Copyright, The Mayo Foundation, 2005 Introduction to Celiac Disease Joseph Murray The Mayo Clinic Rochester, MN

Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005

Introduction to Celiac Disease Introduction to Celiac Disease

Joseph MurrayJoseph Murray

The Mayo ClinicThe Mayo Clinic

Rochester, MNRochester, MN


OutlineOutline

• What is celiac diseaseWhat is celiac disease

• What causes itWhat causes it

• Who gets itWho gets it

• TreatmentTreatment

• Complications and complianceComplications and compliance

• PrognosisPrognosis


Food IntolerancesFood Intolerances

IgE-m ediatedClassic food A llergy

Celiac D isease

Non IgE-m ediated

Im m une-m ediated Pharm acological Toxin Enzym atic Deficiency

Food Intolerance


Anatomy of the Small IntestineAnatomy of the Small Intestine


Normal VilliNormal Villi


What is Celiac Disease?What is Celiac Disease?

• It is a inflammatory state of the small intestine It is a inflammatory state of the small intestine that occurs in genetically predisposed individuals that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.and resolves with exclusion of dietary gluten.

Normal CeliacDisease


What Causes it? What Causes it?


GeneticsHLA

EnvironmentGluten

Immune Response

Inflammation

Pathogenesis of Celiac Disease


Genetics of Celiac DiseaseGenetics of Celiac Disease

• Strong family predispositionStrong family predisposition

Monozygous twins (80%), siblings (10%) kids Monozygous twins (80%), siblings (10%) kids (5-10%)(5-10%)

• Strong HLA association (DQ2 and DQ8) Strong HLA association (DQ2 and DQ8)

• Non HLA genes suspected but not confirmedNon HLA genes suspected but not confirmed

• Certain chromosomal disorders:Certain chromosomal disorders:

Down’s, Turner’s and Williams syndromeDown’s, Turner’s and Williams syndrome



Wheat KernelWheat Kernel

• Bran = fibreBran = fibre• Endosperm = starch and Endosperm = starch and

proteinprotein• Germ = protein and lipidGerm = protein and lipid

• Proteins ( gluten) Proteins ( gluten)

gliadinsgliadins

glutenins glutenins


Wheat Protein Wheat Protein

• Uniquely high in certain amino acids Uniquely high in certain amino acids

Prolines and glutamines pQPQLPY Prolines and glutamines pQPQLPY

• Glutamines can cross-linked to give the grain its Glutamines can cross-linked to give the grain its resiliency and the glue or “gluten” that gives resiliency and the glue or “gluten” that gives bread shape bread shape

• Proline sequences form helices resistant to Proline sequences form helices resistant to digestion digestion Shan, Science 2002


Gluten and DQ2Gluten and DQ2

• Gliadin molecules are presented by the DQ2/8 Gliadin molecules are presented by the DQ2/8 molecules to the T-cells in the gutmolecules to the T-cells in the gut

• Certain gliadin molecules have a greater affinity Certain gliadin molecules have a greater affinity than othersthan others

• Peptides may be processed or altered to make them Peptides may be processed or altered to make them more antigenicmore antigenic

• Immunodominant peptides are digestion resistant ( Immunodominant peptides are digestion resistant ( Proline twists)Proline twists)


Role of Tissue TransglutaminaseRole of Tissue Transglutaminase

• Enzyme present in gutEnzyme present in gut

• Autoantigen recognized by IgA in active CDAutoantigen recognized by IgA in active CD

• Released by fibroblasts in inflammationReleased by fibroblasts in inflammation

• Cross links cystine residuesCross links cystine residues

• Alters gliadin by de-amidating glutamine to Alters gliadin by de-amidating glutamine to glutamateglutamate

• The de-amidated molecule fit perfectly into the The de-amidated molecule fit perfectly into the binding grove of DQ2 or DQ8 binding grove of DQ2 or DQ8


Pathogenesis of Celiac Disease


Villous and Cell Structure Villous and Cell Structure

Fasano, et.al.

Zonulin

Anti-Actin

Metalloprotease

Endothelial injury


Increased Paracellular Permeability Increased Paracellular Permeability

Gliadin

Antigen Presenting Cell

Increased Zonulin release

Fasano, 2002


Triggers for Celiac DiseaseTriggers for Celiac Disease

• Gluten in the infant dietGluten in the infant diet

• Age at introductionAge at introduction

• Amount of glutenAmount of gluten

• Other eventsOther events

PregnancyPregnancy

InfectionsInfections

SurgeriesSurgeries


S p ecu la tion s

o th er g en esau to im m u n ity

g en d er

g as troen te rit isag in g

su rg eryp os t p artu m

L oss o f to le ran ceIn flam m ation

m alab sorp tion

G lu ten S en s it ivity

G lu ten exp osu re

H L A typ e


Evolutionary CollisionEvolutionary Collision

Kasorda, 1992

WheatHuman Immune System


How Does It Present?How Does It Present?

