Mustafa Giaffer Royal Hull Hospitals NHS Trust • So, what exactly is coeliac disease? • Coeliac disease is an autoimmune disease. • Gluten, which is found in wheat, barley and rye triggers an immune reaction in susceptible leading to damage of the lining of the small intestine. Other parts of the body may be affected.

• What food is gluten in? • Gluten is in many common foods like some cereals, bread, barley, oats and pasta. Gliadin protein fraction of wheat, rye, barley, and probably oats

Class II HLA APC cells T-cells (lamina propria) Antigen

T-cell & ↑ IL-2, cytokines, IL-6, TNF  Mucosal Macrophage injury proliferation

• 1% of the population affected • Only 14% are diagnosed • Incidence 17-19 per 100,000 • Affects all age groups • Diagnosed over age of 65 in 20%

• Healthy population: 1:133 • 1st degree relatives: 1:18 to 1:22 • 2nd degree relatives: 1:24 to 1:39

Fasano, et al, Arch of Intern Med, Volume 163: 286-292, 2003 6 Population screened 13145

Healthy Individuals Risk Groups 4126 9019

Symptomatic subjects 1st degree relatives 2nd degree relatives 3236 4508 1275

Positive Negative Positive Negative Positive Negative Positive Negative 31 4095 81 3155 205 4303 33 1242

Prevalence Prevalence Prevalence Prevalence 1:133 1:40 1:22 1:39

Projected number of celiacs in the U.S.A.: 2,115,954 Actual number of known celiacs in the U.S.A.: 40,000 For each known celiac there are 53 undiagnosed patients.

A. Fasano et al., Arch Int Med 2003;163:286-292.7 Most common age of presentation: older child to adult

• Dermatitis Herpetiformis • Iron-deficient anemia • Dental enamel hypoplasia resistant to oral Fe of permanent teeth • Hepatitis • Osteopenia/Osteoporosis • Arthritis • Short Stature • Epilepsy with occipital • Delayed Puberty calcifications

Listed in descending order of strength of evidence

• Antigliadin antibodies (AGA)* • *Antiendomysial antibodies (EMA) • *Anti tissue transglutaminase antibodies (TTG) – first generation (guinea pig protein) – second generation (human recombinant) • HLA typing • *2004 Consensus Conf. Best tests

12 Sensitivities and Specificities of Immunoglobulin A (IgA)–Class Antibodies Against Endomysial Antigen (EMA), Tissue Transglutaminase (tTGA), and Deamidated Gliadin Peptides (DGPs) IgA-Class Antibodies Sensitivity, % Specificity, % EMA 89–92 98–100 tTGA 93–97 95–97 DGPs 84–88 94–99 Normal small intestine Normal villi

Celiac Disease Villous atrophy Duodenal mucosa with expansion of the lamina propria, increased intraepithelial lymphocytes and villous blunting

Marsh- Oberhuber Classification Corazza-Villanacci Classification

Type 1 Grade A Type 2 Type 3a Grade B1 Type 3b Type 3c Grade B2 Type 4 Deleted March 1 Increased IEL Normal villous structure

March 2 Infiltrative-hyperplastic type, which is characterized by a normal villous architecture and crypt hyperplasia with an increased number of IELs ($30 IELs per 100 enterocytes). This stage is only very rarely encountered in patients with CD and has mainly been observed under experimental conditions, after commencement of a GFD or time-dose–related gluten challenge studies,87 and in patients with dermatitis herpetiformis.

March 3 (destructive)

A Mild villous atrophy B Moderate villous atrophy C Severe villous atrophy Symptomatic Manifest Celiac Disease mucosal lesion

Silent Celiac Disease

Latent Celiac Disease Normal Mucosa

Genetic susceptibility: - DQ2, DQ8 Positive serology

18 Silent Latent

• Silent: No or minimal symptoms, “damaged” mucosa and positive serology

Identified by screening asymptomatic individuals from groups at risk such:

• First degree relatives • Down syndrome patients • Type 1 diabetes patients, etc.

19 3 – Asymptomatic

Silent Latent

• Latent: No symptoms, normal mucosa

– May show positive serology. Identified by following in time asymptomatic individuals previously identified at screening from groups at risk. These individuals, given the “right” circumstances, will develop at some point in time mucosal changes (± symptoms)

