1. CELIAC DISEASE Ruben Gonzalez-Vallina, MD. Director Gastroenterology
OutPatient Initiatives
Miami Childen’s Hospital

2. Relevant Disclosures Commercial Interest – None
There is no financial relationships relevant to the content of presentation.

3. 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, including subjects affected by:
- Type 1 diabetes - Williams syndrome
- Down syndrome - Selective IgA deficiency
Turner syndrome - First degree relatives of
individuals with celiac disease

4. Genetic Disorders Down Syndrome: 4-19% Turner Syndrome: 4-8%
Williams Syndrome: 8.2%
IgA Deficiency: 7%
Can complicate serologic screening

5. 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: , 2003

6. Prevalence of Celiac Disease is Higher in Other Autoimmune Conditions
Type 1 Diabetes Mellitus: %
Thyroiditis: 4 - 8%
Arthritis: %
Autoimmune liver diseases: 6 - 8%
Sjögren’s syndrome: %
Idiopathic dilated cardiomyopathy: 5.7%
IgA nephropathy: 3.6%

7. Which Came First?

8. Celiac Disease and Autoimmunity
Prevalence of autoimmune disorders in celiac disease related to duration of gluten exposure
Diagnosed before 2 years of age: 5%
Age 2-10 years: 17%
Greater than age 10 years: 24%
Increased incidence of autoimmune disease in patients with IDDM and ‘silent’ Celiac Disease and their first degree relatives who were EMA+
Ventura et al, Gastro 1999; Not , Diabetologia 2001

9. Pathogenesis Genetic predisposition Environmental triggers Dietary
Non dietary?

10. Pathogenesis Necessary Causes Risk Factors Genetics Gluten Gender
Infant feeding
Infections
Others
Pathogenesis ?
Risk Factors
Celiac disease

11. Genetics Several genes are involved
The most consistent genetic component depends on the presence of HLA-DQ (DQ2 and / or DQ8) genes
Other genes (not yet identified) account for 60 % of the inherited component of the disease
HLA-DQ2 and / or DQ8 genes are necessary (No DQ2/8, no Celiac Disease!) but not sufficient for the development of the disease
Genes ? ? ? ?
HLA +
Gluten
Celiac Disease

12. Dietary Factors Gluten Gliadin Glutenin
Wheat - (15% protein, 75% starch)
Rye prolamines - secalins
Barley prolamines - hordeins
? Oats prolamines - avenins
Gluten
Gliadin
(alcohol soluble)
Prolamine
Glutenin
(alcohol insoluble)

13. Non Dietary Factors Infections Viral infections
sequence homology between a-gliadin & adenovirus type 12 & 7, rubella and human herpesvirus 1
Parasitic infestations
sequence homology between a-gliadin & Plasmodium yoelli
Other ?

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

15. 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

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

17. Typical Celiac Disease

18. Recurrent Aphtous Stomatitis
By permission of C. Mulder, Amsterdam (Netherlands)

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

20. Dermatitis Herpetiformis
Erythematous macule > urticarial papule > tense vesicles
Severe pruritus
Symmetric distribution
90% no GI symptoms
75% villous atrophy
Gluten sensitive
Garioch JJ, et al. Br J Dermatol. 1994;131:822-6.
Fry L. Baillieres Clin Gastroenterol. 1995;9:
Reunala T, et al. Br J Dermatol. 1997;

21. Dermatitis Herpetiformis
By permission of C. Mulder, Amsterdam (Netherlands)

22. Dental Enamel Defects Involve the secondary dentition
This slide demonstrates some of the subtle dental enamel defects that can be seen in a patient with celiac disease. The enamel defects occur in the secondary dentition, which is forming in the gums when a child begins to ingest gluten. The enamel defects are vertical lines which can be seen as notches or linear defects in the teeth in all four quadrants. These patients are at increased risk for caries in unusual locations. Sealants may be protective.
Involve the secondary dentition
May be the only presenting sign of Celiac Disease

23. Low bone mineral density improves in children on a gluten-free diet.
Osteoporosis
Osteomalacia in a celiac patient showing pseudofractures of the pelvis (arrows). Patient was 45 years old and presented with bone pain and proximal muscle weakness (for over 2 years) in the absence of overt GI symptoms. Elevated alkaline phosphatase and absence of Vitamin D stores were seen.
Low bone mineral density improves in children on a gluten-free diet.

24. Short Stature/Delayed Puberty
Short stature in children / teens:
~10% of short children and teens
have evidence of celiac disease
Delayed menarche
Higher prevalence in teens with
Untreated Celiac Disease

25. Fe-Deficient Anemia Resistant to Oral Fe
Most common non-GI manifestation in some adult studies
5-8% of adults with unexplained iron deficiency anemia have Celiac Disease
In children with newly diagnosed Celiac Disease:
 Anemia is common
 Little evidence that Celiac Disease is common in children presenting with anemia

26. Hepatitis
Some evidence for elevated serum transaminases (ALT, AST) in adults with untreated Celiac Disease
 Up to 9% of adults with elevated ALT, AST may have silent Celiac Disease
 Liver biopsies in these patients showed non- specific reactive hepatitis
 Liver enzymes normalized on gluten-free diet

27. Arthritis and Neurological Problems
Arthritis in adults
Fairly common, including those on gluten-free diets
Juvenile chronic arthritis
Up to 3% have Celiac Disease
Neurological problems
Epilepsy with cranial calcifications in adults
Evidence for this condition in children with Celiac Disease is not as strong

28. Celiac Disease Complicated by Enteropathy-Associated T-cell Lymphoma (EATL)
By permission of G. Holmes, Derby (UK)

29. 3 – 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.