And Who Gets It?And Who Gets It?


Classical Celiac DiseaseClassical Celiac Disease

NASPGHAN


Presentation in Children

•Onset after introduction of gluten•Age 6 months to 7 years•Failure to thrive•Abdominal distension •Anorexia•Diarrhea•Steatorrhea•Anemia•Growth failure•Vitamin deficiencies


Gastrointestinal Presentation in AdultsGastrointestinal Presentation in Adults

• Age: May present at any ageAge: May present at any age

• Symptoms may include:Symptoms may include:

Abdominal painAbdominal pain

Heartburn, nausea and vomitingHeartburn, nausea and vomiting

Anemia and fatigueAnemia and fatigue

Malabsorption (steatorrhea rare)Malabsorption (steatorrhea rare)

May have constipation May have constipation Murray et al. AJCN, 2004


Gastrointestinal Presentation in AdultsGastrointestinal Presentation in Adults

• May mimic other GI disorders:May mimic other GI disorders:

Lactose intoleranceLactose intolerance

Irritable Bowel SyndromeIrritable Bowel Syndrome

Inflammatory Bowel Disease Inflammatory Bowel Disease


Specific DeficienciesSpecific Deficiencies

• Fat soluble vitamins: D,E,A,KFat soluble vitamins: D,E,A,K

D; osteomalacia and myopathy*D; osteomalacia and myopathy*

E; Neurological syndromesE; Neurological syndromes

A; night blindnessA; night blindness

K; bleeding, epistaxisK; bleeding, epistaxis

• Iron*Iron*

• FolateFolate

• B12 B12

• Zinc, B6, selenium and othersZinc, B6, selenium and others

* often isolated


Extra-intestinal PresentationExtra-intestinal Presentation

May involve:May involve:

• Musculoskeletal System (joint pain, osteoporosis)Musculoskeletal System (joint pain, osteoporosis)

• Reproductive (infertility, delayed puberty, Reproductive (infertility, delayed puberty, spontaneous recurrent abortions)spontaneous recurrent abortions)

• Hematologic (anemia)Hematologic (anemia)

• HyposplenismHyposplenism

• Dentition (enamel defects)Dentition (enamel defects)


Fe-Deficient AnemiaFe-Deficient Anemia

• Most common non-GI manifestation in some studies

• 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease

• Especially in those resistant to oral iron

• 5-15% of patients undergoing endoscopy for fe deficiency anemia have celiac disease

• 30-50% of patients getting EGD for anemia do not get duodenal biopsies!

Vogelsang, 98; Grisolano, 2004

Harewood, 2003


OsteomalaciaOsteomalacia


Extra-intestinal Presentation

• Neurologic and psychiatric syndromesNeurologic and psychiatric syndromes

neuropathy, ataxia, seizures, dementianeuropathy, ataxia, seizures, dementia

• Fibromylagia, Chronic Fatigue SyndromeFibromylagia, Chronic Fatigue Syndrome

• Skin and mucous membranes (rash, aphthous Skin and mucous membranes (rash, aphthous ulcers)ulcers)

• Dental enamel defectsDental enamel defects

• Dermatitis herpetiformis (caused by gluten)Dermatitis herpetiformis (caused by gluten)


Dermatitis HerpetiformisDermatitis Herpetiformis


Associated ConditionsAssociated Conditions

• Other Autoimmune DiseasesOther Autoimmune DiseasesType 1 Diabetes Mellitus – 3.5-7%Type 1 Diabetes Mellitus – 3.5-7%Thyroiditis – 4%Thyroiditis – 4%Arthritis – 1.5-7.5%Arthritis – 1.5-7.5%Primary Biliary Cirrhosis – 6%Primary Biliary Cirrhosis – 6%

• Congenital DisordersCongenital DisordersDown’s Syndrome – 4-14%Down’s Syndrome – 4-14%Turner Syndrome – 4-8%Turner Syndrome – 4-8%IgA Deficiency – 7%IgA Deficiency – 7%

• Relatives 5-20%Relatives 5-20%

Pietzak et al. Nutrition in Clinical Practice 2001


Celiac Disease: Asymptomatic and Latent FormsCeliac Disease: Asymptomatic and Latent Forms

• AsymptomaticAsymptomatic

No apparent symptoms or associated diseasesNo apparent symptoms or associated diseases

May be first or second-degree relatives of May be first or second-degree relatives of patients with biopsy proven celiac diseasepatients with biopsy proven celiac disease

