diana stuber, ma, rd, cde joslin diabetes center upstate medical university syracuse, ny...

Celiac Disease and Diabetes

Diana Stuber, MA, RD, CDEJoslin Diabetes CenterUpstate Medical UniversitySyracuse, [email protected]

Joslin Diabetes Center 2012

Objectives

Discuss the spectrum of gluten-related disordersDefine celiac disease (CD)Identify key indicators of risk of CDDescribe the treatment of CDDiscuss celiac disease and diabetes


Gluten-Related Disorders

Allergic reactionsWheat allergy (baker’s asthma, food allergy, wheat-dependent exercise-induced anaphylaxis)

Autoimmune reactionsCeliac diseaseDermatitis herpetiformis (DH)Gluten ataxia

Immune-mediated formGluten sensitivity (GS)


Sapone, et al, BMC Medicine. 2012; 10:13

Gluten Sensitivity

Defined as a gluten reaction in which both allergic and autoimmune mechanisms have been ruled outHas been estimated that 18 million in U.S. may have gluten sensitivity*Individuals with GS often have non-GI symptoms like headache, “foggy mind,” joint pain and numbness in the legs, arms or fingers

*BMC Medicine. 2011, 9:23 doi:10.1186/1741-7015-9-2

Gluten Sensitivity

DiagnosisNegative immuno-allergy tests to wheat or negative CD serology where IgA deficiency has been ruled outNormal duodenal biopsy resultsPossible presence of biomarkers of native gluten immune reaction (anti-gliadin antibody positive)With clinical symptoms that can overlap with CD or wheat allergyShow resolution on a gluten-free diet (ideally implemented in blinded fashion to avoid placebo effect)

Celiac Disease

Celiac disease (CD) is an autoimmune disorder occurring in genetically susceptible individuals who develop an immune response to gluten and related proteins found in wheat, barley and ryeThis immune response causes inflammation and atrophy of the small intestine, resulting in malabsorption


Celiac Disease (CD)

It is a unique autoimmune disorder:Both the environmental trigger (gluten) and the autoantigen (tissue transglutaminase or tTG) are known Elimination of the environmental trigger leads to resolution of symptoms and/or some manifestations of the disease


Old Paradigm: A Disease of Small Intestine, Affecting Children

London, year 1938

Celiac diseaseVillous atrophyMalnutrition


New Paradigm:A Multi-Organ Autoimmune Disease, All Ages

Skin and MucosaDermatitis herpetiformisAphthous stomatitisHair loss

HepatitisCholangitis

BoneOsteoporosis, fracturesArthritisDental anomalies

ReproductiveMiscarriage, infertilityDelayed pubertyHair loss

Anemia

Central Nervous SystemAtaxia, seizuresDepression

Carditis, Cardiomyopathy


CD Across the World

Figure 1. World map by WHO Regions, as used as the basis for modeled estimates, showing underlying assumptions about the population prevalence of childhood coeliac disease.

Byass, et al, PLoS ONE. 2011; 6(7):e22774


Prevalence of CD in the USIn general population:

1:100 (1%)With related conditions:

1:56 (1.8%)In 1st degree relatives:

1:22 (4.5%)Monozygotic twins:

1:1.4 (70%)In 2nd degree relatives:

1:39 (2.6%)In African, Hispanic, Asian-Americans:

1:256 (0.4%)

Fasano, et al, Archives of Internal Medicine. 2003; 163:286


In 1st degree relatives:*1:10 (10%)

In sisters 17.6% (29% if DQ2 or DQ8 +)

In brothers10.8% (15% if DQ2 or DQ8 +)

In parents3.4% (6% if DQ2 or DQ8 +)

Monozygous twins**86%

Dizygous twins20%

*Kneepens, et al, Eur J Pediatr. 2012; 171:1011**Greco, et al, Gut. 2002; 50:624

Prevalence of CD in the USIn general population:

1:100 (1%)With related conditions:

1:56 (1.8%)In 1st degree relatives:

1:22 (4.5%)Monozygotic twins:

1:1.4 (70%)In 2nd degree relatives:

1:39 (2.6%)In African, Hispanic, Asian-Americans:

1:256 (0.4%)

Fasano, et al, Archives of Internal Medicine. 2003; 163:286

2-16%4-8%1-8%6-8%2-15%3.6%

4-8%5-12%8%7%

NIH Consensus Development Statement on Celiac Disease, 2004

Autoimmune disordersType 1 diabetesThyroiditisArthritis (RA)Autoimmune liver diseaseSjögren SyndromeIgA nephropathy