30. 3 – 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)

31. Diagnosis Diagnosis of Celiac Disease requires:
characteristic small intestinal histology in a symptomatic child
complete symptom resolution on gluten-free diet
Serological tests may support diagnosis
Select cases may need additional diagnostic testing
The European Society for Pediatric Gastroenterology and Nutrition has published recommendations for the diagnosis of celiac disease. The diagnosis in a symptomatic individual requires demonstration of the characteristic histopathological changes of celiac disease on small intestinal biopsy with subsequent complete symptom resolution on a gluten free diet. A positive serological test before starting treatment, that disappears after a period of some months after starting therapy, is further supportive evidence for the diagnosis. In a study of over 3800 individuals with celiac disease it was found that these criteria were sufficient to confirm the diagnosis in over 95% of cases without the need for additional biopsies. In a few cases, particularly in the young child under two years of age, it may still be necessary to revert to the old three biopsy protocol to confirm the diagnosis.
ESPGAN working group. Arch Dis Child 1990;65:909

32. Serological Tests Antigliadin antibodies (AGA)
Antiendomysial antibodies (EMA)
Anti tissue transglutaminase antibodies (TTG)
first generation (guinea pig protein)
second generation (human recombinant)
HLA typing
Commercially available tests for celiac disease include the antigliadin, anti endomysial and anti tissue-transglutaminase tests. Tissue transglutaminase has been identified as the auto-antigen in celiac disease against which endomysial antibodies are directed. Initial transglutaminase tests used guinea pig protein as the antigen. Cloning of the gene for human transglutaminase has allowed for tests using human recombinant protein.
In addition to antibody tests, some commercial laboratories are offering tests to identify the HLA DQ2 and DQ8 genotypes that are known to be strongly associated with celiac disease.

33. Antigliadin Antibodies
Antibodies (IgG and IgA) to the gluten protein in wheat, rye and barley
Advantages
relatively cheap & easy to perform
Disadvantages
poor sensitivity and specificity
Antigliadin antibodies were the earliest tests developed for use in celiac disease. They are directed against the gliadin fraction of the gluten protein found in wheat. Both an IgA and an IgG based antibody are available. The advantages of the antigliadin tests are that they are relatively cheap and easy to perform. The major disadvantage is that they are relatively poorly sensitive and specific.

34. Endomysial Antibody - EMA
IgA based antibody against reticulin connective tissue around smooth muscle fibers
Advantages
high sensitivity and specificity
Disadvantages
false negative in young children
operator dependent
expensive & time consuming
false negative in IgA deficiency
Endomysial antibodies are IgA based and directed against the reticulin connective tissue around smooth muscle fibers. The test is performed by means of an indirect immunofluorescent assay using monkey esophagus or human umbilical cord as substrate. Either substrate is equally effective. The advantage of this test is that it is highly sensitive and specific. The disadvantages include the fact that it is operator dependent and hence potentially prone to errors in interpretation, it is generally more time consuming to perform and thus more expensive and it does not allow detection of celiac disease in individuals with selective IgA deficiency.

35. Tissue Transglutaminase (TTG)
Normal gut enzyme released during injury and stabilizes the cross-linking of proteins in granulation tissue
Role in Celiac Disease
Modification of gliadin epitopes
Autoantibodies against TTG correlate with active Celiac Disease - ? involved in pathogenesis

36. Tissue Transglutaminase - TTG
IgA based antibody against tissue transglutaminase (Celiac Disease autoantigen)
Advantages
high sensitivity and specificity (human TTG)
non operator dependent (ELISA/RIA)
relatively cheap
Disadvantages
false negative in young children
false negative in IgA deficiency
possibly less specific than EMA
The tissue transglutaminase test is IgA based and performed by means of either an ELISA or RIA technique. The major advantages of the test are that it is highly sensitive and specific, is non operator dependent and is relatively cheap to perform. The disadvantages are that it is unable to detect celiac disease in IgA deficient individuals and it may be less specific than the endomysial antibody.

