Celiac ManagementCeliac Management

Ragnar Hanas, MD, PhDRagnar Hanas, MD, PhDDept. of Pediatrics, Uddevalla, SwedenDept. of Pediatrics, Uddevalla, Sweden

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Why diabetes (type 1) and CD?Why diabetes (type 1) and CD?

Common Common genetic backgroungenetic backgroundd(HLA-marker DQ2, DQ8)(HLA-marker DQ2, DQ8)))

Both have Both have increased gut permeabilityincreased gut permeability (caused by a protein modulator called zonulin),(caused by a protein modulator called zonulin),present even in pre-diabetes (70%), present even in pre-diabetes (70%), several years before onset (in average 3.5 years).several years before onset (in average 3.5 years).Sapone A. Diabetes 2006;55:1443-49.Sapone A. Diabetes 2006;55:1443-49.

Early (< 3 months) introduction of glutenEarly (< 3 months) introduction of gluten increased risk of increased risk of developing diabetes 6- to 9-fold.developing diabetes 6- to 9-fold.Norris, JM. J Am Med Assoc 2003;290:1713-20. Ziegler AG. J Am Med Assoc 2003;290:1721-28.Norris, JM. J Am Med Assoc 2003;290:1713-20. Ziegler AG. J Am Med Assoc 2003;290:1721-28.

Late (> 6 months) introduction of glutenLate (> 6 months) introduction of gluten is a risk factor for is a risk factor for developing antibodies preceding diabetesdeveloping antibodies preceding diabetesWahlberg J. Br J Nutrition 2006;95:603-08.Wahlberg J. Br J Nutrition 2006;95:603-08.

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Zonulin - keeping things in and out of order in the Zonulin - keeping things in and out of order in the gutgut

Blood vesselBlood vessel IntestineIntestine

Endothelial Endothelial cellscells

Tight Tight junctionjunction

CholeraCholerabacteriabacteria

ZotZottoxintoxin

Diarrhea!!Diarrhea!!

➠ Bacteria are flushed out Bacteria are flushed out

The zonulin systemThe zonulin system

Blood vesselBlood vessel IntestineIntestine

ZonulinZonulin

Diarrhea!!Diarrhea!!

Activated by:Activated by:PrematurityPrematurityAny bacteriaAny bacteria(even dead!)(even dead!)ToxinsToxins(food (food poisoning)poisoning)RadiationRadiationChemotherapyChemotherapy

Fasano A. Gut 2001;49:159-62.Fasano A. Gut 2001;49:159-62.

90% of 90% of absorbed absorbed proteins are proteins are converted to converted to peptides that peptides that the immune the immune system will system will not react tonot react to

White White blood blood cellcell

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Type 1 diabetesType 1 diabetes

ZonulinZonulin

Zonulin - role in CD and diabetesZonulin - role in CD and diabetes

➠ GliadinGliadin is presented is presented to immune systemto immune system

➠ Susceptible persons produce antibodiesSusceptible persons produce antibodies

ZonulinZonulin

Gliadin Gliadin from from glutengluten

Celiac diseaseCeliac disease

➠ ???? is presented to is presented to immune systemimmune system

➠ same persons!same persons!Clemente, MG. Gut 2003;52:218-23. Tamara W. PNAS 2005;102:2916-21.Clemente, MG. Gut 2003;52:218-23. Tamara W. PNAS 2005;102:2916-21.

Tolerance?Tolerance?

Food allergy?Food allergy?

AutoimmuneAutoimmunedisease??disease??

Unknown Unknown substancesubstanceCow´s Cow´s milk???milk???(insulin in(insulin inmilk)milk)

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Zonulin - role in the infantZonulin - role in the infant

➠ Many substancesMany substances are presented are presented to immune systemto immune system

➠ Tolerance if presented in the right time window, i.e when breast-feedingTolerance if presented in the right time window, i.e when breast-feedingIvarsson A. Arch Dis Child 2000;89:165-71.Ivarsson A. Arch Dis Child 2000;89:165-71.

Tolerance?Tolerance?

Food allergy?Food allergy?

AutoimmuneAutoimmunedisease??disease??

