Manifestations of Celiac Disease

Conflicts of Interest Disclosure Daniel Leffler, MD, MS I disclose the following financial relationships with commercial entities that produce health care-related products or services relevant to the content I am planning, developing, or presenting: Company Relationship Content Area Prometheus Labs Consultant Celiac Testing Manifestations of Celiac Disease Daniel Leffler MD, MS Director of Clinical Research The Celiac Center Beth Israel Deaconess Medical Center BETH ISRAEL DEACONESS MEDICAL CENTER HARVARD MEDICAL SCHOOL Celiac is an Old Disease 50 A.D. - Aretaeus the Cappadocian If the stomach be irretentive of the food and if it pass through undigested and crude, and nothing ascends into the body, we call such persons koeliacs" 1888 - Samuel Gee separates celiac disease from non-diet responsive chronic malabsorption. On the Coeliac Affection if the disease is to be cured at all it must be by means of diet in the Modern Era: Three Breakthrough Discoveries 1950 - Dicke publishes his medical school thesis: Investigation of the harmful effects of certain cereals on patients with celiac disease 1970 s HLA DQ2 associated with celiac disease/dermatitis herpetiformis 1997 - The role of tissue transglutaminase (ttg) in celiac disease identified Modern Definition of A heightened immune responsiveness to gluten (wheat, rye, barley proteins) leading to an autoimmune enteropathy often with systemic manifestations affecting ~1% of many populations. Other Important Definitions Silent celiac disease: Celiac disease without any apparent symptoms or nutritional deficiency, typically found through screening. Latent : Individuals with a positive modern celiac blood test (EMA, ttg or DGP) but no evidence of intestinal damage.*

Other Important Definitions Gluten intolerance: a condition in which people develop symptoms when exposed to gluten but lack a significant immune reaction. Symptoms of gluten intolerance can be just as severe as in celiac disease but there is no damage to the intestine and modern celiac blood tests are normal. There is no evidence of the complications seen with untreated celiac disease such as malignancy or bone disease. Gluten sensitivity: a broad category that includes all of the above disorders as well as a variety of other less common gluten-related disorders such as gluten ataxia. Three Main Steps in Celiac Pathology Step 1: Gluten enters into the intestinal submucosa Step 2: Gluten is modified by Tissue Transglutaminase (ttg) Step 3: Immune system is activated Only HLA DQ2 and DQ8 are able to bind gluten! Green, Cellier NEJM 2007 Step 1 Step 2 Step 3 Serologic tests Normal intestinal lining Villous atrophy in Gluten is the Major Protein in Wheat Bran: Outer Layer containing: Fiber, B vitamins, Minerals Germ: Inner Layer containing: Minerals, B Vitamins, Vitamin E Endosperm: Middle Layer containing: Gluten: Protein for germination Intestinal lining damaged by Celiac Disease prolamines ( glutenins of wheat gliadins) soluble in acids soluble in and bases ethanol >100 partly homologous gliadin and glutenin chains per wheat variant Toxic Grains are Closely Related is Common and Underdiagnosed Estimated Prevalence: Previous Data: 1/1000 in Europe 1/5000 in the United States* Currently accepted prevalence: 1/100 to 1/250 in the US, Europe, North Africa, the Middle East and India Compare to Type 1 DM 1/500 However: For each patient diagnosed with celiac in the United States there are approximately 50 undiagnosed individuals Modified from Kasarda, D * Talley et al, Am. J. Gastroenterol, 1994

