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Meeting the Nutritional Needs of Adults with Celiac Disease Daniel Leffler, MD, MS Clinical Research Director Celiac Center Beth Israel Deaconess Medical Center www.bidmc.harvard.edu/celiaccenter HARVARD MEDICAL SCHOOL Objectives Define and review pathogensis of celiac disease Identify currently accepted diagnostic testing methods for celiac disease Identify the risk factors and extra-intestinal manifestations associated with celiac disease Learn standard treatment approach Recognize key nutritional deficiencies and standard supplementation recommendations Discuss causes of continued GI symptoms despite a patient’s strict adherence to the GF diet Patient: Jill Initial Visit: May 09 Jill, a 32 year old, has been experiencing fatigue, gas, bloating, and loose stools since a GI virus affected her whole family while on a cruise. All other members recovered while Jill did not. She experimented with the gluten free diet and noticed that her symptoms improved somewhat. Her PCP has sent her to GI for a work-up. Ht: 5’7 Wt: 126# PMHx: anemia SHx: Nonsmoker, minimal alcohol Food allergies/intolerances: lactose What important diseases/ disorders would you elicit in the patient’s family history? Patient: Jill Initial Visit: May 09 Jill, a 32 year old, has been experiencing fatigue, gas, bloating, and loose stools since a GI virus affected her whole family while on a cruise. All other members recovered while Jill did not. Her PCP has sent her to GI for a work-up. Ht: 5’7 Wt: 126# PMHx: anemia Meds: Allegra, Loestrin SHx: Nonsmoker, minimal alcohol Food allergies/intolerances: lactose FHx: breast cancer, autoimmune thyroid disease, Type 1 diabetes, diverticulitis, IBS What are possible causes of Jill’s symptoms? Patient: Jill Differential Ht: 5’7 Wt: 126# Irritable Bowel Syndrome Lactose intolerance Inflammatory Bowel Disease Small intestinal bacterial overgrowth Chronic infection Celiac Disease What makes you suspect celiac disease in Jill? Diseases Associated with Celiac Disease Chronic Diarrhea: 25% First degree relative with celiac: 7-10% Iron deficiency anemia: 10% Type 1 diabetes: 5% Autoimmune thyroid disease: 4% Osteoporosis: 2.5-4% Sjogrens Syndrome: 10% Downs Syndrome: 5% IBS: 4-5% Family history of autoimmune disease What is Celiac Disease? Celiac Disease: A heightened immune responsiveness to gluten (wheat, rye, barley proteins) leading to an autoimmune enteropathy often with systemic manifestations. Pathophysiology Step 1: Gluten Entry into the Submucosa Step 2: Deamidation of Gluten by Tissue Transglutaminase (tTG) Step 3: Immune Activation Only HLA DQ2 and DQ8 are able to bind gluten! *Green, Cellier NEJM 2007 Step 1 Step 2 Step 3 Serologic tests Celiac Disease is Not Rare Estimated Prevalence: • Previously: 1/1000 in Europe & 1/5000 in the U.S.* • Currently: ~1/150 in US, Europe stretching to North India ~ areas with high prevalence of HLA DQ2/DQ8 • Compare to Type 1 diabetes 1/500 However: • Number of known celiacs in the U.S.: ~40,000 • Projected number of celiacs in the U.S.: well > 3 million • For each known celiac there are 53 undiagnosed individuals * Talley et al, Am. J. Gastroenterol, 1994 Not a Pediatric Disorder Until the 1980’s celiac disease was almost exclusively diagnosed in children between the ages of 2 and 8 Currently the average age of diagnosis in the United States is 50 years 2/3 of current diagnoses are female Serologic studies suggest slight female predominance Signs and Symptoms of Celiac Disease Can Present at Any Age to Any Specialty Classic Symptoms Diarrhea Iron deficiency anemia Abdominal Pain Weight Loss/Failure to thrive Fatigue/Lethargy 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 Dermatitis Herpetiformis The skin manifestation of celiac disease Intensely itchy 2-5 mm blisters Extensor surfaces: Elbows > buttocks > knees > trunk > face Onset late childhood/early adult life Auto-antibodies formed in the intestine deposit at the dermal-epidermal junction Gluten responsive but often treated with Dapsone Complications of Undiagnosed and/or Untreated Celiac Disease Malnutrition/malabsorption Anemia Osteopenia/osteoporosis Lymphoma (all, but especially EATL) Carcinoma of the oropharynx, esophagus and small bowel, ? Melanoma Reproductive complications Other autoimmune diseases Infectious complications including sepsis and TB* Decreased quality of life SMR 2-4 times greater