1. Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden
Celiac Management
Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

2. 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:
Early (< 3 months) introduction of gluten increased risk of developing diabetes 6- to 9-fold. Norris, JM. J Am Med Assoc 2003;290: Ziegler AG. J Am Med Assoc 2003;290:
Late (> 6 months) introduction of gluten is a risk factor for developing antibodies preceding diabetes Wahlberg J. Br J Nutrition 2006;95:
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

3. Zonulin - keeping things in and out of order in the gut
Endothelial
cells
The zonulin system
Blood vessel Intestine
Zonulin
Cholera
bacteria
90% of absorbed proteins are converted to peptides that the immune system will not react to
Zot
toxin
Activated by: Prematurity Any bacteria (even dead!)
Toxins
(food poisoning) Radiation
Chemotherapy
Tight
junction
White blood cell
Blood vessel Intestine
Diarrhea!! ➠ Bacteria are flushed out
Diarrhea!!
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Fasano A. Gut 2001;49:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

4. Zonulin - role in CD and diabetes
Celiac disease
Type 1 diabetes
Zonulin
Unknown substance Cow´s milk??? (insulin in milk)
Gliadin from gluten
Gliadin enters lamina propria, is deaminated by tissue transglutamase and recognized by antigen presenting cells in HLA-DQ2/DQ8 individuals (Clemente)
➠ Gliadin is presented to immune system
➠ Susceptible persons produce antibodies
➠ ?? is presented to immune system
➠ same persons!
Zonulin
Tolerance?
Food allergy?
Autoimmune disease??
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Clemente, MG. Gut 2003;52: Tamara W. PNAS 2005;102:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

5. Zonulin - role in the infant
Cases per 1000 births
Coeliac disease in Sweden
The zonulin system
Food protein
Zonulin
Official diet recommendations:
Before 1982: Gluten from ~ 4 months, no strict rules 1982: Gluten from 6 months 1996: Gluten from 4 months, breast-feeding until 6 months
Activated by: Prematurity Infancy?
3-6 months??
Tolerance?
Food allergy?
Autoimmune disease??
➠ Many substances are presented to immune system
➠ Tolerance if presented in the right time window, i.e when breast-feeding
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Ivarsson A. Arch Dis Child 2000;89:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

6. How common is celiac disease (CD)?
Allt från Schober
Symptomatic disease % in non-diabetes, 1-6.4% in persons with type 1 diabetes = 2-10 times the risk Schober E, Horm Res 2002;57(suppl 1): (Austria)
491 persons with diabetes: 5.7% antibody positive (AEA) 1420 first-degree relatives: 1.9% 4000 blood donors: % Not T. Diabetologia 2001;44: (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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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

7. The CD Iceberg Model DIAGNOSED Disease awareness Genetic background
Diagnostic facilities
Gluten intake
Gastrointestinal infections
Others ?
Genetic background
CD definition
Silent disease (relatives)
Others ?
UNDIAGNOSED
Most cases of CD are undiagnosed
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Slide from E Schoeber
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

8. Onset of celiac disease in first year of life
Chronic diarrhoea
à Failure to thrive
à Abdominal distension
Typical symptoms:
Height
Weight
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

9. 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
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

10. 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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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

11. 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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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

12. CD and other diseases Skin: Dermatitis herpetiformis
Reduced fertility Increased 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 diet Gabrielli M. Am J Gastroenterol 2003;98:625-9.
Non-Hodgkin lymphoma (in persons > 20 years of age): 0.92 % of patients with lymphoma had CD 0.42 % of patients in control group had CD Catassi C. JAMA 2002;287:
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

13. Celiac disease - the clinical reality
Tübingen, Germany: 281 patients, 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)
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Sanchez-Albisua I. Diabet Med 2005;22:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

14. Celiac disease - the clinical reality
Multicenter, Italy: 4332 patients, 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
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Cerutti F. Diabetes Care 2004;27:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

15. How do we suspect CD? Gliadin antibodies in children < 2 years age
ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;
Gliadin antibodies in children < 2 years age
TGA (transglutaminase antibodies) is a better test than EMA (endomycial antibodies) in persons > 2 years age
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Slide from E Schoeber
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

16. Gastroscopic biopsy in children
We do most biopsies with the help of a gastroscope
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

17. Gastroscopic biopsy Gullet Gastro- scope
Lower stomach sphincter (pylorus)
Stmall
intestine
Normal intestinal lining (mucosa)
Celiac disease
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

18. 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)
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

19. 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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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

20. The mucosa seen through a microscope
Normal Celiac disease
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

21. Follow-up Gluten-free diet Antibodies
ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;
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 disappear on diet and the person is without symptoms
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

22. HbA1c and insulin requirements in children
18 CD & 26 controls
HbA1c
Insulin, U/kg
Decreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD Mohn A. JPGN 2001;32:37-40.
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Slide from E Schoeber
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

23. 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.
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Slide from E Schoeber
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

24. 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 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
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Sanchez-Albisua I. Diabet Med 2005;22:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

25. 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;
Persons with osteoporosis (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:
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

26. 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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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

27. 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
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Slide from T Battelino
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

28. Risks with the diet?
Higher fat/carbohydrate ratio in GFD which can be difficult for a person with diabetes Am J Clin Nutr 2000;72:76-81.
à Change in body composition with increased body fat stores Am J Clin Nutr 2000;72:76-81.
à Poor vitamin status in 50 % of patients on GFD Aliment Pharmacol Ther 2002;16:
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Slide from T Battelino
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

29. 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 receptor decreased 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.
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Watts T. PNAS 2005;102:
CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

30. To screen or not to screen for CD?
Yes
Most cases asymptomatic GFD eliminates most symptoms Several health risks if untreated Increased cancer risk over a lifetime if untreated No
Difficult diet that many do not follow strictly anyway Does 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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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

31. 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?
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CWD, Orlando R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden