Transcript Document

THE CELIAC PATIENT
Carol E. Semrad, M.D.
Associate Professor of Medicine
The University of Chicago
•
•
•
•
Celiac Disease
Sprue
Gluten-enteropathy
Celiac sprue
Same Disease
Inflammatory disease of the small bowel with
a known trigger
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 5’1”
Duodenum
• 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
Celiac Disease -Trigger
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)
Celiac Disease
GENES
• 95% HLA DQ2 heterodimer
alleles DQA1*0501 and DQB1*0201
(20-30% normals carry these alleles)
• 5% HLA DQ8 heterodimer
alleles DQA1*0301 and DQB1*0302
• Rarely DQ2 half-heterodimer
• Non-HLA genes not yet identified
ADAPTIVE
INNATE
Intraepithelial
CTL
NK-like cells
?
Lamina Propria
Modified from Green and Jabri Lancet. 2003:362;383-91.
Celiac Disease
Prevalence in the U.S.A.
• Based on GI symptoms 1:4500
• Based on Antibody studies 1:250
(performed in blood donors)
~ 1% of the Caucasian population
Classical Celiac Disease
(1:4500)
Atypical
Silent
Latent
Detected by
screening
(1:250)
Different
modes of presentation
presentations of celiac
disease
The clinical
of celiac
disease is changing
Rampertab SD et al., Am J Medicine 2006
Celiac Disease
Clinical Presentation
Classical
Atypical
Silent
• Diarrhea
• Constipation • No sxs/signs
• Positive Ab
• Gas/bloating • Dyspepsia
• Abnormal bx
• Weight loss • Anemia
• Osteoporosis
• Rash
• Neuropathy/ataxia
• Hepatitis
• Dental enamel
hypoplasia
• Infertility
Latent
• No sxs/signs
• Positive Ab
• Normal bx
OR
CD in remission
Celiac Disease
Classic, Atypical, Silent
Latent
Normal
Abnormal
Celiac Disease
Diagnostic Tools
Duodenal biopsy
Serologies
HLA Association
anti-tTG IgA, IgG
anti-EMA IgA
(anti-DGP)
DQ2 A1*05 B1*02
DQ8 A1*03 B1*0302
Half DQ2 heterodimer
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. Gastro2001:120;636
Carroccio et al. Clin Chem 2002:48;1546
ENDOSCOPY
CELIAC DISEASE
Scalloped
Gluten-free diet
Increased IEL
Villous atrophy
Recovering
HISTOLOGY
Normal
Celiac Disease
Who 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
Celiac Disease
Who Should Have Antibody Testing?
• Support diagnosis
• Screening High risk groups
First and second degree relatives
Dermatitits Herpeteformis
Type I Diabetes Mellitus
Autoimmune thyroid disease
Irritable Bowel Syndrome
Primary Biliary Cirrhosis
Turner’s and Down’s Syndrome
Celiac disease
An approach to antibody screening
• tTG IgA antibody and serum IgA level
• If positive, confirm with EMA antibody
Celiac Disease
When 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
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
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
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
RESPONSE TO A GLUTEN-FREE DIET
90% IMPROVE
(within 2 weeks)
10% FAIL TO IMPROVE
Dietary indiscretion
Lactose or fructose Intolerance
Microscopic colitis
Wrong Diagnosis
Pancreatic Insufficiency
Bacterial overgrowth
Refractory sprue
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
-
Celiac Disease
Long Term Complications
• Anemia
• Osteoporosis
• Intestinal T-cell lymphoma
? Video capsule endoscopy screening
• Other Malignancies
Gastrointestinal
Melenoma
Non-Hodgkins Lymphoma
Celiac Disease
Future Treatments
• Bacterial Prolyl Endopeptidase
• Genetically altered wheat grain
• Specific Inhibitors
HLA DQ2
tTG
IL15
• Tight junction modulators
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
How Much Gluten Is Toxic?
CELIAC DISEASE
Dose-dependent Effect of Gliadin
on Small Bowel
Dose of
Gliadin
Symptoms
Permeability
Intestinal
Biopsy
10 mg
No
--
Normal
50 mg*
Yes
--
Minimal changes
100 mg
No
Normal
Minimal changes
500 mg
Yes
Increased
More pronounced
changes
*capsule of gluten
Catassi et al. GUT 1993; 34: 1515
Ciclitira et al. Clin Sci 1984; 66: 357
Catassi et al. Gastroenterol 2005;128:A253
10 mg gliadin ~ 250 mg wheat flour
(less than an 1/8 teaspoon flour)
CELIAC DISEASE
Are Dietary Oats Tolerated?
PATIENT #
DISEASE
STATUS
DIET
DURATION
SXS
SMALL
BOWEL
BIOPSY
26 adults
(26 control)
remission
oats (50-70g)
gluten-free
6 months
no
similar to
pre-oat
19 adults
(21 control)
new
oats (50-70g)
gluten-free
1 year
no
improved
23 adults
(28 control)
remission
oats ad-lib
gluten-free
5 years
no
improved
42 children
(52 control)
new
oats ad-lib
gluten-free
1 year
no
improved
Janatuinen et al. NEJM 1995;333:1033
Gut 2002; 50: 332
Hogberg et al. Gut 2004;53:649