than the general population normalizing within 5 years of gluten withdrawal *Influenza and Pneumococcal vaccines should be considered for newly diagnosed patients Many Medical Specialties are Now Diagnosing Celiac Disease OB/GYN: Infertility, recurrent miscarriage Endocrine: Poorly controlled Type I diabetes, increasing thyroid medication need, early onset or severe osteopenia/ osteoporosis Hematology: Unexplained anemia Neurology: Ataxia, peripheral neuropathy, epilepsy Dental: Enamel defects If you suspect celiac disease, what do you recommend for testing? Improved Diagnostic Tools Prior to 1982: Clinical Suspicion and Biopsy (Endoscopic since 1976, before that Crosby Capsule) 1982: Anti-Gliadin Antibody ELISA Sensitivity/Specificity: 70-80% 1985: Endomysial Antibody Immunofluoresence Sensitivity/Specificity: 95% 1997: Anti-tTG ELISA Sensitivity/Specificity: 95% New ELISA for deamidated antigliadin antibodies have similar accuracy to tTG Celiac Disease: Diagnostic Criteria •Major criteria: Consistent small bowel histology Positive IgA tTG serology •Other supportive criteria: Clinical response to GFD Histologic response to GFD Symptoms, tTG and biopsy relapse with gluten challenge Please Note: ALL diagnostic tests normalize on a GFD so DO NOT start treatment before confirming the diagnosis! Endoscopic Small Intestinal Biopsy for Diagnosis of Celiac Disease Scalloping, Mosaic Pattern, Nodularity Villous Atrophy, Crypt Hyperplasia, Increased IELs Villous Atrophy in Celiac Disease What About Genetic Testing? Celiac General Population DQ2 Positive 79% 30% DQ8 positive 12% 7% DQ2 & DQ8 + 9% 5% DQ2 & DQ8 - <0.1% 62% Sensitivity: 100%; Specificity: 31% NPV: 100%; PPV: 1.5% Excellent at excluding celiac disease but Terrible for diagnosing it Not everyone who feels better on a GFD has Celiac Disease IBS: Abnormalities in movement of the intestines, sensitivity of the nerves of the intestines, or the way in which the brain controls these functions. no structural abnormalities are seen Wheat Allergy: Adverse reactions involving IgE antibodies to one or more proteins found in wheat formal allergy testing. Celiac Disease: A heightened immune responsiveness to gluten (wheat, rye, barley proteins) leading to an small intestinal damage often with systemic manifestations Gluten Intolerance: ??? Gluten Intolerance Gluten intolerance is a “functional” disorder that may mimic celiac disease in terms of symptoms and response to gluten withdrawal Unlike celiac disease, there is no (or minimal) autoimmune or inflammatory component to gluten intolerance, and long-term health is similar to those with irritable bowel syndrome Antigliadin antibodies are commonly elevated in gluten intolerance while IgA tTG levels and duodenal biopsy are normal (unlike celiac disease where all three are usually abnormal) If having celiac disease has been adequately ruled out, the only restriction on your intake of gluten is how much you can comfortably eat Back to Jill Ttg and biopsy confirmed celiac disease What additional labs would you request? Recommended Standard Labs CBC 25 OH Vitamin D B12 Folate Ferritin Lipids TSH +/- Zinc, calcium, albumin, etc • Average 10% incidence of iron deficiency anemia in patients with newly diagnosed CD in the U.S. Patient: Jill Labs: HBG: 11.0 LOW Ferritin: 2.3 LOW 25 OHD:12 LOW B12: 670 Normal IgA-tTG: 82 units Normal HCT: 33.7 LOW Iron: 22 LOW Folate: 12 Normal Zinc: 75 Normal (>20 HIGH) Supplements: Iron Sulfate, multivitamin with Iron Treatment of Celiac Disease Strict gluten free diet is the only accepted treatment for celiac disease Involves avoidance of all wheat, rye and barley products Less than 1 mg of gluten (1/50th of a slice of bread) can cause significant, mucosal inflammation Anatomy of Grain Bran is the Outer Layer containing: • Fiber • B vitamins • Minerals • Protein Endosperm is the Middle Layer containing: • Gluten: Protein needed for germination • Carbohydrates Germ is the Inner Layer containing: • Minerals • B Vitamins • Vitamin E Hidden gluten/cross contamination Social and professional life Diet education and health Health Impact Cost $$$ Label reading Access to GF foods Gluten is Everwhere “Wheat-free” does not necessarily mean “gluten-free.” Breading Broth/Bouillon Candy Coating/Drink mixes Communion wafers Croutons Marinades Panko Pastas Play-Doh Processed luncheon meats Sauces Dry pet food Dressing Flour or cereal products Gravies Imitation