THE CELIAC PATIENT

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THE CELIAC PATIENT

• Carol E. Semrad, M.D.
• Associate Professor of Medicine
• The University of Chicago

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• Celiac Disease
• Sprue
• Gluten-enteropathy
• Celiac sprue
• Inflammatory disease of the small bowel with a
  known trigger

Same Disease
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A Case of Asymptomatic Celiac Disease

• 50 y.o. woman, Italian/Irish
• Daughter diagnosed with celiac disease
• Screening anti-tTG IgA antibody positive
• Occasional indigestion with pasta meals
• PMH Hypothyroidism
• FH Parents of short stature
• Physical examination obese, height 51

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Duodenum
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• Further Studies - Mild
  anemia, transaminitis, iron deficient
  - BMD osteopenia
  
• Diagnosis - Celiac
  disease
• Management
  - Gluten-free diet
  - Iron
  therapy - Further
  evaluation of bone disease - Monitor for
  improvement

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Celiac Disease -Trigger
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Gluten (the protein component of wheat)
Glutenins (alcohol-insoluble fraction)
Gliadin (toxic alcohol-soluble fraction)
Peptides (33-mer not degraded by human
peptidases, contains toxic epitopes)
Amino acids (non-toxic to celiac patients)
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Celiac Disease GENES

• 95 HLA DQ2 heterodimer alleles DQA10501 and
  DQB10201 (20-30 normals carry these alleles)
• 5 HLA DQ8 heterodimer alleles DQA10301 and
  DQB10302
• Rarely DQ2 half-heterodimer
• Non-HLA genes not yet identified

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ADAPTIVE
INNATE
Intraepithelial CTL NK-like cells
?
Lamina Propria
Modified from Green and Jabri Lancet.
2003362383-91.
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Celiac Disease Prevalence in the U.S.A.

• Based on GI symptoms 14500
• Based on Antibody studies 1250 (performed in
  blood donors)
• 1 of the Caucasian population

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Classical Celiac Disease (14500)
Atypical Silent Latent
Detected by screening (1250)
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The clinical presentation of celiac disease is
changing
Rampertab SD et al., Am J Medicine 2006
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Celiac Disease Clinical Presentation

• Classical
• Diarrhea
• Gas/bloating
• Weight loss

• Atypical
• Constipation
• Dyspepsia
• Anemia
• Osteoporosis
• Rash
• Neuropathy/ataxia
• Hepatitis
• Dental enamel hypoplasia
• Infertility

• Silent
• No sxs/signs
• Positive Ab
• Abnormal bx

• Latent
• No sxs/signs
• Positive Ab
• Normal bx
• OR
• CD in remission

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Celiac Disease
Classic, Atypical, Silent
Latent
Normal
Abnormal
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Celiac Disease Diagnostic Tools
Duodenal biopsy Serologies HLA
Association anti-tTG IgA, IgG DQ2 A105
B102 anti-EMA IgA DQ8 A103
B10302 (anti-DGP) Half DQ2 heterodimer
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Antibodies Associated with Celiac Disease IgA
Antibody Sensitivity Specificity Method
Anti-gliadin 57-100 42-98 ELISA
Anti-endomysial 75-98 96-100 Indirect IF
Anti-tissue transglutaminase 98-100
97-98 ELISA False Negative with IgA
deficiency False Positive tTG in IBD,
PBC Positive Predictive Value 100 for
EMA 80 for human tTG
Fasano, Catassi. Gastro2001120636
Carroccio et al. Clin Chem 2002481546
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CELIAC DISEASE

ENDOSCOPY
Normal
Scalloped
Gluten-free diet
HISTOLOGY
Increased IEL
Villous atrophy
Recovering
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Celiac DiseaseWho Should Undergo Duodenal Biopsy?

• High risk with GI symptoms
• Dermatitis Herpetiformis
• Unexplained iron deficiency anemia
• Early osteoporosis/bone fracture
• Neuropathy/ataxia
• Positive screening antibody test

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Celiac DiseaseWho Should Have Antibody Testing?

