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Celiac Disease:Celiac Disease:A Glimpse of the FutureA Glimpse of the Future

Gaetano Morelli MDGaetano Morelli MD

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DefinitionDefinition

Celiac disease is an immune-mediated enteropathy Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in caused by a permanent sensitivity to gluten in genetically susceptible individuals. genetically susceptible individuals.

It occurs in symptomatic subjects with It occurs in symptomatic subjects with gastrointestinal and non-gastrointestinal symptoms, gastrointestinal and non-gastrointestinal symptoms, and in some asymptomatic individualsand in some asymptomatic individuals

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IncidenceIncidence

Age of onset from 6 months to 90+ yearsAge of onset from 6 months to 90+ years

Affects up to 1%, mostly Caucasians, Middle Affects up to 1%, mostly Caucasians, Middle Eastern and West Asians (Indian/Pakistani)Eastern and West Asians (Indian/Pakistani)

Long-term risks includeLong-term risks include OsteoporosisOsteoporosis 2x overall mortality rate2x overall mortality rate 2x risk GI tumours2x risk GI tumours

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Clinical ManifestationsClinical Manifestations

Gastrointestinal Gastrointestinal ((““classicalclassical””))

Non-gastrointestinal Non-gastrointestinal ( ( ““atypicalatypical””))

Asymptomatic Asymptomatic

In addition, Celiac Disease may be associated with other conditions, and mostly with:• Autoimmune disorders• Some syndromes

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The Celiac IcebergThe Celiac IcebergSymptomatic

Celiac Disease

Silent Celiac Disease

Latent Celiac Disease

Genetic susceptibility: - DQ2, DQ8 Positive serology

Manifest mucosal lesion

Normal Mucosa

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Celiac Disease Occurs withCeliac Disease Occurs with

The Big ThreeThe Big Three

Anemia, Iron, Folate,   BAnemia, Iron, Folate,   B1212 deficiency deficiency

Frequent tiredness or chronic fatigue; Frequent tiredness or chronic fatigue;

  Ongoing GI upsetOngoing GI upset Diarrhea &/or  constipationDiarrhea &/or  constipation Abdominal pain, indigestion, bloating, gasAbdominal pain, indigestion, bloating, gas

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Chance of a Positive DiagnosisChance of a Positive Diagnosis

Increases if the Big Three coexists with either:Increases if the Big Three coexists with either:Thyroid disease    Thyroid disease    Type I diabetes mellitus  Type I diabetes mellitus  Down syndrome         Down syndrome         Abnormal liver function- transaminases especiallyAbnormal liver function- transaminases especiallyOsteoporosis  Osteoporosis  Undefined neurological disorder/epilepsy        Undefined neurological disorder/epilepsy         Infertility/recurrent miscarriageInfertility/recurrent miscarriage

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Screen these for the Big 3Screen these for the Big 3

Infertility (unexplained)Infertility (unexplained)OsteoporosisOsteoporosisFatigueFatigueSero-negative Sero-negative rheumatoid arthritisrheumatoid arthritisDepressionDepressionFractured NOFFractured NOFImpaired memoryImpaired memoryDermatitis herpetiformisDermatitis herpetiformisCerebral calcification Cerebral calcification epilepsy epilepsy

Idiopathic ataxia or Idiopathic ataxia or neuropathy neuropathy SjogrenSjogren’’s syndrome s syndrome Idiopathic ataxiaIdiopathic ataxia IgA deficiencyIgA deficiencyPrimary biliary cirrhosisPrimary biliary cirrhosisDowns syndromeDowns syndromeTurner syndromeTurner syndromeLiver failure Liver failure Thyroiditis Thyroiditis Diabetes (Type 1)Diabetes (Type 1)AddisonAddison’’s diseases disease

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Clinical Associations: Clinical Associations: Disease AssociationsDermatitis herpetiformis 100%Diabetes mellitus (Type 1) 2-16%Thyroiditis 3-5%Selective IgA deficiency 8-29% Addison’s disease 1%Primary biliary cirrhosis 6-7%Liver failure (transplant) 4%Sjogren’s syndrome 15%Idiopathic ataxia or neuropathy 17%Idiopathic ataxia 13%Epilepsy 2%Cerebral calcification and epilepsy 77%Down syndrome 4-19%Turner syndrome 4-8%

“Clinical syndromes”Anemia (all comers) 3-12%Steatorrhea 8%Irritable bowel syndrome 0-7%Fatigue 2%Osteoporosis 3%Infertility (unexplained) 2-8%Sero-negative rheumatoid arthritis ?Depression ?Fractured NOF ?Impaired memory ?

