Ragnar Hanas, MD, PhD
Dept. of Pediatrics, Uddevalla, Sweden

 Common genetic backgroun d
(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 diabetes
Wahlberg J. Br J Nutrition 2006;95:603-08.
22;02 2R. Hanas, CWD 2006

Zonulin - keeping things in and out of order in the gut
90% of absorbed proteins are converted to peptides that the immune system will not react to
Endothelial cells
Blood vessel
The zonulin system
Cholera bacteria
Zot toxin
Zonulin
Tight junction
White blood cell
Intestine Blood vessel
Diarrhea!!
➠
Bacteria are flushed out
Intestine
Activated by:
Prematurity
Any bacteria
(even dead!)
Toxins
(food poisoning)
Radiation
Chemotherapy
Diarrhea!!
22;02 Fasano A. Gut 2001;49:159-62.
3R. Hanas, CWD 2006

Zonulin - role in CD and diabetes
Celiac disease Type 1 diabetes
Gliadin from gluten
Zonulin
Unknown substance
Cow ´s milk???
(insulin in milk)
Zonulin
➠
Gliadin is presented
➠
??
is presented to to immune system
➠
Susceptible persons produce antibodies immune system
➠ same persons!
22;02 Clemente, MG. Gut 2003;52:218-23. Tamara W. PNAS 2005;102:2916-21.
Tolerance?
Food allergy?
Autoimmune disease??
4R. Hanas, CWD 2006

Zonulin - role in the infant
The zonulin system Coeliac disease in Sweden
Cases per 1000 births
Food protein
Zonulin
Activated by:
Prematurity
Infancy?
3-6 months??
6
5
4
3
2
1
1975 1980 1985 1990 1995
Tolerance?
Official diet recommendations:
Food allergy?
Before 1982: Gluten from ~ 4
Autoimmune months, no strict rules disease??
1982: Gluten from 6 months
➠
Many substances are presented
1996: Gluten from 4 months, breast-feeding until 6 months to immune system
➠
Tolerance if presented in the right time window, i.e when breast-feeding
22;02 Ivarsson A. Arch Dis Child 2000;89:165-71.
5R. Hanas, CWD 2006

 Symptomatic disease 0.1-0.29% 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):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
Healthy siblings
Healthy children
4.3%
3.8%
0.69%
Healthy adults 0.45%
Sumnik Z. Eur J Pediatr 2005;164:9-12 (Czech Republic)
22;02 6R. Hanas, CWD 2006

Genetic background
CD definition
Silent disease
(relatives)
Others ?
DIAGNOSED
UNDIAGNOSED
Disease awareness
Diagnostic facilities
Gluten intake
Gastrointestinal infections
Others ?
 Most cases of CD are undiagnosed
22;02 Slide from E Schoeber 7R. Hanas, CWD 2006

Height
Weight
Typical symptoms:
 Chronic diarrhoea
 Failure to thrive
 Abdominal distension
8R. Hanas, CWD 2006 22;02

Height
Weight
Diagnosis:  Biopsy from intestinal cell wall lining with
Watson ´s capsule
 Premedication but not general anesthesia
9R. Hanas, CWD 2006 22;02

Secondary to malabsorption
 Anaemia due to iron deficiency
 Short stature, growth failure
 Bone loss (osteopenia)
 Recurrent abdominal pain
 Flatulence
 Fatty liver
22;02 10R. Hanas, CWD 2006

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)
22;02 11R. Hanas, CWD 2006

 Skin: Dermatitis herpetiformis
 Reduced fertility
Increased abortion rates
 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;287:1413-19.
22;02 12R. Hanas, CWD 2006

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)
22;02 Sanchez-Albisua I. Diabet Med 2005;22:1079-82..
13R. Hanas, CWD 2006

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
22;02 Cerutti F. Diabetes Care 2004;27:1294-8.
14R. Hanas, CWD 2006

 Gliadin antibodies in children < 2 years age
 TGA (transglutaminase antibodies) is a better test than EMA
(endomycial antibodies) in persons > 2 years age
22;02 Slide from E Schoeber 15R. Hanas, CWD 2006

22;02
We do most biopsies with the help of a gastroscope
16R. Hanas, CWD 2006

Gastroscope
Gullet
Stmall intestine
Lower stomach sphincter
(pylorus)
22;02
Normal intestinal lining
(mucosa)
Celiac disease
17R. Hanas, CWD 2006

DCCT
 The purpose of the villi is to increase the absorption area of the intestinal mucosa to ~ 200 square meters (~250 square yards)
22;02 18R. Hanas, CWD 2006

 When the villi are destroyed by celiac antibodies the absorption area decreases to ~ 2 square meters (~2 square yards)
22;02 19R. Hanas, CWD 2006

22;02
Normal Celiac disease
20R. Hanas, CWD 2006

 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
22;02 21R. Hanas, CWD 2006

 Decreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD
Mohn A. JPGN 2001;32:37-40.
22;02 Slide from E Schoeber 22R. Hanas, CWD 2006

 Increase in hypoglycemia 6 months before and up to 6 months after diagnosis
Mohn A. JPGN 2001;32:37-40.
22;02 Slide from E Schoeber 23R. Hanas, CWD 2006

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
22;02 Sanchez-Albisua I. Diabet Med 2005;22:1079-82..
24R. Hanas, CWD 2006

 Normal mortality in children, twofold increase in overall mortality in adults.
Logan, RFA Gastroenterology 1989;97:265.
 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;12:433-42.
22;02 25R. Hanas, CWD 2006

 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.
22;02 26R. Hanas, CWD 2006

Happy without celiac diet?
Switzerland:
 Classical celiac disease
– 1/1000
 ”Asymptomatic disease”
– 1/137
 Almost 1% of the population has celiac disease??!!
Swiss Med Weekly 2002;132:43-47
22;02 Slide from T Battelino 27R. Hanas, CWD 2006

Risks with the diet?
 Higher fat/carbohydrat e ratio in GFD which can be difficult for a person with diabetes
Am J Clin Nutr 2000;72:76-81.
 Change in body composition with increased body fat stores
Am J Clin Nutr 2000;72:76-81.
 Poor vitamin status in 50 % of patients on
GFD
Aliment Pharmacol Ther 2002;16:1333-9.
22;02 Slide from T Battelino 28R. Hanas, CWD 2006

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.
 The rats that did not get diabetes produced no diabetes antibodies.
22;02 Watts T. PNAS 2005;102:2916-21.
29R. Hanas, CWD 2006

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
22;02 30R. Hanas, CWD 2006

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?
22;02 31R. Hanas, CWD 2006