Celiac Disease: You ve Come A Long Way Baby!

Celiac Disease: You ve Come A Long Way Baby! Celiac Disease (CD): How You ve Changed Increasing numbers of people have celiac disease Changing ways in which celiac disease presents A better understanding of what leads to CD Advances in the diagnosis of CD Improving dietary treatment Better prognosis Non-celiac gluten sensitivity (NCGS) New therapies and prevention of CD New Definitions and Terminology Celiac disease (CD): a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals Other terms including celiac sprue, sprue, gluten intolerance and gluten-sensitive enteropathy are no longer recommended Classical and non-classical celiac disease Asymptomatic or subclinical celiac disease Potential celiac disease Ludvigsson, J et al, Gut, in press Varying Forms of Celiac Disease Classical celiac disease of childhood Late onset, non-specific GI symptoms Dermatitis herpetiformis Extra-intestinal presentations (many) Associated conditions (many) Silent or asymptomatic celiac disease (relatives) Latent or potential celiac disease Celiac Disease is No Longer a Rare Disease Prevalence of up to ~1:100 in most genetically susceptible populations compared to older data of 1 in 2000 (Canada) to 1 in 5000 (USA) However less than 10-15% of current cases of CD have been diagnosed in the US CD is 4 to 4.5 times more prevalent than 50 yrs ago Cause of CD epidemic unknown Dietary grains with increased gluten, increased wheat in diets worldwide Other environmental factors, enteric infections Microbiota Fasano et al, Arch Int Med, 163:286, 2003 Rubio-Tapa, A et al, Gastroenterology, 137: 88, 2009 AGA Technical Review, Gastroenterology, 131:1981, 2006 Virta et al, Scand J Gatroenterol, 44:933, 2009 Changes in the Populations Affected by Celiac Disease Celiac disease is not just a disease of whites All genetically susceptible populations report similar seroprevalance including South Asia, North Africa, Mediterranean, Middle East Women are not necessarily more often affected by CD than men Seroprevalence M=F, however diagnosis M<F Celiac disease is not just for kids Average age of diagnosis in 5 th decade Page 1 1

Classical Celiac Disease: No Longer the Common Form of CD Haas & Haas, Management of Celiac Disease. 1951 Failure to thrive Weight loss Protuberant abdomen Bloating Diarrhea, steatorrhea Abdominal pain Dramatic response to gluten free diet Clinical Presentations: Non-specific GI Symptoms Altered bowel habit Diarrhea, constipation, combination Bloating, dyspepsia, heartburn Abdominal discomfort Over 4-fold increase prevalence of celiac disease in IBS cases compared to controls in a meta-analysis Ford, et al, Arch Int Med 13:651, 2009 ACG recommendations for evaluation of IBS include screening for celiac disease but not infection, IBD, colorectal cancer Symptoms and Conditions That Should Prompt Consideration of Celiac Disease First and second degree relatives GI symptoms Extraintestinal presentations Dermatitis herpetiformis Iron deficiency Folate deficiency Osteopenic bone disease Chronic fatigue Neuropsychiatric manifestations Short stature Infertility Obstetrical complications Miscellaneous conditions IgA deficiency IgA nephropathy Down s syndrome Turner s syndrome Autoimmune endocrine disorders Insulin-dependent diabetes mellitus Autoimmune thyroid disease Autoimmune adrenal disease Autoimmune connective tissue disorders Sjogren s syndrome Rheumatoid arthritis Systemic lupus erythematosis Hepatobiliary conditions Primary sclerosing cholangitis Primary biliary cirrhosis Autoimmune cholangitis Elevated transaminases Other inflammatory luminal GI disorders Lymphocytic gastritis Microscopic colitis Inflammatory bowel disease Crowe, SE, In The Clinic : Celiac Disease, Ann Int Med, 154:ITC5-14, 2011 CD is Found in Every Body Type: From Thin to Super Obese Kupfer, S. et al, DDW 2012 Who Develops Celiac Disease? Genetic and Other Factors 70% concordance in twins 10-15% prevalence in first degree relatives Other genetic factors - genes on chromosomes 5, 16,?6 GWAS have identified at least 26 celiac genetic risk variants many contain immune-related genes controlling adaptive immune response Increased frequency of HLA haplotypes - DR3-DQ2, Environmental factors -? Infectious DR5/7-DQ2, DR4-DQ8 agents Other factors involved since Viral infections most with these haplotypes Cytokines released during infection affecting APCs (e.g., dendritic cells) do not get celiac disease Cross-reactive amino acid (confer ~40% of risk) sequences - Adenovirus, H. pylori Why Celiac Disease Develops? Dietary Factors Gluten/Prolamines Cereal prolamines initiate immune-mediated mucosal damage in genetically predisposed individuals» Gliadin (wheat)» Secalin (rye)» Hordein (barley) Prolamines are not intrinsically toxic At least 50 peptides recognized by T cells of celiac patients have been identified (in α-gliadin and glutinins) Not all subjects respond to all peptides No one peptide is recognized by all patients 33mer peptide from α2-gliadin contains HLA-DQ2 binding sequences that can be deamidated by TG2 (TTG) Page 2 2