A Myopic Impression The classic presentation of celiac disease: White, preferably of Irish or Italian decent Early childhood onset Symptoms of diarrhea, abdominal pain, weight loss and failure to thrive An Expanded Perspective can present at any age to any specialty Clinical practice has not caught up with epidemiology Celiac testing with IgA ttg is inexpensive and underused Mean duration of symptoms prior to diagnosis is 6-10 years 4-5% of IBS pts. meeting ROME criteria really have celiac Non-Classic Symptoms Account for >60% of New Diagnoses! Sanders et al. Gut 2001, Green et al. AJG 2001 The Protean Clinical Manifestations of Can present at any age to any specialty Classic Symptoms -Diarrhea -Iron deficiency anemia -Abdominal Pain -Weight Loss/Failure to thrive -Fatigue/lethargy gy -Bloating/gas -Dermatitis herpetiformis Non-Classic Symptoms -Asymptomatic -LFT elevations -Constipation -Aphthous ulcers -Nausea/Vomiting -Heartburn/GERD -Hyposplenia -Pancreatitis -Arthralgias/Myalgias -Neuropathy/Ataxia -Alopecia -Headaches -Osteopenia/Osteoporosis -Dental defects -Fertility problems -Cognitive impairment Risk Factors for Chronic Diarrhea: 25% First degree relatives: 7-10% Iron deficiency anemia: 10% Dyspepsia/chronic abdominal pain: 5% Irritable bowel syndrome: 4% Type 1 diabetes: 5% Autoimmune thyroid disease: 4% Osteoporosis 2.5-4% Sjogrens Syndrome 10% Downs Syndrome 5% Screening for celiac disease becomes cost effective when prevalence is ~4% Irritable Bowel Syndrome and IBS is the most common GI disorder affecting ~20-30% of the general population ~4% of people with IBS really have celiac Serologic testing ti for celiac is cost effective in IBS Recent IBS diagnostic guidelines support routine celiac testing in patients with presumed/suspected IBS. Affects Gastrointestinal Motility In addition to IBS, celiac disease is associated with: Reflux Constipation Gastroparesis Dumping Syndrome Symptoms typically respond to the GFD but resolution may be delayed Sanders DS et al. Gut 2001, Spiegel BM et al. Gastro 2004, Brant L et al. ACG 2009 Nachman F. et. al. AJG 2010

Improved Awareness 11% celiac diagnosis initiated by primary care physicians compared to 65% by gastroenterologists and 24% by other non-gi specialists Serologic testing for celiac disease should be considered whenever there are persistent signs/symptoms not readily explained by another condition Zipser et al. JGIM 2005, Catassi et al. AJG 2007, Berti et al. Dig Liv Dis 2006 Diagnostic Tests for have Improved Dramatically Prior to 1982: Clinical Suspicion and Biopsy (Endoscopic since 1976, before that Crosby Capsule) 1982: Anti-Gliadin Antibody ELISA Sensitivity/Specificity: y 70-80% 1985: Endomysial Antibody Immunofluoresence Sensitivity/Specificity: 95% Expensive and technically difficult 1997: Anti-tTG ELISA Sensitivity/Specificity: 95% Inexpensive and reliable Reasons for the Recent Increase in Celiac Diagnosis ttg testing has led to a rapid increase in celiac disease diagnosis Most of the recent increase is due to improved awareness and testing However, the true prevalence of celiac disease is also increasing at a rate similar to most other autoimmune disorders Approximate 4 fold increase over the last 40 years Although modern serologic testing is very sensitive, in most populations the positive predictive value is not sufficient for conclusive diagnosis Test Sensitivity (Range) Specificity (Range) PPV* NPV* IgA AGA 85 (57-100) 90 (47-94) 18 99 IgG AGA 85 (42-100) 80 (50-94) 31 99 EMA 95 (86-100) 99 (97-100) 83 99 IgA anti-ttg 98 (78-100) 98 (90-100) 72 99 IgG anti-ttg 70 (45-95) 95 (94-100) 42 99 IgA anti-dgp 88 (74-100) 95 (90-99) 44 99 IgG anti-dgp 80 (63-95) 98 (90-99) 68 99 IgA/IgG anti- 97 (75-99) 95 (87-100) 51 99 DGP * pretest probability of 5% Leffler, Schuppan AJG 2010 in press Symptom Improvement on a GFD Wheat Allergy: Adverse reactions involving IgE antibodies to one or more proteins found in wheat Consider formal allergy testing esp. with a history of atopy. Gluten Intolerance: Functional symptoms related to gluten exposure without an immune response Up to 60% of patients with IBS will report improvement on a gluten free diet Estimated that 75% of people following a gluten free diet do not have celiac disease : Diagnostic Criteria Major criteria: Consistent small bowel histology Positive IgA ttg serology (95% sens & spec) Other supportive criteria: Clinical or histological response to GFD Relapse with gluten challenge HLA DQ2 or DQ8 (absence excludes CD) Biopsy proven dermatitis herpetiformis Family history (1st degree relatives: prevalence 11%) Major criteria tests normalize on a GFD so DO NOT start treatment before confirming the diagnosis!!!

