Primary Care Approach to Primary Care Approach to Celiac DiseaseCeliac Disease

What Celiac Disease IsWhat Celiac Disease Is

• Gluten-sensitive enteropathy/celiac Gluten-sensitive enteropathy/celiac disease/non-tropical sprue/celiac sprue – disease/non-tropical sprue/celiac sprue – all refer to same conditionall refer to same condition

• Genetically linkedGenetically linked– HLA DQ2 or DQ8 – present in 35-40% of North HLA DQ2 or DQ8 – present in 35-40% of North

AmericansAmericans– Must have one of these genotypes to have Must have one of these genotypes to have

sprue (only 2-5% of those with one of them get sprue (only 2-5% of those with one of them get sprue)sprue)

– QuestionQuestion: Why don’t the other 95-98% get : Why don’t the other 95-98% get sprue?sprue?

Modifiers of Incidence and Modifiers of Incidence and Severity of Celiac SprueSeverity of Celiac Sprue• IncreaseIncrease risk or risk or worsenworsen course – children course – children

effectedeffected– Early exposure to glutenEarly exposure to gluten– Early enteropathic virus exposure (Rotavirus)Early enteropathic virus exposure (Rotavirus)– Change in bowel flora (? early antibiotics)Change in bowel flora (? early antibiotics)– Short duration of or no breastfeedingShort duration of or no breastfeeding

Modifiers of Incidence and Modifiers of Incidence and Severity of Celiac SprueSeverity of Celiac Sprue• DecreaseDecrease risk risk

– Breastfeeding Breastfeeding • Begin early and continue especially during ages 4-7 Begin early and continue especially during ages 4-7

monthsmonths

• Do it while introducing glutenDo it while introducing gluten

• Continue longerContinue longer

– Delay introduction of glutenDelay introduction of gluten• Beginning between 4-7 months when immune Beginning between 4-7 months when immune

response is “tolerogenic”response is “tolerogenic”

– Prevent infections rather than treating them - ? Prevent infections rather than treating them - ? avoid antibiotics + immunize (?Rotavirus)avoid antibiotics + immunize (?Rotavirus)

What Celiac Disease is What Celiac Disease is (cont.)(cont.)• Food “allergy” / autoimmune disease in those Food “allergy” / autoimmune disease in those

genetically susceptiblegenetically susceptible– Gluten = one of commonest ingredients in human Gluten = one of commonest ingredients in human

dietdiet– Gliadin fraction incompletely cleaved in small bowelGliadin fraction incompletely cleaved in small bowel– Resultant peptides get into lamina propria through Resultant peptides get into lamina propria through

leaky intercellular junctionsleaky intercellular junctions– Deamidated by tTG – negative chargeDeamidated by tTG – negative charge– Affinity for HLA DQ2/8 molecules on APC’s which Affinity for HLA DQ2/8 molecules on APC’s which

activates CD4 T lymphocytes – release of activates CD4 T lymphocytes – release of proinflammatory cytokinesproinflammatory cytokines

– B lymphocytes activated – gliadin and tTG antibodiesB lymphocytes activated – gliadin and tTG antibodies

What Celiac Disease is NotWhat Celiac Disease is Not

• Uncommon – up to 1% of US population Uncommon – up to 1% of US population • Present only in Caucasians of Northern Present only in Caucasians of Northern

European extractionEuropean extraction• Seen mostly in childrenSeen mostly in children

– most common in 10-40 age group and beyond most common in 10-40 age group and beyond – possibly related to longer breast feeding and possibly related to longer breast feeding and

later introduction of glutenlater introduction of gluten

What Celiac Disease is Not What Celiac Disease is Not (cont.)(cont.)• Most often symptomatic in classic sense Most often symptomatic in classic sense

when diagnosedwhen diagnosed– atypical presentationsatypical presentations– screening results – 7:1 previously unknown vs screening results – 7:1 previously unknown vs

knownknown

• Stable in terms of prevalence – has increased Stable in terms of prevalence – has increased 4X in past 45 years – possibly related to 4X in past 45 years – possibly related to change in wheat and bread processing and change in wheat and bread processing and early childhood infectionsearly childhood infections

