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Zöliakie

Pathogenese, Klinik, Epidemiologie, Diagnostik, Therapie
  • Detlef SchuppanEmail author
Leitthema

Zusammenfassung

Die Zöliakie wird durch den Verzehr glutenhaltiger Getreide (Weizen, Dinkel, Roggen, Gerste) hervorgerufen. Mit einer Prävalenz um 1 % ist sie die häufigste nichtinfektiöse chronisch-entzündliche Erkrankung des Darmes weltweit. Sie kann sich in jedem Alter manifestieren: klassisch mit Bauchschmerzen, Diarrhoe, Gedeihstörungen oder Gewichtsverlust, überwiegend jedoch mit indirekten Auswirkungen einer Malabsorption (Anämie, Osteoporose) oder mit assoziierten Autoimmunerkrankungen, z. B. der Bauchspeicheldrüse (Typ-1-Diabetes), der Schilddrüse oder der Haut (Dermatitis herpetiformis). Die Pathogenese der Zöliakie ist gut untersucht. So wird das Speicherprotein Gluten nur unvollständig verdaut und aktiviert in der Dünndarmschleimhaut der Patienten entzündliche T‑Zellen, die zu einer Atrophie der resorptiven Villi führen. Voraussetzung hierfür ist das Vorliegen einer genetischen Prädisposition (die Moleküle HLA-DQ2 [HLA – human lymphocyte antigen] oder HLA-DQ8 auf antigenpräsentierenden Immunzellen). Ferner verstärkt das im Darm freigesetzte Enzym Gewebetransglutaminase (TG2) durch Deamidierung die Immunogenität des Glutens. Der Antikörpertest gegen das Autoantigen TG2 ist einer der besten diagnostischen Tests in der Medizin und sichert, gemeinsam mit endoskopisch gewonnenen Dünndarmbiopsien, die Diagnose der Zöliakie. Trotzdem ist die Erkrankung bei 80–90 % der Betroffenen immer noch unerkannt. Die unbehandelte Zöliakie kann zu schweren Komplikationen führen. Hierzu gehören die Folgen der Malabsorption, Malignome (u. a. das intestinale T‑Zell-Lymphom) und wahrscheinlich auch die Bahnung von Autoimmunerkrankungen. Die Therapie, eine strikt glutenfreie Diät (GFD), ist schwierig und nicht immer wirksam. Alternative, unterstützende pharmakologische Therapien werden dringend benötigt und sind derzeit in Entwicklung.

Schlüsselwörter

Autoimmunerkrankungen Diagnose Gluten Therapie Zöliakie 

Celiac disease

Pathogenesis, clinics, epidemiology, diagnostics, therapy

Abstract

Celiac disease is induced by the consumption of gluten containing cereals (wheat, spelt, barley, rye). With a prevalence of ~ 1 %, it is the most common non-infectious chronic inflammatory intestinal disease worldwide. It manifests in all age groups, either classically with abdominal pain, diarrhoea and growth failure or weight loss, more commonly with indirect consequences of malabsorption, such as anaemia and osteoporosis, or with associated autoimmune diseases like type 1 diabetes, autoimmune thyroiditis or dermatitis herpetiformis. The pathogenesis of celiac disease is well explored. Gluten, the cereal storage protein, is not completely digested and reaches the intestinal mucosa where it activates inflammatory T cells, which cause atrophy of the resorptive villi. This T‑cell activation requires a genetic predisposition (the molecules HLA-DQ2 or -DQ8 on antigen-presenting immune cells). Moreover, the enzyme tissue transglutaminase (TG2) which is released in the mucosa increases the immunogenicity of the gluten peptides by a deamidation reaction. The test for serum antibodies to the autoantigen TG2 is one of the best diagnostic markers in medicine, which in combination with endoscopically obtained biopsies, secures the diagnosis of celiac disease. Despite these tools celiac disease is severely underdiagnosed, with 80–90 % of those affected being undetected. The untreated condition can lead to grave complications. These include the consequences of malabsorption, cancers (especially intestinal T‑cell lymphoma), and likely also the promotion of autoimmune diseases. The therapy of celiac disease, a strict gluten-free diet, is difficult to maintain and not always effective. Alternative, supporting pharmacological therapies are urgently needed and are currently in development.