The zonulin systemThe zonulin system

ZonulinZonulin

Activated by:Activated by:PrematurityPrematurityInfancy?Infancy?3-6 months??3-6 months?? 1975 1980 1985 1990 19951975 1980 1985 1990 1995

Cases per 1000 birthsCases per 1000 births

Coeliac disease in SwedenCoeliac disease in Sweden

665544332211

Official diet recommendations:Official diet recommendations:

Before 1982:Before 1982: Gluten from ~ 4 Gluten from ~ 4 months, no strict rulesmonths, no strict rules1982:1982: Gluten from 6 months Gluten from 6 months1996:1996: Gluten from 4 months, Gluten from 4 months, breast-feeding until 6 monthsbreast-feeding until 6 months

Food proteinFood protein

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How common is celiac disease (CD)?How common is celiac disease (CD)?

Symptomatic disease 0.1-0.29% in non-diabetes,Symptomatic disease 0.1-0.29% in non-diabetes,1-6.4% in persons with type 1 diabetes1-6.4% in persons with type 1 diabetes= 2-10 times the risk= 2-10 times the risk Schober E, Horm Res 2002;57(suppl 1):97-100. (Austria)Schober E, Horm Res 2002;57(suppl 1):97-100. (Austria)

Children with diabetesChildren with diabetes 4.3%4.3%Healthy siblingsHealthy siblings 3.8%3.8%Healthy childrenHealthy children 0.69%0.69%Healthy adultsHealthy adults 0.45%0.45%Sumnik Z. Eur J Pediatr 2005;164:9-12 (Czech Republic)Sumnik Z. Eur J Pediatr 2005;164:9-12 (Czech Republic)

491 persons with diabetes: 491 persons with diabetes: 5.7% antibody positive (AEA)5.7% antibody positive (AEA)1420 first-degree relatives: 1420 first-degree relatives: 1.9%1.9%4000 blood donors:4000 blood donors: 0.25%0.25% Not T. Diabetologia 2001;44:151-5. (Italy)

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The CD Iceberg ModelThe CD Iceberg Model

Most cases of CD are undiagnosedMost cases of CD are undiagnosed

UNDIAGNOSEDUNDIAGNOSED

DIAGNOSEDDIAGNOSED

Genetic backgroundGenetic background

CD definitionCD definition

Silent diseaseSilent disease(relatives)(relatives)

Others ?Others ?

Disease Disease awarenessawareness

Diagnostic Diagnostic facilitiesfacilities

Gluten intakeGluten intake

Gastrointestinal Gastrointestinal infectionsinfections

Others ?Others ?

Slide from E SchoeberSlide from E Schoeber

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Onset of celiac disease in first year of lifeOnset of celiac disease in first year of life

Chronic diarrhoeaChronic diarrhoea

Failure to thriveFailure to thrive

Abdominal distensionAbdominal distension

Typical Typical symptoms:symptoms:

Height

Weight

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Onset of celiac disease in first year of lifeOnset of celiac disease in first year of life

Biopsy from intestinal Biopsy from intestinal cell wall lining with cell wall lining with Watson´s capsuleWatson´s capsule

Premedication but not Premedication but not general anesthesiageneral anesthesia

Diagnosis:Diagnosis:

Height

Weight

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Atypical symptoms of celiac diseaseAtypical symptoms of celiac disease

Secondary to malabsorptionSecondary to malabsorption

Anaemia due to iron deficiencyAnaemia due to iron deficiency

Short stature, growth failureShort stature, growth failure

Bone loss (osteopenia)Bone loss (osteopenia)

Recurrent abdominal painRecurrent abdominal pain

FlatulenceFlatulence

Fatty liverFatty liver

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Atypical symptoms of celiac diseaseAtypical symptoms of celiac disease

Independent of malabsorptionIndependent of malabsorption

Dental enamel deficiencyDental enamel deficiency

Ataxia (unsteady gait)Ataxia (unsteady gait)

Alopecia (localised hair loss)Alopecia (localised hair loss)

InfertilityInfertility

Laboratory abnormalities (transaminases)Laboratory abnormalities (transaminases)

Recurrent aphthous stomatitisRecurrent aphthous stomatitis

Epilepsy (with or without calcifications on CT scan)Epilepsy (with or without calcifications on CT scan)

Polyneuropahty (peripheral neuronal disease)Polyneuropahty (peripheral neuronal disease)

Heart problems (dilative cardiomyopathy)Heart problems (dilative cardiomyopathy)

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CD and other diseasesCD and other diseases

Skin: Dermatitis herpetiformisSkin: Dermatitis herpetiformis

Reduced fertilityReduced fertilityIncreased abortion ratesIncreased abortion rates

Migraine: 4 patients experienced improvements in attacks and Migraine: 4 patients experienced improvements in attacks and CT showed normalization of brain uptake of tracers after dietCT showed normalization of brain uptake of tracers after dietGabrielli M. Am J Gastroenterol 2003;98:625-9.Gabrielli M. Am J Gastroenterol 2003;98:625-9.

