Coeliac disease

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Coeliac disease is gluten-induced enteropathy and affects around 1% of whom many are undiagnosed.

Info bulb.pngGluten is the storage protein in cereals, especially Wheat.

The most toxic fraction of it is the α-1-Gliadin.

This was established around 1970.

Gluten-derived peptides stimulate T-cells to mount an immunologically-mediated inflammatory response, causing damage to the small bowel mucosa. Histologically, an infiltrate of lymphocytes is seen and the fine structure of the villi is lost (villus atrophy) resulting in malabsorption.

  • Associated with HLA B8, DR3 and DQw2
    • HLA-DQ2 in between 90 to 95%
    • Absence of HLA-DQ2 and HLA-B8 actually has a very high negative predictive value[1] but does not help economic screening (30-40% of the Western population is DQ2/DQ8).
  • Environmental factors are important
    • Breast feeding protects
    • Gluten introduction after 4 months protects but after 7 months may increase risk. Perhaps it is the overlap of gluten challenge with breast feeding that is most protective[2].
    • Rotavirus in infancy[3]

Contents

Clinical Presentation

Coeliac disease can present at any time in life. There is a peak in childhood between the ages of 1-5 years. There is a further peak between the ages of 30-40 and a further small peak later in life.

The estimated prevalence is 0.3-1.0%, although the accurate figures are difficult to obtain as choice of diagnostic test varies. There is also a spectrum of disease, with a proportion of patients with subclinical disease. The genetic background also influences rates of disease. It is more common in people of Western European origin; said to be rare in Asians and Africans, but may be due to under-reporting.

Childhood

Info bulb.pngCoeliac disease was differentiated from other causes of childhood failure to thrive such as cystic fibrosis, during the 20th century.

Complications:

Novacek G, Miehsler W, Wrba F, Ferenci P, Penner E, Vogelsang H. Prevalence and clinical importance of hypertransaminasaemia in coeliac disease. European journal of gastroenterology & hepatology. 1999 Mar; 11(3):283-8.</ref>

LogoKeyPointsBox.pngConsider with:

Symptoms

Signs

Gastro-intestinal

Differential diagnosis

Investigations

LogoKeyPointsBox.pngDiagnosed through a combination of:
  • Serology,
  • Histology, and
  • Resolution of symptoms with a gluten-free diet.

Serology is sensitive and specific, but not sufficiently accurate to be used alone. As a gluten-free diet is a significant restriction to most patients, confirmation of the diagnosis requires small bowel biopsy while the patient is still on gluten (a 4-6 week period of gluten-containing diet is advised).

Coeliac disease can still be present even if serology (3-22% seronegative, although this depends on which antibody is used). Histology may also be negative, perhaps reflecting the patchy nature of the disease.[6] [7]

Oral,[8] nasal[9] and rectal[10] biopsies following local challenge have been investigated as an alternative means of obtaining a tissue diagnosis, but are not in routine clinical use.

Serology

Test for antibodies:[11] [12]

  • Anti-tissue transglutaminase antibody (generally the first choice test)[13] - usually given as a titre
  • Anti-endomysial antibodies (endomysium = layer of connective tissue that ensheaths muscle layer)
  • Anti-gliadin antibodies. This is less accurate. Gliadin is a mixture of wheat-derived polypeptides, extracted from gluten using alcohol. Antibodies to more specific components can be used, e.g. deamidated gliadin peptide
  • Serum IgA (IgA deficiency can result in falsely negative serology, and selective IgA deficiency is 10 times more common in those with coeliac disease than general population); IgG antibodies may be positive in this situation aiding diagnosis.