Diagnostic Algorithm High Risk: Chronic diarrhea Weight loss Iron def. anemia Family hx of celiac + lesser symptoms or nutritional deficiencies Biopsy + IgA anti-ttg + Duodenal Biopsy Biopsy Normal Not or latent Suspicion of High Risk IgA-anti-tTG & Total IgA IgA-tTG & Total IgA Normal Low Risk IgA anti-ttg & Total IgA Undetectable IgG anti-dgp & Duodenal Biopsy Biopsy Normal Not Leffler, Schuppan AJG, In Press Biopsy + Genetic Testing HLA DQ2 and DQ8 are prerequisite for celiac disease ~40% of the general population carry these genes Extremely high negative predictive value and extremely low positive predictive value Useful as a rule out in patients on a gluten free diet or young ttg negative patients Emerging Understanding of Non-GI Manifestations of Clinical appreciation for the spectrum of celiac disease has been slowly growing OB/Gyn: infertility, recurrent miscarriage, IUGR Endocrine: Type I DM, increasing thyroxine need, early onset or severe osteopenia/ osteoporosis Heme: unexplained anemia, resistance to oral iron Neurology: ataxia, peripheral neuropathy, epilepsy Dental: Enamel defects Research is beginning to explain many of these seemingly unrelated signs and symptoms Antibodies to Tissue Transglutaminase (ttg) are Diagnostic and Pathogenic Antibodies to ttg are produced when ttg is bound to gluten at the time of antigen presentation IgA ttg antibodies are highly sensitive and specific c for celiac disease Different ttg binding leads to different antibodies Sollid JBC 2004, Detrich Gut, 2003 The Transglutaminase Family Class Location Clinical Relevance TG 1 Keratinocytes congenital ichthyosis TG 2 (tissue transglut.) GI, kidney, lung, RBC, WBCs, smooth muscle, endothelium, etc celiac disease, cirrhosis, diabetic nephropathy, cystic fibrosis, malignancies TG 3, 5 Skin dermatitis herpetiformis, wound healing TG 4 Prostate prostate cancer TG 6 Brain gluten ataxia TG 7, 8?? Factor XIII Plasma coagulation/fibrin stabilization Dermatitis Herpetiformis Skin lesion recognized as pathognomonic of celiac disease since 1967 Intensely pruritic 2-5 mm blisters, urticarial plaques & excoriations Primarily on extensor surfaces: Elbows > buttocks > knees > trunk > face Onset late childhood/early adult life Responds slowly but completely to gluten withdrawal Fry et al. Lancet 1967