Genetic disordersTurners syndromeDowns syndromeWilliams syndromeIgA deficiency


CD Prevalence is Increasing

The total prevalence of CD nearly doubled in the last 20 years in Finland1

Prevalence of CD has increased more than 4-fold in the U.S. in the last 50 years2

CD prevalence increased 2-fold in the study group and 5-fold overall in the U.S. since 19743

From 1999 to 2008, cases of celiac disease in the U.S. increased 5-fold4

1) Lohi, et al, Ailment Pharmacol Ther. 2007; 26:12172) Rubio-Tapia, et al., Gastroenterology, 2009; 137:883) Catassi, et al, Ann Med, 2010; 42:5304) Riddle, et al, Am J Gastroenterol, 2012; 107:1248

Prerequisite for CD: HLA-DQ2/DQ8


~ 30% of the general population has DQ2 or DQ8Homozygous HLA-DQ2 may increase the risk and severity of CD, including refractory CD (binds a wider range of gluten peptides)

At least one in 20 who carry HLA-DQ2 will develop CDAbout one in 150 who have HLA-DQ8 will develop CDThose with other HLA-DQ genes are protected against CDOver 90% of CD patients have HLA-DQ2 heterodimer

Since 30% of population may carry HLA-DQ2 but only about 1% of the population has CD, other non-HLA genes must be involved

Common disease variants

Heap, G. A. et al. Hum. Mol. Genet. 2009 18:R101-106R; doi:10.1093/hmg/ddp001

IL18RAP

Environmental TriggersThe “hygiene hypothesis”

Humans have adapted to a pathogen-rich environment that no longer exists in industrialized societiesThis change has reduced the exposure of the immune system to antigensThe immune system overreacts, favoring the development of chronic inflammatory conditions(Recent reports suggest that part of susceptibility alleles for autoimmune disease might be maintained in human population because they confer increased resistance against infection)


Environmental TriggersWhat we eat, when we start eating “it” and how much

Gut is leakier < 4 months, so when babies eat gluten before 4 months it might increase the risk of CD - cereals too late (after 6 months) may miss the window for developing toleranceBreast feeding through introduction of cereals may be protectiveChange from rice as staple grain to wheat may cause increase in prevalence in South Asia and West Pacific regions


Environmental TriggersModern varieties of wheat have greater amounts of celiac disease epitopesGerms, viruses, chemicals, surgeries or other stresses we are exposed to that may cause a disturbance of the mucosal integrity (leaky gut)


“Gluten” proteins

E

E

Injury

Villous atrophy

Digestion

Resistant peptides

Deamidation

HLA-DQ2

T-cell

IFN

CD Pathogenesis

Q

tissue transglutaminase(tTG)


Normal small bowel Celiac disease

Gluten (> 4hr)

Gluten-free diet


Clinical Manifestation:Malabsorptive

ClassicNear/total malabsorption; usual age at

presentation: 6-24 months

DiarrheaAbdominal distensionAnorexiaFailure to thrive/wt lossAbdominal painVomitingConstipation

AtypicalSome malabsorption; usual age at

presentation: older child to adult

AnemiaShort statureOsteopeniaRecurrent abortionsHepatic steatosisAbdominal pain

60% of newly diagnosed children and 41% of adults in US had no symptomsOnly 35% newly diagnosed had diarrhea

Fasano, et al, Arch Int Med. 2003; 163:286


Clinical Manifestation:Absorption Independent

Most common age at presentation: older child to adult

Dermatitis herpetiformisDental enamel hypoplasiaAtaxiaAlopeciaPrimary biliary cirrhosisIsolated hypertransaminasemiaRecurrent aphthous stomatitisFertility problems

Myasthenia gravisRecurrent pericarditisPsoriasisPolyneuropathyEpilepsyVasculitisDilative cardiomyopathyHypo/hyperthyroidismIntestinal lymphoma

May be related to autoimmune inflammation or tTG targets: 9 identified human transglutaminase enzymesTG2 in CD, TG3 in DH, TG6 in gluten ataxia


Associated Conditions:Dermatitis Herpetiformis and Dental Enamel Defects


Screening/Diagnosis CDTest Sensitivity % Specificity % Comments

IgA-tTg* 98 (86-100) 98 (90-100) Lower cost, ease of test, reliability – for initial screening

IgG/IgA-DPG-AGA* 97 (75-99) 95 (87-100) Very good in children <2 yr; can identify CD in pts with IgA deficiency

IgA-EMA 95 (86-100) 99 (97-100) Operator dependent, prone to subjective error, expensive

