copyright, the mayo foundation, 2005 introduction to celiac disease joseph murray the mayo clinic...
TRANSCRIPT
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Anatomy of the Small IntestineAnatomy of the Small Intestine
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Normal VilliNormal Villi
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
What Causes it? What Causes it?
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
GeneticsHLA
EnvironmentGluten
Immune Response
Inflammation
Pathogenesis of Celiac Disease
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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)
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Pathogenesis of Celiac Disease
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Villous and Cell Structure Villous and Cell Structure
Fasano, et.al.
Zonulin
Anti-Actin
Metalloprotease
Endothelial injury
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Increased Paracellular Permeability Increased Paracellular Permeability
Gliadin
Antigen Presenting Cell
Increased Zonulin release
Fasano, 2002
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Evolutionary CollisionEvolutionary Collision
Kasorda, 1992
WheatHuman Immune System
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
How Does It Present?How Does It Present?
And Who Gets It?And Who Gets It?
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Classical Celiac DiseaseClassical Celiac Disease
NASPGHAN
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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)
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
OsteomalaciaOsteomalacia
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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)
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Dermatitis HerpetiformisDermatitis Herpetiformis
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Celiac Disease Pathology Intraepithelial lymphocytes
Crypt Hyperplasia
Increasedlymphocytesmacrophages,plasma cells andeosinophils
Villous atrophy
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Treatment of Celiac DiseaseTreatment of Celiac Disease
Gluten Free RouletteGluten Free Roulette
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Enteropathy Associated LymphomaEnteropathy Associated Lymphoma
Celiac disease
Lymphoma
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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?
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
“What some call health, if purchased by perpetual anxiety about diet, isn’t much better than tedious disease”
George Dennison Prentice, 1860
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Predigestion Strategy?Predigestion Strategy?
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
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
Copyright, The Mayo Foundation, 2005Copyright, The Mayo Foundation, 2005
Another Food Safety Issue?
Camp Ripley, MN