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Celiac Disease Michelle V. Smedley, MD Connecticut GI, PC 10-28-09 Celiac Disease Definition Epidemiology Pathogenesis Diagnosis Treatment Definitions: Celiac disease: An autoimmune enteropathy (small bowel) with gluten as a trigger. A permanent food intolerance to storage proteins of wheat, rye, and barley (gluten) characterized by chronic but reversible changes predominantly in the proximal small intestine leading to decreased digestion of food, decreased absorption of nutrients, and increased net secretion of water and solute. gluten- non- Celiac sprue, gluten-sensitive enteropathy, or non-tropical sprue. Why the concern? Nearly 3 million people in the United States are estimated to have celiac disease1 1 in 133 people in the United States 11 years is the average time that patients experience symptoms before being diagnosed with celiac disease More than half of patients who are diagnosed with celiac disease do not present with diarrhea 1. US Department of Health and Human Services. NIH Consensus Statement on Celiac Disease. Bethesda, MD: US Department of Health and Human Services; 2004. NIH Consensus and State-of-the-Science Statements; vol 21, no 1. http://consensus.nih.gov/2004/2004CeliacDisease118PDF.pdf. Published June 28-30, 2004. Accessed August 23, 2007. Celiac Disease Definition Epidemiology Pathogenesis Diagnosis Treatment Epidemiology- Epidemiology-key points Not just Caucasians Not just children Not only diarrhea and weight loss We are only seeing the “tip of the celiac iceberg” Epidemiology Worldwide 1:100 to 1:300 people are affected Female to male 2:1 Clinically i t during Cli i ll severe picture d i pregnancy or postpartum Association with diabetes type I, Down’s syndrome, autoimmune thyroid disease, microscopic colitis, and chronic fatigue Celiac in Children Presents between 6 and 24 months of age Chronic diarrhea, anorexia, abdominal distension and pain, and failure to thrive or g ; y weight loss; some may also have vomiting g Between 8 and 10 percent of children with apparent "idiopathic" short stature Delayed menarche Chronic constipation, recurrent abdominal pain MODE OF PRESENTATION DIAGNOSIS AFTER 1993 N=170 Abd pain Other 5% 5% W t loss 6% Bone disease 6% Diarrhea 43% Anemia 8% Incidental 10% Screening 17% Lo et al, Dig Dis Sci, 2003;48: 395 Classic Celiac Disease Malabsorption Diarrhea,steatorrhea, fatigue, abdominal pain, anemia and weight loss P t i infants 9- th d i in • Presents in i f t 9-24 months and again i 3rd-4th decades 3rd- breast- • This is in part due to longer periods of breast- feeding and the later introduction of gluten in the infant diet. 2- • 1:1 female:male in children; 2-3:1 in adults Atypical Celiac Disease extra- Minimal GI complaints, but extra- intestinal symptoms Iron def, IBS, infertility, HA, ataxia with occipital calcifications, seizures, and polyneuropathy GERD and gastritis are also seen Most frequent presentation. Disease can present at any age “Silent”Celiac disease villous atrophy in asymptomatic patients symptomatic:7- 1 symptomatic:7-8 asymptomatic patients Refractory Celiac . No longer responsive to diet jejuno- Ulcerative jejuno-ileitis ( p y EATCL(enteropathy associated T cell lymphoma) Refractory Celiac Severe villous atrophy and malabsorption with either no response to or no further response to GFD. Two types: One an expansion of normal IEL in the biopsy and this type responds to steroids/immunosuppressives; yp p pp the second as expanded IEL of CD3 lymphocytes. This is IL- thought to result from IL-15 stimulation and predates lymphoma but the treatment is similar to the first type Sometimes avoiding triggering foods is beneficial IL- Research on blocking IL-15 is ongoing. Who to test? symptoms- Anyone with symptoms-irritable bowel syndrome- syndrome-D or lactose intolerance Diabetes type I, Down’s syndrome, autoimmune thyroid disease, microscopic colitis, and chronic g fatigue Infertility Osteoporosis Iron def anemia, low albumin, hypertransaminasemia