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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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Slide1 l.jpg

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

Cholera

bacteria

Zonulin

Zot

toxin

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

Tight

junction

White blood cell

Blood vessel Intestine

Diarrhea!!➠ Bacteria are flushed out

Diarrhea!!

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

Endothelial

cells

Activated by:PrematurityAny bacteria(even dead!)

Toxins

(food poisoning)Radiation

Chemotherapy

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

Zonulin

➠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)

Zonulin

Tolerance?

Food allergy?

Autoimmunedisease??

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

654321

Zonulin

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??

Tolerance?

Food allergy?

Autoimmunedisease??

➠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.


How common is celiac disease cd l.jpg
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)


The cd iceberg model l.jpg
The CD Iceberg Model

DIAGNOSED

Disease awareness

Diagnostic facilities

Gluten intake

Gastrointestinal infections

Others ?

Genetic background

CD definition

Silent disease(relatives)

Others ?

UNDIAGNOSED

  • 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

Height

Weight


Onset of celiac disease in first year of life9 l.jpg
Onset of celiac disease in first year of life

Height

Weight

Diagnosis:

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

  • Premedication but not general anesthesia


Atypical symptoms of celiac disease l.jpg
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


Atypical symptoms of celiac disease11 l.jpg
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)


Cd and other diseases l.jpg
CD and other diseases

  • Skin: Dermatitis herpetiformis

  • Reduced fertilityIncreased abortion rates

Lymfom

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.


Celiac disease the clinical reality l.jpg
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..


Celiac disease the clinical reality14 l.jpg
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.


How do we suspect cd l.jpg
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


Gastroscopic biopsy in children l.jpg
Gastroscopic biopsy in children

We do most biopsies with the help of a gastroscope


Gastroscopic biopsy l.jpg

Normal intestinal lining(mucosa)

Lower stomach sphincter(pylorus)

Celiac disease

Gastroscopic biopsy

Gullet

Gastro-

scope

Stmall

intestine


A healthy mucosa with villi fingers l.jpg
A healthy mucosa with villi (“fingers”)

DCCT

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


Flat mucosa from patient with celiac disease l.jpg
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)



Follow up l.jpg
Follow-up

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

HbA1c

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


Hypoglycemia l.jpg
Hypoglycemia

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


Celiac disease what happens in the long run l.jpg
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..


Long term health risks in untreated cd l.jpg
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.


Cancer risks in untreated cd l.jpg
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.


Happy without celiac diet l.jpg
Happy without celiac diet?

Switzerland:

  • 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


Risks with the diet l.jpg
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


Can cd be treated with drugs l.jpg
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.


To screen or not to screen for cd l.jpg
To screen or not to screen for CD?

Yes

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

No

  • 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


Celiac disease and diabetes open questions l.jpg
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?