HLA typing 98% Good negative predictive value

IgA deficiency* Ig-A antibodies will be negative; test IgG-tTg and/orDPG

Biopsy Poor High Damage can be pathcy; depends on grade cut-off point, biopsy orientation, pathologist


* Celiac Panel at Upstate Medical University

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease.Husby, S; Koletzko, S; Korponay-Szabo, IR; Mearin, ML; Phillips, A; Shamir, R; Troncone, R; Giersiepen, K; Branski, D; Catassi, C; Lelgeman, M; Maki, M; Ribes-Koninckx, C; Ventura, A; Zimmer, KP; for the ESPGHAN Working Group on Coeliac Disease Diagnosis, on behalf of the ESPGHAN Gastroenterology Committee

Journal of Pediatric Gastroenterology & Nutrition. 54(1):136-160, January 2012.DOI: 10.1097/MPG.0b013e31821a23d0


Copyright 2012 by ESPGHAN and NASPGHAN. Published by Lippincott Williams & Wilkins, Inc.

7

FIGURE 1 . Symptomatic patient. CD = coeliac disease; EMA = endomysial antibodies; F/u = follow-up; GFD = gluten-free diet; GI = gastroenterologist; HLA = human leukocyte antigen; IgA = immunoglobulin A; IgG = immunoglobulin G; OEGD = oesophagogastroduodenoscopy; TG2 = transglutaminase type 2.


Copyright 2012 by ESPGHAN and NASPGHAN. Published by Lippincott Williams & Wilkins, Inc.

8

FIGURE 2 . Asymptomatic patient. See Fig. 1 for definitions.


Biopsy

AGA recommends ≥4 biopsy samples of the small intestine (distal duodenum)Of 132,352 pts with biopsy (2005-2009), only 35% had at least 4 biopsies (ave. was 2)*With suspected malabsorption/CD, 39.5% had ≥4 biopsiesDiagnosis of CD was doubled in pts with at least 4 biopsies2012 ESPGHAN Guidelines for the Diagnosis of Coeliac Disease recommends at ≥ 1 biopsy from the duodenal bulb and ≥ 4 from D2 and D3**

*Lewohl, et al, Gastrointestinal Endoscopy. 2011; 74:103**Husby, et al, J Ped Gastroenterol and Nutr. 2012; 54:136


Histological Features

Normal 0 Infiltrative 1 Hyperplastic 2

Partial atrophy 3a Subtotal atrophy 3b Total atrophy 3c

Horvath K. Recent Advances in Pediatrics. 2002.


Diabetes and CD

Type 1 diabetes occurs in about one in 300 individuals and is associated with other autoimmune diseases*

Autoimmune thyroid disease in 15-30%Celiac disease in 4-9%Addison disease in 0.5%

Additional autoimmune disease was found in 33% of patients at onset of type 1 diabetes*


*Triolo, et al, Diabetes Care. 2011; 34:1211

Diabetes and CD

All adult patients with Type 1 diabetes should be screened at least once, then every 2-3 years, or with GI symptoms or “brittle diabetes”Pediatric patients are screened at diagnosis, then yearly, or with GI symptoms or failure-to-thriveIn other endocrine patients consider screening with non-response to thyroid hormone replacement, “unexplained” or resistant-to-treatment osteoporosis, or “classic” symptoms of CD


Diabetes and CD

Diabetes-specific symptoms in CD may includeUnpredictable blood sugars (“brittle diabetes”)Hypoglycemia within 2 hours of a mealHypoglycemia that doesn’t respond to treatment

Treatment of low blood glucoseUse glucose tablets, juice, regular soda, raisinsMilk might not be toleratedPotato or corn chips may be used, but are slower to act because of fat content

Diabetes and CD

A1C may not improve with GFDNutrient absorption improvesInsulin requirements may increasePts may gain weight, even without weight loss prior to diagnosis of CD, but some overweight/obese adults lose wt*Hypoglycemia may be less frequent

*Cheng, et al, J Gastroenterol. 2010; 44:267


Diabetes and CD

“Starter menus” for CD may be inconsistent in carbs and carb content is not usually provided*Carb and fat content of GF substitutes are often higher than the gluten-containing versionPrior to CD diagnosis, cholesterol levels may be low, but as the mucosa heals total cholesterol levels may rise (and HDL may improve**)

*Counting Gluten-Free Carbohydrates can be found at www.csaceliacs.org**Capristo, et al, J Gastroenterol. 2009; 43:946