Current Diagnostic Criteria Characteristic histological findings Clinical, serological, and in some cases, histological response to a gluten free diet Rarely necessary to observe clinical and histological response to gluten challenge Intestinal biopsies are the only method by which celiac disease can be diagnosed However, for dermatitis herpetiformis a classical skin biopsy is sufficient for diagnosis Schuppan et al, Gastroenterology, 137:1912, 2009 AGA Technical Review, Gastroenterology, 131:1981, 2006 Performance of Serologic Tests in Adults before 2004 NIH Consensus Conference Test Sensitivity Specificity AGA IgA < 80% in 50% > 80% in most AGA IgG variable non-specific EMA IgA 96-97% ME, 90% HUV 100% ME, HUV ttg IgA 90% GP, 98%HR 95% GP, 98% HR ttg IgG 40%, but higher in IgA deficiency 98% Rostom et al, Gastroenterology, 128:S38, 2005 More Recent Performance of Diagnostic Tests for Identifying CD 16 studies included (N=6085 subjects) EMA IgA (N=8 studies) Sensitivity 0.90 (95% CI, 0.80-0.95) Specificity 0.99 (95% CI, 0.98-1.00) TTG IgA (N=7 studies) Sensitivity 0.89 (95% CI, 0.82-0.94) Specificity 0.98 (95% CI,0.95-0.99) TTG IgA and EMA IgA have high sensitivity and specificity for diagnosing celiac disease in adults with abdominal symptoms in primary care or other unselected populations Van der Windt et al, JAMA, 303:1738, 2010 New Tests: Deamidated Gliadin Peptide (DGP) Antibodies Serum from celiac with active disease preferentially recognize deamidated gliadin peptides IgA and IgG antibodies to deamidated gliadin peptides (DGP) are more sensitive and specific tests than IgA and IgG antigliadin antibodies (AGA) Farrell & Kelly, NEJM, 346:180, 2002 Schwertz et al, Clin Chem, 50:2370, 2004 Agardh, Clinical Gastroenterology & Hepatology, 5: 1276, 2007 What are the Best Serological Tests for Screening in 2012? Depends on prevalence and age of population being examined Overall, ttg IgA is recommended to screen for celiac disease but lower sensitivity ( 90% ) reported in routine practice 1 in 10 will be falsely negative EMA IgA is helpful when positive ttg, EMA less sensitive for milder histologic stages Traditional AGA no longer used as a first line antibody test except in young children Check total IgA for assays with narrow range of normal Antibodies to GDP are less sensitive than to ttg * AGA Technical Review, Gastroenterology, 131:1981, 2006 * Lewis, NR, Aliment Pharmacol Ther, 31: 73, 2010 Page 3 3