Non-Hodgkin lymphoma (in persons > 20 years of age):Non-Hodgkin lymphoma (in persons > 20 years of age):0.92 % of patients with lymphoma had CD0.92 % of patients with lymphoma had CD0.42 % of patients in control group had CD0.42 % of patients in control group had CDCatassi C. JAMA 2002;287:1413-19.Catassi C. JAMA 2002;287:1413-19.

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Celiac disease - the clinical realityCeliac disease - the clinical reality

Tübingen, Germany: 281 patients, 1.4-25 yearsTübingen, Germany: 281 patients, 1.4-25 years

18 (6.4%) were positive for EMA, an additional 44 (15.7%) for 18 (6.4%) were positive for EMA, an additional 44 (15.7%) for gliadin antibodiesgliadin antibodies

18 (6.4%) were recommended biopsy18 (6.4%) were recommended biopsy

12 accepted biopsy12 accepted biopsy

8 had celiac disease8 had celiac disease

3 had abdominal symptoms, 2/3 better with diet3 had abdominal symptoms, 2/3 better with diet

3 had iron deficiency anemia, all better with diet3 had iron deficiency anemia, all better with diet

All had normal height and weight, but for those complying with All had normal height and weight, but for those complying with diet there was an increase in heightdiet there was an increase in height

HbA1c improved from 8% to 7.3% (p=0.05)HbA1c improved from 8% to 7.3% (p=0.05)

Sanchez-Albisua I. Diabet Med 2005;22:1079-82..Sanchez-Albisua I. Diabet Med 2005;22:1079-82..

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Celiac disease - the clinical realityCeliac disease - the clinical reality

Multicenter, Italy: 4332 patients, 1.4-25 yearsMulticenter, Italy: 4332 patients, 1.4-25 years

292 (6.8%) were biopsy confirmed CD292 (6.8%) were biopsy confirmed CD

Higher risk in girls (odds ratio ~2)Higher risk in girls (odds ratio ~2)

In 11%, CD was diagnosed before diabetesIn 11%, CD was diagnosed before diabetes

CD was 3 times more common in children < 4 years age, CD was 3 times more common in children < 4 years age, compared to > 9 yearscompared to > 9 years

Cerutti F. Diabetes Care 2004;27:1294-8.

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How do we suspect CD?How do we suspect CD?

Gliadin antibodies in children < 2 years ageGliadin antibodies in children < 2 years age

TGA (transglutaminase antibodies) is a better test than EMA TGA (transglutaminase antibodies) is a better test than EMA (endomycial antibodies) in persons > 2 years age(endomycial antibodies) in persons > 2 years age

Slide from E SchoeberSlide from E Schoeber

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Gastroscopic biopsy in childrenGastroscopic biopsy in children

We do most biopsies with the help of a gastroscopeWe do most biopsies with the help of a gastroscope

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Gastroscopic biopsyGastroscopic biopsy

Normal intestinal liningNormal intestinal lining(mucosa)(mucosa) Celiac diseaseCeliac disease

Lower stomach sphincterLower stomach sphincter(pylorus)(pylorus)

Gastro-Gastro-scopescope

GulletGullet

Stmall Stmall intestineintestine

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A healthy mucosa with villi (“fingers”)A healthy mucosa with villi (“fingers”)

DCCT

The purpose of the villi is to increase the absorption area of the The purpose of the villi is to increase the absorption area of the intestinal mucosa to ~ 200 square meters (~250 square yards)intestinal mucosa to ~ 200 square meters (~250 square yards)

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Flat mucosa from patient with celiac Flat mucosa from patient with celiac diseasedisease

When the villi are destroyed by celiac antibodies the absorption When the villi are destroyed by celiac antibodies the absorption area decreases to ~ 2 square meters (~2 square yards)area decreases to ~ 2 square meters (~2 square yards)