20 • Food hypersensitivity: cow’s milk, soy, fish, rice, chicken, etc • Peptic ulcer disease • Helicobacter pylori–associated gastroduodenitis • Drugs: NSAIDs, proton-pump inhibitor • Infections: viral enteritis, Giardia organisms, Cryptosporidium • organisms, etc • Immune dysregulation: rheumatoid arthritis, Hashimoto thyroiditis, • SLE, autoimmune enteropathy • Immunodeficiency: common variable immune deficiency • Graft-versus-host disease • Inflammatory bowel disease • Bacterial overgrowth • Lymphocytic and collagenous colitis • Irritable bowel syndrome • Infections: tropical sprue • Refractory sprue • Collagenous sprue • Immune dysregulation: autoimmune enteropathy • Immunodeficiency: common variable immune deficiency • Graft-versus-host disease • Inflammatory bowel disease: Crohn disease • Drugs: mycophenolate mofetil, colchicine • Chemoradiation therapy • Nutritional deficiency • Eosinophilic enteritis • Bacterial overgrowth • Lymphoma • Positive antibody- negative histology • Positive antibody only IEL • Negative antibody positive histology • Pre-biopsy diet • Number of biopsies obtained • Biopsy site • Orientation • Repeat biopsy • chronic or intermittent diarrhoea • failure to thrive or faltering growth (in children) • persistent or unexplained gastrointestinal symptoms including nausea and vomiting • prolonged fatigue ('tired all the time') (NICE has a pathway on chronic fatigue syndrome / • myalgic encephalomyelitis) • recurrent abdominal pain, cramping or distension • sudden or unexpected weight loss • unexplained iron-deficiency anaemia, or other unspecified anaemia.

• Addison’s • Amenorrhoea • aphthous stomatitis (mouth ulcers) • autoimmune liver conditions • autoimmune myocarditis • chronic thrombocytopenia purpura • dental enamel defects • depression or bipolar disorder (NICE has produced pathways on depression and bipolar • disorder) • Down's syndrome • epilepsy (NICE has produced a pathway on epilepsy) • low-trauma fracture • lymphoma • metabolic bone disease (such as rickets or osteomalacia) • microscopic colitis • microscopic colitis • persistent or unexplained constipation (NICE has produced a pathway on constipation) • persistently raised liver enzymes with unknown cause • polyneuropathy • recurrent miscarriage • reduced bone mineral density • sarcoidosis • Sjögren's syndrome • Turner syndrome • unexplained alopecia • unexplained subfertility • Cancer risk • Non-Hodgkin lymphoma 2-4 x • Small bowel adenocarcinoma risk ?

• Osteoporosis • Chronic liver disease • Chronic ill health

Removal of gluten is essential!

70% response

• Amaranth • Potato • Arrowroot • Quinoa • Buckwheat • Rice • Corn • Sorghum • Flax • Tapioca • Millet • Teff or Tef • Montina • Flours made from nuts, beans • Oats* and seeds

*most are cross-contaminated with gluten 29 • OBVIOUS SOURCES • Bread • Bagels • Cakes • Cereal • Cookies • Pasta / noodles • Pastries / pies • Rolls

30 • Seasonings and spice blends or mixes • Malt/ malt extract/ flavoring • Brown rice syrup • Natural Flavors (most are GF) • Soy sauce and soy solids • Hydrolyzed Plant/Vegetable Protein • Bouillon • Caramel Coloring (most is GF)

31 • Lipstick/Gloss/Balms • Communion Wafers/Sacrament Bread • Mouthwash/Toothpaste • Play Dough • Stamp and Envelope Glues (Urban legend) • Vitamin, Herb, and Mineral products • Prescription or OTC Medications (www.glutenfreedrugs.com)

32 • No response to GFD • Family screening • Long term follow up

refractory non-compliant inadvertent intake another diagnosis

Dewar D, Johnson MW, Ciclitira PJ, GUT 2005 • Check diagnosis correct • Consider second diagnosis • pancreatic insufficiency • Check Compliance • inadvertent/intentional • Refractory sprue

• REPEAT DUODENAL BIOPSY • Ability to manage emotions – depression, anxiety • Ability to resist temptation – exercising restraint • Feelings of deprivation • Fear generated by inaccurate information

37 • Complete gluten avoidance is extremely difficult • Exposure to trace amounts of gluten common even if product is sold as NATURALLY gluten-free • Safe threshold for gluten exposure = 10-100 mg

• Daily intake of 30 mg of gliadin seems not to harm the intestinal mucosa • Amount of residual gluten in gluten-free products and the total intake of these products must be considered

• Studies from 1970’s suggested that oats were toxic in CD • Oats contain a protein-avenin • Avenin- similar to wheat gliadin • Both are prolamins –rich in glutamine and proline, both amino acids

40 • Oats can be symptomatically tolerated by most patients with coeliac disease; however, the long‐term effects of a diet containing oats remain unknown. Patients with coeliac disease wishing to consume a diet containing oats should therefore receive regular follow‐up, including small bowel biopsy at a specialist clinic for life.

Postgrad Med J. 2006 Oct; 82(972): 672–678. • 5% of cases • Can be primary or secondary • Persistent symptoms + severe villous atrophy after 6 MONTHS on GFD • Exclude other small bowel conditions

Treatment: Prednisolone + Azathioprine >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

• 3-7% of the population • Usually in patients with IBS • Negative coeliac antibody / negative histology

Probably no effect Thank you