Skin rash (DH) Peripheral neuropathy Natural History Lymphomas Small bowel adenocarcinoma Oropharyngeal tumors Infertility Osteoporosis Stunted growth Autoimmune diseases Lymphoma NHL- extra- EATL or NHL-intestinal or extra-intestinal Risk increased 80 times in initial reports More recent studies:UK study with 25 year f/u:1/5684 pt.years(py)for SB lymphoma and 1/1421py for NHL; Swedish study with 56 cases of lymphoma in 11,650 CD patients: 43% had EATL and relative risk of B cell extra- NHL was 2.2 and intestinal and extra-intestinal NHL was 3.6. Dermatitis Herpetiformis papulo- Pruritic papulo-vesicular rash over extensor surfaces, knees,elbows and face sub- Diagnosis based on IGA deposits in uninvolved sub- epidermal basement membrane against dermal tTG g 85% of DH patients will have small bowel biopsies consistent with CD but no minimal GI symptoms Rash responds to diet Collagen Vascular Disease The prevalence of autoimmune disorders in patients with CD is significantly more frequent; 14% versus 2.8% Interestingly, the risk of autoimmune disorders appears to increase with the duration of disease as a function of # of years to diagnosis due to longer exposure to foreign antigens. False + ASCA in celiac and false + IGA anti tTG in Crohn’s disease Epidemiology- Epidemiology-Diabetes Both CD and DM share high carriage of DQ2 and DQ8- DQ8-Almost 100% with CD and 73% in IDDM Studies have found ranges of CD in diabetics from 1- 1-12% by serology and 1-11% by biopsy and slightly hi h frequencies i children.Average risk 2-5% i higher f i in hild A i k 2- in 3- adults and 3-8% in children. Be aware of the association and evaluate in the setting of appropriate symptoms like diarrhea, IDA, unexplained hypoglycemia, weight loss etc. Epidemiology-Thyroid and Liver Epidemiology- disease Literature doesn’t provide compelling evidence for screening 1.5- CD in patients with thyroid disease. Ranges of CD from 1.5- 6.7%; highest in patients over 65. Especially hypothyroidism. PBC(0- CD is associated with PBC(0-6%), autoimmune liver disease NASH(2.9- and NASH(2.9-6.4%) with a lesser assoc. to PSC(3.4) Isolated AST elevations may be the only manifestation of CD 1.5- and occurs in 1.5-9% of cases of AST elevation of ? Etiology. The AST level normalizes with GFD. tTG- EMA is more sensitive than tTG-GP in liver disease when screening for CD. Epidemiology- Epidemiology-other associated diseases Downs syndrome patients are at least 5x more likely to have CD than average risk populations. syndrome- There is increased frequency of CD in Turner’s syndrome-6.3% pooled frequency. 2.1- Infertility is seen with women who have CD with frequencies of 2.1- 4 1%(pooled risk 3.7%). There is lower fertility that normalizes with 4.1%(pooled 3 7%) GFD. Women with CD have later menarche and more still births but similar # of pregnancies. Aberrant sperm and hormone profiles in men normalize on GFD IBD, IGA nephropathy, addison’s, occipital calcifications with ataxia, neuropathy, HA and seizures are associated with CD Relatives at risk The consensus risk of CD in 1st degree relatives 5- approaches 5-10% with 2nd degree relatives 2.5- averaging 2.5-5.5%. Identical twins have rates as high as 70%. An infectious trigger for CD Frequency of Rotovirus infections and development of infection- infections- CD. Risk with one infection-1.94;two infections-3.76 in DQ2 infants ype de o us protein ay set off CD owing o Type 12 Adenovirus p o e may se o C o g to similarity to gliadin peptide Breast Feeding may be protective in preventing CD. Introduction of Gluten before 4 months of age had increased risk of CD whereas after 7 months of age had marginal risk Celiac Disease Definition Epidemiology Pathogenesis Diagnosis Treatment Pathogenesis Food intolerance that initiates complex adaptive and immune reactions that result in chronic intestinal mucosal inflammation with structural and functional implications It is unclear why tTG antibodies are so specific why elderly patients can present with CD what