• Benign if mild and therefore undiagnosed – Benign if mild and therefore undiagnosed – 4x mortality4x mortality

Diagnosis - ClinicalDiagnosis - Clinical

• Classic presentationClassic presentation– Tip of the Iceberg - diarrhea, weight loss, Tip of the Iceberg - diarrhea, weight loss,

malabsorption malabsorption

• Awareness of different presentationsAwareness of different presentations– Silent/subclinical – few symptoms, +tTG aby, Silent/subclinical – few symptoms, +tTG aby,

abnormal biopsyabnormal biopsy– Latent - no/few symptoms, + tTG aby, normal Latent - no/few symptoms, + tTG aby, normal

biopsy,biopsy,– Refractory Refractory – AtypicalAtypical

Atypical presentations (% risk)Atypical presentations (% risk)

• GI – IBS symptoms (4-5%)GI – IBS symptoms (4-5%)• Extra intestinalExtra intestinal

– Abnormal LFT’s (1.5-9%)Abnormal LFT’s (1.5-9%)– Iron deficiency anemia (2-15%)Iron deficiency anemia (2-15%)– Osteoporosis (1-3%)Osteoporosis (1-3%)– ArthritisArthritis– Neuropsychiatric diseasesNeuropsychiatric diseases

• Ataxia, depression, anxiety, epilepsy, headachesAtaxia, depression, anxiety, epilepsy, headaches

– Unexplained Infertility (2-4%)Unexplained Infertility (2-4%)– Chronic fatigue syndrome (2%)Chronic fatigue syndrome (2%)– Pancreatitis – acute and chronic; macroamylasemiaPancreatitis – acute and chronic; macroamylasemia

Relationship between Celiac Relationship between Celiac Disease (CD) and IBSDisease (CD) and IBS• 4-5% prevalence of CD in IBS patients4-5% prevalence of CD in IBS patients

• Gluten sensitivity (GS) – atypical abnormal Gluten sensitivity (GS) – atypical abnormal immune response to glutenimmune response to gluten– tTG negative but HLA DQ2 or 8 +tTG negative but HLA DQ2 or 8 +– May have mild biopsy change only – increased May have mild biopsy change only – increased

lymphocyteslymphocytes– IBS symptoms may happen in GS with only these IBS symptoms may happen in GS with only these

mild changesmild changes

Relationship between Celiac Relationship between Celiac Disease (CD) and IBSDisease (CD) and IBS• GS may be a middle ground overlap GS may be a middle ground overlap

between IBS and CDbetween IBS and CD

• May respond to gluten-free dietMay respond to gluten-free diet

• ““Between CD and IBS: The No Man’s Land Between CD and IBS: The No Man’s Land of GS”of GS”

Associated Conditions (% risk)Associated Conditions (% risk)

• Autoimmune endocrine disordersAutoimmune endocrine disorders– Diabetes mellitus, type 1 (2-8% - highest in children)Diabetes mellitus, type 1 (2-8% - highest in children)– Thyroid disease (3%)Thyroid disease (3%)– Adrenal diseaseAdrenal disease

• Autoimmune connective tissue disordersAutoimmune connective tissue disorders– SjogrensSjogrens– RARA– LupusLupus

• Liver diseasesLiver diseases– PSCPSC– PBC (0-6%)PBC (0-6%)– Autoimmune hepatitis (3-6%)Autoimmune hepatitis (3-6%)– Autoimmune cholangitisAutoimmune cholangitis– Elevated AST/ALTElevated AST/ALT

Associated Conditions - Associated Conditions - continuedcontinued

• SkinSkin– Dermatitis herpetiformisDermatitis herpetiformis

• Other GIOther GI– Microscopic colitis (15-27%)Microscopic colitis (15-27%)– GI lymphomas and other cancersGI lymphomas and other cancers

• 3x risk of small bowel lymphomas in untreated CD3x risk of small bowel lymphomas in untreated CD• Risk falls to that of normal population after on gluten-free Risk falls to that of normal population after on gluten-free

diet for 5 yearsdiet for 5 years

• MiscellaneousMiscellaneous– IgA deficiencyIgA deficiency– IgA nephropathyIgA nephropathy– Down’s (3-12%)Down’s (3-12%)– Turner’sTurner’s

