Nutritional Science Research: Celiac Disease & Risk of Subsequent Type I Diabetes

1. Celiac Disease and Risk
of Subsequent Type I
Diabetes: A general
population cohort study
of children and
adolescents
Journal of Diabetes Care
Mike Schiemer and Ryan Blaney

2. Celiac Disease
• Aka: Gluten Intolerance
• Not to be confused with a wheat allergy, body
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reacts to wheat protein only
Autoimmune Disease of small bowel
Reaction to gliadin, a gluten protein found in
wheat and hybrid wheat/rye Triticeae proteins,
some also react to oats due to crosscontamination with gluten containing products
Occurs in about 1% of North American and
European populations but increasing reports due
to screening asymptomatic individuals

3. Cell-mediated Immune Responses
• Upon exposure to gliadin, the
enzyme tissue transglutaminase
modifies the protein and immune
system cross-reacts with bowel
tissue, creating inflammation
• leads to flattening of the lining of
the small intestine, significantly
reducing nutrient absorption.

4. Symptoms of Celiac Disease
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Often diagnosed as IBS before proper screening
Diarrhoea or constipation
Weight Loss
Stunted Growth in Children
Fatigue
Primarily a bowel disease but these symptoms may be limited or
absent
Older children and adults have malabsorptive problems and
anaemia due to reduced iron absorption
Abdominal pain, cramping, bloating, abdominal distention due to
gas production
Mouth ulcers may be present
Lactose intolerance can develop as symptoms worsen
Longstanding disease may cause ulcering of the small bowels or
stricturing (narrowing due to scarring)

5. Malabsorption-Related
Problems
• Fatigue or lack of energy due to carbohydrate
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and fat malabsorption
Reduced Vitamin D and Calcium absorption may
lead to osteopenia or osteoporosis.
10% of those with Celiac have coagulation
problems due to decreased Vitamin K absorption
Can potentially cause bacterial overgrowth of
small intestine leading to further malabsorption
even after treatment

6. Diagnosis
• All tests lose there usefullness if patient consuming a
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gluten-free diet
Intestinal damage begins to heal within weeks of gluten
being removed from the diet, and antibody levels decline
over months, if no gluten consumed a 10g per day intake
will elicit a proper diagnosis
Serology by blood test is 98% effective, all positive blood
tests must be followed by endoscopic examination and a
biopsy of 4-8 sites in duodenum to be 100% sure
Blood tests detect IgA against endomysium or tissue
transglutaminase
Some experts also require or encourage blood tests for
electrolyte, calcium, liver enzymes, vitamin B12, and folic
acid levels. Coagulation testing for Vitamin K deficiency,
bone scan for checking Vitamin D or calcium deficiencies

7. Pathology determined by the "Marsh classification”:
• Marsh stage 0: Normal mucosa
• Marsh stage 1: Increased number of intra-epithelial
lymphocytes
• Marsh stage 2: Proliferation of the crypts of Lieberkuhn
• Marsh stage 3: Partial or complete villous atrophy
• Marsh stage 4: Hypoplasia of small bowel architecture

8. Prophylaxis/Treatment
• One study suggested that exposure to wheat,
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barley, or rye before full GI development caused five
times the risk over those exposed at 4 to 6 months
Another study contradicts these results and shows
early exposure can be protective to disease
development
Breastfeeding may also reduce risk significantly for
the first 6 months before gluten exposure
Only real “cure” is the preventative measure of a
lifelong diet avoiding gluten although some major
symptoms may still occur even with strict dieting
Now there is a much higher selection of gluten-free
foods at supermarkets, restaurants, etc.

9. Introduction
• Looks at incidence of type 1 diabetes
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diagnosis prior to celiac diagnosis.
Previous studies looked at prevalence of
opposite scenario
Focused on children diagnosed before the
age of 20.
Hypothesized that prior celiac diagnosis will
result in significant increased risk for type 1
diabetes

10. Introduction
• Majority of individuals with celiac disease exhibit
HLA-DQ2, with a smaller group being positive for
HLA-DQ8
• Studies have proven that children with diabetes
are at increase risk for celiac disease (5 to 10 fold
risk increased for celiac)
• It has also been suggested that early gluten
introduction may be a common risk factor for both
diseases.
• Cronin and Shanahan have demonstrated that
some 15% of individuals with both diseases may
first receive diagnosis of celiac disease.

11. Introduction
• This study did not give incidence ratios
• It was unclear if individuals with type 1
diabetes and simultaneously diagnosed
with celiac disease were included.

12. Introduction
• The main objective was to estimate the
association of celiac disease with subsequent type
1 diabetes (before 20yoa) p=9,243 with celiac
disease compared with 45,680 age + sex matched
individuals without celiac disease
• The second objective was to study the risk of type
1 diabetes stratified for age at diagnosis of celiac
disease.
• Hypothesis: celiac disease diagnosed at early age
and consequent early introduction of gluten-free
diet would be associated with a lower risk of type
1 diabetes.

13. Research/Methods
• Approved by research ethics committee of Karolinska
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Institute.
No participants contacted, information was made
anonymous before analysis
Used hospital inpatient diagnosis of celiac disease
between 1964 and 2003 through Sweedish national
inpatient register.
Celiac diagnosed by various ICD codes.
For each individual with celiac disease, Statistics Sweden
indentified up to five reference individuals matched for age,
sex, calendar, year, and area of residence at time of
diagnosis
Restricted measurements to individuals diagnosed with
type 1 diabetes before age of 20.