Keywords

Autoimmune disease Celiac disease Diagnosis Gluten Therapy 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

D. Schuppan gibt an, dass er Patentinhaber für den Antikörpertest gegen Transglutaminase 2 ist. Hier besteht kein Interessenkonflikt.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Hardwick C (1939) Prognosis in coeliac disease: a review of seventy-three cases. Arch Dis Child 14:279–294CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Paveley WF (1988) From Areteus to Crosby a history of coeliac disease. Br Med J 297:1646–1649CrossRefGoogle Scholar
  3. 3.
    Berge-Henegouwen GP van, Mulder CJ (1993) Pioneer in the gluten free diet: Willem-Karel Dicke 1905–1962, over 50 years of gluten free diet. Gut 34:1473–1475CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mulder CJJ, Dicke WK, Dicke KA (2014) The role of gluten in coeliac disease. In: Thompson G (Hrsg) Pioneers of medicine without a nobel prize. Imperial College Press, London, S 41–54CrossRefGoogle Scholar
  5. 5.
    Dieterich W, Ehnis T, Bauer M et al (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3:797–801CrossRefPubMedGoogle Scholar
  6. 6.
    Rampertab SD, Pooran N, Brar P, Singh P, Green PH (2006) Trends in the presentation of celiac disease. Am J Med 119:355.e9–355.e14CrossRefGoogle Scholar
  7. 7.
    Schuppan D, Zimmer KP (2013) The diagnosis and treatment of celiac disease. Dtsch Arztebl Int 110:835–846PubMedPubMedCentralGoogle Scholar
  8. 8.
    Husby S, Koletzko S, Korponay-Szabo IR et al (2012) European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54:136–160CrossRefPubMedGoogle Scholar
  9. 9.
    Felber J, Aust D, Baas S et al (2014) Results of a S2k-consensus conference of the german society of gastroenterology, digestive- and metabolic diseases (DGVS) in conjunction with the german Coeliac society (DZG) regarding coeliac disease, wheat allergy and wheat sensitivity. Z Gastroenterol 52:711–743CrossRefPubMedGoogle Scholar
  10. 10.
    Schuppan D, Junker Y, Barisani D (2009) Celiac disease: from pathogenesis to novel therapies. Gastroenterology 137:1912–1933CrossRefPubMedGoogle Scholar
  11. 11.
    Stein J, Schuppan D (2014) Coeliac disease – new pathophysiological findings and their implications for therapy. Viszeralmedizin 30:156–165CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wieser H (2007) Chemistry of gluten proteins. Food Microbiol 24:115–119CrossRefPubMedGoogle Scholar
  13. 13.
    Anjum FM, Khan MR, Din A et al (2007) Wheat gluten: high molecular weight glutenin subunits–structure, genetics, and relation to dough elasticity. J Food Sci 72:R56–63CrossRefPubMedGoogle Scholar
  14. 14.
    Ricaño-Ponce I, Wijmenga C, Gutierrez-Achury J (2015) Genetics of celiac disease. Best Pract Res Clin Gastroenterol 29:399–412CrossRefPubMedGoogle Scholar
  15. 15.
    Marild K, Ye W, Lebwohl B et al (2013) Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol 13:109CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Stene LC, Honeyman MC, Hoffenberg EJ et al (2006) Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 101:2333–2340CrossRefPubMedGoogle Scholar
  17. 17.
    Chandesris MO, Malamut G, Verkarre V et al (2010) Enteropathy-associated T‑cell lymphoma: a review on clinical presentation, diagnosis, therapeutic strategies and perspectives. Gastroenterol Clin Biol 34:590–605CrossRefPubMedGoogle Scholar
  18. 18.
    Catassi C, Bearzi I, Holmes GK (2005) Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology 128(Suppl 1):S79–86CrossRefPubMedGoogle Scholar
  19. 19.
    Leffler DA, Schuppan D (2010) Update on serologic testing in celiac disease. Am J Gastroenterol 105:2520–2524CrossRefPubMedGoogle Scholar
  20. 20.
    Dieterich W, Laag E, Schöpper H et al (1998) Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology 115:1317–1321CrossRefPubMedGoogle Scholar
  21. 21.
    Lau NM, Green PH, Taylor AK et al (2013) Markers of celiac disease and gluten sensitivity in children with autism. PLoS ONE 8: doi:10.1371/journal.pone.0066155Google Scholar
  22. 22.
    Liu E, Lee HS, Aronsson CA et al (2014) TEDDY study group. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med 371:42–49CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Marsh MN (1992) Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity („celiac sprue“). Gastroenterology 102:330–354CrossRefPubMedGoogle Scholar
  24. 24.
    Oberhuber G, Caspary WF, Kirchner T, Borchard F, Stolte M (2001) Diagnosis of celiac disease and sprue. Recommendations of the german society for pathology. Pathologe 22:72–81CrossRefPubMedGoogle Scholar
  25. 25.
    Chang F, Mahadeva U, Deere H (2005) Pathological and clinical significance of increased intraepithelial lymphocytes (IELs) in small bowel mucosa. APMIS 113:385–399CrossRefPubMedGoogle Scholar
  26. 26.