Family History: 1st degree relative 4-18%Identical twin 70-95%

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Dermatitis herpetiformisDermatitis herpetiformis

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Silent: Silent: No or minimal symptoms, No or minimal symptoms, ““damageddamaged”” mucosa and mucosa and

positive serologypositive serology

Identified by screening asymptomatic individuals Identified by screening asymptomatic individuals from groups at risk such:from groups at risk such:

First degree relativesFirst degree relatives Down syndrome patientsDown syndrome patients Type 1 diabetes patients, etc.Type 1 diabetes patients, etc.

AsymptomaticAsymptomatic

Silent Latent

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Latent: Latent: No symptoms, normal mucosaNo symptoms, normal mucosa

May show positive serology. Identified by following in time May show positive serology. Identified by following in time asymptomatic individuals previously identified at screening from asymptomatic individuals previously identified at screening from groups at risk. These individuals, given the groups at risk. These individuals, given the ““rightright”” circumstances, circumstances, will develop at some point in time mucosal changes (will develop at some point in time mucosal changes (± symptoms)± symptoms)

Asymptomatic

Silent Latent

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Associated ConditionsAssociated Conditions

Relatives IDDM Thyroiditis Downsyndrome

0

4

8

12

16

20

per

cen

tag

e

GeneralPopulation

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RelativesRelatives

Healthy population: Healthy population: 1:1331:133

1st degree relatives: 1st degree relatives: 1:18 to 1:221:18 to 1:22

2nd degree relatives: 2nd degree relatives: 1:24 to 1:391:24 to 1:39

Fasano, et al, Arch of Intern Med, Volume 163: 286-292, 2003

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““Mines” Mines” of Celiac Disease are Found Amongof Celiac Disease are Found Among

Relatives Patients with

short stature, anemia, fatigue, hypertransaminasemia

Associateddiseases

autoimmune disorders, Down’s, IgA deficiency, neuropathies, osteoporosis, infertility

“Healthy” groups

blood donors, students, general population

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Celiac Disease Epidemiological Study in USACeliac Disease Epidemiological Study in USA

Prevalence1:39

Prevalence1:22

Population screened13145

Positive31

Negative4095

Positive81

Negative3155

Positive205

Negative4303

Positive33

Negative1242

Prevalence1:40

Symptomatic subjects3236

1st degree relatives4508

2nd degree relatives1275

Healthy Individuals4126

Risk Groups9019

Prevalence1:133

Projected number of celiacs in the U.S.A.: 2,115,954Actual number of known celiacs in the U.S.A.: 40,000For each known celiac there are 53 undiagnosed patients.

A. Fasano et al., Arch Int Med 2003;163:286-292.

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Celiac Disease IcebergsCeliac Disease Icebergs

0

2

4

6

8

10

Overall

Diagnosed

Ireland Italy Netherlands Sweden USA

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Disease MechanismDisease Mechanism

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The Cause of Celiac DiseaseThe Cause of Celiac Disease

Gluten proteins

E

E

Injury

Villous atrophy

Digestion

Resistant peptides

Deamidation

HLA-DQ2

T-cell

IFN

2020

HLA-DQ in Celiac DiseaseHLA-DQ in Celiac Disease

European Genetics Cluster on Celiac Disease; n=1007

88.0%

5.7%

6.0%

0.4%

DQA1*05 & DQB1*02(HLA-DQ2)DQA1*05 or DQB1*02

DQ1*03 & DQB1*0302(HLA-DQ8) Other

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DQA1*05 or DQB1*02DQA1*0301 + DQB1*0302

Present AbsentCeliac: 99.6% 0.4%Non-celiac: 35% 65%

HLA-DQ Genes Have Strong HLA-DQ Genes Have Strong Negative Predictive ValueNegative Predictive Value

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Diagnostic principlesDiagnostic principles

Confirm diagnosis before treatingConfirm diagnosis before treating Diagnosis of Celiac Disease mandates a strict Diagnosis of Celiac Disease mandates a strict

gluten-free diet for lifegluten-free diet for lifefollowing the diet is not easyfollowing the diet is not easy

QOL implicationsQOL implications

Failure to treat has potential long term Failure to treat has potential long term adverse health consequencesadverse health consequences

increased morbidity and mortalityincreased morbidity and mortality

DiagnosisDiagnosis

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Serological TestsSerological Tests

Role of serological tests:Role of serological tests:

Identify symptomatic individuals who need a Identify symptomatic individuals who need a biopsybiopsy

Screening of asymptomatic “at risk” Screening of asymptomatic “at risk” individualsindividuals

Supportive evidence for the diagnosisSupportive evidence for the diagnosis

Monitoring dietary complianceMonitoring dietary compliance

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Serological TestsSerological Tests

