Matt Johnson + David Dewar Professor Paul Ciclitira St Thomas’ Hospital, London

1. COELIAC DISEASE Matt Johnson + David Dewar Professor Paul Ciclitira St Thomas’ Hospital, London

5. Mortality • Almost all mortality in CD is due to malignancy • >50% due to EATCL • Other tumours = mouth, oesophagus, sb • Mortality 1.9-3.4x control population • Holmes et al : 2x control pop1 • Mortality normal after 5 yrs on GFD2 1Holmes GK et al (1976) Gut 17(8): 612-9 2Holmes GK et al (1989) Gut 30(3): 333-8

6. Prevalence of coeliac disease • Sweden 1:67 antibody positive • Ireland 1:100 • England 1:150 • Europe 1:300 • N America 1:300 • Australia 1:300

7. Cereal Taxonomy Family GRAMINEAE Subfamily FESUCOIDEAE PANICOIDEAE Tribe TRITICEAE AVENEAE ORYZEAE TRIPSACEAE Subtribe TRITICINAE Genus TRITICUM SECALE HORDEUM AVENA ORYZA ZEA SpeciesWHEAT RYE BARLEY OATS RICE MAIZE

8. Are oats safe in coeliac disease? Pure oat products are probably safe: • Janatuinen et al 2002 Gut. (Finland) • 5 year follow up of oat and non-oat eating coeliacs • No clinical, serological and histological differences at 5 years. • UK oat products may have contamination (harvesting, milling, food preparation) • Gluten free = Food industry standards 200 ppm

12. Tissue transglutaminase • Auto-antigen target of anti-endomyseal antibodies • Intracellular, released during inflammation • Cross links matrix proteins, stabilising connective tissue during inflammation. • Deamidates specific glutamine residues. • Creation of neo-epitopes with gluten

19. TAKE THAT VILLUSES GLUTEN

20. Pathology – the coeliac lesion • Villus atrophy • Crypt hyperplasia • Loss of enterocyte height • Lamina propria infiltration • Increased intra-epithelial lymphocytes • Increased mitotic activity

21. Intra-epithelial lymphocytes

22. NORMAL SMALL INTESTINE COELIAC DISEASE

23. Clinical categories of coeliacs • Coeliac disease • Undiagnosed coeliac disease • Silent coeliac disease • Latent coeliac disease

24. Clinical features in adults • Lethargy “Tired all the time” • Anaemia (Fe, folate, B12 and mixed) • Abdominal pain • Non-specific abdominal symptoms • Diarrhoea • Weight loss • Osteoporosis • Sub-fertility

25. Associations • Dermatitis herpetiformis • IgA deficiency • SBBO • Hyposplenism • Autoimmune conditions • Thyroid disease • Type 1 diabetes • Addison’s • Sjogrens syndrome

26. AD and age at diagnosis: GroupPrevalence AD A1 – age<2yrs 5.1% A2 – age 2-10yrs 17% A3 – age>10yrs 23.6% • Prevalence of autoimmune disease is related to duration of gluten exposure Ventura A (1999) Gastroenterology 117:297-303

27. Osteoporosis • 47% women < 50% men on GFD have osteopenia / osteoporosisa • Improvement 1 year post treatmentb aMcFarlane (1995) Gut 36:710-14 bValdimarsson (1996) Gut 38:322-7

28. DERMATITIS HERPETIFORMIS

29. Dermatitis Herpetiformis • 2 -3% • IgA deposition at the basement membrane • Rx • 1) GFD = 6-12/12 • 2) Dapsone

30. SBBO • 8% of non-responsive coeliac patients • Symptoms • Diarrhoea > Pain > Weight loss > Bloating > Flatulence > Nausea > Steatorrhoea • Nutritional deficiencies • Vit D (tetany) > Vit A (night blindness) > Cobalamin (neuropathy) > Vit B12 (macrocytosis) • Ix = H2 Lactose / Glucose breath test • Rx = 7-10/7 course of • Co-amoxiclav + Metronidazole • Cephalexin + Co-trimoxazole • Gentamicin + Metronidazole

31. Hyposplenism • ? 80% of coeliac patients have evidence of hyposplenism {Vasquez 1991} • Features • Howell Jolly bodies, target cells, thrombocytopenia • Mx • Meningococcal, Pneumococcal + HIB vaccinations • Prophylactic antibiotics