• LatentLatent

Positive serology with negative small bowel Positive serology with negative small bowel biopsiesbiopsies


Celiac Disease: EpidemiologyCeliac Disease: Epidemiology

• First identified in EuropeFirst identified in Europe

• Prevalence is 1 in 90-300Prevalence is 1 in 90-300 Diagnosis rate is lower ( 1:2000) Diagnosis rate is lower ( 1:2000)

• One of most frequent genetic based diseasesOne of most frequent genetic based diseases

• Studies in Latin American, African, & Asian Studies in Latin American, African, & Asian countries indicate CD is worldwidecountries indicate CD is worldwide

Worldwide average prevalence estimated ~ 1%Worldwide average prevalence estimated ~ 1%

Fasano, et al.Gastroenterology 2001

Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005 Calendar Year By Decade

1950-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2001

0

2

4

6

8

10

12

CeliacDH

Age and Sex Adjusted Incidence Rates Among Olmsted County ResidentsIn

cid

ence

/100

,000


Age at diagnosis

Inci

den

ce/1

00,0

00

0

1

2

3

4

5

0-3 4-18 19-44 45-64 65+

Females

Total

Males

Crude Incidence of Celiac Disease in Olmsted Co.1950-2001 by Diagnosis age

Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005CP1002147- 2

Celiac Icebergs (circa 1996)Celiac Icebergs (circa 1996)

U.S.A.U.S.A. FinlandFinland IrelandIreland DenmarkDenmark SwedenSweden Italy‡Italy‡

0.20.22.7 2.5

0.460.46 1.01.0 0.80.8

4.07.7

8.25.3 5.01.01.0

**

*Active case finding*Active case finding ‡‡ RegionalRegional variationvariation


Natrona County, Wyoming Natrona County, Wyoming

• ~ 20 cases in population of 40,000~ 20 cases in population of 40,000

• Annual health fair screeningAnnual health fair screening

• 32/4036 had positive TTg 32/4036 had positive TTg andand EMA EMA

• 15/16 biopsied cases proven to have CD15/16 biopsied cases proven to have CD

• 1: 126 adults with celiac disease1: 126 adults with celiac disease

• 1/2 had GI symptoms mostly constipation1/2 had GI symptoms mostly constipation

• Two had family members with CDTwo had family members with CD


Making the DiagnosisMaking the Diagnosis

• SuspicionSuspicion

• Serology testsSerology tests

Tissue transglutaminase antibodiesTissue transglutaminase antibodies

Endomysial antibodiesEndomysial antibodies

• Intestinal biopsy ( gold standard)Intestinal biopsy ( gold standard)

• Response to a gluten free dietResponse to a gluten free diet


Celiac Disease Pathology Intraepithelial lymphocytes

Crypt Hyperplasia

Increasedlymphocytesmacrophages,plasma cells andeosinophils

Villous atrophy


0 1 2 3 4

Gluten Sensitive EnteropathyGluten Sensitive EnteropathyGluten Sensitive EnteropathyGluten Sensitive Enteropathy

Upper Intestinal LesionsUpper Intestinal LesionsUpper Intestinal LesionsUpper Intestinal Lesions

CP1027863- 2Marsh Classification Marsh Classification


Negative

High RiskClinical

MalabsorptionSyndrome

Low RiskFamily History

AnemiaType 1 Diabetes

DiarrheaInfertility

GI BiopsyRequired*

Mayo Clinic Celiac Disease Algorithm

Risk of Celiac Diseasew/ Autoimmune Liver

Disease, Heart Failure, or Active Thyroid Disease

tTG IgA tTG IgG

tTG IgA tTG IgG

EMA IgAtTG IgG

GI BiopsyRequired*

AND

Any positive result

PositivePositive

Celiac Disease

Celiac DiseaseVery Unlikely

Celiac DiseaseLikely


Treatment of Celiac DiseaseTreatment of Celiac Disease

Gluten Free RouletteGluten Free Roulette


Nuts and Bolts of a Gluten Free Diet Nuts and Bolts of a Gluten Free Diet • Avoid the offending grainsAvoid the offending grains

WheatWheat

BarleyBarley

Rye Rye

Wheat-like grainsWheat-like grains

SpeltSpelt

KamutKamut

““Most corn or rice commercial cereals are Most corn or rice commercial cereals are NOTNOT GF GF


How Much Gluten is Too Much?How Much Gluten is Too Much?

• Threshold for damage is 20-100 mgs/day?Threshold for damage is 20-100 mgs/day?

