Download Celiac Disease

Celiac Disease
Equipping primary care physicians
to manage most patients
Eric Poulin, MD
First Light Health System
Mora, Minnesota
Celiac Disease:Objectives
• Discuss definitions
• Review pathophysiology and epidemiology
• Discuss associated diseases
• Equip primary care physicians to manage most
patients
Celiac Disease:Definitions
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Classical CD
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Atypical CD
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Typical GI symptoms
Fully developed gluten-induced villous atrophy resulting in intestinal malabsorption
Few or no GI symptoms
Associated diagnoses, i.e. iron deficiency, osteoporosis, infertility
Fully developed gluten-induced villous atrophy resulting in intestinal malabsorption
Silent CD
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Asymptomatic
No associated diagnoses
Positive serologic testing in a higher risk patient
Some degree of gluten-induced villous atrophy is present (or assumed to be present)
Celiac Disease:Definitions
classical
atypical
&
silent
Doc, what do I eat?
Celiac Disease:Pathophysiology
1. Disorder of small bowel malabsorption.
2. Small bowel mucosa is damaged by inflammation, mediated by the immune
system.
3. Immune system attack over time results in villous atrophy, crypt hyperplasia, and
lymphocytic infiltration.
Celiac Disease:Pathophysiology
celiac
normal
Celiac Disease:Pathophysiology
This inflammatory process can cause the “classic” symptoms:
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Abd pain
Diarrhea
Bloating
Gas
Fatigue
Weight Loss (failure to thrive; delayed puberty)
It can also cause a “classic” inflammatory skin rash,
herpetiformis.
dermatitis
Celiac Disease:Pathophysiology
• Dermatitis Herpetiformis
– DDx:
herpes simplex
scabies
neurotic excoriation
atopic dermatitis
Celiac Disease:Pathophysiology
• Dermatitis Herpetiformis
– Severely pruritic, erythematous, vesicular rash
– Tends to occur in large symmetrical groups, on extensor surfaces: elbows,
knees, scalp, buttocks, back of neck
– Recurrent: lesions in various stages of healing
– A “regular” skin biopsy is non-specific.
– dermal microabscesses, with PMNs and eosinophils, at tips of dermal papillae
– Send skin biopsy in special media to dermatopathologist for IgA
immunofluoresence.
Celiac Disease:Pathophysiology
• Mucosal damage interferes with digestion and absorption
Nutrient deficiency
Resulting Disease/Symptom
Iron
Microcytic Anemia
Calcium
Osteoporosis, early onset
Vit D
Osteoporosis, and ?
Vit B12, Folate
Macrocytic Anemia, Peripheral Neuropathy
Vit A
Night Blindness
“Nutrient Excess”
Resulting Disease/Symptom
Lactose
Lactose Intolerance
Fats
Steatorrhea
Celiac Disease:Pathophysiology

Other deficiencies (B vitamins, micronutrients, magnesium, etc.) may be
cause of non-specific neurological symptoms:
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headaches
ataxia
poor memory
depression
seizures
Celiac Disease:Pathophysiology
• What triggers the immune system, the inflammatory
reaction?
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History
– Willem Karel Dicke
– Dutch pediatrician, 1944  wheat bread
– Gluten identified about 10 years later by British
Celiac Disease:Pathophysiology
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When the gluten protein is ingested by a genetically susceptible person, an
enzyme present in the small bowel mucosa, tissue transglutaminase, binds to and
modifies the protein, making an antigen that is part “auto-” and part
environmental (gluten).
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This “modified” autoantigen is presented to both T cells (cell mediated) and B cells
(humoral) which begin and continue the destructive inflammatory process.
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Unlike other autoimmune diseases, however, celiac disease is reversible, by
eliminating the environmental factor (gluten).
Celiac Disease:Pathophysiology
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The gluten protein is present in wheat, barley, and rye.
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The gluten protein is present in “regular” oats due to cross-contamination in the
field, in harvesting, and in processing.
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How much gluten is needed to stimulate the immune response?
– Very small quantities.
• Studies show 10-50 parts per million
(Fasano, 2007)
• The USDA/FDA will add gluten to the “allergy declaration” at the bottom
of ingredient lists using a 20 ppm cut-off.
Celiac Disease:Pathophysiology
• Remember: celiac disease is more similar to an autoimmune disease than
an “intolerance” (i.e. lactose intolerance) or “sensitivity” or “allergy”.
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Elimination of gluten from the diet eventually ends the inflammatory
response in most patients.
– Many patients will become less “sensitive” and less symptomatic after several
years of strict adherence to GFD.
Celiac Disease:Epidemiology
• Who is “genetically susceptible”?
– Those with human leukocyte antigen (HLA) DQ2 or DQ8 receptors on their white blood
cells—these genes are located on chromosome 6.
– Other unidentified genetic programming is also involved.
– Monozygotic twins show 70% concordance.
– One of the highest risk factors is first-degree relatives.
– Ethnic distribution:
• highest risk – Europeans (Irish, Italians)
• lowest risk – African, Japanese, Chinese
Celiac Disease:Epidemiology
• Prevalence in North America
– Approximately 1:100, or 1%
– Rises to 1:22 among first-degree relatives, almost 5%
• Associated with other diseases (increased prevalence)
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Type I Diabetes
Down Syndrome & Turner Syndrome
Autoimmune thyroiditis (Hashimoto’s, Graves, multi-nodular goiter)
Microscopic Colitis
Infertility
Celiac Disease:Diagnosis
• Newly Proposed Diagnostic Rule:
Fasano’s 4 of 5:
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5.
