac disease without villous atrophy in children: a prospective study. J Pediatr. 2010;157(3):373–80, 80 e1.PubMedCrossRefGoogle Scholar
  195. 195.
    Tosco A, Salvati VM, Auricchio R, Maglio M, Borrelli M, Coruzzo A, et al. Natural history of potential celiac disease in children. Clin Gastroenterol Hepatol. 2011;9(4):320–5, quiz e36.PubMedCrossRefGoogle Scholar
  196. 196.
    Borrelli M, Salvati VM, Maglio M, Zanzi D, Ferrara K, Santagata S, et al. Immunoregulatory pathways are active in the small intestinal mucosa of patients with potential celiac disease. Am J Gastroenterol. 2013;108(11):1775–84.PubMedCrossRefGoogle Scholar
  197. 197.
    Biagi F, Corazza GR. Defining gluten refractory enteropathy. Eur J Gastroenterol Hepatol. 2001;13(5):561–5.PubMedCrossRefGoogle Scholar
  198. 198.
    Al-Toma A, Verbeek WH, Hadithi M, von Blomberg BM, Mulder CJ. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut. 2007;56(10):1373–8.PubMedCentralPubMedCrossRefGoogle Scholar
  199. 199.
    Malamut G, Cellier C. Refractory celiac disease. Expert Rev Gastroenterol Hepatol. 2014;8(3):323–8.PubMedCrossRefGoogle Scholar
  200. 200.
    Nijeboer P, van Wanrooij RL, Tack GJ, Mulder CJ, Bouma G. Update on the diagnosis and management of refractory coeliac disease. Gastroenterol Res Pract. 2013;2013:518483.PubMedCentralPubMedCrossRefGoogle Scholar
  201. 201.
    Biagi F, Corazza GR. Mortality in celiac disease. Nat Rev Gastroenterol Hepatol. 2010;7(3):158–62.Google Scholar
  202. 202.
    Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet. 2001;358(9279):356–61.PubMedCrossRefGoogle Scholar
  203. 203.
    Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009;137(1):88–93.PubMedCentralPubMedCrossRefGoogle Scholar
  204. 204.
    Lohi S, Maki M, Rissanen H, Knekt P, Reunanen A, Kaukinen K. Prognosis of unrecognized coeliac disease as regards mortality: a population-based cohort study. Ann Med. 2009;41(7):508–15.Google Scholar
  205. 205.
    Metzger MH, Heier M, Maki M, Bravi E, Schneider A, Lowel H, et al. Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989–1998. Eur J Epidemiol. 2006;21(5):359–65.PubMedCrossRefGoogle Scholar
  206. 206.
    Solaymani-Dodaran M, West J, Logan RF. Long-term mortality in people with celiac disease diagnosed in childhood compared with adulthood: a population-based cohort study. Am J Gastroenterol. 2007;102(4):864–70.PubMedCrossRefGoogle Scholar
  207. 207.
    Hischenhuber C, Crevel R, Jarry B, Maki M, Moneret-Vautrin DA, Romano A, et al. Review article: safe amounts of gluten for patients with wheat allergy or coeliac disease. Aliment Pharmacol Ther. 2006;23(5):559–75.PubMedCrossRefGoogle Scholar
  208. 208.
    Siegel M, Garber ME, Spencer AG, Botwick W, Kumar P, Williams RN, et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci. 2012;57(2):440–50.PubMedCrossRefGoogle Scholar
  209. 209.
    Pinier M, Verdu EF, Nasser-Eddine M, David CS, Vezina A, Rivard N, et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. 2009;136(1):288–98.PubMedCrossRefGoogle Scholar
  210. 210.
    Sollid LM, Khosla C. Novel therapies for coeliac disease. J Intern Med. 2011;269(6):604–13.PubMedCentralPubMedCrossRefGoogle Scholar
  211. 211.
    Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol. 2013;25(3):410–7.PubMedCentralPubMedCrossRefGoogle Scholar
  212. 212.
    Xia J, Bergseng E, Fleckenstein B, Siegel M, Kim CY, Khosla C, et al. Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorg Med Chem. 2007;15(20):6565–73.PubMedCentralPubMedCrossRefGoogle Scholar
  213. 213.
    Rauhavirta T, Oittinen M, Kivisto R, Mannisto PT, Garcia-Horsman JA, Wang Z, et al. Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J Clin Immunol. 2013;33(1):134–42.PubMedCrossRefGoogle Scholar
  214. 214.
    Pinier M, Fuhrmann G, Verdu EF, Leroux JC. Prevention measures and exploratory pharmacological treatments of celiac disease. Am J Gastroenterol. 2010;105(12):2551–61, quiz 62.PubMedCrossRefGoogle Scholar
  215. 215.
    Setty M, Discepolo V, Abadie V, Kamhawi S, Mayassi T, Kent A, Ciszewski C, Maglio M, Kistner E, Bhagat G, Semrad C, Kupfer SS, Green PH, Guandalini S, Troncone R, Murray JA, Turner JR, Jabri B. Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease. Gastroenterol. 2015. pii: S0016–5085(15)00685-X. doi: 10.1053/j.gastro.2015.05.013.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Comer Children’s HospitalUniversity of ChicagoChicagoUSA
  2. 2.Department of Translational Medical Science—Section of PediatricsUniversity of Naples “Federico II”NapoliItaly
  3. 3.Department of MedicineUniversity of ChicagoChicagoUSA

Personalised recommendations