Microsoft PowerPoint - Celiac Sm

Document Sample
Microsoft PowerPoint - Celiac Sm Powered By Docstoc
					      Celiac Disease
          Michelle V. Smedley, MD
            Connecticut GI, PC
                 10-28-09




        Celiac Disease

Definition
Epidemiology
Pathogenesis
Diagnosis
Treatment
Definitions:



 Celiac disease: An autoimmune enteropathy (small bowel) with
                                           gluten as a trigger.

A permanent food intolerance to storage proteins of wheat, rye, and
  barley (gluten) characterized by chronic but reversible changes
predominantly in the proximal small intestine leading to decreased
digestion of food, decreased absorption of nutrients, and increased
                  net secretion of water and solute.

               gluten-                          non-
 Celiac sprue, gluten-sensitive enteropathy, or non-tropical sprue.




                            Why the concern?
        Nearly 3 million people in the United States are
        estimated to have celiac disease1
        1 in 133 people in the United States
        11 years is the average time that patients
        experience symptoms before being diagnosed
        with celiac disease
        More than half of patients who are diagnosed
        with celiac disease do not present with diarrhea

 1. US Department of Health and Human Services. NIH Consensus Statement on Celiac Disease. Bethesda, MD: US Department
 of Health and Human Services; 2004. NIH Consensus and State-of-the-Science Statements; vol 21, no 1.
 http://consensus.nih.gov/2004/2004CeliacDisease118PDF.pdf. Published June 28-30, 2004. Accessed August 23, 2007.




                                  Celiac Disease
        Definition
        Epidemiology
        Pathogenesis
        Diagnosis
        Treatment
     Epidemiology-
     Epidemiology-key points

   Not just Caucasians
   Not just children
   Not only diarrhea and weight
   loss
   We are only seeing the “tip of the
   celiac iceberg”




           Epidemiology
Worldwide 1:100 to 1:300 people are
affected
Female to male 2:1
Clinically         i t   during
Cli i ll severe picture d i pregnancy
or postpartum
Association with diabetes type I, Down’s
syndrome, autoimmune thyroid disease,
microscopic colitis, and chronic fatigue




        Celiac in Children
Presents between 6 and 24 months of age
Chronic diarrhea, anorexia, abdominal
distension and pain, and failure to thrive or
    g      ;          y
weight loss; some may also have vomiting   g
Between 8 and 10 percent of children with
apparent "idiopathic" short stature
Delayed menarche
Chronic constipation, recurrent abdominal
pain
   MODE OF PRESENTATION
       DIAGNOSIS AFTER 1993
              N=170

                      Abd pain    Other
                        5%         5%
              W t loss
                6%
       Bone disease
           6%
                                                        Diarrhea
                                                          43%
           Anemia
             8%



             Incidental
                10%

                                 Screening
                                   17%




                                             Lo et al, Dig Dis Sci, 2003;48: 395




 Classic Celiac Disease
Malabsorption
 Diarrhea,steatorrhea, fatigue, abdominal
 pain, anemia and weight loss
    P      t i infants 9-     th    d    i in
  • Presents in i f t 9-24 months and again i
    3rd-4th decades
    3rd-
                                             breast-
  • This is in part due to longer periods of breast-
    feeding and the later introduction of gluten in the
    infant diet.
                                 2-
  • 1:1 female:male in children; 2-3:1 in adults




   Atypical Celiac Disease
                            extra-
 Minimal GI complaints, but extra-
intestinal symptoms
 Iron def, IBS, infertility, HA, ataxia with
 occipital calcifications, seizures, and
 polyneuropathy
 GERD and gastritis are also seen
 Most frequent presentation.
 Disease can present at any age
       “Silent”Celiac disease
villous atrophy in asymptomatic
patients
    symptomatic:7-
  1 symptomatic:7-8 asymptomatic patients




        Refractory Celiac
. No longer responsive to diet
             jejuno-
  Ulcerative jejuno-ileitis
         (       p y
  EATCL(enteropathy associated T cell
  lymphoma)




           Refractory Celiac

Severe villous atrophy and malabsorption with either no
response to or no further response to GFD.
Two types: One an expansion of normal IEL in the biopsy
and this type responds to steroids/immunosuppressives;
          yp     p                            pp
the second as expanded IEL of CD3 lymphocytes. This is
                       IL-
thought to result from IL-15 stimulation and predates
lymphoma but the treatment is similar to the first type
Sometimes avoiding triggering foods is beneficial
                       IL-
Research on blocking IL-15 is ongoing.
             Who to test?
              symptoms-
Anyone with symptoms-irritable bowel
syndrome-
syndrome-D or lactose intolerance
Diabetes type I, Down’s syndrome, autoimmune
thyroid disease, microscopic colitis, and chronic
    g
fatigue
Infertility
Osteoporosis
Iron def anemia, low albumin,
hypertransaminasemia
Skin rash (DH)
Peripheral neuropathy




