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Sheryl Pfeil, MDProfessor of Clinical Medicine

Division of Gastroenterology, Hepatology and Nutrition

Department of Internal MedicineThe Ohio State University Wexner Medical Center

Understanding Celiac Disease Diagnostic Challenges

Celiac DiseaseCeliac Disease• Immune mediated systemic disorder triggered by

gluten and related prolamins

• Occurs in genetically susceptible individuals who have HLA-DQ2 and/or HLA-DQ8 haplotypes

• Inflammatory enteropathy with variable severity

• Range of GI and/or systemic symptoms

• Presence of celiac-specific autoantibodies

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Celiac DiseaseCeliac Disease• Affects ~ 1% of the USA population

• Small bowel inflammation, villous atrophy, crypt hyperplasia, intraepithelial lymphocytes

• Malabsorption- improves with withdrawal of gluten

• Variable degree of symptoms and small bowel damage

• Diagnosis across the age spectrum

Celiac Disease: Why DiagnoseCeliac Disease: Why Diagnose

• Differentiate from non-celiac gluten sensitivity

• Identify risk for nutritional deficiency, complications

• Determine necessity of lifelong adherence to gluten-free diet

• Screen family members

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Celiac Disease: Why DiagnoseCeliac Disease: Why Diagnose

• May have impaired absorption, nutrient deficiencies (fat soluble vitamins, iron, potentially folate, vitamin B 12)

• Without gluten free diet have increased risk of intestinal malignancies

• Diet is costly, challenging, risk for nutrient deficiencies

Non-Celiac Gluten Sensitivity Non-Celiac Gluten Sensitivity

• Poorly defined syndrome: No test for NCGS

• Variable combination of intestinal and extraintestinal symptoms that occur after ingestion of gluten (hours to days) and disappear quickly upon withdrawal

• Must exclude celiac disease and wheat allergy

• Possibly related to fructans (FODMAPs)

• Symptoms often IBS-like but more commonly have extraintestinal symptoms (HA, fatigue, joint/muscle pain)

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Who to Test?Who to Test?• GI symptoms suggestive of malabsorption: diarrhea,

weight loss, postprandial pain, bloating

• Symptoms/signs: iron deficiency, elevated transaminases, osteopenia, etc.

• First-degree relatives of celiac patients?

• Unexplained elevation of LFT’s

• Type 1 diabetes mellitus

Anorexia Weight LossNausea Vomiting

Diarrhea Steatorrhea

Pain Bloating Flatulence

Transaminitis

Abdominal

DistensionConstipation

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Dermatitis herpetiformis Aphthous ulcers

Short stature

Rickets

Osteopenia

Osteoporosis

Arthritis

Fractures

Celiac DiseaseNon Gastrointestinal Symptoms

Elevated Transaminases in Celiac Disease

Elevated Transaminases in Celiac Disease

• Mild elevation (2-3 times upper limit of normal)

• AST and ALT

• Majority normalize within 4-8 months of GFD

• Persistent elevation: check for autoimmune hepatitis or other condition

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Anemia as Manifestation of Celiac Disease

Anemia as Manifestation of Celiac Disease

• Most iron deficiency

• More common in patients with atrophic mucosa

Dermatitis HerpetiformisDermatitis Herpetiformis• Considered a skin presentation of celiac

disease

• Symmetric pruritic blisters and excoriations

• Elbows (90%), knees (30%), shoulders, buttocks, sacrum, face

• Skin biopsy: typical IgA deposits

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Miscellaneous ExtraintestinalManifestations

Miscellaneous ExtraintestinalManifestations

• Low bone mineral density

• Oral aphthous ulcers

• Arthritis and arthralgias

• Neuropsychiatric symptoms (HA, “foggy mind”)

• Amenorrhea, infertility or recurrent pregnancy loss

Familial Risk of Celiac DiseaseFamilial Risk of Celiac Disease

• Monozygotic twins: 75%

• HLA-identical siblings: 40%

• First degree relatives: 5-11%

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Genetic Risks for Celiac DiseaseGenetic Risks for Celiac Disease