Histology

  • Distal duodenal biopsies via upper GI endoscopy or, if possible, jejunal biopsy. The latter is commonly done by enteroscopy) but in the past was done with a Crosby capsule and in the future might be done with a mechanical pill.
  • It is not known what the optimum number of duodenal biopsies is, with recommendations (rather than evidence) suggesting between 3 and 6, depending on the reference: 3[14], >3[15], 4[16][17] and 3-5[18]. The 2014 BSG guidelines recommend a minimum of 4 biopsies.[19]
  • Traditionally D2 biopsies are recommended, but changes maybe seen in D1 too and maybe the only part of the duodenum affected.[20][21][22]
  • Main histological features may include:[23]
    • villous atrophy; the ratio of the villous height to crypt depth can be formally measured, with a normal range of between 3-5:1
    • crypt hyperplasia (although in severe cases, there can be crypt loss as well)
    • thickening of basement membrane
    • reduction in number of goblet cells
    • increased intra-epithelial lymphocytes (>25 per 100 epithelial cells)
    • inflammatory cells within the lamina propria
    • neutrophils, eosinophils and an expanded sub-epithelial collage plate can also be seen
  • The above features may not be specific to coeliac disease. Other dieseases which may show similar features include: bacterial overgrowth syndromes, dermatitis herpetiformis, giardiasis, inflammatory bowel disase, tropical sprue and any other cause of enteritis.
  • Histological features graded according to Marsh classification.

Haplotyping

HLA DQ2 or DQ8 are found in up to 25% of the UK population and is therefore not felt to be helpful in diagnosis (although as mentioned above, absence of those HLA types makes coeliac very unlikely).

Treatment

Gluten withdrawal (all barley, rye and wheat are potentially harmful - oats are actually gluten-free but so frequently cross contaminated in the food chain that care is needed. The recommendation by some not to use oats should probably be modified as their use from pure food sources improves quality of life[24] ).

In the UK a reasonably wide range of gluten-free foods including flour and mixes for bread, cake and biscuits are available on prescription under suitable rules and only for people diagnosed as coeliac. The vast majority of the 30% who fail to respond do so because they fail to adhere to diet.

These prescriptions were identified as a waste of doctors' time, and adding nothing to treatment by the Cabinet Office working party on reducing paperwork, and were to be abolished in favour of simply funding issue of the substances from Pharmacies. However unattributed and vaguely defined fears of misuse lead to this being aborted. It seems a reasonable practice to issue a considerable number of prescriptions for moderate amounts of these things in one go, for use over a period of months, in order to avoid waste of time. Guidance is provided by the charity, Coeliac UK.[25]

Immunosuppression

This has a limited role in refractory cases (which always have to have investigation to exclude intestinal lymphoma or refractory sprue). Corticosteroids can improve symptoms[26]. Other immunosuppressives, including infliximab might promote a transition to lymphoma, even if case reports also suggest they can be used successfully.

Refractory coeliac disease (refractory sprue)

  • Important as associated with significant morbidity and mortality especially if clonal expansion of lymphocytes in the intestine (type 2 refractory sprue).
  • Defined by persistent symptoms and villous atrophy despite strict gluten-free diet
  • About 5% all cases