14. Methods
• Follow up time began 1 year after study entry.
• Ended on the date of first discharge diagnosis of
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type 1 diabetes, emigration, death, or age 20 years
Identified 9,733 individuals with celiac disease
between 1964 and 2003
Excluded 233 individuals with type 1 diabetes
diagnosed before celiac disease.
Study based upon 9,243 individuals with celiac
disease diagnosed before 20yo and 45,680 age,
period, and sex matched individuals without celiac
disease
All participants were type 1 free at start of follow up

15. Methods
• Used cox regression to estimate association of celiac disease
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with type 1 diabetes.
Estimated the risk of ketoacidosis before age 20 years.
Individuals only compared with matched reference individuals
Stratification for sex and age was chosen <2 or 3 years to
maximize study power
Individuals diagnosed with celiac disease between 0-1yo
were used as the reference category and compared with
those between 1 and <2yo
At a significance level of 5% the study had an 80% power to
detect an increased risk of subsequent type 1 diabetes.

16. Results
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Median age was 1 year (range 0-19).
Majority was female.
Median age at first diabetes diagnosis was
10 years (2-19)
• The median duration from diagnosis of
celiac to diagnosis of diabetes was 8.1
years

17. Table 1
Atopic
Dermatitis of
the Arm
(celiac
patient)

18. Results
• Children with celiac disease were at increased risk
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of type one diabetes (based upon 300 positive
results)
Age of first celiac diagnosis displayed no
significance to subsequent diagnosis of diabetes
(p=.211)
Risk estimates after stratification for age at
diagnosis and sex were similar to risk estimates
for type 1 diabetes before age of 20.
Individuals with celiac disease were at a
significantly increased risk of subsequent
ketoacidosis. (based upon 13 positive results)
Results were only significant for females

19. Conclusion
• The study found a statistically significant positive
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association of celiac disease with subsequent type 1
diabetes and with ketoacidosis before the age of 20.
There was no statistically significant difference in risk of
subsequent type 1 diabetes between individuals with a
diagnosis of celiac disease at 0-2 years and those
diagnosed after 2 years of age.
To knowledge of authors, there exists only one previous
similar study though no incidence ratios were given.
The significance of the studies results is only further
enhanced by the use of several reference individuals for
each of the studied individuals.
The large population provided high statistical power and
allowed for sub analysis.

20. Table 2

21. Conclusion
• Increased risk of diabetes was seen (300 cases) 2-3 fold greater
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than reference individuals
Could be attributed to various factors such as environmental or
genetic susceptibility.
Gluten is a necessary trigger for celiac disease so feeding pattern
may have been a factor.
Daisy and BABY DIAB studies found a four to fivefold increase risk
in children exposed to gluten before age of 4 months.
Risk estimates were substantially lower than prior findings of
diabetes diagnosis followed by celiac disease
An explanation could be that those with more severe autoimmune
disease have an earlier symptomatic onset of type 1 diabetes.
An alternative explanation is that the inflammation associated with
celiac disease remained for a period after diagnosis.
No strong evidence suggested that early diagnosis of celiac disease
could help protect against type 1 diabetes

22. Conclusion
• The association could be a result of shared HLA characteristics
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or an interaction between food introduction and genetic
susceptibility.
Approximately 1/3rd of celiac patients are positive for HLA-DQ2
and this is a positive risk factor for type 1 diabetes so the
increased risk could be attributed entirely to HLA characteristics.
False negative celiac disease is unlikely since <1% of reference
population should be affected by celiac disease.
All children in Sweden are hospitalized upon diagnosis of type 1
diabetes so sensitivity to diabetes should be high in this study.
In conclusion, the cohort study found a 2-3fold risk increase of
type 1 diabetes before age of 20. Shared nutritional factors and
common HLA profiles may explain the significance.
The risk increase for type 1 diabetes is low considering that 95%
of individuals with celiac disease are HLA-DQ2 positive.

23. Experiment Critique
• Family history of subjects not taken into account
• Many subjects taken from decades ago and the
diagnosis of type 1 diabetes may have been
inconsistent with rates from the last few years
• Study isolated to a set of hospital records in
Sweden, primarily Caucasian and middle class.
• Subjects were anonymous so there was no telling
what these subjects diet consisted of.
• Also the prevalence of celiac disease within the
subjects siblings and parents could not be noted.

24. Further Experimentation
• Use more current records to account for
present day type 1 diabetes diagnosis,
compare rate of increased susceptibility
from this study to a current one
• Focus on other geographical or
demographical areas
• Take more detailed records of subjects to
determine secondary variables that could
account for different results

25. Works Cited
• Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, Eisenbarth GS: One
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third of HLA DQ2 homozygous patients with type 1 diabetes express celiac
disease-associated transglutaminase autoantibodies. ] Autoimmun 13:143-148,
1999.
Dube C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, Sampson M,
Zhang L, Yazdi F, Mamaladze V, Pan I, Macneil J, Mack D, Patel D, Moher D:
The prevalence of celiac disease in average-risk and at-risk Western European
populations: a systematic review. Gastroenterology 128: S57-S67, 2005
Ekbom, Anders; Jonas F Ludvigsson, Johnny Ludvigsson, Scott M
Montgomery. Celiac Disease and Risk of Subsequent Type 1
Diabetes: A general population cohort study of children and
adolescents. J. Diabetes Care . Alexandria: Nov 2006. Vol. 29, Iss.
11; pg. 2483.
Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan
H, Neugut AI: Characteristics of adult celiac disease in the USA: results of a
national survey. Am J Gastroenterol 96:126-131, 2001
Murray JA: Celiac disease in patients with an affected member, type 1 diabetes,
irondeficiency, or osteoporosis? Gastroenterology 128:552-556, 2005
Rapoport MJ, BistritzerT, Vardi O, Broide E, Azizi A, Vardi P: Increased
prevalence of diabetes-related autoantibodies in celiac disease. J Pediatr