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The mucosa seen through a microscopeThe mucosa seen through a microscope

NormalNormal Celiac diseaseCeliac disease

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Follow-upFollow-up

Gluten-free dietGluten-free diet

AntibodiesAntibodies

New biopsyNew biopsy::< 2 years at diagnosis:< 2 years at diagnosis:

# 2 after 1 year of gluten-free diet# 2 after 1 year of gluten-free diet# 3 after provocation with gluten-containing diet# 3 after provocation with gluten-containing diet

> 2 years at diagnosis:> 2 years at diagnosis: No re-biopsy if antibodies disappear No re-biopsy if antibodies disappear on diet andon diet and the person is without symptoms the person is without symptoms

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HbA1c and insulin requirements in children HbA1c and insulin requirements in children

Decreased insulin requirements the year before diagnosis and Decreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD slight increase in HbA1c after GFD Mohn A. JPGN Mohn A. JPGN

2001;32:37-40.2001;32:37-40.

Hb

A1

cIn

sulin

, U

/kg

Slide from E SchoeberSlide from E Schoeber

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Hypoglycemia Hypoglycemia

Increase in hypoglycemia 6 months before and up to 6 months Increase in hypoglycemia 6 months before and up to 6 months after diagnosis after diagnosis Mohn A. JPGN Mohn A. JPGN

2001;32:37-40.2001;32:37-40. Slide from E SchoeberSlide from E Schoeber

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Celiac disease - what happens in the long Celiac disease - what happens in the long run?run?

Cork, Ireland: 28-year follow-up of 50 adults with childhood Cork, Ireland: 28-year follow-up of 50 adults with childhood diagnosis of CD (not diabetes)diagnosis of CD (not diabetes)

CD for 22-45 yearsCD for 22-45 years

Diet: Diet: 50% fully compliant50% fully compliant18% partially compliant18% partially compliant32% not adhering to diet32% not adhering to diet

Motivation:Motivation: Avoidance of symptoms rather than avoidance of Avoidance of symptoms rather than avoidance of complicationscomplications

Iron deficiency:Iron deficiency: 86% of women, 21% of males 86% of women, 21% of males

Bone mineral density:Bone mineral density: Normal in 68% Normal in 68%2.6% osteoporosis2.6% osteoporosis

Quality of lifeQuality of life scores were normal scores were normal

Sanchez-Albisua I. Diabet Med 2005;22:1079-82..Sanchez-Albisua I. Diabet Med 2005;22:1079-82..

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Long-term health risks in untreated CDLong-term health risks in untreated CD

Persons withPersons with osteoporosisosteoporosis (and no other disease) (and no other disease) have more CD than in the general population.have more CD than in the general population.

Lindh, E J.Intern.Med.1992;231:403Lindh, E J.Intern.Med.1992;231:403

Reduced Reduced bone mineralizationbone mineralization in asymptomatic CD patients. in asymptomatic CD patients. Mazure, R Am.J.Gastroenterol 1994;89:2130Mazure, R Am.J.Gastroenterol 1994;89:2130

Bone densityBone density and metabolism normal after long-term GFD in and metabolism normal after long-term GFD in young young persons with CD.persons with CD. Mora, S Mora, S

Am.J.Gastroenterol.1999;94:389Am.J.Gastroenterol.1999;94:389

Normal Normal mortalitymortality in children, twofold increase in overall in children, twofold increase in overall mortality in adults. mortality in adults. Logan, RFA Gastroenterology 1989;97:265.Logan, RFA Gastroenterology 1989;97:265.

Only 30% of children and adolescents complied with a strict Only 30% of children and adolescents complied with a strict gluten-free diet, but gluten-free diet, but growth parametersgrowth parameters were unaffected by were unaffected by dietary compliance. dietary compliance. Westman E. JPEM 1999Westman E. JPEM 1999;;1212::433433--

42.42.

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Cancer risks in untreated CDCancer risks in untreated CD

The risk of developing cancer is not The risk of developing cancer is not increased when compared with the increased when compared with the general population in celiac patients who general population in celiac patients who have taken a GFD for five years or more. have taken a GFD for five years or more. Holmes, GKT. Gut 1989;30:333.Holmes, GKT. Gut 1989;30:333.