End-Stage Renal Disease in CD

People with biopsy-proven celiac disease are at three-fold increased risk of future end-stage renal diseaseIncreased risk of ESRD is seen irrespective of age at CD diagnosisAdjusting for diabetes had only a marginal effect on risk estimate

Welander, et al, Gut. 2012; 61:64

Treatment of Celiac Disease

Currently, the only treatment is a life-long gluten-free diet (GFD)Eliminate gluten, expand repertoire of GF foods, optimize nutrient intakeGFD should not be recommended unless diagnosis is confirmed


Potential Treatments/Prevention Measures in Celiac Disease

a b

c

d

d

ae

b-c

Wheat flour

Celiac-safe flour

Gluten

Endopeptidase

Polymeric binder

Vaccines andBiological therapies

Modulation of the cytokine network, cell markers and cell recruitment


(i) Modulator of paracellular permeability

ZonulinGI LUMEN

LAMINAPROPRIA

Deamidation by tTG2

HLA-DQ2/8

ActivatedLTCD4+

APC(ii) TG-inhibitor

Pinier, et al, Am J Gastroenterol. 2010; 105:2551

Gluten-Containing GrainsWheat:

BranBulgurCouscousCracked WheatDurum FlourFarinaGraham FlourMatzoSemolinaWheat BranWheat GermWheat Starch

Barley:MaltMalt BeveragesMalt ExtractMalt FlavoringMalted MilkMalt SyrupMalt Vinegar

Rye

Wheat varieties:EinkornEmmerKamutSpelt (Dinkel)Triticale


FALCPA (Food Labels)Food Allergen Labeling and Consumer Protection Act, 2004

Applied to labels of FDA regulated foods starting Jan. 1, 2006USDA regulated foods do not require identification of allergensLabels must state if the food contains:


MilkEggsFishTree nuts

Crustacean shellfishPeanutsWheatSoynuts

FALCPA (Food Labels)

Define “gluten-free”Proposed 20 ppm0.0007 oz gluten per lb of food50 mg gluten per day probably safe, = 0.0018 oz/day

Develop rules that permit the use of “gluten-free” on the food label

Labels that state “naturally gluten-free food” may not be gluten-free*

FDA solicited more comments in 2011Expected to publish rules by the end of fiscal 2012


*Thompson, et al, J Am Diet Assoc. 2010;110:937

Naturally Gluten-free Foods(If processed without gluten)

Fresh, frozen or canned fruits and vegetables Fresh meats, poultry, seafood, fish, game, eggs, some processed meats, dried peas, beans, lentils, tofuMilk, yogurt, aged, natural cheeseOils, tree nuts, seeds, natural peanut butter, salad dressing, spreads

Honey, sugar, pure maple syrup, corn syrup, jams, jellies, candy, ice creamPure spices and herbs, salt, soy sauce without wheat, cider, wine, distilled and non-malt vinegarsCoffee ground from whole beans, brewed tea, distilled alcoholic beverages


Gluten-Free Grains/StarchesAmaranthArrowrootWhole-bean flourBuckwheatCorn*, cornstarchFlaxJob’s tearsMilletNut floursOats, oat bran, oat gum**

Pea flourPotato, sweet potato, yam, potato flour, potato starchQuinoaRice, wild rice, rice bran, rice flourSagoSorghumSoyTapiocaTeff

*Some with CD reacted to corn**Controversial


Gluten-Free Grains/Starches

Oats:The immunogenicity of oat varies according to the cultivar*After resolution of symptoms up to ½ cup dry rolled oats or ¼ cup dry steel cut oats per day

Barley lines that lack D and C-hordeins were found to be 20-fold less immunotoxic than wild-type barley**


*Comino, et. al., Gut. 2011; 60:915**Tanner, et. al., Ailment Pharmacol Ther. 2010; 32:1184

Nutritional Adequacy of the GFDPatients with no nutritional deficiencies have the same nutritional requirements as the general populationHealing takes 6 months to 2 years, although complete recovery in adults is rare*Lactose intolerance is common at diagnosisStudies suggest that osteopenia and vitamin and mineral deficiencies resolve on the dietGF foods may be lower in thiamin, riboflavin, niacin, folate, iron, and fiber (not fortified)

A GF daily multivitamin may be recommended in patients with CD

*Rubio-Tapia, et al, Am J Gastroenterol. 2010 Medscape posted: 01/23/2011


Nutrient Dense Gluten-free FoodsNutrient Vegetables Fruits Protein Dairy GF Grains

Calcium Leafy greens, sea vegetables

Fortified orange juice, dried fruit

Ca-rich soy products, beans, sardines (with bones)