• Symptoms are not a good indicatorSymptoms are not a good indicator

• tTg antibodies positive > 1gram/daytTg antibodies positive > 1gram/day

• Cheating > 1/month ---> chronic injuryCheating > 1/month ---> chronic injury

• Variable sensitivityVariable sensitivity


Codex Alimentaris 2004Codex Alimentaris 2004

• Naturally gluten free foods: 20 PPMNaturally gluten free foods: 20 PPM

• Rendered gluten free foods: 200 PPM Rendered gluten free foods: 200 PPM

• Draft documentDraft document

• Some countries allow gluten-reduced wheat Some countries allow gluten-reduced wheat starchstarch

• New tests for gluten contaminationNew tests for gluten contamination


Non-Responsive Celiac DiseaseNon-Responsive Celiac Disease

• Diet, diet and diet!!! ( > 50%)Diet, diet and diet!!! ( > 50%)

• Lymphocytic colitisLymphocytic colitis

• Pancreatic insufficiencyPancreatic insufficiency

• ? Bacteria overgrowth? Bacteria overgrowth

• True refractory sprueTrue refractory sprue


Potential Sources of ContaminationPotential Sources of Contamination

• Commercial cerealsCommercial cereals• Eating outEating out• Communion wafersCommunion wafers• LipstickLipstick• Airborne flour/ starchAirborne flour/ starch• ““Soy” sauces made with wheatSoy” sauces made with wheat• Mislabeled or unlisted ingredients Mislabeled or unlisted ingredients • MedicationMedication


Ingredients to QuestionIngredients to Question((maymay contain gluten) contain gluten)

• Seasonings and spice blends or mixesSeasonings and spice blends or mixes

• Modified food starchModified food starch

• Malt/ malt extract/ flavoringMalt/ malt extract/ flavoring

• Modified hop extract and yeast-malt Modified hop extract and yeast-malt sprout extractsprout extract

• DextrinDextrin

• Caramel colorCaramel color

NASPGHAN


Complications Associated with Untreated DiseaseComplications Associated with Untreated Disease

• Mortality rate in patients with untreated celiac disease Mortality rate in patients with untreated celiac disease is is TWO FOLD GREATERTWO FOLD GREATER at every age at every age

Gastrointestinal malignanciesGastrointestinal malignancies

• OsteoporosisOsteoporosis

• Stunted growth Stunted growth

• InfertilityInfertility

• Chronic ill healthChronic ill health

• All can be prevented with early treatmentAll can be prevented with early treatmentCorrao et al.. Lancet 2001


Dangers of Non-ComplianceDangers of Non-Compliance

• Increased mortality Increased mortality Holmes et al. 1989 Corrao et al.

• Osteoporosis Osteoporosis Cellier Cellier

• LymphomaLymphoma

• Other cancersOther cancers• Psychological effects Psychological effects hallerthallert


Enteropathy Associated LymphomaEnteropathy Associated Lymphoma

Celiac disease

Lymphoma


Does Silent Celiac Disease Matter?Does Silent Celiac Disease Matter?

• Are those identified less sick that clinically diagnosed Are those identified less sick that clinically diagnosed CDCD

• What is the benefit or negative effects of a GFD in What is the benefit or negative effects of a GFD in people found by screening people found by screening

• Are they any less likely to comply with a gluten free Are they any less likely to comply with a gluten free diet?diet?

• Affect mortality?Affect mortality?


“What some call health, if purchased by perpetual anxiety about diet, isn’t much better than tedious disease”

George Dennison Prentice, 1860


The FutureThe Future

• Bioengineer wheat free of antigenic moietiesBioengineer wheat free of antigenic moieties• Block DQ interaction with glutenBlock DQ interaction with gluten

? Block TTg*? Block TTg*• Predigest peptide fragmentsPredigest peptide fragments• Prevent or reverse sensitivity Prevent or reverse sensitivity • Block gliadin effects on permeabilityBlock gliadin effects on permeability• Block de-amindationBlock de-amindation• Re establish toleranceRe establish tolerance

* TTG-IgA block the active site


Predigestion Strategy?Predigestion Strategy?


SummarySummary

• Celiac disease is common Celiac disease is common • Largely unrecognized until recentlyLargely unrecognized until recently• Many challenges in treatment Many challenges in treatment • Gluten free diet not simple Gluten free diet not simple • Widespread use of grain proteins in foodWidespread use of grain proteins in food• Food ingredient source identificationFood ingredient source identification• Regulation ( Food Allergy Act of 2004) Regulation ( Food Allergy Act of 2004) • Defining acceptable thresholds and verificationDefining acceptable thresholds and verification


Another Food Safety Issue?

Camp Ripley, MN

Documents

Copyright, The Mayo Foundation, 2005 Introduction to Celiac Disease Joseph Murray The Mayo Clinic Rochester, MN