1. Celiac Disease:
A Glimpse of the Future
Gaetano Morelli MD
1

2. Definition
Celiac disease is an immune-mediated
enteropathy caused by a permanent sensitivity
to gluten in genetically susceptible individuals.
It occurs in symptomatic subjects with
gastrointestinal and non-gastrointestinal
symptoms, and in some asymptomatic
individuals
2

3. Incidence
Age of onset from 6 months to 90+ years
Affects up to 1%, mostly Caucasians, Middle
Eastern and West Asians (Indian/Pakistani)
Long-term risks include
 Osteoporosis

2x overall mortality rate

2x risk GI tumours
3

4. Clinical Manifestations
Gastrointestinal (“classical”)
Non-gastrointestinal ( “atypical”)
Asymptomatic
In addition, Celiac Disease may be associated with other
conditions, and mostly with:
• Autoimmune disorders
• Some syndromes
4

5. The Celiac Iceberg
Symptomatic
Manifest
Celiac Disease
mucosal lesion
Silent Celiac
Disease
Latent Celiac Disease Normal
Mucosa
Genetic susceptibility: - DQ2, DQ8
Positive serology
5

6. Celiac Disease Occurs with
The Big Three
Anemia, Iron, Folate, B12 deficiency
Frequent tiredness or chronic fatigue;
Ongoing GI upset
 Diarrhea &/or constipation

Abdominal pain, indigestion, bloating, gas
6

7. Chance of a Positive Diagnosis
Increases if the Big Three coexists with either:
Thyroid disease
Type I diabetes mellitus
Down syndrome
Abnormal liver function- transaminases especially
Osteoporosis
Undefined neurological disorder/epilepsy
Infertility/recurrent miscarriage
7

8. Screen these for the Big 3
Infertility (unexplained) Idiopathic ataxia or
Osteoporosis neuropathy
Fatigue Sjogren’s syndrome
Sero-negative Idiopathic ataxia
rheumatoid arthritis IgA deficiency
Depression Primary biliary cirrhosis
Fractured NOF Downs syndrome
Impaired memory Turner syndrome
Dermatitis Liver failure
herpetiformis Thyroiditis
Cerebral calcification Diabetes (Type 1)
epilepsy Addison’s disease
8

9. Clinical Associations:
“Clinical syndromes” Disease Associations
Anemia (all comers) 3-12% Dermatitis herpetiformis 100%
Steatorrhea 8% Diabetes mellitus (Type 1) 2-16%
Irritable bowel syndrome 0-7% Thyroiditis 3-5%
Fatigue 2% Selective IgA deficiency 8-29%
Osteoporosis 3% Addison’s disease 1%
Infertility (unexplained) 2-8% Primary biliary cirrhosis 6-7%
Sero-negative rheumatoid arthritis ? Liver failure (transplant) 4%
Depression ? Sjogren’s syndrome 15%
Fractured NOF ? Idiopathic ataxia or neuropathy 17%
Impaired memory ? Idiopathic ataxia 13%
Epilepsy 2%
Family History: Cerebral calcification and epilepsy 77%
1st degree relative 4-18% Down syndrome 4-19%
Identical twin 70-95% Turner syndrome 4-8%
9

10. Dermatitis herpetiformis
10

11. Asymptomatic
Silent Latent
Silent:
No or minimal symptoms, “damaged” mucosa and
positive serology
Identified by screening asymptomatic individuals
from groups at risk such:

First degree relatives
 Down syndrome patients
 Type 1 diabetes patients, etc.
11

12. Asymptomatic
Silent Latent
Latent: No symptoms, normal mucosa

May show positive serology. Identified by following in time
asymptomatic individuals previously identified at screening from
groups at risk. These individuals, given the “right” circumstances,
will develop at some point in time mucosal changes (± symptoms)
12

13. Associated Conditions
20
16
percentage
12
8
4
General
0 Population
Relatives IDDM Thyroiditis Down
syndrome
13

14. Relatives
Healthy population: 1:133
1st degree relatives: 1:18 to 1:22
2nd degree relatives: 1:24 to 1:39
Fasano, et al, Arch of Intern Med, Volume 163: 286-292, 2003
14