bacon Imitation seafood Lipstick and lip balm Seasonings Self-basting poultry Soup bases Thickeners (Roux) Toothpaste Dental pumice Medications A Month in the Life of a Celiac Patient: Attempting the Gluten-Free Diet Gluten Exposure on a “GlutenFree” Diet Restaurant Crosscontamination Ate Mislabeled Food Ate a Serving of Pasta Thinking It Was “Gluten Free” Typical Gluten Threshold Time Persistent Symptoms & Inflammation General Nutrition Review: Jill’s Initial Visit Review gluten free diet – safe/toxic ingredients Monitor and recommend adequate calcium and vitamin D intake. Assess/recommend multivitamin Check all medications, supplements and body care products for gluten Review 3-day food record Recommend local/national support group, resources Educate on safe dining out techniques and cross contamination Request labs Dietary and Health Concerns Enrichment/Fortification: Most GF cereals, pasta and bread are NOT enriched and are low in: B vitamins – thiamin, riboflavin, niacin, iron, folate Weight Gain on GF Diet: Excessive reliance on protein-rich, high fat foods High carbohydrate, low fiber content of some gluten-free grains Coexisting Food Intolerances: lactose, soy, fructose, etc. Lactose: Found in 30-60% in newly diagnosed Caused by intestinal injury in untreated CD May resolve on treatment w/ GF diet Fructose: Increasingly common cause of GI symptoms Does not typically resolve on a gluten-free diet Need: Low-fat, high fiber, nutrient-rich GF foods, and free of some common food intolerances Results of 2005 GF Diet Survey: Percentage of People with Celiac Disease Meeting Recommended Amounts of Nutrients Women Fiber (46%) Grain foods (21%) Iron (44%) Calcium (31%) Men Fiber (88%) Grain foods (63%) Iron (100%) Calcium (63%) Thompson T, Dennis M, Higgins LA, Lee AR, Sharrett MK. Gluten-free diet survey: are Americans with coeliac disease consuming recommended amounts of fibre, iron, calcium and grain foods? Journal of Human Nutrition and Dietetics. 2005;18(3):163-9. Safe Grains, Starches & Flours Arrowroot Amaranth Quinoa Rice bran Sago Buckwheat Flax Sorghum Millet Corn (maize) Seed flours (sesame) Soy (soya) Teff (tef) Tapioca (also called cassava or manioc) Legume flours (garbanzo/ chickpea, lentil, pea) Rice - brown, white, wild, Basmati, etc Potato starch, potato flour, sweet potato flour Montina® (Indian Rice Grass) Nut flours (almond, hazelnut, pecan) Bean flours (garfava, romano) © M. Dennis, S. Case, 2008 *As appeared in Practical Gastroenterology, April 2004. GF Grains & Their Fiber Content 14 12 10 8 6 Fiber per cup 4 2 0 Po W Q Te Ta En u h ff pi ta r in oc ich ite to ric oa ed a St ar co e f ch lo rn ur flo ur So M Bu Am i l rg ck l ar hu et w he ant m h at Iron & Routine Supplementation ~95% of patients w/ celiac disease will resolve their anemia after one year on the gf diet* 50% replete their iron stores in the same time period A multivitamin/mineral is recommended for those with celiac disease based on age, gender, lab studies and diet history Men do not need iron in a multivitamin unless they are anemic. Iron supplementation, when needed, should be discontinued when ferritin is normal If anemia or other significant nutrient deficiencies persist after more than a year on the gluten free diet, assess for hidden gluten intake and refer to celiacproficient MD Efficacy of gfd alone on recovery from iron deficiency anemia in adult celiac patients, Am J Gastro, 2001. Bone Disease At celiac disease diagnosis: ~10-30% have osteoporosis ~40% have osteopenia 15% improvement over the first year of treatment (bisphosphonates ~5%) Hazard ratio for fracture is 1.30 (1.16–1.46) Vit D/Ca++ 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 Key Points: Celiac Disease & Bone Metabolism Vitamin D and calcium deficiency are common across the United States – ½ of Americans have suboptimal levels Vit D/Ca++ absorption may not completely normalize with GFD Patients with celiac should have adequacy of the Vit D/Ca++ regimen checked after 6 months of GFD We are looking for: Normal ca, alb, phos 25 OHD >30 ng/ml (or 40) PTH <65 (maybe <46) Calcium Absorption Fraction 25(OH)D Is Essential for Calcium Absorption Calcium Absorption Plateaus at Serum 25(OH)D Levels 32 ng/mL 0.5 0.4 0.3 0.2 Bischoff HA et al. J Bone Miner Res. 2003; 18: 343–351. Heaney RP et al. J Am Coll Nutr. 2003; 22: 142–146. 0.1 Barger-Lux MJ et al. J Clin Endocrinol Metab. 2002; 87: 4952–4956. 