Ten cases of lymphoma were found in Ten cases of lymphoma were found in Switzerland, 5 with malabsorption but Switzerland, 5 with malabsorption but none had diabetes.none had diabetes.Lang-Muritano M. Pediatric Diabetes 2002;3:42-45.Lang-Muritano M. Pediatric Diabetes 2002;3:42-45.

Calculated risk:Calculated risk:1/8,000 persons with diabetes will get lymphoma over 60 1/8,000 persons with diabetes will get lymphoma over 60 years – years – do these have untreated CD?do these have untreated CD?Lang-Muritano M. Pediatric Diabetes 2002;3:42-45.Lang-Muritano M. Pediatric Diabetes 2002;3:42-45.

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Happy without celiac diet?Happy without celiac diet?

Switzerland: Switzerland:

Classical celiac disease Classical celiac disease – 1/1000– 1/1000

””Asymptomatic disease”Asymptomatic disease” – 1/137 – 1/137

Almost 1% of the population Almost 1% of the population has celiac disease??!!has celiac disease??!!

Swiss Med Weekly 2002;132:43-47Swiss Med Weekly 2002;132:43-47

Slide from T BattelinoSlide from T Battelino

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Risks with the diet?Risks with the diet?

Higher Higher fat/carbohydratfat/carbohydrate ratio in GFD which e ratio in GFD which can be difficult for a person with diabetescan be difficult for a person with diabetes Am J Clin Nutr 2000;72:76-81.Am J Clin Nutr 2000;72:76-81.

Change in Change in body compositionbody composition with increased with increased body fat storesbody fat stores Am J Clin Nutr 2000;72:76-81.Am J Clin Nutr 2000;72:76-81.

Poor Poor vitamin statusvitamin status in 50 % of patients on in 50 % of patients on GFDGFD Aliment Pharmacol Ther 2002;16:1333-9.Aliment Pharmacol Ther 2002;16:1333-9.

Slide from T BattelinoSlide from T Battelino

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Can CD be treated with drugs??Can CD be treated with drugs??

In diabetes-prone rats, intestinal production of In diabetes-prone rats, intestinal production of zonulin increased at age 50 days.zonulin increased at age 50 days.

This resulted in a decreased intestinal barrier This resulted in a decreased intestinal barrier functionfunction

Diabetes antibodies appeared after 2-3 weeksDiabetes antibodies appeared after 2-3 weeks

This was followed by high blood glucose This was followed by high blood glucose levels and clinical diabeteslevels and clinical diabetes

Blocking the zonulin receptorBlocking the zonulin receptordecreased diabetes by 70% in spite of decreased diabetes by 70% in spite of continued high release of zonulin into the continued high release of zonulin into the intestine.intestine.

The rats that did not get diabetes produced no The rats that did not get diabetes produced no diabetes antibodiesdiabetes antibodies..Watts T. PNAS 2005;102:2916-21.

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To screen or not to screen for CD?To screen or not to screen for CD?

YesYes

Most cases asymptomaticMost cases asymptomaticGFD eliminates most symptomsGFD eliminates most symptomsSeveral health risks if untreatedSeveral health risks if untreatedIncreased cancer risk over a lifetime if untreatedIncreased cancer risk over a lifetime if untreated

NoNo

Difficult diet that many do not follow strictly anywayDifficult diet that many do not follow strictly anywayDoes a GFD really prevent cancer?Does a GFD really prevent cancer?

Our routinesOur routines

First screening 6-12 months after diagnosisFirst screening 6-12 months after diagnosis

Repeated every 2-3 years and if there are Repeated every 2-3 years and if there are symptomssymptoms

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Celiac disease and diabetes – open questionsCeliac disease and diabetes – open questions

Whom to screen?Whom to screen?

When to screen? When to screen?

How often and for how long to screen?How often and for how long to screen?

Is a second biopsy necessary, or can we rely on Is a second biopsy necessary, or can we rely on antibody results?antibody results?

What is the natural course of potential or silent CDWhat is the natural course of potential or silent CD(positive antibodies, positive biopsy)(positive antibodies, positive biopsy)??

Shall patients with latent or potential CD Shall patients with latent or potential CD (positive antibodies, (positive antibodies, negative first biopsy) negative first biopsy) have repeated biopsies?have repeated biopsies?

How How do wedo we improve acceptance of GFD and compliance to improve acceptance of GFD and compliance to GFDGFD??