15. “Mines” of Celiac Disease are Found Among
Relatives Patients with
Associated
short stature, anemia, fatigue, diseases
hypertransaminasemia “Healthy”
groups
autoimmune disorders, Down’s, IgA deficiency,
neuropathies, osteoporosis, infertility
blood donors, students, general population
15

16. Celiac Disease Epidemiological Study in USA
Population screened
13145
Healthy Individuals Risk Groups
4126 9019
Symptomatic subjects 1st degree relatives 2nd degree relatives
3236 4508 1275
Positive Negative Positive Negative Positive Negative Positive Negative
31 4095 81 3155 205 4303 33 1242
Prevalence Prevalence Prevalence Prevalence
1:133 1:40 1:22 1:39
Projected number of celiacs in the U.S.A.: 2,115,954
Actual number of known celiacs in the U.S.A.: 40,000
For each known celiac there are 53 undiagnosed patients.
16
A. Fasano et al., Arch Int Med 2003;163:286-292.

17. Celiac Disease Icebergs
10
Overall
8
Diagnosed
6
4
2
0
Ireland Italy Netherlands Sweden USA
17

18. Disease Mechanism
18

19. The Cause of Celiac Disease
HLA-DQ2
Digestion Deamidation
E
E T-cell
IFNγ Injury
Gluten Resistant
proteins peptides
Villous atrophy 19

20. HLA-DQ in Celiac Disease
European Genetics Cluster on Celiac Disease; n=1007
0.4%
6.0%
5.7%
DQA1*05 & DQB1*02
(HLA-DQ2)
DQA1*05 or DQB1*02
DQ1*03 & DQB1*0302
(HLA-DQ8)
Other
88.0%
20

21. HLA-DQ Genes Have Strong
Negative Predictive Value
DQA1*05 or DQB1*02
DQA1*0301 + DQB1*0302
Present Absent
Celiac: 99.6% 0.4%
Non-celiac: 35% 65%
21

22. Diagnosis
Diagnostic principles
Confirm diagnosis before treating

Diagnosis of Celiac Disease mandates a strict
gluten-free diet for life
following the diet is not easy
QOL implications
Failure to treat has potential long term
adverse health consequences
increased morbidity and mortality
22

23. Serological Tests
Role of serological tests:
Identify symptomatic individuals who need a
biopsy
Screening of asymptomatic “at risk”
individuals
Supportive evidence for the diagnosis
Monitoring dietary compliance
23

24. Serological Tests
Antigliadin antibodies (AGA) *
Antiendomysial antibodies (EMA) *
Anti tissue transglutaminase antibodies (TTG) *
– first generation (guinea pig protein)
– second generation (human recombinant)
HLA typing
* 2004 Consensus Conf. Best tests
24

25. Sensitivity and Specificity of
Serologic Tests
SERUM TESTS SENSITIVITY SPECIFICITY
IgA EMA 85-98% 97-100%
IgA tTG 90-98% 94-99%
IgA AGA 75-90% 82-95%
IgG AGA 69-85% 73-90%
25

26. Histological Features
Normal 0 Infiltrative 1 Hyperplastic 2
Partial atrophy 3a Subtotal atrophy 3b Total atrophy 3c
26
Horvath K. Recent Advances in Pediatrics, 2002.

27. Treatment
Only treatment for
celiac disease is a
gluten-free diet (GFD)
 Strict, lifelong diet

Avoid:
Wheat
Rye
Barley
27

28. Oats –are they Safe?
Studies from 1970’s suggested that oats
were toxic in CD
Oats contain a protein-avenin
Avenin- similar to wheat gliadin
Both are prolamins –rich in glutamine and
proline, both amino acids
28

29. OATS
Avenin- proportion of proline and glutmaine
is very low in oats compared to gliadin in
wheat
2004, Random. Clin Trial in children fed
GFD vs. GFD with oats
Hogberg Gut May 1, 2004 53(5)649-654.
29

30. Findings
First large study to indicate that oats in GFD do
not prevent normalization of the small bowel
tissue or celiac markers.
Other evidence supporting the safety of oats;
G. Kilmartin Gut, January 1, 2003
In CD, oats are not toxic and immunogenic,
Srinivasan BMJ 1996:1300-01
30