explains the diversified symptoms noted with today’s CD Understanding the pathophysiology of villous injury could lead to novel therapies IMMUNOLOGIC MECHANISM OF GLIADIN INDUCING VILLOUS ATROPHY LAMINA PROPRIA Gliadin peptide tTG DQ2/DQ8 Deamidated gliadin peptide T cell receptor IFN-γ CD4 Pathogenesis T- B- Activation of T-cell and B-cell immune response to gluten in a person who is genetically susceptible. HLA- Genetic testing in 95% of CD pts is HLA- HLA- DQ2 the rest are positive for HLA-DQ8 Pathology Proximal small bowel (where gluten 1st encounters mucosal immune system) Symptoms tend to correlate with degree of villous atrophy but can be discordant Pathologic changes are reversible with GFD Celiac Disease Definition Epidemiology Pathogenesis Diagnosis Treatment Diagnosis EMA: IGA antibodies to endomysium(smooth muscle connective tissue);antigen in endomysium is tTG Immunoflourescence, ME or HUC b t t substrates Pooled spec./sens.:97.4;99.6/100;90% Most sensitive serologic marker and especially good with liver disease and children Expensive, time consuming and potential observer error Diagnosis • tTG: bacterial prolyl-endopeptidases tTG is a ubiquitous prolyl- intracellular enzyme released by inflammatory and endothelial cells and fibroblasts in response to inflammation or irritation Cross links to proline rich peptides like gluten and d i t l t i d i deaminates glutamine rendering a negatively ti l charged gluten peptide with increased binding to DQ2/8 that facilitates T cell stimulation Quant. enzyme linked immunoadsorbant assay Pooledspec./sens.:GP/HUr90;95.3/95.1;98.3% False + anti tTG with CHF,IBD,arthritis, liver disease; Most false+ with GP anti tTG Helpful hints with CD serologies Both EMA and tTG can become negative on GFD and a persistent titer can be helpful in defining compliance with GFD EMA and tTG Correlate with villous atrophy(<50% M2) For those patents who have empirically re- started GFD before CD is diagnosed, re- expose to gluten for 6 weeks then retest IGA antibodies to prove CD Diagnosis IGA- IGA-AGA: immuno- Predates EMA and tTG, enzyme linked immuno- adsorbant assay specificity/sensitivity(85- Low specificity/sensitivity(85-95%) AGA no longer recommends IGA deficiency: Most common type of immune deficiency 8-10% with celiac are IGA deficient anti- IGG anti-tTG approaches 100% sensitivity AGA doesn’t recommend routine IGA level unless CD strongly suspected and EMA/tTG are neg.; consider HLA DQ2/8 Diagnosis DQ8- DQ2 and DQ8- HLA class II heterodimers 48- Present in 30% general public; 48-65% asymtomatic relatives of CD patients and 73% of diabetics Almost 100% of CD patients are positive for DQ2 or Dq8; DQ2 in 95%, DQ8 in 5% 100% negative predictive value for CD Diagnosis Small bowel biopsy AGA consensus paper:gold standard and should be done on all before GFD EMA and tTG correlate most with villous atrophy and can negative in milder histologies The small biopsy can be patchy and biopsy can be falsely negative Celiac Disease Definition Epidemiology Pathogenesis Diagnosis Treatment Gluten Free Diet Your treatment plan Gluten- Gluten-free diet Referral to dietician or support group Bone density check iron, folate, B12, Check iron folate B12 and vitamin D level Advise screening for first and second degree relatives Counsel on lactose intolerance Pneumo- Pneumo-vax due to associated hyposplenism Treatment Compliance socio- Compliance correlates with parental socio-economic status and both knowledge and understanding of the disease by both parent and child. sy p o a c children e d o ess compliant; Asymptomatic c d e tend to be less co p a ; children with CD diagnosed before 4 y.o. tended to be more compliant. Membership in local support groups seems to foster compliance. Cross- Cross-contamination If your gluten free foods come into contact with foods that contain gluten For example, crumbs from regular wheat bread can find their way into jams, spreads, or aren t condiments if people aren't careful to use a fresh knife or utensil each