Milk, yogurt, cheese, fortified soymilk

Quinoa , brown rice

Iron Spinach, other leafy greens

Beef , poultry, fish, seafood (heme)Beans, tofu (nonheme)

Amaranth, teff, buckwheat, quinoa

Magnesium Leafy greens, peas

Bananas, dried apricots, avocados

Vitamin D Plant oils (eg, olive)

Avocados Salmon, nuts, enriched eggs

Fortified milk

Vitamin E Leafy greens, vegetable oils

Kiwi, mango Nuts, seeds GF whole grains

Vitamin K Leafy greens, broccoli, soybean oil

Milk, dairy


Nutrient Dense Gluten-free FoodsNutrient Vegetables Fruits Protein Dairy GF Grains

Thiamin Pork, ham, bacon, liver, legumes, nuts

Whole grains

Riboflavin Leafy greens vegetables

Meat Milk, yogurt, cottage cheese

Whole-grain or enriched breads and cereals

Niacin Eggs, meat, poultry, fish , nuts, other protein-rich foods

Milk Whole-grain or enriched breads and cereals

Vitamin B6 Green and leafy vegetables

Fruits Meats, fish, poultry, shellfish, legumes

Whole grains

Folate Leafy green vegetables

Legumes, seeds, liver

B-12 Animal products

Fiber Vegetables, Fresh fruits Legumes, seeds Whole grains


The Gluten-Free Diet

There are many new gluten-free foods availableThe compound annual growth rate for gluten-free products rose 28% in the U.S. over the last 4 yearsThe U.S. market is predicted to hit $4.2 billion by the end of this year and $6.6 billion by 2017More major food manufacturers are labeling their foods as gluten-freeThe IRS allows a tax deduction for the increased cost of gluten-free foods


GFD: Cost

Naturally GF foods cost less than GF substitutesPotatoesRiceCorn, corn tortillas

Homemade foods may cost less than processed GF foods like bread, pizza, canned or frozen mealsThe cost of GF foods replaces the cost of “pills”


The GFD is Challenging

The diagnosis can be “shocking” and depression or sadness are commonGluten is found in ~ 90% of processed foodsHard to tell whether foods contain gluten

Labels can be unreliable and difficult to understandGluten is a hidden ingredient in many food and non-food items (pharmaceuticals, vitamins, cosmetics, other products)


GFD: Cross Contamination

Cultivation of grains (leftover wheat seeds in the field)

Harvesting and shipping of grains (bins, rail cars, trucks) Processing (shared equipment)

Stores (bulk sale bins/scoops)

HomeShared kitchen items such as toasters, counters, utensils (no wooden spoons, wooden cutting boards, etc.), storage containers, jars of jam, peanut butter, and other spreads (no double-dipping), hand towels...

RestaurantsPans, grills, deep-fat fryers used for multiple foodsServing utensils used in buffetsKitchen and wait staff: “Educate, separate, sanitize”


The GFD is Challenging

It is hard to eat out*There may be limited availability and variety of GF foodsThe price is high and to some the palatability lowAll these factors can lead to problems with the adoption of and adherence to the diet


*Gluten Intolerance Group Restaurant Dining: Seven Tips for Staying Gluten-Free at www.gluten.net

Summary

Gluten-related disorders include wheat allergy, celiac disease and gluten sensitivityThe incidence of CD is increasingThe risk of CD is higher in Type 1 DM and other autoimmune diseasesAsk pts about diarrhea, abdominal pain and “rashes” Refer your patients with CD to the dietitian


Resources: Celiac OrganizationsAmerican Celiac Society59 Crystal AvenueWest Orange, NJ 07052 973-325-8837Email: [email protected]

Celiac Disease Foundation 13251 Ventura Blvd, Suite 1Studio City, CA 91604818-990-2354 www.celiac.orgemail: [email protected]

Canadian Celiac Association90 Britannia Road East, Unit 11Misissauga, ON L4Z 1W6Canada905-507-6208 or 800-363-7296www.celiac.ca

Gluten Intolerance Group of North America15110 10th Ave SW, Suite ASeattle, WA 98166-1820206-246-6652www.gluten.netemail: [email protected]

Celiac Sprue Association/ USA IncP.O. Box 31700Omaha, NE 68131-0700402-558-0600www.csaceliacs.orgemail: [email protected]

Celiac.comwww.celiac.com

Gluten Free Mallwww.glutenfreemall.com707-509-4528 (Information)800-986-2705 (Orders only)


diana stuber, ma, rd, cde joslin diabetes center upstate medical university syracuse, ny...

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