Diagnosis - LabsDiagnosis - Labs• tTG IgA antibody *** tTG IgA antibody ***

– Sensitive (95-98%)Sensitive (95-98%)– Specific (90-98%)Specific (90-98%)– Relatively less expensive ($11.20)Relatively less expensive ($11.20)– False negative – IgA deficiencyFalse negative – IgA deficiency– False positive – autoimmune diseases, liver False positive – autoimmune diseases, liver

disease, inflammatory bowel disease, CHFdisease, inflammatory bowel disease, CHF

• DGP IgG (deaminated gliadin DGP IgG (deaminated gliadin peptide) antibody – if IgA absentpeptide) antibody – if IgA absent

Diagnosis – Labs (cont.)Diagnosis – Labs (cont.)

• Endomysial antibodyEndomysial antibody– Sensitive (100%)Sensitive (100%)– Specific (90-97%)Specific (90-97%)– More expensive ($55.00)More expensive ($55.00)

• Gliadin antibodiesGliadin antibodies– Too non-specific and less sensitiveToo non-specific and less sensitive

• Genetic testing – HLA DQ2,8 ($187.45)Genetic testing – HLA DQ2,8 ($187.45)

Diagnosis - Small Bowel BiopsyDiagnosis - Small Bowel Biopsy

• Gold standardGold standard

• Disease can be patchyDisease can be patchy

• Findings not 100% specificFindings not 100% specific– Especially true of mild changes – NSAIDS, H. Especially true of mild changes – NSAIDS, H.

pylori, Crohn’s, gluten sensitivity (GS)pylori, Crohn’s, gluten sensitivity (GS)

TreatmentTreatment• Gluten free dietGluten free diet

– Don’t empirically try without diagnosis Don’t empirically try without diagnosis • IBS patients can feel some better off gluten tooIBS patients can feel some better off gluten too

• Needs life long commitment to diet if has sprueNeeds life long commitment to diet if has sprue

– Strict diet can decrease and even eliminate Strict diet can decrease and even eliminate increased risk of GI lymphomas and other GI increased risk of GI lymphomas and other GI cancerscancers

– Strict diet may help associated diseases as wellStrict diet may help associated diseases as well– Nutrition consult very importantNutrition consult very important

• EncouragementEncouragement

Difficulties of DietDifficulties of Diet• $ $

• Social/familySocial/family

• BoringBoring

• Tricky – additives,etcTricky – additives,etc

• Increase fat and calories to make Increase fat and calories to make interesting – weight gaininteresting – weight gain

• Nutrient and fiber deficientNutrient and fiber deficient

• Reduction of beneficial gut bacteriaReduction of beneficial gut bacteria

Follow Up After Dietary Follow Up After Dietary TreatmentTreatment• tTG in 6 months to see if normalizes – may tTG in 6 months to see if normalizes – may notnot

correlate with biopsies or symptomscorrelate with biopsies or symptoms

• F/U small bowel biopsy done after 6 months of F/U small bowel biopsy done after 6 months of gluten-free diet gluten-free diet ifif clinically clinically notnot doing well. Not doing well. Not critical if asymptomatic and tTG is negativecritical if asymptomatic and tTG is negative

• DEXA scanDEXA scan

• See someone on care team every year as well See someone on care team every year as well as nutritionist – more frequently if other as nutritionist – more frequently if other related associated diseases or if not doing related associated diseases or if not doing well.well.

