Celiac Disease

Dr Ajeet Kumar Lohana

Senior Registrar Gastroenterology
ATMC

Date 4 May 2021

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Objectives
1. Definition of the Celiac disease and Gluten ?
2. Pathophysiology of Celiac disease?
3. Epidemiology of the Celiac disease?
4. When to suspect Celiac disease?
5. What is serologic testing of CD?
6. The prevalence of the HLA Haplotypes?
7. The role of Genetic testing and Endoscopy?
8. What is Marsh Classification?
9. Immunohistochemical testing on biopsies ? IEL,
CD3 and CD8 markers?
10. Treatment of Celiac disease
11. Conclusion
 What is Celiac disease?

• Abnormal small intestine lining from injury

• Injury is result of gluten induced inflammation
• It is an autoimmune reaction with common
triggers
• The risk is genetically inherited
• Malabsorption occurs as a result
 What is Gluten
• 10-15% extractable protein portion of
wheat
• Subdivided into gliadin & glutenin
– Gliadin 15,000 molecular weight
– Active factor in small bowel injury
– Fraction 3, <1,000 mw sub-fraction
 What is gluten sensitive enteropathy?
• Protein gluten in wheat, rye, & barley, +/-
oats injures sensitive small intestine
• Chronic small intestine injury
=enteropathy
• Injured small intestine = malabsorption
• Abnormal immune system reaction
results in extra-intestinal symptoms &
signs
• Intestinal injury & symptoms resolve with
gluten-free die.
 What happens in Celiac disease?
• Proteins in wheat, rye, barley resistant to
digestion in stomach and by pancreatic
enzymes
• Make way into lining, possibly pre-injured by
infection, predisposed by genetic HLA type
• Activate T lymphocytes that release
chemicals (cytokines) causing inflammation
& damage
• Damaged lining malabsorbs nutrients &
vulnerable to more injury
 Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
 Autoimmune gut inflammation in Celiac
disease

• “ B lymphocytes” white blood cells produce

IgA & IgG class antibodies against tTG,
endomysium (EMA), & gliadin

• Increase T-lymphocytes recruited

(intraepithelial lymphocytosis) and chemicals
released damage occurs to intestinal villi
(atrophy/blunting) further increasing leaky gut
 Who gets Celiac, Whose at Risk?
• Genetic predisposition
– HLA DQ2, DQ8 in >90%
• Sometimes occurs after trigger such as
surgery, pregnancy, childbirth, viral
infection, emotional stress
• Breast feeding appears to be protective
• Age at which & how much
gluten introduced may affect
 How common is Celiac Disease?

• More common than previously thought

• 1% or 1/100 of general population
– 3 million Americans may be affected
• Several European studies 1/152 to 1/300
in Ireland, UK, Italy & Sweden
• US blood donor screening 1/133-1/250
compared to previous 1/6000 estimated
prevalence of Celiac disease
“Iceberg hidden epidemic” of Celiac
disease & non-celiac gluten
sensitivity
•1% worldwide have Celiac disease by specific
serology testing (EMA or tTG)

•Up to 12% of population is gluten sensitive (GS) by

serology testing “ n o t specific” for Celiac
disease

•40% of U.S. HLA DQ2 or DQ8+, the major genes

predisposing to CD
Clues that celiac should be
considered-screen

Copyright (c) 2014 Scot M.

Lewey, DO, FACP, FACG - Peak
Gastroenterology
Celiac is frequently missed by primary care physicians

Primary Care Physician Awareness Percentage

Wheat intolerance 95%

Onset of symptoms in adults existed 32%

Diarrhea as a symptom 90%

IBS symptoms are common 71%
Chronic abdominal pain common 67%
Fatigue is common 54%
Depression & irritability common 24%
Associated with diabetes 13%
Associated with anemia 45%
Associated with osteoporosis 45%
Diagnosed by blood tests 44%
Prevalence of potentially gluten sensitive HLA
DQ genes

HLA DQ TYPE PREVALENCE

HLA DQ2 31%

HLA DQ8 12%

HLA DQ1,7 18%

HLA DQ1,9 1%
How does gluten trigger autoimmune celiac disease?