           Natural History
Lymphomas
Small bowel adenocarcinoma
Oropharyngeal tumors
Infertility
Osteoporosis
Stunted growth
Autoimmune diseases
                 Lymphoma


         NHL-             extra-
EATL or NHL-intestinal or extra-intestinal
Risk increased 80 times in initial reports
More recent studies:UK study with 25 year f/u:1/5684
pt.years(py)for SB lymphoma and 1/1421py for NHL;
Swedish study with 56 cases of lymphoma in 11,650
CD patients: 43% had EATL and relative risk of B cell
                                 extra-
NHL was 2.2 and intestinal and extra-intestinal NHL
was 3.6.




       Dermatitis Herpetiformis
         papulo-
Pruritic papulo-vesicular rash over extensor surfaces,
knees,elbows and face
                                                    sub-
   Diagnosis based on IGA deposits in uninvolved sub-
   epidermal basement membrane
  against dermal tTG
    g
   85% of DH patients will have small bowel biopsies
   consistent with CD but no minimal GI symptoms
   Rash responds to diet
 Collagen Vascular Disease
The prevalence of autoimmune disorders in
patients with CD is significantly more
frequent; 14% versus 2.8%
Interestingly, the risk of autoimmune
disorders appears to increase with the
duration of disease as a function of # of years
to diagnosis due to longer exposure to
foreign antigens.
False + ASCA in celiac and false + IGA anti
tTG in Crohn’s disease
       Epidemiology-
       Epidemiology-Diabetes
Both CD and DM share high carriage of DQ2 and
DQ8-
DQ8-Almost 100% with CD and 73% in IDDM
Studies have found ranges of CD in diabetics from
                         1-
1-12% by serology and 1-11% by biopsy and slightly
hi h frequencies i children.Average risk 2-5% i
higher f        i in hild     A         i k 2-   in
            3-
adults and 3-8% in children.
Be aware of the association and evaluate in the
setting of appropriate symptoms like diarrhea, IDA,
unexplained hypoglycemia, weight loss etc.




Epidemiology-Thyroid and Liver
Epidemiology-
           disease
Literature doesn’t provide compelling evidence for screening
                                                         1.5-
CD in patients with thyroid disease. Ranges of CD from 1.5-
6.7%; highest in patients over 65. Especially hypothyroidism.
                       PBC(0-
CD is associated with PBC(0-6%), autoimmune liver disease
     NASH(2.9-
and NASH(2.9-6.4%) with a lesser assoc. to PSC(3.4)
Isolated AST elevations may be the only manifestation of CD
              1.5-
and occurs in 1.5-9% of cases of AST elevation of ? Etiology.
The AST level normalizes with GFD.
                             tTG-
EMA is more sensitive than tTG-GP in liver disease when
screening for CD.




Epidemiology-
Epidemiology-other associated
          diseases
Downs syndrome patients are at least 5x more likely to have CD
than average risk populations.
                                                  syndrome-
There is increased frequency of CD in Turner’s syndrome-6.3%
pooled frequency.
                                                                 2.1-
Infertility is seen with women who have CD with frequencies of 2.1-
4 1%(pooled risk 3.7%). There is lower fertility that normalizes with
4.1%(pooled         3 7%)
GFD. Women with CD have later menarche and more still births but
similar # of pregnancies. Aberrant sperm and hormone profiles in
men normalize on GFD
IBD, IGA nephropathy, addison’s, occipital calcifications with ataxia,
neuropathy, HA and seizures are associated with CD
            Relatives at risk

The consensus risk of CD in 1st degree relatives
             5-
approaches 5-10% with 2nd degree relatives
           2.5-
averaging 2.5-5.5%.
Identical twins have rates as high as 70%.




  An infectious trigger for CD

  Frequency of Rotovirus infections and development of
                       infection-      infections-
  CD. Risk with one infection-1.94;two infections-3.76 in
  DQ2 infants
    ype       de o us protein ay set off CD owing o
  Type 12 Adenovirus p o e may se o C o g to
  similarity to gliadin peptide
  Breast Feeding may be protective in preventing CD.
  Introduction of Gluten before 4 months of age had
  increased risk of CD whereas after 7 months of age
  had marginal risk




            Celiac Disease
Definition
Epidemiology
Pathogenesis
Diagnosis
Treatment
                   Pathogenesis
  Food intolerance that initiates complex adaptive
  and immune reactions that result in chronic
  intestinal mucosal inflammation with structural and
  functional implications
  It is unclear why tTG antibodies are so specific
  why elderly patients can present with CD
  what explains the diversified symptoms noted with
  today’s CD
  Understanding the pathophysiology of villous
  injury could lead to novel therapies