• Support diagnosis
• Screening High risk groups First and second
  degree relatives Dermatitits Herpeteformis Typ
  e I Diabetes Mellitus Autoimmune thyroid
  disease Irritable Bowel Syndrome Primary
  Biliary Cirrhosis Turners and Downs Syndrome

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Celiac diseaseAn approach to antibody screening

• tTG IgA antibody and serum IgA level
• If positive, confirm with EMA antibody

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Celiac DiseaseWhen is HLA Genotyping Helpful?

• Family Members -Negative predictive value
• Difficulty in securing a diagnosis
• - Self-started a gluten-free diet
• - Equivocal small bowel biopsy findings
• - Positive antibody with normal biopsy
• - IgA deficiency

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Celiac Disease Evaluation

• Bone mineral density study - abnormal bone
  mass in 60 - men women - if abnormal
  obtain 25-OH Vit D, PTH, calcium, 24 hour
  urine calcium
• Vitamin/mineral levels in those with evidence of
  malabsorption/diarrhea - Iron studies and
  folate - Vitamin A, B12, zinc

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Celiac Disease Treatment

• Life-long strict gluten-free diet -
  knowledgeable nutritionist - celiac center web
  sites/support groups (U. Chicago, Columbia,
  Mayo Clinic, Stanford, U. Maryland, B.I.
  Boston)
• Oats are tolerated by most
• Daily multiple vitamin and calcium
• Folic Acid for women of child-bearing age
• No initial role for bisphosphonates

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Celiac Disease Monitoring

• Resolution of symptoms
• tTG antibodies for dietary adherence (?
  correlation between Ab titer and histology)
• Weight (risk for obesity)
• Cholesterol level
• Bone Mineral Density

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RESPONSE TO A GLUTEN-FREE DIET 90
IMPROVE 10 FAIL TO IMPROVE (within 2
weeks) Dietary indiscretion Lactose or
fructose Intolerance Microscopic colitis
Wrong Diagnosis Pancreatic
Insufficiency Bacterial overgrowth Refract
ory sprue
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Refractory Sprue Continued symptoms and small
bowel atrophy despite a strict gluten-free diet

• TYPE I
• - normal T-lymphocytes population
• - often responds to steroids, good prognosis
• TYPE II
• -abnormal T cell population (CD3, CD8-)
  T-cell receptor- g gene rearrangements
  - often requires parenteral nutrition
• - progression to lymphoma
  
• - poor prognosis
• - trials with cytotoxic chemo or stem cell
  transplant

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Celiac Disease Long Term Complications

• Anemia
• Osteoporosis
• Intestinal T-cell lymphoma ? Video capsule
  endoscopy screening
• Other Malignancies Gastrointestinal Meleno
  ma Non-Hodgkins Lymphoma

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Celiac Disease Future Treatments

• Bacterial Prolyl Endopeptidase
• Genetically altered wheat grain
• Specific Inhibitors HLA DQ2 tTG
  IL15
• Tight junction modulators

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Summary CELIAC DISEASE

• T-cell mediated small bowel mucosa inflammation
• Triggered by gluten in the diet in those
  genetically predisposed
• Malabsorption of nutrients
• Presents age 2 yrs, young adults, or any age
• Diagnosis made by abnormal small bowel biopsy
  that reverts to normal on a gluten-free diet
• Treatment is a life-long strict GF-diet

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How Much Gluten Is Toxic?
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CELIAC DISEASE
Dose-dependent Effect of Gliadin on Small Bowel
capsule of gluten
Catassi et al. GUT 1993 34 1515 Ciclitira et
al. Clin Sci 1984 66 357 Catassi et al.
Gastroenterol 2005128A253
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10 mg gliadin 250 mg wheat flour(less than an
1/8 teaspoon flour)
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CELIAC DISEASE
Are Dietary Oats Tolerated?
Janatuinen et al. NEJM 19953331033 Gut 2002
50 332 Hogberg et al. Gut 200453649