? Proposed New Criteria for Diagnosis Four out of five sufficient to diagnose CD? Typical symptoms of CD High titer of serum CD IgA class autoantibodies HLA DQ2 and/or HLA-DQ8 genotypes Celiac enteropathy by small bowel biopsy Response to a GFD This proposal remains controversial amongst other experts in the field Catassi & Fasano, Am J Med, 123:691, 2010 Sapone, et al, BMC Medicine, 2012 New ESPGHAN Guidelines for the Diagnosis of CD in Children Children with symptoms of CD Symptoms Positive serology Histology If TTG IgA titers > 10X upper limit normal option to diagnose without biopsy but strict protocol of further lab testing recommended (verify TTG with EMA to exclude a false positive, HLA testing) JPGN, 154:136, 2012 Endoscopic Findings in Celiac Disease Flattened or absence of folds Notching or scalloping of folds Fissuring of mucosa New endoscopes are better at detecting these findings and can target where biopsies should be obtained Oxentenko, Am J Gastroenterol, 97:933, 2002 New Information Has Led to Increasing Biopsy-Based Diagnosis Rates Taking at least one biopsy from the duodenal bulb increases detection rates in adults and children Hopper, AD, et al, Endoscopy 39:219, 2007 Bonamico, M et all, JGN, 47, 618, 2008 Weir, DC, et al Am J Gastroenterol 2009 Taking a minimum of 4 biopsies increases the rate of diagnosis of CD for 4 versus <4 biopsies: 1.8% vs 0.7% (P < 0.0001) Rates of diagnosis continue to increase for every additional biopsy taken Lebwohl, B., et al, Gastrointestinal Endoscopyy, 74:103, 2011 Growing Use of HLA DQ Genetic Screening Tests Increased frequency of certain HLA haplotypes in celiac disease DR3-DQ2 or DR5/7-DQ2-95% DR4-DQ8-5% Only HLA DQ2 or DQ8 positive subjects are at risk of getting celiac disease Helpful test for its NPV Risk of celiac disease and HLA status DQ2 and DQ8 negative - < 0.1X Pietzak, M, Clin Gastro & Hepatol, 7:996, 2009 When to Use Genetic Testing How to test: PCR of RNA extracted from cells in a cheek swab or blood sample Who to test: Close relatives of patients with confirmed CD wishing to know if they are at risk of developing CD Patients on a gluten free diet who are candidates to undergo a gluten challenge to confirm possible CD Equivocal histology and serology findings in which a negative test result would make CD highly unlikely How often to test: Once in a lifetime Crowe, SE, In The Clinic : Celiac Disease, Ann Int Med, 154:ITC5-14, 2011 Page 4 4

Screening Family Members: Who Is at Risk of Celiac Disease? Relatives: Who and How to Screen Index case has proven celiac disease Relative is interested in being screened Relative is willing to undergo diagnostic testing Relative is willing to undergo treatment Relative will derive benefit from treatment If relative is symptomatic, approach is diagnostic not screening Relatives: Who and How to Screen Relative is an appropriate candidate? No counsel relative and family Yes, get genetic testing First degree relative s risk unknown HLA - 10-15% DQ2 or DQ8+ - 20-30% HLA DQ2 or 8 positive, Check serology ttg IgA positive Perform EGD + Bx ttg IgA negative, not IgA deficient Repeat every few years HLA-DQ2 and 8 negative not at risk for celiac disease Just Because Someone is Better on a Gluten Free Diet Does Not Mean CD Placebo response in IBS up to 70% Gluten (increased prolamines) is hard to digest, increases stool volume Gluten free diet often eliminates other dietary factors Potentially other mechanisms explain benefit Gluten free diet show benefits in IBS PPV of symptom improvement after gluten withdrawal for CD only 36% in one study Biesickierski, et al, Am J Gastroenterol, 106:508, 2011 Campanella et al, Scand J Gastroenterol, 43:1311, 2008 CD or Non-celiac Gluten Sensitivity? Celiac disease: Immune disorder in which gluten causes intestinal damage Non-celiac gluten sensitivity: Various definitions non-intestinal presentations, symptoms consistent with functional GI disorders but respond to GFD May have positive antibody tests May have HLA DQ2 or DQ8 genes Typically responds to gluten withdrawal However, much more than gluten may be removed in a gluten-free diet No criteria to define NCGS and we do not know how commonly this occurs Page 5 5

