Meeting the Nutritional Needs of Adults with

Celiac Disease

Daniel Leffler, MD, MSClinical Research Director

Celiac CenterBeth Israel Deaconess

Medical Centerwww.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 SyndromeLactose intoleranceInflammatory Bowel DiseaseSmall intestinal bacterial overgrowthChronic infectionCeliac 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.

PathophysiologyStep 1: Gluten Entry into the Submucosa

*Green, Cellier NEJM 2007

Step 2: Deamidation of Gluten by Tissue Transglutaminase (tTG)Step 3: Immune Activation Only HLA DQ2 and DQ8 are able to bind gluten!

Step 1

Step 2 Step

3

Serologic tests

Celiac Disease is Not Rare

* Talley et al, Am. J. Gastroenterol, 1994

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

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 femaleSerologic studies suggest slight female

predominance

Signs and Symptoms of Celiac Disease

Can Present at Any Age to Any SpecialtyNon- Classic Symptoms

AsymptomaticLFT elevationsConstipationAphthous ulcersNausea/VomitingHeartburn/GERDHypospleniaPancreatitisArthralgias/MyalgiasNeuropathy/AtaxiaAlopeciaHeadachesOsteopenia/OsteoporosisDental defectsFertility problemsCognitive impairment

Classic Symptoms

Diarrhea Iron deficiency anemiaAbdominal PainWeight Loss/Failure to thriveFatigue/LethargyBloating/GasDermatitis herpetiformis

Dermatitis Herpetiformis

The skin manifestation of celiac disease Intensely itchy 2-5 mm blistersExtensor surfaces: Elbows > buttocks > knees > trunk > faceOnset late childhood/early adult lifeAuto-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 anemiaNeurology: 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

anti-gliadin antibodies have similar accuracy to tTG

Celiac Disease: Diagnostic Criteria

Consistent small bowel histology Positive IgA tTG serology

Clinical response to GFD Histologic response to GFD Symptoms, tTG and biopsy relapse with

gluten challenge

•Major criteria:

•Other supportive criteria:

Please Note: ALL diagnostic tests normalize on a GFD so DO NOT start treatment before confirming the diagnosis!

Endoscopic Small Intestinal Biopsyfor 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

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: ???

Not everyone who feels better on a GFD has Celiac Disease

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 HCT: 33.7 LOW

Ferritin: 2.3 LOW Iron: 22 LOW 25 OHD:12 LOW Folate: 12

Normal B12: 670 Normal Zinc: 75 Normal

IgA-tTG: 82 units 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

Impact

Cost - $$$

Label reading

Diet education and health

Social and professional life

Access to GF foods

Hidden gluten/cross contamination

Health

Gluten is Everwhere

“Wheat-free” does not necessarily mean “gluten-free.”Breading

Broth/BouillonCandy

Coating/Drink mixes Communion wafers

Croutons

DressingFlour or cereal products

GraviesImitation bacon Imitation seafood

Lipstick and lip balm

MarinadesPankoPastas

Play-DohProcessed luncheon meats

SaucesDry pet food

SeasoningsSelf-basting poultry

Soup bases Thickeners (Roux)

Toothpaste Dental pumiceMedications

RestaurantCross-

contamination

Ate Mislabeled

Food

Ate a Serving of Pasta

Thinking It Was “Gluten

Free”

Gluten Exposure

on a “Gluten-

Free” Diet

TimePersistent

Symptoms & Inflammation

Typical Gluten Threshold

A Month in the Life of a Celiac Patient: Attempting the Gluten-Free Diet

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

Need: Low-fat, high fiber, nutrient-rich GF foods, and

free of some common food intolerances

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 CDMay resolve on treatment w/ GF diet

Fructose: Increasingly common cause of GI symptomsDoes not typically resolve on a gluten-free diet

Dietary and Health Concerns

WomenFiber (46%)Grain foods

(21%)Iron (44%)Calcium (31%)

MenFiber (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.

Results of 2005 GF Diet Survey:Percentage of People with Celiac Disease Meeting Recommended

Amounts of Nutrients

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.

0

2

4

6

8

10

12

14

Fiber per cup

GF Grains & Their Fiber Content

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 celiac-proficient 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, phos25 OHD >30 ng/ml (or 40)PTH <65 (maybe <46)

25(OH)D Is Essential for Calcium Absorption

Adapted from Heaney RP. Am J Clin Nutr. 2004;80(suppl):1706S–1709S. Reproduced with permission form The American Journal of Clinical Nutrition.

Calcium Absorption Plateaus at Serum 25(OH)D Levels 32

ng/mL

0 403224168 645648

Serum 25(OH)D, ng/mL

0.5

0.4

0.3

0.2

0.1

0.0

Calc

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Ab

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Fra

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on

Bischoff HA et al. J Bone Miner Res. 2003; 18: 343–351.

Heaney RP et al. J Am Coll Nutr. 2003; 22: 142–146.

Barger-Lux MJ et al. J Clin Endocrinol Metab. 2002; 87: 4952–4956.

Holick MF et al. J Clin Endocrinol Metab. 2005;90:3215–3224.

Vitamin D Levels of <30 ng/mL:Prevalent Across Latitudes in the United States

●

●

P = NS for Test of Trend.

N=198/362

(54.7%)

N=342/642

(53.3%)

N=259/532

(48.7%)

National Osteoporosis Foundation:

March 2007 RecommendationsRecommended Intake for Adults ≥50 Years

Calcium Calcium

(mg/day(mg/day))

Vitamin DVitamin D33

(IU/day)(IU/day)

Previous Previous (2003)(2003)11 12001200 400400–800–800

March March 2007 2007 updateupdate22

12001200 800–800–10001000Revised 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.21. 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 D3 Intake. Available at: http://www.nof.org/prevention/calcium_and_VitmaminD.htm. Accessed April 24, 2007.

Jill’s Follow-up at 6 months

Weight stableBrother has celiac diseaseFollowing the gluten-free diet carefullyLabs:

Iron, B12 improved; 25 OHD: 37ng/mLtTG: 26 units

Still complaining of mild gas, bloating & loose stool

What do you suspect is the issue now?

Other included: • Peptic ulcer disease•Crohn’s disease• Duodenal cancer• Food allergy•Gastroparesis

“Non-Responsive” Celiac Disease:Persistent or recurrent signs/symptoms despite

confirmed & treated CD. It occurs in ~10% of patients.

Leffler et al. CGH 2006

Refractory Sprue

Persistent small intestinal villous atrophy not responding primarily or secondarily to a strict gluten-free diet.

Wide spectrum of disease•Weight loss is almost always a

presenting symptomOccurs in ~1% of patientsPredominantly treated symptomaticallyPotential 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 testingMost 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 DiseaseDo:

• 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