    IMMUNOLOGIC MECHANISM OF
  GLIADIN INDUCING VILLOUS ATROPHY
           LAMINA PROPRIA



 Gliadin peptide
       tTG                  DQ2/DQ8
   Deamidated
gliadin peptide             T cell receptor
                                              IFN-γ
                         CD4




                   Pathogenesis
                T-         B-
  Activation of T-cell and B-cell immune
  response to gluten in a person who is
  genetically susceptible.
                                      HLA-
  Genetic testing in 95% of CD pts is HLA-
                                HLA-
  DQ2 the rest are positive for HLA-DQ8
          Pathology

Proximal small bowel (where gluten 1st
encounters mucosal immune system)
Symptoms tend to correlate with
degree of villous atrophy but can be
discordant
Pathologic changes are reversible with
GFD
        Celiac Disease
Definition
Epidemiology
Pathogenesis
Diagnosis
Treatment




               Diagnosis
     EMA:
            IGA antibodies to endomysium(smooth
            muscle connective tissue);antigen in
            endomysium is tTG
            Immunoflourescence, ME or HUC
              b t t
            substrates
            Pooled spec./sens.:97.4;99.6/100;90%
            Most sensitive serologic marker and
            especially good with liver disease and
            children
            Expensive, time consuming and potential
            observer error
                 Diagnosis
    • tTG:
        bacterial prolyl-endopeptidases tTG is a ubiquitous
                  prolyl-
        intracellular enzyme released by inflammatory and
        endothelial cells and fibroblasts in response to
        inflammation or irritation
        Cross links to proline rich peptides like gluten and
        d      i t        l t   i       d i
        deaminates glutamine rendering a negatively   ti l
        charged gluten peptide with increased binding to
        DQ2/8 that facilitates T cell stimulation
        Quant. enzyme linked immunoadsorbant assay
        Pooledspec./sens.:GP/HUr90;95.3/95.1;98.3%
        False + anti tTG with CHF,IBD,arthritis, liver
        disease; Most false+ with GP anti tTG




Helpful hints with CD serologies
 Both EMA and tTG can become negative on
 GFD and a persistent titer can be helpful in
 defining compliance with GFD
 EMA and tTG Correlate with villous
 atrophy(<50% M2)
 For those patents who have empirically
                                       re-
 started GFD before CD is diagnosed, re-
 expose to gluten for 6 weeks then retest IGA
 antibodies to prove CD




                 Diagnosis
 IGA-
 IGA-AGA:
                                       immuno-
   Predates EMA and tTG, enzyme linked immuno-
   adsorbant assay
       specificity/sensitivity(85-
   Low specificity/sensitivity(85-95%)
   AGA no longer recommends
 IGA deficiency:
   Most common type of immune deficiency
   8-10% with celiac are IGA deficient
       anti-
   IGG anti-tTG approaches 100% sensitivity
   AGA doesn’t recommend routine IGA level unless
   CD strongly suspected and EMA/tTG are neg.;
   consider HLA DQ2/8
               Diagnosis
        DQ8-
DQ2 and DQ8-
 HLA class II heterodimers
                                48-
 Present in 30% general public; 48-65%
 asymtomatic relatives of CD patients and 73%
 of diabetics
 Almost 100% of CD patients are positive for
 DQ2 or Dq8; DQ2 in 95%, DQ8 in 5%
 100% negative predictive value for CD




               Diagnosis
Small bowel biopsy
 AGA consensus paper:gold standard and should be
 done on all before GFD
 EMA and tTG correlate most with villous atrophy and
 can negative in milder histologies
 The small biopsy can be patchy and biopsy can
 be falsely negative




           Celiac Disease
Definition
Epidemiology
Pathogenesis
Diagnosis
Treatment
          Gluten Free Diet




        Your treatment plan
Gluten-
Gluten-free diet
Referral to dietician or support group
Bone density check
        iron, folate, B12,
Check iron folate B12 and vitamin D level
Advise screening for first and second degree
relatives
Counsel on lactose intolerance
Pneumo-
Pneumo-vax due to associated hyposplenism




                Treatment
Compliance
                                      socio-
  Compliance correlates with parental socio-economic
  status and both knowledge and understanding of the
  disease by both parent and child.
    sy p o a c children e d o       ess compliant;
  Asymptomatic c d e tend to be less co p a ;
  children with CD diagnosed before 4 y.o. tended to be
  more compliant.
  Membership in local support groups seems to foster
  compliance.
       Cross-
       Cross-contamination
If your gluten free foods come into contact with
foods that contain gluten
For example, crumbs from regular wheat bread
can find their way into jams, spreads, or
                       aren t
condiments if people aren't careful to use a fresh
knife or utensil each time.
Condiments in squeezable bottles or using
separate jams and spreads is a great idea for
people with celiac disease.
                      gluten-
Separate toaster for gluten-free bread




      Kitchen contamination
If someone in your family bakes with
products that contain gluten, you need to
thoroughly clean appliances, utensils, and
work surfaces before preparing your
gluten-
gluten-free products. Remember to wash
your hands thoroughly and often.




