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Pathogenesis of Celiac Disease

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					    Celiac Disease-A not so
     Uncommon Disorder
           Frank A. Hamilton, M.D., MPH
            National Institutes of Health
National Institute of Diabetes, Digestive and Kidney
                       Diseases
                   August 19, 2005



                                                       1
                        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
                                                                2
           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



                                                             3
       The Celiac Iceberg
 Symptomatic
                                             Manifest
Celiac Disease
                                             mucosal lesion



                  Silent Celiac
                     Disease

           Latent Celiac Disease             Normal
                                             Mucosa

        Genetic susceptibility: - DQ2, DQ8
                 Positive serology

                                                              4
     Gastrointestinal Manifestations
               (“Classic”)
Most common age of presentation: 6-24 months

•   Chronic or recurrent diarrhea      • Abdominal pain
•   Abdominal distension               • Vomiting
•   Anorexia                           • Constipation
•   Failure to thrive or weight loss   • Irritability

Rarely: Celiac crisis


                                                          5
Typical Celiac Disease




                         6
             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




                                    Listed in descending order of strength of evidence 7
Dermatitis herpetiformis




                           8
            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.

                                                        9
               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)



                                                                  10
                  Associated Conditions
             20

             16
percentage




             12

              8

              4
                                                              General
              0                                               Population
                  Relatives   IDDM   Thyroiditis     Down
                                                   syndrome

                                                                           11
               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
                                                                                12
       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
• Fertility problems     disorders
                       • Intestinal lymphoma
                                               13
              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




                                                      14
  “Mines” of Celiac Disease Were
                    Found Among:
   Relatives          Patients with
                                       Associated
short stature, anaemia, fatigue,       diseases
hypertransaminasemia                                   “Healthy”
                                                        groups
 autommune disorders, Down s, IgA deficiency,
 neuropathies, osteoporosis, infertility

          blood donors, students, general population


                                                                   15
             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.
                                                              A. Fasano et al., Arch Int Med 2003;163:286-292.
                                                                                                                  16
Celiac Disease Prevalence Data
        Geographic Area         Prevalence on clinical diagnosis*     Prevalence on screening data
             Brazil                             ?                                 1:400
           Denmark                           1:10,000                             1:500
            Finland                          1:1,000                              1:130
           Germany                           1:2,300                              1:500
             Italy                           1:1,000                              1:184
          Netherlands                        1:4,500                              1:198
            Norway                            1:675                               1:250
            Sahara                              ?                                 1:70
           Slovenia                             ?                                 1:550
            Sweden                            1:330                               1:190
        United Kingdom                        1:300                               1:112
             USA                             1:10,000                             1:133
      Worldwide (average)                    1:3,345                              1:266

*based on classical, clinical presentation


                                                      Fasano & Catassi, Gastroenterology 2001; 120:636‑651. 17
     Celiac Disease Icebergs
10

                       Overall
 8
                       Diagnosed

 6


 4


 2


 0
     Ireland   Italy    Netherlands   Sweden   USA

                                                     18
              The 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.


                                             19
      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



                                                     20
           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

                                          21
              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

                                                   22
Treatment
 • Only treatment for
   celiac disease is a
   gluten-free diet (GFD)
   – Strict, lifelong diet
   – Avoid:
      • Wheat
      • Rye
      • Barley


                             23
      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
                                       24
               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.
                                       25
                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

                                               26
Sources of Gluten
       • OBVIOUS SOURCES
         –   Bread
         –   Bagels
         –   Cakes
         –   Cereal
         –   Cookies
         –   Pasta / noodles
         –   Pastries / pies
         –   Rolls



                               27
 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
                                          28
Barriers to Compliance
       • Ability to manage emotions –
         depression, anxiety
       • Ability to resist temptation –
         exercising restraint
       • Feelings of deprivation
       • Fear generated by
         inaccurate information


                                          29
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



                                                               30
  Histological Features



    Normal 0            Infiltrative 1       Hyperplastic 2




Partial atrophy 3a   Subtotal atrophy 3b     Total atrophy 3c

                               Horvath K. Recent Advances in Pediatrics, 2002.   31

				
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