0.0 0 8 16 24 32 40 48 56 64 Serum 25(OH)D, ng/mL Adapted from Heaney RP. Am J Clin Nutr. 2004;80(suppl):1706S–1709S. Reproduced with permission form The American Journal of Clinical Nutrition. Vitamin D Levels of <30 ng/mL: Prevalent Across Latitudes in the United States N=259/532 (48.7%) ● N=342/642 (53.3%) ● N=198/362 (54.7%) P = NS for Test of Trend. Holick MF et al. J Clin Endocrinol Metab. 2005;90:3215–3224. National Osteoporosis Foundation: March 2007 Recommendations Recommended Intake for Adults ≥50 Years Calcium Vitamin D3 (mg/day) (IU/day) Previous (2003)1 March 2007 update2 1200 400–800 1200 800–1000 Revised March 13, 2007, after careful consideration and review of a growing body of evidence that individuals 50 years and older are not getting enough calcium and vitamin D3, both in the United States and worldwide.2 1. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Available at: http://www.nof.org/physguide/index.asp. Accessed April 24, 2007. 2. National Osteoporosis Foundation. National Osteoporosis Foundation’s Updated Recommendations for Calcium and Vitamin D 3 Intake. Available at: http://www.nof.org/prevention/calcium_and_VitmaminD.htm. Accessed April 24, 2007. Jill’s Follow-up at 6 months Weight stable Brother has celiac disease Following the gluten-free diet carefully Labs: Iron, B12 improved; 25 OHD: 37ng/mL tTG: 26 units Still complaining of mild gas, bloating & loose stool What do you suspect is the issue now? “Non-Responsive” Celiac Disease: Persistent or recurrent signs/symptoms despite confirmed & treated CD. It occurs in ~10% of patients. Other included: • Peptic ulcer disease •Crohn’s disease • Duodenal cancer • Food allergy •Gastroparesis Other 8% IBS 18% Refractory Sprue Eating 11% Small Intestinal Disorder Bacterial 6% Overgrowth 6% Gluten Exposure 36% Microscopic Disaccharidase Colitis Deficiency 7% 9% Leffler et al. CGH 2006 Refractory Sprue Persistent small intestinal villous atrophy not responding primarily or secondarily to a strict glutenfree diet. Wide spectrum of disease • Weight loss is almost always a presenting symptom Occurs in ~1% of patients Predominantly treated symptomatically Potential for progression to Enteropathy Associated T Cell Lymphoma (EATL) Trier JS et al. 1978, 1991, 1998 Small Intestinal Bacterial Overgrowth • Abnormally high bacterial populations in the upper bowel • May complicate nearly any GI or endocrine disorder including: – celiac disease, diabetes, Crohns, IBS, scleroderma, partially obstructing lesions, small bowel diverticula, gastroparesis or any intestinal dysmotility syndrome, fistulas, chronic pancreatitis,etc. • Can lead to carbohydrate, protein, fat malabsorption, inflammation, macrocytic anemia, & toxin production Most frequent symptoms: •Gas & bloating •Cramps •Weight loss •Diarrhea Diagnosis: Clinical evaluation and diagnostic testing Most common tool: Breath test Treatment: Antibiotics www.uptodateonline.com Accessed 10/07 Key Elements in the Management of Celiac Disease • • • • • • Consultation with a skilled dietitian Education about the disease Lifelong adherence to a gluten-free diet Identification and treatment of nutritional deficiencies Access to an advocacy group Continuous long-term follow-up by a multidisciplinary team NIH Consensus Development Conference on Celiac Disease, 2004 Celiac Disease Resources Internet Sites: • Gluten Intolerance Group of North America; www.gluten.net • Celiac Disease Foundation; www.celiac.org • NIH: http//:digestive.niddk.nih.gov/ddiseases/pubs/celiac • www.HealthyVilli.org • www.celiac.com • Celiac Sprue Association of the USA, Inc.; www.csaceliacs.org • Canadian Celiac Association/L’association Canadienne de la Maladie Coeliaque; www.celiac.ca • ADA: Celiac Disease; www.nutritioncaremanual.org and the Evidence Analysis Library Do’s & Don’ts of Celiac Disease Do: • Think of it (unexplained GI symptoms, anemia, suspicious low BMD, fertility issues, autoimmune diseases) • Test for it by IgA tTG serology and total IgA • Recommend a biopsy (before starting a GFD!) • Refer to a skilled celiac dietitian • Suggest a local support group • Assess for related conditions such as bone density & thyroid • Follow up on tTG and symptoms • Treat nutritional deficiencies Don’t: • Order anti-gliadin antibody serology • Recommend a GFD without a verified diagnosis • Neglect the follow up CELIAC DISEASE… it’s a GUT REACTION. www.bidmc.harvard.edu/celiaccenter