• HLA DQ2 (~95%) or HLA DQ 8 (~5%)

• Present in almost all if absent, NPV>99%

• Prevalent in population so PPV only ~12%

When to Consider Testing Asymptomatic Patients

When to Consider Testing Asymptomatic Patients

• First degree relatives of CD patients (especially if symptoms); risk 20% siblings and 10% other FDR

• Type I diabetes if symptoms (3-10% prevalence)

• Elevated transaminases without other etiology (normalize in >95% on GFD)

• Autoimmune thyroid or liver disease

• Down or Turner syndrome (prevalence 10% in Down’s syndrome)

• IgA deficiency

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Diagnostic Testing for Celiac Disease: What NOT to do

Diagnostic Testing for Celiac Disease: What NOT to do

• Try gluten free diet before testing

• Have a myopic view of clinical features of celiac disease

• Order the wrong antibody test

• Ask if symptoms follow gluten ingestion

DeamidatedGliadin Peptide

Ab’s

Gliadin Ab’sGliadin Ab’s

Testing for Celiac DiseaseTesting for Celiac Disease• Serology endoscopy

• High suspicion but serology negative endoscopy

Esophagus

Endoscope

Light

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Celiac DiseaseCommercially Available

Serologic Tests

Celiac DiseaseCommercially Available

Serologic Tests

• Gliadin – IgA AGA & IgG AGA

• Transglutaminase – IgA tTG (IgG tTG)

• Endomysium – IgA EMA (IgG EMA)

• Deamidated gliadin peptides– IgA DGP & IgG DGP

Test Sensitivity (%) Specificity (%)

Antigliadin antibody IgG (AGA-IgG)

83–100 47–94

Antigliadin antibody IgA (AGA-IgA)

52–100 72–100

Tissue Transglutaminase antibody IgA (tTG-IgA)

90–100 95–100

Anti-EMA antibody IgA (EMA-IgA)

93–100 98–100

Deamidated gliadin antibody IgA (DGP-IgA)

80–91 91–95

Deamidated gliadin antibody IgG (DGP-IgG)

88–95 86–98

Table of Sensitivity and Specificity of Serological Tests for Celiac Disease Table of Sensitivity and Specificity of Serological Tests for Celiac Disease

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Endoscopic "Clues" in Celiac Disease

Endoscopic "Clues" in Celiac Disease

Scallop Shell

Celiac Disease

Endoscopy in Celiac DiseaseEndoscopy in Celiac Disease

• Atrophy

• Visible fissures and nodular appearance

• Scalloping of the margins of folds

• If endoscopy is normal, still MUST biopsy

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Endoscopy in Celiac DiseaseEndoscopy in Celiac Disease• EGD sufficient (not enteroscopy)• Minimum of 6 biopsies (4 distal duodenum and 2

bulb)• Histology includes lymphocyte infiltration in

epithelium, crypt hyperplasia, progressive flattening of villi

• Histologic changes graded by severity (Marsh/Oberhuber stages 0-3)

Normal Partial atrophy

Unremarkable Small BowelUnremarkable Small Bowel

Low power shows usual villous architecture

High power shows usual distribution of intraepithelial lymphocytes

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Classic Findings in Celiac Disease

Classic Findings in Celiac Disease

Low power shows villous blunting

High power shows increased intra-epithelial lymphocytes

Capsule Endoscopy in Celiac Disease

Capsule Endoscopy in Celiac Disease

• Not a first-line test

• Villi are readily visualized

• Does not permit biopsy

• Useful for patchy disease (before enteroscopy) or complicated CD (stenosis, ulcers, lymphoma)

• Used for patients with positive serology, unable/unwilling to have EGD

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Celiac MimicsCeliac Mimics• Tropical sprue

• Small intestinal bacterial overgrowth

• Autoimmune enteropathy

• Immune deficiencies: CVID

• Medications: olmesartan

• Crohn’s disease

• Peptic disease

• Giardiasis

• Whipple disease

• Hypogammaglobulinemia

…and others

What To Do in the Already Gluten Free Patient?

What To Do in the Already Gluten Free Patient?

• If less than a month, serology and histology often still abnormal

• Check HLA testing

• Consider gluten challenge (3 g/d for 2-8 weeks) followed by serology and biopsy

• Treat as if celiac disease

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Diagnosis of Celiac DiseaseDiagnosis of Celiac Disease• Clinical features + positive serology +

villous atrophy: celiac disease

• Gluten free diet

• Follow symptoms and serologies

• Repeat EGD not required

Patient with Clinical Features but Negative Serologies

Patient with Clinical Features but Negative Serologies

• Ig A deficiency: check Ig G antibodies

• Prior gluten restriction (gluten challenge or HLA test)

• False negative serology

• Consider other causes (eg wheat allergy)

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Celiac HLA HaplotypesCeliac HLA Haplotypes

• More than 99% of celiac patients: HLA DQ2 and/or DQ8 positive

• Caution: 40% of general population HLA DQ2 and/or DQ8 positive

• Negative testing essentially excludes celiac disease

• Positive testing does not diagnose celiac disease

Patient with Positive Serologiesand Normal Biopsies

Patient with Positive Serologiesand Normal Biopsies

• False positive anti-TTG

• Patchy disease or inadequate sampling

• Latent celiac disease

Silent Celiac Disease

Latent Celiac Disease

Symptomatic Celiac Disease

Mucosal Lesion

No Mucosal Lesion

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Recommendations for Initial Evaluation

Recommendations for Initial Evaluation

• Identify clinical symptoms or family history that trigger testing

• Obtain an lg A TTG antibody and a total lg A level

• If serologies positive refer for EGD

• If serologies negative, confirm gluten ingestion and consider GI referral

Treatment of Celiac DiseaseTreatment of Celiac Disease• Lifelong gluten free diet

• Refer to dietitian

• Decline and normalization of antibody levels by 12-24 months (80% test neg after 6-12 months of GFD)

• Normalization of antibodies does not fully correlate with resolution of villous atrophy

• Check CBC, iron, LFT’s, calcium, vitamin D, thyroid tests at diagnosis (and consider other labs as indicated)

• Consider bone densitometry

• Annual follow up

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Non-responsive Celiac DiseaseNon-responsive Celiac Disease

• Review original diagnosis/exclude alternative diagnosis

• Review diet adherence – serologic testing to confirm GFD

• Evaluate for associated disorders: microscopic colitis, pancreatic insufficiency

• Evaluate for complications: enteropathy associated lymphoma, refractory celiac disease

• Repeat EGD

Medical Nutrition Therapy for Celiac

Disease

Kristen M. Roberts, PhD, RDN, LDAssistant Professor - Clinical

Department of Internal MedicineDivision of Gastroenterology, Hepatology

and NutritionThe Ohio State University Wexner Medical Center

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ObjectivesObjectives• Identify the common nutritional

deficiencies associated with Celiac Disease (CeD).

• Demonstrate the ability to identify foods restricted for CeD medical nutrition therapy.

• Outline the steps to prevent cross contamination of gluten in daily life.

• Need for Registered Dietitian referral for Medical Nutrition Therapy

Defining GlutenDefining Gluten

• Specific prolamins toxic to the small intestine:• Gliadin (wheat)• Secalin (rye)• Hordein (barley)

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Treatment for CeD is a Gluten Free Diet

Treatment for CeD is a Gluten Free Diet

• Omit all ingredients derived from wheat, rye and barely• Wheat: Flour, white flour, plain flour, bromated

flour, enriched flour, phosphated flour, self-rising flour, durum flour, graham flour, farina, semolina

• Rye• Barley: Beer, ale, porter, stout, and other such

fermented beverages, malt (beverages, chocolate, vinegar)

Dietary Pattern Recommended for CeD

Dietary Pattern Recommended for CeD

Fruits

Vegetables

Meats, beans, legumes

Dairy

Gluten-free grains

AmaranthQuinoaBuckwheatMilletTeffNut floursMontinaSorghumArrowrootWild RiceRice, all formsCorn: corn bran, corn grits, hominy, hasa marinaPotato: potato starch & potato flourSoyTapiocaBean

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Contamination is a Problem!