31. Sources of Gluten
OBVIOUS SOURCES

Bread

Bagels

Cakes

Cereal

Cookies

Pasta / noodles

Pastries / pies

Rolls
31

32. Treatment – 6 Elements in RX
Consultation with a skilled dietitian
Education about the disease
Lifelong adherence to a gluten-free diet
Identification and treatment of
nutritional deficiencies
Access to an advocacy group
Continuous long-term follow-up by a
multidisciplinary team
32

33. Barriers to Compliance
Ability to manage emotions –
depression, anxiety
Ability to resist temptation –
exercising restraint
Feelings of deprivation
Fear generated by
inaccurate information
33

34. Factors that Improve Adherence
Internal Adherence Factors Include:
Knowledge about the gluten-free diet
Understanding the risk factors and serious
complications can occur to the patient
Ability to break down big changes into smaller steps

Ability to simplify or make behavior routine
Ability to reinforce positive changes internally
Positive coping skills
Ability to recognize and manage mental health issues
Trust in physicians and dietitians
34

35. Approach to CD
Moderate to
high probability
IgA TTG and
duodenal biopsy
+ serology + serology - serology - serology
- histology + histology + histology - histology
Review or Exclude other causes of Diagnosis
Celiac
repeat biopsy celiac-like enteritis excluded
35

36. Approach to CD
Low probability
Test for IgA TTG
Positive Negative
Perform biopsy CD excluded
36

37. Conclusion
Celiac disease is
 common: 1% community
 GI symptoms are often absent or mild
 Fatigue, anaemia, headaches are common
 Celiac serology is a cheap and effective screen
 Gene testing can exclude celiac disease
 Gastroscopy and duodenal biopsy are essential
 Family testing is important
 Gluten free diet is complex - a skilled dietician is essential
37

38. Global Village of Celiac Disease
In many areas of the world Celiac
Disease is one of the commonest,
lifelong disorders affecting around
1% of the general population.
Most cases escape diagnosis and
are exposed to the risk of
complications.
Active Celiac Disease case-finding is
needed but mass screening should
be considered.
The impact of Celiac Disease in the
developing world needs further
evaluation.
38

39. Gastrointestinal Manifestations (“Classic”)
Most common age of presentation: 6-24 months
Chronic or recurrent diarrhea • Abdominal pain
• Vomiting
Abdominal distension
• Constipation
Anorexia
• Irritability
Failure to thrive or weight loss
39

40. Typical Celiac Disease
40

41. Non Gastrointestinal Manifestations
Most common age of presentation: older child to adult
• Dermatitis Herpetiformis • Iron-deficient anemia
• Dental enamel hypoplasia resistant to oral Fe
of permanent teeth • Hepatitis
• Osteopenia/Osteoporosis • Arthritis
• Short Stature • Epilepsy with occipital
• calcifications
Delayed Puberty
41

42. Major Complications of Celiac Disease
Short stature Osteoporosis
Dermatitis Gluten ataxia and
herpetiformis other neurological
Dental enamel disturbances
hypoplasia Refractory celiac
Recurrent stomatitis disease and related
disorders
Fertility problems
Intestinal lymphoma
42

43. Epidemiology
The “old” Celiac Disease Epidemiology:
• A rare disorder typical of infancy
• Wide incidence fluctuates in space (1/400 Ireland
to 1/10000 Denmark) and in time
• A disease of essentially European origin
43

44. Normal Celiac
Gluten
Wheat
Rye
Barley
44

45. Identification of the Components of Gluten
Responsible for the Intestinal Damage
Gluten 1g
Or
Gluten peptide
p56-74 50mg
Placed in small
intestine
45

46. A-Gliadin 57-73 QE65:
TCR-DQ2 interaction
T cell receptor
F P P P P Q
QLQ
P Q E L Y
PQS
HLA-DQ2
Anderson RP et al Nat Med 2000 46
Arentz-Hansen H. et al J Exp Med 2000

47. Gliadin Susceptibility to
Digestive Proteases
Gastric/pancreatic/brush
border proteases
α2-gliadin Protease-resistant 33mer
Shan L. et al Science 2002 47