Dermatitis Herpetiformis is the Model for Understanding Outside the Gut Antibodies to transglutaminase or T cells primed to react to transglutaminase Antibodies deposit at Dermal-Epidermal junction The DH Model Applies to Neurological Manifestations of Celiac IgA IgA/ TG2 TG2 Antibodies to TG2/TG6 or TG reactive T cells Perivascular and Purkinje cell antibodies deposits IgA TG6 IgA/TG6 Dermatitis Dapsone / sulfapyridine Complement activation Cytokine release Neutrophil infiltrate Zone et al. J. Investigative Dermatology, 2009 Murray, et al. Int. J. Derm, 2003 Complement activation? Cerebellar Atrophy Vasculitis? Neuropathy Hadjivassiliou et al. Lancet 2010, Hadjivassiliou et al. Ann Neurology, 2009 Neurological Manifestations of Traditionally attributed to nutritional deficiencies Nerve pathology commonly reveals inflammation Patients with unexplained ataxia/neuropathy have >10 fold increased risk of celiac 10-20% of celiac patients have neurological symptoms Neurological Manifestations of Neurological Presentation Peripheral Neuropathy Depression/Anxiety Headache/Migraine Ataxia Encephalopathy Myopathy Epilepsy Frequency Common Common Common Uncommon Uncommon Uncommon Rare Hadjivassiliou Lancet, 1996, Hadjivassiliou Lancet Neurology, 2010 Hadjivassiliou Lancet, 1996, Bushara, Gastro 2005, Hadjivassiliou Lancet Neurology, 2010 And to Reproductive Manifestations of IgA Infertility Impaired fetal growth C-section IgA/ TG2 TG2 Antibodies to TG2 or TG reactive T cells Effects on nutrient transfer, placental growth? Inflammation? Placental antibodies deposits Placental ttg activity in untreated celiac disease Anjum et al. Reproductive Biology and Endocrinology, 2009 Normal Placental ttg activity Reproductive Manifestations of Typical newly diagnosed patient is a woman around the age of 40 who has been symptomatic but undiagnosed for 10 years Much of the childbearing years are affected Celiac disease can have nutritional and direct inflammatory effects on reproduction Ludvigsson JF et al, Gastroenterology 2005, Shah S, et al, Woman s Health 2010

Reproductive Manifestations of Fertility Prevalence of celiac disease in women with unexplained infertility 4-8 fold increased Limited data suggest improvement on the GFD Pregnancy outcomes Miscarriage, intrauterine growth retardation, low birth weight, C-section and preterm birth are increased in untreated celiac disease Data suggest normalization of these risks on the GFD Ludvigsson JF et al, Gastroenterology 2005, Shah S, et al, Woman s Health 2010 as a Multi-System Autoimmune Disorder Different variations of ttg antibodies damage different organs Hadjivassiliou et al. Lancet Neuro 2010 Lane Hamilton Syndrome IgA Nephropathy MPGN Cardiomyopathy, IHD Fertility Dermatitis Herpetiformis Classic Celiac + Manifestations in: Lung, Liver, Kidney, Blood Vessels, Placenta, etc Suspected Causes of Other Signs & Symptoms Fatigue/Malaise/Poor concentration Nutritional deficiencies e.g. B vitamins, carnitine Inflammatory cytokines produced in the intestine Pancreatitis Blockage of pancreatic secretions Liver function test abnormalities Related autoimmunity Inflammatory cytokines produced in the intestine Auto-antibody targeting of liver proteins Ludvigsson JF et al, CGH 2007, Hallart C et al, AP&T, 2009 & Bone Metabolism At celiac disease diagnosis: ~10-30% have osteoporosis ~40% have osteopenia Hazard ratio for fracture is 1.30 (1.16 1.46) Due to a combination of nutritional deficiencies e.g. Vitamin D, Calcium and antibodies to osteoprotegerin Significant improvement is common over the first year of treatment Vitamin D/Calcium deficiency result in greater risk of bone loss, fractures, falls, and perhaps infections, autoimmune diseases and cancer Meyer D, AJG 2001; McFarlane et al., Gut 1996; West et al., Gastroenterology 2003 & Bone Metabolism Vitamin D and calcium deficiency are common ½ of Americans have suboptimal levels Vitamin D and calcium absorption may not fully normalize on a GFD Recommend ~1200 mg calcium and 800-1000 IU vitamin D3 per day based on National Osteoporosis Foundation guidelines Patients with celiac should have vitamin D and calcium status checked after 6 months and a DEXA after 12 months on a GFD Goals: 25 OHD >32 ng/ml (or 40) National Osteoporosis PTH Foundation. <65 Physician s (maybe Guide <46) to Prevention and Treatment of Osteoporosis. Available at: http://www.nof.org/physguide/index.asp. Accessed April 24, 2007. Treatment of Strict gluten free diet is the only accepted treatment for celiac disease The GFD is one of the more challenging treatments we assign patients Involves avoidance of all wheat, rye and barley products Less than 50 mg of gluten (1/30th of a slice of bread) can cause significant, sustained mucosal inflammation GFD