Antigliadin antibodies (AGA) *Antigliadin antibodies (AGA) *

Antiendomysial antibodies (EMA) *Antiendomysial antibodies (EMA) *

Anti tissue transglutaminase antibodies (TTG) *Anti tissue transglutaminase antibodies (TTG) *– first generation (guinea pig protein)first generation (guinea pig protein)

– second generation (human recombinant)second generation (human recombinant)

HLA typing HLA typing

* 2004 Consensus Conf. Best tests* 2004 Consensus Conf. Best tests

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Sensitivity and Specificity of Sensitivity and Specificity of Serologic TestsSerologic Tests

SERUM TESTSSERUM TESTS SENSITIVITYSENSITIVITY SPECIFICITYSPECIFICITY

IgA EMAIgA EMA 85-98%85-98% 97-100%97-100%

IgA tTGIgA tTG 90-98%90-98% 94-99%94-99%

IgA AGAIgA AGA 75-90%75-90% 82-95%82-95%

IgG AGAIgG AGA 69-85%69-85% 73-90%73-90%

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Histological FeaturesHistological Features

Normal 0 Infiltrative 1 Hyperplastic 2

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

Horvath K. Recent Advances in Pediatrics, 2002.

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TreatmentTreatment

Only treatment for Only treatment for celiac disease is a celiac disease is a gluten-free diet (GFD)gluten-free diet (GFD) Strict, lifelong dietStrict, lifelong diet Avoid:Avoid:

WheatWheat

RyeRye

Barley Barley

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Oats –are they Safe?Oats –are they Safe?

Studies from 1970Studies from 1970’’s suggested that oats s suggested that oats were toxic in CDwere toxic in CDOats contain a protein-aveninOats contain a protein-aveninAvenin- similar to wheat gliadinAvenin- similar to wheat gliadinBoth are prolamins –rich in glutamine and Both are prolamins –rich in glutamine and proline, both amino acidsproline, both amino acids

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OATSOATS

Avenin- proportion of proline and glutmaine Avenin- proportion of proline and glutmaine is very low in oats compared to gliadin in is very low in oats compared to gliadin in wheatwheat2004, Random. Clin Trial in children fed 2004, Random. Clin Trial in children fed GFD vs. GFD with oatsGFD vs. GFD with oats

Hogberg Gut May 1, 2004 53(5)649-654.Hogberg Gut May 1, 2004 53(5)649-654.

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FindingsFindings

First large study to indicate that oats in GFD do First large study to indicate that oats in GFD do not prevent normalization of the small bowel not prevent normalization of the small bowel tissue or celiac markers.tissue or celiac markers.Other evidence supporting the safety of oats; Other evidence supporting the safety of oats; G. Kilmartin Gut, January 1, 2003G. Kilmartin Gut, January 1, 2003In CD, oats are not toxic and immunogenic, In CD, oats are not toxic and immunogenic, Srinivasan BMJ 1996:1300-01Srinivasan BMJ 1996:1300-01

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Sources of GlutenSources of Gluten

OBVIOUS SOURCESOBVIOUS SOURCES BreadBread BagelsBagels CakesCakes CerealCereal CookiesCookies Pasta / noodlesPasta / noodles Pastries / piesPastries / pies RollsRolls

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Treatment – 6 Elements in RXTreatment – 6 Elements in RXCConsultation with a skilled dietitianonsultation with a skilled dietitianEEducation about the disease ducation about the disease LLifelong adherence to a gluten-free diet ifelong adherence to a gluten-free diet IIdentification and treatment of dentification and treatment of nutritional nutritional deficiencies deficiencies AAccess to an advocacy group ccess to an advocacy group CContinuous long-term follow-up by a ontinuous long-term follow-up by a multidisciplinary team multidisciplinary team

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Barriers to ComplianceBarriers to Compliance

Ability to manage emotions – Ability to manage emotions – depression, anxietydepression, anxiety

Ability to resist temptation – Ability to resist temptation – exercising restraintexercising restraint

Feelings of deprivationFeelings of deprivation

Fear generated by Fear generated by

inaccurate information inaccurate information

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Factors that Improve AdherenceFactors that Improve AdherenceInternal Adherence Factors Include:Internal Adherence Factors Include:

Knowledge about the gluten-free dietKnowledge about the gluten-free dietUnderstanding the risk factors and serious Understanding the risk factors and serious complications can occur to the patientcomplications can occur to the patientAbility to break down big changes into smaller stepsAbility to break down big changes into smaller steps

Ability to simplify or make behavior routineAbility to simplify or make behavior routine