               Resources
Registered dietician familiar with diet and
resources.
  Mary Noon , RD
  Greater New Haven Celiac Group
  www.connceliac.org
  Living without magazine.
  Clan Thompson Newsletter(free).
  CSA( Celiac Sprue Association).
                         Follow-
                         Follow-up
Patient should be followed on a regular basis by
an health care professional and dietician.
   Since symptoms don’t have to correlate with adherence to GFD, it is
   recommended to repeat an IGA EMA or tTG after 6 months of GFD to
              p
   define compliance.
   Children’s histology can resolve quicker and more completely than adults
   who can take over 2 years for their mucosa to normalize.
    • Persistence of histologic abnormalities in adults may not speak to dietary
      indescretion alone




                         Follow-
                         Follow-up
Rebiopsy is not considered necessary unless response to
GFD is needed to confirm a seronegative case for diagnosis
      re-
or to re-evaluate refractory symptoms or recurrent symptoms.
Recurrent symptoms are most often compliance issues
Recurrent symptoms may signify a complication or an
              s            diagnosis.
associated vs. additional diagnosis
    Consider a complication:(lymphoma or
    malignancy);associated conditions:(microscopic colitis or
    IBS) versus additional diagnoses like pancreatic
    insufficiency or lactose intolerance especially with
    recurrent diarrhea.
          Future Therapy
                              prolyl-
Specific proteases (bacterial prolyl-
endopeptidases) to break down gluten
epitopes in food
             HLA-       HLA-
Blockade of HLA-DQ2 and HLA-DQ8 interaction
with gliadin
Inducing immune tolerance to wheat
epitopes
 Creating new wheats with different
proline/glutamine sequences
          IL-
Blocking IL-15, tTG, zonulin




          Future Therapy
Search for less toxic cereals would reduce
immune reaction
  Several cereals are being analyzed for
  immunogenic stimulation of IFN gamma and T
     ll
  cells
  ?? Genetically engineered cereals
  An Ethiopean cereal, Tef, does not seem to
  stimulate T cells




          Future Therapy
          Prolyl-
Bacterial Prolyl-endopeptidases
  Facilitate more complete digestion of toxic
  gliadin peptides
                                            anti-
  Reduced symptoms but did not alter IGA anti-
  tTG levels or improve biopsy.
  Problem may be duration needed to digest
  the gluten to less toxic sequences
      Gluten free restaurants
         Pizza1
Famous Pizza1 P.T. Barnum Sq.
Bethel,
CT-06801Pizza
CT-
          Grill1462 Portland-
Eggs Up Grill1462 Portland-Cobalt Road
Portland,
CT-06480American
CT-
               Inc.28
Bruno's Pizza Inc.28 State Route 39
New Fairfield,
CT-
CT-06812Pizza
                                    Bakery286
Dee's One Smart Cookie Gluten Free Bakery286 Tryon Street
Glastonbury,
CT-06033Cafe
CT-
        Grill100
Burtons Grill100 Evergreen Way
South Windsor,
CT-06074American, Grills, Seafood
CT-
Max Restaurant chain




             American Celiac Disease Alliance
                     2504 Duxbury Place
                    Alexandria, VA 22308
                    Phone (703) 622-3331
               Email: info@americanceliac.org
              Internet: www.americanceliac.org




         National Foundation for Celiac Awareness
                         P.O. Box 544
                      Ambler, PA 19002
                    Phone: 215–325–1306
                Email: info@celiaccentral.org
               Internet: www.celiaccentral.org
      Gluten Intolerance Group of North America
                31214 124th Avenue SE
                   Auburn, WA 98092
                 Phone: 253–833–6655
                   Fax: 253–833–6675
                 Email: info@gluten.net
                Internet: www.gluten.net




             Celiac Disease Foundation
             13251 Ventura Boulevard, #1
                 Studio City, CA 91604
                Phone: 818–990–2354
                  Fax: 818–990–2379
                 Email: cdf@celiac.org
               Internet: www.celiac.org




               Key Points
Diagnosis made with small bowel biopsy
showing characteristic changes and
clinical response to gluten free diet
   yp
Atypical ppresentations are most common
Serology testing for screening at risk
patients and first degree relatives should
be screened
Compliance with diet is the key to
treatment

				
DOCUMENT INFO