Untreated has Consequences Malnutrition/malabsorption Refractory celiac disease Osteopenia/osteoporosis Lymphoma (all but especially EATL) Carcinoma of the oropharynx, esophagus and small bowel Reproductive complications Other autoimmune diseases Infectious complications including sepsis and TB Decreased quality of life Overall Mortality Risk in Celiac Disease Mortality may be increased with latent CD, but optimal management is controversial Mortality improves, but may not return to baseline after diagnosis Argues for the need for continued monitoring and new therapies Ludvigsson JF, et al. JAMA. 2009;302:1171-8. Inflammation (Marsh Stage 1-2) n=13306 Celiac disease (villous atrophy) n=29096 Latent celiac disease (positive antibodies with normal smallintestinal mucosa) n=3719 HR=hazard ratio MR=mortality rate HR in 1 st year of follow-up HR over time, 1 st year excluded Absolute MR/1000 Person-years, 1 st year excluded 4.66 1.41 22.0 2.8 1.26 9.6 1.81 1.27 6.6 Beers/Lagers Breading Broth/Bouillon Candy Drink mixes Communion wafers Croutons Flour or cereal products Dressing/Gravy Imitation bacon Imitation seafood Frozen Vegetables Marinades Matzo/matzoh meal Gluten is Everywhere Wheat-free Gluten-free. Panko Pasta Play-Doh (if eaten) Processed luncheon meats Rice pilaf Sauces/spreads Seasonings/Spice Blends Seasoned chips, nuts, seeds Self-basting poultry Soup stock Thickeners (Roux) Supplements Medications Barriers/Challenges to Staying Gluten Free Hidden gluten/cross contamination Social and professional life Diet education and health Psychological well-being Impact Access to gluten-free foods Health Label reading Cost Ongoing support and education is crucial to keeping a successful GFD All patients should be referred to advocacy/support groups Leffler et al. AP&T 2007, Leffler et al. Dig Dis Sci 2008, Leffler et al. CGH 2009, Zarkadas et al. J Hum Nutr Dietet 2006; 19:41-49. Dietary and Health Concerns Enrichment/Fortification: Most GF cereals, pasta and bread are NOT fortified Low: thiamin, riboflavin, niacin, iron, folate Weight Gain on GF Diet: Excessive reliance on protein-rich, high fat foods Low Fiber Content Constipation/IBS Coexisting Food Intolerances: Lactose soy, fructose intolerance: > 30% of patients Thompson T, Dennis M, Higgins LA, Lee AR, Sharrett MK. Journal of Human Nutrition and Dietetics. 2005;18(3):163-9. Monitoring Nutritional deficiencies are common Vitamin D, Iron, B12, +/- Zn, others Minimum of 1200mg Ca/800 IU Vitamin D Gluten Free Multivitamin All patients referred to experienced RD Assess for related conditions BMD (one year after starting treatment) TSH (~every two years) LFTs (~every two years) Follow-Up ttg (yearly) Iron Stores (yearly until stable in normal range) Symptoms (yearly) Participation in a support/advocacy group

Summary Celiac disease can present at any age and effect any organ system Testing for celiac disease using IgA tissue transglutaminase (ttg) is accurate and cost- effective Have a low threshold for ordering an IgA ttg Testing should be done before initiation of a gluten free diet All patients should be advised to maintain a strict gluten free diet and be referred to a skilled dietitian NIH Recommendations for Celiac Disease Management Consultation with a skilled dietician Education about the disease Lifelong adherence to a gluten-free diet Identification & treatment of nutritional deficiencies Access to a support and advocacy group Continuous long-term follow up by a multidisciplinary team National Institutes of Health Consensus Development Conference Statement on, June 28-30, 2004. Gastroenterology 2005;128(4 Suppl 1):S1-9.