time. Condiments in squeezable bottles or using separate jams and spreads is a great idea for people with celiac disease. gluten- Separate toaster for gluten-free bread Kitchen contamination If someone in your family bakes with products that contain gluten, you need to thoroughly clean appliances, utensils, and work surfaces before preparing your gluten- gluten-free products. Remember to wash your hands thoroughly and often. Resources Registered dietician familiar with diet and resources. Mary Noon , RD Greater New Haven Celiac Group www.connceliac.org Living without magazine. Clan Thompson Newsletter(free). CSA( Celiac Sprue Association). Follow- Follow-up Patient should be followed on a regular basis by an health care professional and dietician. Since symptoms don’t have to correlate with adherence to GFD, it is recommended to repeat an IGA EMA or tTG after 6 months of GFD to p define compliance. Children’s histology can resolve quicker and more completely than adults who can take over 2 years for their mucosa to normalize. • Persistence of histologic abnormalities in adults may not speak to dietary indescretion alone Follow- Follow-up Rebiopsy is not considered necessary unless response to GFD is needed to confirm a seronegative case for diagnosis re- or to re-evaluate refractory symptoms or recurrent symptoms. Recurrent symptoms are most often compliance issues Recurrent symptoms may signify a complication or an s diagnosis. associated vs. additional diagnosis Consider a complication:(lymphoma or malignancy);associated conditions:(microscopic colitis or IBS) versus additional diagnoses like pancreatic insufficiency or lactose intolerance especially with recurrent diarrhea. Future Therapy prolyl- Specific proteases (bacterial prolyl- endopeptidases) to break down gluten epitopes in food HLA- HLA- Blockade of HLA-DQ2 and HLA-DQ8 interaction with gliadin Inducing immune tolerance to wheat epitopes Creating new wheats with different proline/glutamine sequences IL- Blocking IL-15, tTG, zonulin Future Therapy Search for less toxic cereals would reduce immune reaction Several cereals are being analyzed for immunogenic stimulation of IFN gamma and T ll cells ?? Genetically engineered cereals An Ethiopean cereal, Tef, does not seem to stimulate T cells Future Therapy Prolyl- Bacterial Prolyl-endopeptidases Facilitate more complete digestion of toxic gliadin peptides anti- Reduced symptoms but did not alter IGA anti- tTG levels or improve biopsy. Problem may be duration needed to digest the gluten to less toxic sequences Gluten free restaurants Pizza1 Famous Pizza1 P.T. Barnum Sq. Bethel, CT-06801Pizza CT- Grill1462 Portland- Eggs Up Grill1462 Portland-Cobalt Road Portland, CT-06480American CT- Inc.28 Bruno's Pizza Inc.28 State Route 39 New Fairfield, CT- CT-06812Pizza Bakery286 Dee's One Smart Cookie Gluten Free Bakery286 Tryon Street Glastonbury, CT-06033Cafe CT- Grill100 Burtons Grill100 Evergreen Way South Windsor, CT-06074American, Grills, Seafood CT- Max Restaurant chain American Celiac Disease Alliance 2504 Duxbury Place Alexandria, VA 22308 Phone (703) 622-3331 Email: email@example.com Internet: www.americanceliac.org National Foundation for Celiac Awareness P.O. Box 544 Ambler, PA 19002 Phone: 215–325–1306 Email: firstname.lastname@example.org Internet: www.celiaccentral.org Gluten Intolerance Group of North America 31214 124th Avenue SE Auburn, WA 98092 Phone: 253–833–6655 Fax: 253–833–6675 Email: email@example.com Internet: www.gluten.net Celiac Disease Foundation 13251 Ventura Boulevard, #1 Studio City, CA 91604 Phone: 818–990–2354 Fax: 818–990–2379 Email: firstname.lastname@example.org Internet: www.celiac.org Key Points Diagnosis made with small bowel biopsy showing characteristic changes and clinical response to gluten free diet yp Atypical ppresentations are most common Serology testing for screening at risk patients and first degree relatives should be screened Compliance with diet is the key to treatment
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