Ability to reinforce positive changes internallyAbility to reinforce positive changes internallyPositive coping skillsPositive coping skillsAbility to recognize and manage mental health issuesAbility to recognize and manage mental health issuesTrust in physicians and dietitiansTrust in physicians and dietitians

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Approach to CDApproach to CD

Moderate tohigh probability

IgA TTG andduodenal biopsy

+ serology- histology

+ serology+ histology

- serology+ histology

- serology- histology

Review orrepeat biopsy

CeliacExclude other causes of

celiac-like enteritisDiagnosisexcluded

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Approach to CDApproach to CD

Low probability

Test for IgA TTG

PositivePerform biopsy

NegativeCD excluded

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ConclusionConclusionCeliac disease isCeliac disease is

common: 1% communitycommon: 1% community GI symptoms are often absent or mildGI symptoms are often absent or mild Fatigue, anaemia, headaches are commonFatigue, anaemia, headaches are common Celiac serology is a cheap and effective screenCeliac serology is a cheap and effective screen Gene testing can exclude celiac diseaseGene testing can exclude celiac disease Gastroscopy and duodenal biopsy are essentialGastroscopy and duodenal biopsy are essential Family testing is importantFamily testing is important Gluten free diet is complex - a skilled dietician is essentialGluten free diet is complex - a skilled dietician is essential

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Global Village of Celiac DiseaseGlobal Village of Celiac Disease

In many areas of the world Celiac In many areas of the world Celiac Disease is one of the commonest, Disease is one of the commonest, lifelong disorders affecting around lifelong disorders affecting around 1% of the general population.1% of the general population.

Most cases escape diagnosis and Most cases escape diagnosis and are exposed to the risk of are exposed to the risk of complications.complications.

Active Celiac Disease case-finding is Active Celiac Disease case-finding is needed but mass screening should needed but mass screening should be considered. be considered.

The impact of Celiac Disease in the The impact of Celiac Disease in the developing world needs further developing world needs further evaluation.evaluation.

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Gastrointestinal Manifestations (Gastrointestinal Manifestations (““ClassicClassic””))

Most common age of presentation: 6-24 monthsMost common age of presentation: 6-24 months

Chronic or recurrent diarrheaChronic or recurrent diarrheaAbdominal distensionAbdominal distensionAnorexiaAnorexiaFailure to thrive or weight lossFailure to thrive or weight loss

• Abdominal pain• Vomiting• Constipation• Irritability

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Typical Celiac DiseaseTypical Celiac Disease

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Non Gastrointestinal ManifestationsNon Gastrointestinal Manifestations

• Dermatitis HerpetiformisDermatitis Herpetiformis• Dental enamel hypoplasia Dental enamel hypoplasia

of permanent teethof permanent teeth• Osteopenia/OsteoporosisOsteopenia/Osteoporosis• Short StatureShort Stature• Delayed PubertyDelayed Puberty

• Iron-deficient anemia resistant to oral Fe• Hepatitis• Arthritis• Epilepsy with occipital calcifications

Most common age of presentation: older child to adult

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Major Complications of Celiac DiseaseMajor Complications of Celiac Disease

Short statureShort stature

Dermatitis Dermatitis herpetiformisherpetiformis

Dental enamel Dental enamel hypoplasiahypoplasia

Recurrent stomatitisRecurrent stomatitis

Fertility problemsFertility problems

Osteoporosis Osteoporosis

Gluten ataxia and Gluten ataxia and other neurological other neurological disturbancesdisturbances

Refractory celiac Refractory celiac disease and related disease and related disordersdisorders

Intestinal lymphomaIntestinal lymphoma

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EpidemiologyEpidemiologyThe “old” Celiac Disease Epidemiology:The “old” Celiac Disease Epidemiology:

• A rare disorder typical of infancy• Wide incidence fluctuates in space (1/400 Ireland

to 1/10000 Denmark) and in time• A disease of essentially European origin

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Gluten

WheatRye

Barley

Normal Celiac

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Identification of the Components of Gluten Identification of the Components of Gluten Responsible for the Intestinal DamageResponsible for the Intestinal Damage

Gluten 1gOr

Gluten peptidep56-74 50mg

Placed in small intestine

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P P

E L YPPQS

QLQQP

Q

PF

T cell receptor

HLA-DQ2Anderson RP et al Nat Med 2000Arentz-Hansen H. et al J Exp Med 2000

A-Gliadin 57-73 QE65: A-Gliadin 57-73 QE65: TCR-DQ2 interactionTCR-DQ2 interaction

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Gliadin Susceptibility to Gliadin Susceptibility to Digestive ProteasesDigestive Proteases

Gastric/pancreatic/brush border proteases

2-gliadin Protease-resistant 33mer

Shan L. et al Science 2002