Typical symptoms of celiac disease (clinical suspicion)
High titers of TTG-IgA or endomysial-IgA (EMA) antibodies
HLA-DQ2 or DQ8 genotypes
Celiac enteropathy on small bowel biopsy
Response to gluten-free diet
Catassi, Fasano, American Journal of Medicine, 2010
Celiac Disease:Diagnosis
• Serology:
Antibody
Sensitivity
Specificity
TTG-IgA
94%
98.7%
EMA
93%
99.7%
Lewis NR, Aliment Pharmacol Ther, 2006
Remember:
– Patients must be eating gluten!
– The higher the titer, the more convincing the result.
– IgA testing is only accurate if IgA deficiency is ruled out.
• Up to 5% of celiac patients are IgA deficient.
– IgG class of antibodies is much less sensitive and specific.
– IgA may not be reliable in infants and toddlers.
Celiac Disease:Diagnosis
• Genetic testing (HLA-DQ2 or DQ8):
– High sensitivity: 99-100%.
• Good for “ruling out” celiac disease.
– Poor specificity: 57%
• One third of the general US population is HLA-DQ2 +
– Consider in:
– infants and toddlers
– Patients already eating a gluten-free diet
Celiac Disease:Diagnosis
• Small bowel biopsy
• 4-6 (or more?) biopsies from 2nd or 3rd portion of
duodenum, often random
• Biopsy location can be guided by magnification, staining
techniques, narrow band imaging (?)
• Video capsule endoscopy:
– sensitivity – 83%. specificity – 98%. no complications (no risk).
Celiac Disease:Diagnosis
Several pathological classification systems
1. Marsh, stages 0-4
2. March-Oberhuber, stages 0-4, with 3a, 3b, 3c added
A
B1  B2
3.
Celiac Disease:Diagnosis
normal
flattening of folds
Celiac Disease:Diagnosis
normal
mucosal fissuring
Celiac Disease:Diagnosis
• “Alternative” testing methods:
– TTG-IgA levels in stool samples ? (EnteroLab)
– TTG-IgA levels in saliva samples (Cyrex labs)
• Italian study in 2010 with 4048 children, ages 6-8.
Bonamico, M., J Pediatric Gastroenterol Nutr. 2011 Jan
– 32 children saliva positive, 9 “borderline”.
– 31/32 and 3/9 were positive with serum testing.
– 28/34 had villous atrophy on biopsy.
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1 had “Marsh 1” pathology; 3 were not biopsied, but started on GFD
– Prevalence in this study:
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28 + 19 known CD in this population = 47/4048 = 1.2%
Ratio of symptomatic to asymptomatic patients: 1:1.6
Celiac Disease:Diagnosis
• Non-specific lab abnormalities
– ALT, AST are mildly elevated
– Albumin may be low
• After diagnosis is made, remember to test for associated diseases:
• DEXA for bone mineral density
• TSH and thyroid exam for autoimmune thyroid disease
• Hgb, and further w/u if anemic (iron studies, B12, RBC folate)
Celiac Disease:Diagnosis
• What is “response to gluten-free diet”?
– Classic symptoms resolve
• “Doc, I feel much better.”
– Associated diagnoses improve
• Iron tabs or meaty diet correct iron deficiency anemia.
• Repeat BMD testing shows improvement on GFD and calcium+D.
» younger patients can see dramatic BMD improvement
– Diagnostic testing returns to normal, after 6 months on GFD
• Previously high-titer serology is normal.
• Repeat duodenal biopsies are normal.
Celiac Disease:Treatment
• But doc, what can I eat?
Simple Low Carb Diet
Simple GF Diet
sweets
breads
pasta
potatoes
rice
Wheat
Barley
Rye
Oats
• Infants
– Breast feeding to 6 months
– Delayed introduction of gluten to 6 months
Celiac Disease:Treatment
• Major difficulty of GF diet is eating out.
– Cross-contamination
• Deep fry oil
• Preparation
– No ingredient lists
– Embarrassment among peers
Celiac Disease:Treatment
• Major difficulty of GF diet is home kitchen
environment.
– Cross-contamination
• Separate items at meal-time
• Separation of utensils and appliances (toaster, butter)
• Non-food exposures
– Children: Play-Doh
– Adults: work environment (example: animal feed)
Celiac Disease:Take home points—slide one
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High index of suspicion in symptomatic GI disease, i.e. irritable bowel syndrome,
chronic diarrhea, etc.
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High index of suspicion in malabsorption diseases and autoimmune diseases.
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Start out testing with TTG-IgA serology and consider the degree of abnormality in
the result, and clinical risk factors.
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Use Fasano’s 4 out of 5 diagnostic method:
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Typical symptoms of celiac disease (clinical suspicion)
High titers of TTG-IgA or endomysial-IgA (EMA) antibodies
HLA-DQ2 or DQ8 genotypes
Celiac enteropathy on small bowel biopsy
Response to gluten-free diet
Celiac Disease:Take home points—slide two
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After diagnosis, remember:
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Test for associated diseases
Test immediate family members (higher risk group)
Refer to a skilled dietician familiar with CD
Repeat testing to confirm good control, after about 6 months
Educate patients: celiac disease is a type of autoimmune disease:
– The reason for strict gluten avoidance (over 20 ppm):
immune system triggering  inflammation  damage.
– Think of possible cross-contamination