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Celiac Management. Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden. Why diabetes (type 1) and CD?. Allt från Schober. Common genetic backgroun d (HLA-marker DQ2, DQ8) )

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Celiac Management

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

Why diabetes type 1 and cd l.jpg
Why diabetes (type 1) and CD?

Allt från Schober

  • Common genetic background(HLA-marker DQ2, DQ8))

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

  • Early (< 3 months) introduction of gluten increased risk of 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.

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

Zonulin keeping things in and out of order in the gut l.jpg

The zonulin system






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



White blood cell

Blood vessel Intestine

Diarrhea!!➠ Bacteria are flushed out


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



Activated by:PrematurityAny bacteria(even dead!)


(food poisoning)Radiation


Blood vessel Intestine

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

Zonulin role in cd and diabetes l.jpg

Type 1 diabetes

Unknown substanceCow´s milk???(insulin inmilk)

Gliadin from gluten


➠Gliadin is presented to immune system

➠ Susceptible persons produce antibodies

➠?? is presented to immune system

➠ same persons!

Zonulin - role in CD and diabetes

Celiac disease

Gliadin enters lamina propria, is deaminated by tissue transglutamase and recognized by antigen presenting cells in HLA-DQ2/DQ8 individuals (Clemente)



Food allergy?


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

Zonulin role in the infant l.jpg

Coeliac disease in Sweden

Cases per 1000 births



1975 1980 1985 1990 1995

Official diet recommendations:

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

Zonulin - role in the infant

The zonulin system

Food protein

Activated by:PrematurityInfancy?

3-6 months??


Food allergy?


➠Many substances are presented to immune system

➠ Tolerance if presented in the right time window, i.e when breast-feeding

Ivarsson A. Arch Dis Child 2000;89:165-71.

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How common is celiac disease (CD)?

Allt från Schober

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

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

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

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The CD Iceberg Model


Disease awareness

Diagnostic facilities

Gluten intake

Gastrointestinal infections

Others ?

Genetic background

CD definition

Silent disease(relatives)

Others ?


  • Most cases of CD are undiagnosed

Slide from E Schoeber

Onset of celiac disease in first year of life l.jpg

Typical symptoms:

  • Chronic diarrhoea

    à Failure to thrive

    à Abdominal distension

Onset of celiac disease in first year of life



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Onset of celiac disease in first year of life




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

  • Premedication but not general anesthesia

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Atypical symptoms of celiac disease

Secondary to malabsorption

  • Anaemia due to iron deficiency

  • Short stature, growth failure

  • Bone loss (osteopenia)

  • Recurrent abdominal pain

  • Flatulence

  • Fatty liver

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Atypical symptoms of celiac disease

Independent of malabsorption

  • Dental enamel deficiency

  • Ataxia (unsteady gait)

  • Alopecia (localised hair loss)

  • Infertility

  • Laboratory abnormalities (transaminases)

  • Recurrent aphthous stomatitis

  • Epilepsy (with or without calcifications on CT scan)

  • Polyneuropahty (peripheral neuronal disease)

  • Heart problems (dilative cardiomyopathy)

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CD and other diseases

  • Skin: Dermatitis herpetiformis

  • Reduced fertilityIncreased abortion rates


20-92 år, 653 pat.

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

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

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Celiac disease - the clinical reality

Tübingen, Germany: 281 patients, 1.4-25 years

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

  • 18 (6.4%) were recommended biopsy

  • 12 accepted biopsy

  • 8 had celiac disease

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

  • 3 had iron deficiency anemia, all better with diet

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

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

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

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Celiac disease - the clinical reality

Multicenter, Italy: 4332 patients, 1.4-25 years

  • 292 (6.8%) were biopsy confirmed CD

  • Higher risk in girls (odds ratio ~2)

  • In 11%, CD was diagnosed before diabetes

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

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

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How do we suspect CD?

ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;143-145

  • Gliadin antibodies in children < 2 years age

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

Slide from E Schoeber

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Gastroscopic biopsy in children

We do most biopsies with the help of a gastroscope

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Normal intestinal lining(mucosa)

Lower stomach sphincter(pylorus)

Celiac disease

Gastroscopic biopsy






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A healthy mucosa with villi (“fingers”)


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

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Flat mucosa from patient with celiac disease

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

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ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;143-145

  • Gluten-free diet

  • Antibodies

  • New biopsy:< 2 years at diagnosis: # 2 after 1 year of gluten-free diet # 3 after provocation with gluten-containing diet

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

Hba1c and insulin requirements in children l.jpg


Insulin, U/kg

HbA1c and insulin requirements in children

18 CD & 26 controls

  • Decreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD Mohn A. JPGN 2001;32:37-40.

Slide from E Schoeber

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18 CD & 26 controls

  • Increase in hypoglycemia 6 months before and up to 6 months after diagnosis Mohn A. JPGN 2001;32:37-40.

Slide from E Schoeber

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Celiac disease - what happens in the long run?

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

  • CD for 22-45 years

  • Diet: 50% fully compliant 18% partially compliant 32% not adhering to diet

  • Motivation: Avoidance of symptoms rather than avoidance of complications

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

  • Bone mineral density: Normal in 68% 2.6% osteoporosis

  • Quality of life scores were normal

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

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Long-term health risks in untreated CD

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

ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;143-145

  • Persons withosteoporosis (and no other disease) have more CD than in the general population.Lindh, E J.Intern.Med.1992;231:403

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

  • Bone density and metabolism normal after long-term GFD in young persons with CD.Mora, S Am.J.Gastroenterol.1999;94:389

  • Only 30% of children and adolescents complied with a strict gluten-free diet, but growth parameters were unaffected by dietary compliance. Westman E. JPEM 1999;12:433-42.

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Cancer risks in untreated CD

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

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

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

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Happy without celiac diet?


  • Classical celiac disease – 1/1000

    à ”Asymptomatic disease” – 1/137

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

Swiss Med Weekly 2002;132:43-47

Slide from T Battelino

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Risks with the diet?

  • Higher fat/carbohydrate ratio in GFD which can be difficult for a person with diabetesAm J Clin Nutr 2000;72:76-81.

    à Change in body composition with increased body fat storesAm J Clin Nutr 2000;72:76-81.

    à Poor vitamin status in 50 % of patients on GFDAliment Pharmacol Ther 2002;16:1333-9.

Slide from T Battelino

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Can CD be treated with drugs??

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

  • This resulted in a decreased intestinal barrier function

  • Diabetes antibodies appeared after 2-3 weeks

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

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

    à The rats that did not get diabetes produced no diabetes antibodies.

Watts T. PNAS 2005;102:2916-21.

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To screen or not to screen for CD?


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


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

Our routines

  • First screening 6-12 months after diagnosis

  • Repeated every 2-3 years and if there are symptoms

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Celiac disease and diabetes – open questions

  • Whom to screen?

  • When to screen?

  • How often and for how long to screen?

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

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

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

  • How do we improve acceptance of GFD and compliance to GFD?