Approach to Patients - Primary Approach to Patients - Primary CareCare• High index of suspicionHigh index of suspicion

– Typical symptomsTypical symptoms– Atypical presentations ***Atypical presentations ***– Associated diseases ***Associated diseases ***

• tTG blood test – check IgA level tootTG blood test – check IgA level too• If + send to GI for EGD and small bowel If + send to GI for EGD and small bowel

biopsiesbiopsies• Screening – not general mass screening but Screening – not general mass screening but

family relatives of patients with spruefamily relatives of patients with sprue– 11stst degree relatives (10-15% risk) degree relatives (10-15% risk)– 22ndnd degree relatives (2.6-5.5% risk) degree relatives (2.6-5.5% risk)

Challenging ScenariosChallenging Scenarios• Patient already on a gluten-free dietPatient already on a gluten-free diet

• False + tTGFalse + tTG

• Abnormal small bowel biopsy with Abnormal small bowel biopsy with negative tTGnegative tTG

What about the Patient What about the Patient already on a Gluten-free already on a Gluten-free Diet?Diet?• Accurate diagnosis of CD is importantAccurate diagnosis of CD is important

• Beneficial response to gluten-free diet Beneficial response to gluten-free diet does not make the diagnosis of CD – does not make the diagnosis of CD – overlap with IBS and GSoverlap with IBS and GS

• What to challenge with?What to challenge with?– Hopefully 4 slices of whole wheat bread/dHopefully 4 slices of whole wheat bread/d

• For how long?For how long?– 6 weeks and recheck tTG to see if now +6 weeks and recheck tTG to see if now +

Gluten Challenge Follow UpGluten Challenge Follow Up

• If tTG negative at 6 weeks, recheck at 3 If tTG negative at 6 weeks, recheck at 3 and 6 months and if no symptoms and tTG and 6 months and if no symptoms and tTG negative at 6 months likely does not have negative at 6 months likely does not have CDCD

• When to do small bowel biopsy?When to do small bowel biopsy?– When tTG becomes +When tTG becomes +

False Positive tTGFalse Positive tTG• Autoimmune diseasesAutoimmune diseases

• Liver diseaseLiver disease

• Inflammatory bowel diseaseInflammatory bowel disease

• CHFCHF

SolutionSolution: small bowel biopsy, ?genetic : small bowel biopsy, ?genetic testingtesting

Abnormal Small Bowel Biopsy Abnormal Small Bowel Biopsy with Negative tTGwith Negative tTG

• False negative tTG – really has celiac False negative tTG – really has celiac sprue (classic pathology)sprue (classic pathology)– IgA deficiencyIgA deficiency– Partially treated celiac sprue – takes proximal Partially treated celiac sprue – takes proximal

small bowel longer to heal than more distal small bowel longer to heal than more distal partsparts

• Other causes (non-classic pathology): Other causes (non-classic pathology): NSAIDS, Crohn’s, H. pylori, gluten NSAIDS, Crohn’s, H. pylori, gluten sensitivity (GS)sensitivity (GS)

When to Consider Genetic When to Consider Genetic TestingTesting• tTG unreliable – IgA deficiencytTG unreliable – IgA deficiency

• Patient off gluten and won’t go back on or Patient off gluten and won’t go back on or gets too sick if goes back ongets too sick if goes back on

• To avoid unnecessary endoscopyTo avoid unnecessary endoscopy– ChildrenChildren– + family history of celiac sprue but negative + family history of celiac sprue but negative

tTGtTG

Future TreatmentFuture Treatment• Alter gluten in wheat, barley, and rye to Alter gluten in wheat, barley, and rye to

make it less immunogenic: enzymes, make it less immunogenic: enzymes, bacterial fermentation, genetic bacterial fermentation, genetic manipulationmanipulation

• Oral enzymes to break down gluten – less Oral enzymes to break down gluten – less immunogenicimmunogenic

• Complexing gliadins in gut – decreases Complexing gliadins in gut – decreases gliadin digestiongliadin digestion

Future TreatmentFuture Treatment• Sealing tight junctionsSealing tight junctions

• Interfering with immune recognitionInterfering with immune recognition– tTG/DQ2/DQ8 inhibitorstTG/DQ2/DQ8 inhibitors

• Restoring immune tolerance toward glutenRestoring immune tolerance toward gluten– Vaccination with toxic gluten peptidesVaccination with toxic gluten peptides– Dermal inoculation with hookworm antigenDermal inoculation with hookworm antigen

• Biologic agents/bone marrow transplantsBiologic agents/bone marrow transplants