    Taavela J, Koskinen O, Huhtala H et al (2013) Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. PLoS ONE 8:e76163 doi:10.1371/journal.pone.0076163CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Leffler D, Schuppan D, Pallav K et al (2013) Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 62:996–1004CrossRefPubMedGoogle Scholar
  28. 28.
    Singh P, Arora S, Lal S, Strand TA, Makharia GK (2015) Risk of celiac disease in the first- and second-degree relatives of patients with celiac disease: a systematic review and meta-analysis. Am J Gastroenterol 110:1539–1548CrossRefPubMedGoogle Scholar
  29. 29.
    Reilly NR, Green PH (2012) Epidemiology and clinical presentations of celiac disease. Semin Immunopathol 34:473–478CrossRefPubMedGoogle Scholar
  30. 30.
    Barada K, Abu Daya H, Rostami K, Catassi C (2012) Celiac disease in the developing world. Gastrointest Endosc Clin N Am 22:773–796CrossRefPubMedGoogle Scholar
  31. 31.
    Laass MW, Schmitz R, Uhlig HH et al (2015) The prevalence of celiac disease in children and adolescents in germany. Dtsch Arztebl Int 112:553–560PubMedPubMedCentralGoogle Scholar
  32. 32.
    Rubio-Tapia A, Kyle RA, Kaplan EL et al (2009) Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 137:88–93CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ventura A, Magazzu G, Greco L (1999) 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 117:297–303CrossRefPubMedGoogle Scholar
  34. 34.
    Kahaly GJ, Schuppan D (2015) Celiac disease and endocrine autoimmunity. Dig Dis 33:155–161CrossRefPubMedGoogle Scholar
  35. 35.
    Sollid LM, Jabri B (2013) Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 13:294–302CrossRefPubMedGoogle Scholar
  36. 36.
    Vriezinga SL, Auricchio R, Bravi E et al (2014) Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med 371:1304–1315CrossRefPubMedGoogle Scholar
  37. 37.
    Lionetti E, Castellaneta S, Francavilla R et al (2014) SIGENP (italian society of pediatric gastroenterology, hepatology, and nutrition) working group on weaning and CD risk. introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med 371:1295–1303CrossRefPubMedGoogle Scholar
  38. 38.
    Hummel S, Pflüger M, Hummel M, Bonifacio E, Ziegler AG (2011) Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34:1301–1305CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Catassi C, Elli L, Bonaz B et al (2015) Diagnosis of non-celiac gluten sensitivity (NCGS): the salerno experts’ criteria. Nutrients 7:4966–4977CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Fasano A, Sapone A, Zevallos V, Schuppan D (2015) Nonceliac gluten sensitivity. Gastroenterology 148:1195–1204CrossRefPubMedGoogle Scholar
  41. 41.
    Schuppan D, Pickert G, Ashfaq-Khan M, Zevallos V (2015) Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. Best Pract Res Clin Gastroenterol 29:469–476CrossRefPubMedGoogle Scholar
  42. 42.
    Fritscher-Ravens A, Schuppan D, Ellrichmann M et al (2014) Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 147:1012–1020CrossRefPubMedGoogle Scholar
  43. 43.
    Junker Y, Zeissig S, Kim SJ et al (2012) Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 209:2395–2408CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rao SS, Yu S, Fedewa A (2015) Systematic review: dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome. Aliment Pharmacol Ther 41:1256–1270CrossRefPubMedGoogle Scholar
  45. 45.
    Roshan B, Leffler DA, Jamma S et al (2011) The incidence and clinical spectrum of refractory celiac disease in a north american referral center. Am J Gastroenterol 106:923–928CrossRefPubMedGoogle Scholar
  46. 46.
    Malamut G, Meresse B, Cellier C, Cerf-Bensussan N (2012) Refractory celiac disease: from bench to bedside. Semin Immunopathol 34:601–613CrossRefPubMedGoogle Scholar
  47. 47.
    Gils T van, Nijeboer P, Wanrooij RL van, Bouma G, Mulder CJ (2015) Mechanisms and management of refractory coeliac disease. Nat Rev Gastroenterol Hepatol 12:572–579CrossRefPubMedGoogle Scholar
  48. 48.
    Shah S, Akbari M, Vanga R et al (2014) Patient perception of treatment burden is high in celiac disease compared with other common conditions. Am J Gastroenterol 109:1304–1311CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lundin KE, Sollid LM (2014) Advances in coeliac disease. Curr Opin Gastroenterol 30:154–162CrossRefPubMedGoogle Scholar
  50. 50.
    Lähdeaho ML, Kaukinen K, Laurila K et al (2014) Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 146:1649–1658CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Institut für Translationale Immunologie, Zentrum für Zöliakie und Dünndarmerkrankungen und Forschungszentrum für Immuntherapie (FZI), UniversitätsmedizinJohannes Gutenberg-Universität MainzMainzDeutschland
  2. 2.Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

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