Between Celiac Disease & Irritable Bowel Syndrome: The No Man s Land of Gluten Sensitivity Verdu et al, Am J Gastroenterol, 104:1587, 2009 Improvements in the Gluten-Free Diet Improved GF products Increased availability of GF foods Increased awareness of CD and the GFD Gluten-free foods are the fastest growing sector of the food industry for several years now Focus on naturally GF foods, what we can eat Focus on nutrition Awareness of additional GF grains Labeling in the USA for gluten since 2008 Increased Information on CD and the Gluten Free Diet Increased numbers of celiac disease foundations and support groups An explosion of on-line information Increased awareness of CD by health professionals Increased research being conducted Celiac disease is becoming a household term However Not All Information is Correct as the Following Examples Illustrate Avoid gluten-containing shampoos, creams and lotions Only beauty/health items that are ingested are a concern» Lipstick, chapstick, toothpaste, medications, etc You need separate sets of utensils, dishes, appliances, etc. Only upright toasters, difficult to clean items Buy only gluten free cleaning products Your pets should eat gluten-free Selected Resources for Patients with Celiac Disease and Their Families Websites Celiac Disease Foundation (CDF), www.celiac.org Gluten Intolerance Group of NA (GIG), www.gluten.net National Foundation for Celiac Awareness, www.celiaccentral.org Canadian Celiac Association (CCA), www.celiac.ca Celiac Sprue Association (CSA), www.csaceliacs.org Books Case, Shelley, The Gluten Free Diet, 2011 Blumer, I. & Crowe, Sheila, Celiac Disease for Dummies, Wiley, 2010 Dennis, M., Leffler, D ed. Real Life with Celiac Disease: Troubleshooting and Thriving on a Gluten Free Diet, AGA Institute Press, 2010 Page 6 6

The GFD: Still Room for Improvement Perceived Treatment Burden of Celiac Disease (CD) is High Eating out of the home Peer pressure for children, teens Less acceptable taste, texture of foods Cost (~3 times higher), availability, labeling Unclear how much gluten, if any, is safe New FDA guidelines 20 ppm (up to 10 mg/ day safe) Shah, S. et al, DDW 2012 Serious Heath Risks Associated with Celiac Disease Have Decreased Severe malabsorption is less often seen Infertility, miscarriages, IUGR improve on a GFD Malignancy risk is much lower than reported when I was in medical school (50 to 100 times increased) versus 4 times increased above the general population now Small increase in mortality (mortality rates in 22 studies ranged from 0.52 to 3.9) which goes back to baseline after being on a GFD Biagi, F & Corazza, G.R, Nature Reviews GI & Hep, 2010 Rubio-Tapa, A et al, Gastroenterology, 137: 88, 2009 Beyond the Diagnosis: Emerging Guidelines for Follow-up of Patients with Celiac Disease Correct nutritional deficiencies Follow ttg IgA until it is normal Consider checking ttg IgA every 1-2 years thereafter Repeat DEXA scan every 2 years if abnormal In some instances repeat EGD with biopsy Promote general good health (exercise, cease smoking, maintain normal BMI, adhere to screening guidelines) Crowe, SE, In The Clinic : Celiac Disease, Ann Int Med, 154:ITC5-14, 2011 Advances in Preventing Celiac Disease Determining the optimum time to introduce gluten in the diet of infants at risk of developing celiac disease Larazotide Acetate (AT-1001) Zonulin Zonulin Current recommendations include an early time of introduction of gluten while mother is still breast feeding X Zonulin Zonulin anti-ttg DQ2 blocking Peptide therapy peptide Trials studying different times of introduction of gluten in infant diets are underway in USA, Finland, Italy Endopeptidases (ALV-003, ANPEP) Kagnoff, J Clin Invest, 117:41, 2007 Page 7 7

We ve Come a Long Way Baby Increased awareness Better diagnostic tests Greater understanding of the disease Better gluten-free foods More resources and support groups The recent developments in the world of celiac disease would astound my mother-inlaw, Kay Ernst, cofounder of CCA in 1972, who passed away in 2002 Still Room for Improvement: What the Future May Hold Better ways to determine risk Improved diagnostic tests New treatments Prevention of celiac disease Increased awareness Additional advances in knowledge Improved coverage of medical costs Chapter 16, Blumer & Crowe, Celiac Disease for Dummies, 2010 Advice for Patients and Families Take charge of your celiac health Become an expert on your condition Get the most out of your visits with health care professionals Be prepared, bring medications, write down your questions, bring a family member or friend to appointments, bring resources Make notes, ask questions, get follow up Be an advocate for you and your family Don t Miss the Boat - Be Aware of Emerging Information on Celiac Disease Chapter 15, Blumer & Crowe, Celiac Disease for Dummies, 2010 Page 8 8