37. Serological Test Comparison
Sensitivity % Specificity %
AGA-IgG 69 – – 90
AGA-IgA 75 – – 95
EMA (IgA) 85 – – 100
TTG (IgA) 90 – – 97
This slide summarizes the sensitivities and specificities for the various antibody tests.
Farrell RJ, and Kelly CP. Am J Gastroenterol 2001;96:

38. HLA Tests HLA alleles associated with Celiac Disease
DQ2 found in 95% of celiac patients
DQ8 found in remaining patients
DQ2 found in ~30% of general population
Value of HLA testing
High negative predictive value
Negativity for DQ2/DQ8 excludes diagnosis of Celiac Disease with 99% confidence
The role of HLA testing in celiac disease needs to be addressed. It is known that over 95% of all individuals with celiac disease are HLA DQ2 positive and virtually all the rest are positive for the HLA DQ8 genotype. However, about 30% of the general population is also HLA DQ2 positive. Thus, while these tests will likely demonstrate a high degree of sensitivity for celiac disease, they will be poorly specific. In contrast, knowing an individual is neither HLA DQ2 nor DQ8 positive may be helpful to the clinician as this almost completely eliminates the possibility the individual has celiac disease.
Schuppan. Gastroenterology 2000;119:234
Kaukinen. Am J Gastroenterol 2002;97:695

39. HLA Tests Potential role for DQ2/DQ8 asymptomatic relatives
Down, Turner & Williams syndrome
type 1 diabetes
diagnostic dilemmas
Determining the HLA type may be of benefit in some asymptomatic individuals with negative serological antibody tests who belong to a group considered at increased risk for celiac disease. These include individuals who are relatives of a confirmed case of celiac disease and those with Down syndrome, Turner syndrome or William syndrome and type 1 diabetes. It is known that some such individuals with initial negative serological tests will subsequently become positive and have biopsy changes compatible with celiac disease over a period of time if testing is repeated at intervals. Knowing an individual belonging to one of these groups was negative for both HLA DQ2 and DQ8 enables the physician to reassure them there is no further need to test them for celiac disease.
HLA typing for the celiac disease haplotypes may also help in some cases where the diagnosis is not clear, either because the individual never had a biopsy prior to starting treatment or because the histological features are not difficult to interpret. Once again, in these cases the absence of either of the HLA types virtually eliminates the likelihood of celiac disease in the individual.

40. Endoscopic Findings Scalloping Normal Appearing Scalloping Nodularity
A small intestinal biopsy and histological evaluation for the characteristic changes of celiac disease remains an essential component for confirming the diagnosis. Most biopsies today are obtained by means of an upper GI endoscopy with intubation of the duodenum. There are some macroscopical that are suggestive of celiac disease including a scalloped appearance along the duodenal folds and mucosal nodularity as shown in this slide. However, these findings are by no means reliable and mucosal biopsies are always needed.
Normal Appearing
Scalloping
Nodularity

41. Not recommended for initial diagnosis
Fantastic Voyage
Not recommended for initial diagnosis
Celiac Normal

42. Patterns of Mucosal Immunopathology
Type Type Type Type 3
Normal
Celiac Diseae
(latent)
Infilitrative
Celiac
Giardiasis
Milk intolerance
Tropical sprue
Marasmus
GVHR
Hyper plastic
Celiac
Giardiasis
Milk intolerance
Tropical sprue
Marasmus
GVHR
Flat destructive
Celiac
Giardiasis
Milk intolerance
Tropical sprue
Marasmus
GVHR
Marsh has described a progression of changes in the small intestinal mucosa. The earliest changes involve an increased mucosal cellular infiltrate, and in particular there is an increase in the number of intra-epithelial lymphocytes (Marsh type 1 or infiltrative stage). The next step is progressive elongation of the intestinal crypts (Marsh type II or hyperplastic stage) superimposed on the increased cellular infiltrate. The final step is progressive flattening of the intestinal villi superimposed on the cellular infiltrate and crypt hyperplasia (Marsh type III or destructive stage).
While the histological changes, and in particular the Marsh type III changes, are characteristic for celiac disease they are by no means pathognomonic and may also be seen with other conditions. It is the constellation of clinical features, histological findings, response to therapy and serological findings that ultimately enable a confident diagnosis of confirmed celiac disease.
Marsh, Gastroenterology 1992, Vol 102:

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

44. How much exposure is safe?
Complete gluten avoidance is extremely difficult
Exposure to trace amounts of gluten common even if product is sold as NATURALLY gluten-free
Safe threshold for gluten exposure = mg
Daily intake 30 mg of gliadin seems not to harm the intestinal mucosa
Amount of residual gluten in gluten-free products and the total intake of these products must be considered

45. 50 mg gluten

46. Gluten-Containing Grains to Avoid
Wheat Bulgar Filler
Wheat Bran Couscous Graham flour
Wheat Starch Durum Kamut
Wheat Germ Einkorn Matzo
Flour/Meal Barley Emmer
Semolina Barley Malt/ Extract Faro
Spelt Rye Triticale

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

48. Sources of Gluten POTENTIAL SOURCES Candy Communion wafers
Cured Pork Products
Drink mixes
Gravy
Imitation meat / seafood
Sauce
Self-basting turkeys
Soy sauce

49. Ingredients to Question (may contain gluten)
Seasonings and spice blends or mixes
Modified food starch
Malt/ malt extract/ flavoring
Modified hop extract and yeast-malt sprout extract
Dextrin
Caramel color

50. Thank You, Gracias!!

51. THANK-YOU