External Links

References

  1. Hadithi M, von Blomberg BM, Crusius JB, Bloemena E, Kostense PJ, Meijer JW, Mulder CJ, Stehouwer CD, Peña AS. Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease. Annals of internal medicine. 2007 Sep 4; 147(5):294-302.
  2. Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. The American journal of clinical nutrition. 2002 May; 75(5):914-21.
  3. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, Taki I, Norris JM, Erlich HA, Eisenbarth GS, Rewers M. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. The American journal of gastroenterology. 2006 Oct; 101(10):2333-40.(Link to article – subscription may be required.)
  4. Hagander B, Berg NO, Brandt L, Nordén A, Sjölund K, Stenstam M. Hepatic injury in adult coeliac disease. Lancet (London, England). 1977 Aug 6; 2(8032):270-2.
  5. Lindberg T, Berg NO, Borulf S, Jakobsson I. Liver damage in coeliac disease or other food intolerance in childhood. Lancet (London, England). 1978 Feb 18; 1(8060):390-1.
  6. Furse RM, Mee AS. Atypical presentation of coeliac disease. BMJ. 2005 Apr 2;330(7494):773-4. Direct link: http://bmj.bmjjournals.com/cgi/content/full/330/7494/773
  7. Sanders DS, Hurlstone DP, McAlindon ME, Hadjivassiliou M, Cross SS, Wild G, Atkins CJ. Antibody negative coeliac disease presenting in elderly people--an easily missed diagnosis. BMJ. 2005 Apr 2;330(7494):775-6. Direct link: http://bmj.bmjjournals.com/cgi/content/full/330/7494/775 One author of this work has subsequently resigned from his position and as of October 2009 is under going a Fitness to Practise Hearing by the GMC relating to events after this paper was published
  8. Lähteenoja H, Mäki M, Viander M, Toivanen A, Syrjänen S. Local challenge of oral mucosa with gliadin in patients with coeliac disease. Clinical and experimental immunology. 2000 Apr; 120(1):38-45.
  9. Torre P, Fusco S, Quaglia F, La Rotonda ML, Paparo F, Maglio M, Troncone R, Greco L. Immune response of the coeliac nasal mucosa to locally-instilled gliadin. Clinical and experimental immunology. 2002 Mar; 127(3):513-8.
  10. Loft DE, Marsh MN, Sandle GI, Crowe PT, Garner V, Gordon D, Baker R. Studies of intestinal lymphoid tissue. XII. Epithelial lymphocyte and mucosal responses to rectal gluten challenge in celiac sprue. Gastroenterology. 1989 Jul; 97(1):29-37.
  11. Watson RG. Diagnosis of coeliac disease. BMJ. 2005 Apr 2;330(7494):739-40. Direct link: http://bmj.bmjjournals.com/cgi/content/full/330/7494/739
  12. Scoglio R, Di Pasquale G, Pagano G, Lucanto MC, Magazzu G, Sferlazzas C. Is intestinal biopsy always needed for diagnosis of celiac disease? Am J Gastroenterol. 2003 Jun;98(6):1325-31.
  13. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997 Jul;3(7):797-801.
  14. Lewis NR, Scott BB. Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Alimentary pharmacology &amp;amp; therapeutics 2006;24:47-54. (Direct link – subscription may be required.)
  15. Shidrawi RG, Przemioslo R, Davies DR, Tighe MR, Ciclitira PJ. Pitfalls in diagnosing coeliac disease. Journal of Clinical Pathology. 1994;47:693-4.
  16. Olds G, McLoughlin R, O'Morian C, Sivak MV. Celiac disease for the endoscopist. Gastrointestinal Endoscopy. 2002;56:407-15. (Direct link - pdf)
  17. Frenz MB, Mee AS. Making the diagnosis of coeliac disease: is there a role for push enteroscopy? European Journal of Gastroenterology & Hepatology. 2004;16:1127-9.
  18. Dickson BC, Streutker CJ, Chetty R. Coeliac disease: an update for pathologists. Journal of Clinical Pathology. 2006;59:1008-16. (Direct link – subscription may be required.)
  19. Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, Green PH, Hadjivassiliou M, Holdoway A, van Heel DA, Kaukinen K, Leffler DA, Leonard JN, Lundin KE, McGough N, Davidson M, Murray JA, Swift GL, Walker MM, Zingone F, Sanders DS. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014 Aug; 63(8):1210-28.(Link to article – subscription may be required.). Link to pdf
  20. Bonamico M, Thanasi E, Mariani P, Nenna R, Luparia RP, Barbera C, Morra I, Lerro P, Guariso G, De Giacomo C, Scotta S, Pontone S, Carpino F, Magliocca FM. Duodenal bulb biopsies in celiac disease: a multicenter study. Journal of pediatric gastroenterology and nutrition. 2008 Nov; 47(5):618-22.
  21. Evans KE, Aziz I, Cross SS, Sahota GR, Hopper AD, Hadjivassiliou M, Sanders DS. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. The American journal of gastroenterology. 2011 Oct; 106(10):1837-742.(Link to article – subscription may be required.)
  22. Kurien M, Evans KE, Hopper AD, Hale MF, Cross SS, Sanders DS. Duodenal bulb biopsies for diagnosing adult celiac disease: is there an optimal biopsy site? Gastrointestinal endoscopy. 2012 Jun; 75(6):1190-6.(Link to article – subscription may be required.)
  23. Dickson BC, Streutker CJ, Chetty R. Coeliac disease: an update for pathologists. Journal of clinical pathology. 2006 Oct; 59(10):1008-16.(Link to article – subscription may be required.)
  24. Rashid M, Butzner D, Burrows V, Zarkadas M, Case S, Molloy M, Warren R, Pulido O, Switzer C. Consumption of pure oats by individuals with celiac disease: A position statement by the Canadian Celiac Association. Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 2007 Oct; 21(10):649-51.
  25. Coeliac UK Advice to medical practitioners on prescribing gluten-free products
  26. Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N, Brousse N. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet. 2000 Jul 15; 356(9225):203-8.
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