Contamination is a Problem!

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OatsOats• Oats do not contain gliadin, secalin or hordein,

but often contaminated with prolamins.

Koerner et al, Food Additives & Contaminations:Part A.2011;28:6,705-710

Table 1. Gluten content as a function of type of oat product.

Type of oat Range (mg kg-1 )

Median (mg kg-1 )

Mean (mg kg-1 )

Steel-cut oats 55–1467 660 645+512

Rolled/flaked/ oatmeal

0–2485 81 316+497

Quick/minute oats

13–3784 534 655+694

Oat bran 37–3469 280 704+862

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OatsOats• Certified Gluten Free Oats are

recommended

Safe Limit for Gluten Consumption

Safe Limit for Gluten Consumption

• Virtually impossible to be completely gluten-free

• 10 mg to 30 mg considered safe for most

• 1 slice of Bread ~2500mg of gluten • 62,000 ppm gliadin • 1/50th to 1/500th of piece bread

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Food Allergen Labeling and Consumer Protection Act

2006 (FALCPA)

Food Allergen Labeling and Consumer Protection Act

2006 (FALCPA)• Covers the top 8 allergens in the US

• Wheat, eggs, milk, peanuts, tree nuts, shellfish, fish, soybean

• NOTE: Rye, oats, barley are not part of the top 8 allergens!

• Allergens can be listed within the ingredient list or in the ‘contains statement’

Defining “Gluten Free” on Packaging

Defining “Gluten Free” on Packaging

• FALCPA directed FDA to develop regulations for the voluntary labeling of gluten-free foods

• When can “Gluten Free” be used on packaging?

• No wheat, barley or rye are included or an ingredient derived from one of these grains that has not been processed to remove gluten

• A product with less than 20 parts per million of gluten (ex: wheat starch)

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Gluten Content in GF Foods in the US

Gluten Content in GF Foods in the US

Thompson T and Simpson S. European Journal of Clinical Nutrition. 2015;69:143-146

Prevention of ContaminationPrevention of Contamination

Hom

e

• Toaster• Butter• Condiment• Cutting

boards• Cooking

pans

Res

taur

ant

• GF menu

• Cooking practices

• Fried foods?

• Avoid salad bars

Gro

cery

Sto

re

• Avoid bulk bins

• Wash produce

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Nutritional Concerns for Patients with CeD

Nutritional Concerns for Patients with CeD

• Common nutrient deficiencies: iron, folate, vitamin B12, calcium, vitamin D1

• Deficiencies manifest as:

• Musculoskeletal abnormalities

• Short stature

• Dental enamel defects of unknown etiology

• Cutaneous defects: ulcerations

• Weight loss

• Etiology: Malabsorption and poor diet quality1

1Vici et al. Clin Nutr. 2016

Potentialnutritional deficiencies of a GF Diet

Improvementafter starting GF Diet

May be inadequate after starting GF diet (consult with RD)

Iron X X

Zinc X X

Folate X X

Carbohydrate X

Fiber X

Niacin X

B12 X

Calcium X X

Phosphorus X

Academy of Nutrition and Dietetics, Evidence Based Library

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Registered Dietitian Nutritionist (RDN) Referral

Registered Dietitian Nutritionist (RDN) Referral

• All RDNs have passed registration confirming the ability to educated a patient on the parameters of a gluten free diet

• For a list of specialists, see http://www.eatright.org/find-an-expertfor a RDN in your area

Medical Nutrition Therapy Goals

Medical Nutrition Therapy Goals

• Identify gluten-containing grains that need avoided

• Identify gluten-free grains that can be included• How to read a food label• Identify grocers selling gluten-free products• Discuss nutritional risks of the gluten-free

nutrition prescription • Plan healthful, gluten-free meals at home• Explain cross-contamination and prevention

tactics• Identify supplements and medications that

contain gluten• CeD support groups, online resources

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Resources for Providers and Patients

Resources for Providers and Patients

• Medications: www.glutenfreedrugs.com

• Recipes and support groups: www.glutenfreegang.org

• Regulations and testing: www.glutenfreewatchdog.org