Coeliac disease is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. It is diagnosed through a combination of clinical presentation, serology testing, and small intestinal biopsy showing villous atrophy. While serology tests are highly sensitive for classical coeliac disease, many atypical presentations involve seronegative or partial villous atrophy cases that can easily be missed. Adherence to a lifelong gluten-free diet is currently the only treatment, though enzymatic degradation of gluten may provide an alternative in the future.

1. Coeliac Disease Kamran Rostami Honorary Clinical Lecturer School of Medicine University of Birmingham

2. Objectives What is coeliac disease? What is the prevalence of CD in UK and the rest of the world? Symptoms, Clinical presentation and associated conditions with CD. What is the differences between Microcytic and Macrocytic Anaemia? What do you know about lactose intolerance? Pathogenesis and Complications of untreated CD. How do you diagnose CD and what are the pitfalls? What is the treatment of CD

3. Definition immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. A unique autoimmune disorder: environmental trigger (gluten) and the autoantigen (tissue Transglutaminase)

4. Diagnosis of Coeliac Disease and pitfalls Clinical Serological Histological Rostami K, Danciu M. Endoscopy and small-bowel biopsy in celiac disease: indications and implications. Endoscopy 2007;39:573 Green PH, Rostami K, Marsh MN. Diagnosis of coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:389-400

5. Serology in Coeliac Disease High estimation of sensitivity in the most studies Biopsy only seropositive Rolling out the diagnosis Serologic tests, in clinical practice, lack the sensitivity reported in the literature. Rostami K, Mulder CJ et al. What a clinician should know about coeliac disease autoantibodies. Eur J Gastroenterol Hepatol. 2004;16:715-6. Abrams JA, Green PH. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci. 2004;49:546-50.

6. Elderly and antibodies Negative serology should not necessarily reassure the clinician Elderly patients following a gluten-free diet will see improvements in their symptoms and be committed to the diet despite their age David S Sanders et al Antibody negative coeliac disease presenting in elderly people—an easily missed diagnosis BMJ 2005; 330: 775-776

7. Serology sensitivity Rostami, Mulder et al. American J Gastroenterol 1999;94:888-894

8. Modified Marsh Classification Rostami, Mulder et al. American J Gastroenterol 1999;94:888-894

9. Marsh I or Infiltrative lesion Non specific Known as lymphocytic enteritis Occasionally positive serology Common presentation in latent Coeliac Disease Often missed by pathologist as they do not count Rostami K, Mulder C et al. Modified Marsh Classification THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 4, 1999 © 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc.

10. Marsh II Hyperplastic lesion Rostami K, Mulder C et al. Modified Marsh Classification THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 4, 1999 © 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc. Very common IBS Could present with symptoms Do you treat this?

11. Marsh IIIa or Partial Villous Atrophy (Destructive) Should the relatives of coeliacs -with clinical compliants undergo a small bowel biopsy, in spite of their negative serology ? A complex and prevalent variety of coeliac subgroups Easily missed Negative in serology 60-70% Common presentation in First degree relatives other at high risk 20% of first degree relatives had coeliac disease Rostami K,Mulder C. et al Eur.J.Gastroenterol.Hepatol 2000; 12:51-56 Rostami K, Mulder C et al. Modified Marsh Classification THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 4, 1999 © 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc.

12. Marsh IIIb or Subtotal Villous Atrophy Rostami K, Mulder C et al. Modified Marsh Classification THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 4, 1999 © 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc. Less common and easier to recognise About 70% present with positive serology Very closed to the classical presentation

13. Marsh IIIc or Total Villous Atrophy Rostami K, Mulder C et al. Modified Marsh Classification THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 94, No. 4, 1999 © 1999 by Am. Coll. of Gastroenterology ISSN 0002-9270/99/$20.00 Published by Elsevier Science Inc. Classical Coeliac Disease Serology positive in almost 100% if not IgA-deficient

14. Correlation between sero-sensitivity, endoscopy and Histology Dickey W. Endoscopic markers for celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2006;3:546-51. 31% sensitivity for serology 100% sensitivity for serology

15. Coeliac disease IgG/IgA  -gliadin IgA  -tTG/EMA Mucosal biopsy 3-4 samples Gluten Free Diet Childeren < 2 yrs (-> IgG/IgA  -gliadin Symptoms but no antibodies =>DQ2/8 and biopsy IgA deficiency (prevalence 2% in CD vs 0.2% in normal population) Gluten Free Diet Repeat biopsy Schuppan et al Dig Liv Dis October 2004;10:358-360

16. Seropositive with normal histology Atypical localisation Bulb Terminal ileum False positive Liver dis Autoimmune Brocchi et al. Adult coeliac disease diagnosed by endoscopic biopsies in the duodenal bulb. Eur J Gastroenterol Hepatol. 2005;17:1413-5. Villanacci V et al. Histological aspects of the terminal ileum: a windows on coeliac disease too? Dig Liver Dis. 2006;38:820-2. Microenteropathy

17. Endoscopy Entire small bowels Normal Duodenal biopsy do not exclude diagnosis Segmental biopsy would be required Green PH, Rostami K, Marsh MN. Diagnosis of coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:389-400

18. Pitfalls If the symptoms persist Repeat serology Repeat biopsy Serology does not exclude Diagnosis

19. Which of the following is the most common reason for failing to respond to a gluten free diet? A The diagnosis was wrong B Non-concordance with diet C Lactose intolerance D Pancreatic insufficiency E Small bowel lymphoma

20. Coeliac Keystone The enzymatic degradation of gluten might become an alternative to the gluten-free diet Exogenous prolyl-endopeptidases Vora H et al. A scaleable manufacturing process for pro-EP-B2, a cysteine protease from barley indicated for celiac sprue. Biotechnol Bioeng. 2007 Mar 26; [Epub ahead of print]

21. Summary and conclusion Coeliac Disease is a common condition Atypical cases are predominant Seronegative are under-diagnosed Look for them and you find them Duodenal biopsy do not exclude the diagnosis Segmental biopsy in difficult cases FU and repeating the tests is a key to diagnosis GFD improve life qualities at any age

22. Thank you! Any question?