32. Microscopic colitis (5%) • The Cochrane database = 5 RCTs • 3 x Budesonide 9mg od tapering over 8/52 • significant symptomatic and histological benefit • anecdotal evidence suggesting long term remission. • 1 x Bismuth subsalicylate (n=12), three chewable 262mg tablets tds for 8/52 • symptomatic and histological improvement • with resolution of the collagenous band • Pepto-Bismol has three different potential modes of action as an antibacterial, anti-inflammatory and anti-diarrhoeal • Denol does not have the subsalicylate component • 1 x High dose Prednisolone (50mg) • can provide symptom relief, but often without histological improvement • relapses are common • Given the evidence, we advocate using • 1st and 2nd line therapy = Budesonide and bismuth subsalicylate (Pept-Bismol) • 3rd line = consider trying mesalazine in LC and cholestyramine in CC

33. Ulcerative jejunitis • Rare (6th decade) • Related to Enteropathy-associated T cell lymphoma (EATL) • Gastroscopy / Enteroscopy - May be segmental • Laparoscopy and full thickness biopsy • CT / repeat barium studies • T Cell receptor PCR monoclonality • UCL – Prof. Isaacson • Atypical gTcell receptor abnormalities • Steroids, nutritional support, close observation

35. MRI CT

36. Diagnosis • Serology • D2 Bx (≥3 biopsies with jumbo forceps) • Repeat biopsy on gluten-free diet • Repeat challenge (>10g per day, 2/52) • ESPGAN guidelines

37. Coeliac antibodies • Anti-reticulin, anti-gliadin, anti-jejunal • Anti-endomysial • Anti-tissue transglutaminase

38. Serological screening tests

39. Developments in serological tests • IgA deficiency occurs in 2-3% of coeliacs • Coeliacs disease occurs in 8% of IgA deficients • Serology Ix • IgG1 subgroup testing more specific than IgG • Combine both IgA and IgG1 EMA/tTG testing • 10-15% are symptomatic • Recurrent sinopulmonary infections • AI associations • Anaphylactic Transfusion Reactions • GI Disorders (failure to clear large proteins from GI mucosal barrier

40. Using Serology to Monitor Patients • IgA gliadin and TTG normalise on a strict GFD after 3-6/12 • Must have pre-treatment levels • IgG gliadin can be used but takes longer to normalise • IgA endomyseal is costly and more difficult to quantify

41. Screening Relatives Fraser J: GUT; 2004 • 1st Degree relatives = 5%-15% • 2nd Degree relatives no increased prevalence • 11.4% of these would be missed using IgA EMA in isolation and so an algorithm has been devised • Coeliac disease can occur in antibody negative individuals and that biopsy is recommended if there is a high index of suspicion.

42. Algorithm for Screening 1 Relatives

43. Treatment of coeliac disease • Gluten-free diet • Avoidance of wheat, rye and barley • Oats (probably OK) • Dietician • Codex Alimentarius • Coeliac societies handbook

44. Treatment of coeliac disease • Gluten-free diet • Avoidance of wheat, rye and barley • Oats (probably OK) • Dietician • Codex Alimentarius • Coeliac societies handbook • BUT NOT CORNFLAKES

45. Efficacy of Gluten-free diet • 70% respond symptomatically • 30% refractory non-compliant inadvertent intake another diagnosis

46. Dewar D, Johnson MW, Ciclitira PJ, GUT 2005

47. Gluten-free diet failure • Check diagnosis correct • Consider second diagnosis • pancreatic insufficiency • Check Compliance • inadvertent/intentional • Refractory sprue • REPEAT DUODENAL BIOPSY

48. Pitfalls • Insufficient advice (or effort) • Malted cereals + Cornflakes • Beer contamination • Cooking sauces • Oat contamination

49. Refractory coeliac disease • Continued symptoms Prednisolone 7.5-20 mg • Consider an immuno-modulator (AZA) • Unwell Weight loss Hypoalbuminaemia Dehydration Steatorrhoea Prednisolone 0.5 mg/kg

50. CD in the Elderly (5-20%)Johnson,MW: GUT; 2003 >65yrs <65yrs Stata p values Overall D2 Bx rate 276/628 (43.9%) 222/576 (38.8%) 0.07 Anaemia 223/351 (63.5%) 96/118 (81.4%) 0.0003 Malabsorption 27/30 (90%) 77/79 (97.5%) NS Atypical Dyspepsia 16/113 (14.2%) 38/204 (18.6%) NS Abdominal pain 11/122 (9.8%) 38/204 (38%) 0.03 Altered Bowel habit 10/11 (90.9%) 12/16 (75%) NS Weight loss 18/64 (28.1%) 22/36 (61.1%) 0.0012 Profound Tiredness 1/2 (50%) 0/0 NA No. with combinations 3/57 (5.3%) 3/71(4.2%) NS No. diagnosed 4/628 (0.64%) 17/576 (2.95%) 0.0001. Mortality 1/276 (3.6 per 1000) 0/222 0.0038