• Fractions of gluten proteins in

intestine get through intestinal
barrier (leaky gut)
• Tissue transglutamidase type 2
(tTG) enzyme
converts gluten to toxic gliadin
fragments
• These toxic gliadin proteins
interact with white blood cells
via surface HLA DQ2 &/or DQ8
protein molecules
How is Celiac Sprue diagnosed?
 Positive specific blood test
 Tissue transglutaminase antibody (tTG)
 Endomysial antibody (EMA)
 Serology less reliable < 5 yr old age

 Abnormal biopsy of small bowel

 Villous blunting/atrophy, crypt hyperplasia, intra-
epithelial lymphocytes
 Patchy distribution, multiple biopsies needed

 Symptom improvement on a gluten-free diet

& normalization of serologies and/or biopsy
 Celiac Blood Tests
 IgA endomysial antibody (IgA EMA)
 IgA tissue transglutaminase antibody (IgA tTG)
 Positive >90% of untreated Celiacs
 Can be negative in mild disease, IgA
deficient, immunosuppressives
 Rarely positive in non-Celiacs
 Since 10% Celiac are IgA deficient tests could be
negative in those individuals
 IgG antigliadin more sensitive in this setting
but accused on having high false positive
 “ N o r m a l ” individuals, probably NCGS/latent
Celiacs; c o w ’ s milk allergy and post-viral
enteritis
 Endomysial IgA antibody (EMA)
 Bind to endomysium, connective tissue
around smooth muscle
 Produces a characteristic staining pattern
seen under immunofluorescence
 Simply reported as either positive or
negative
 If positive, considered diagnostic
 May be misinterpreted by some labs
Anti-Tissue transglutaminase antibodies (tTG)

• Enzyme present throughout body (brain, skin,

and intestine)
 Antigen directed against EMA
 Positive in setting of characteristic biopsy is
definitive for Celiac
 Falsely negative when IgA deficient (10-20% of
Celiac disease patients)
 Only positive in 40%, usually negative in early
or mild celiac
“Non-specific” Celiac Tests
• Antigliadin antibodies (AGA) more sensitive
detecting gluten sensitivity
• AGA used to monitor compliance or hidden
exposure
• Becomes positive early and stays positive
later
• Increased sensitivity of IgG antigliadin
accused of high false positives
– Reportedly positive in “ n o r m a l ”
individuals, c o w ’ s milk allergy, post-viral
infection, Cr ohn ’ s disease
• More likely reflects non-Celiac gluten sensitive
individuals and early Celiac
Natural History of Positive Endomysial Antibody
(EMA) With Normal Duodenal Biopsy

• 96% who tried GFD improved

• 88% on normal diet developed villous
atrophy on follow-up biopsies
• Positive (EMA) indicates gluten
sensitivity, even if biopsy is normal
• Positive EMA is not a false positive
test
 “Normal biopsies” do
not exclude Celiac
disease
• Positive endomysial antibody
with “ n o r m a l ” biopsy but
abnormal immuhistochemistry
stains

• All became EMA negative on

gluten free diet who tried GFD
 Seronegative Celiac Disease
Celiac disease with negative blood
tests
• Celiac disease
• 71% total villous atrophy (TVA)
• 29% had partial villous atrophy
(PVA)
• 67% with PVA had a negative
EMA
• 23% with TVA had a negative
EMA
• You can be a Celiac with NEGATIVE
EMA blood test!
• Abrams et.al. Dig Dis Sci. 2004 Apr;49(4):546-50
Celiac Disease Villous Atrophy

Copyright (c) 2014 Scot M.

Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Scalloped Folds & Mosaic Mucosal
Pattern

Copyright (c) 2014 Scot M.

Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
 Celiac Specific Blood Tests
 IgA endomysial antibody (IgA EMA)

 IgA tissue transglutaminase antibody (IgA

tTG)

 Positive >90% of untreated Celiacs

 Can be negative in mild disease,
 Can be negative in IgA deficient or
immunosuppressived
 Rarely positive in non-Celiacs
 EMA negative reported that are severe,
more likely men, and higher risk of
lymphoma
 Celiac Specific Blood Tests
• IgA endomysial antibody (IgA EMA)
• IgA tissue transglutaminase antibody (IgA
tTG)
• Positive >90% of untreated Celiacs
– Can be negative in mild disease, IgA deficient,
immunosuppressives
• Rarely positive in non-Celiacs
• Since % Celiac are IgA deficient tests could
be negative in those individuals
• IgG antigliadin more sensitive in this setting
but high false positive
– Normal individuals, c o w ’ s milk allergy, post-
viral
 Definitive Diagnosis of Celiac
Disease
• Concordant positive serology + biopsy
• Presumptive diagnosis made
• Gluten-free diet started
• Symptoms resolve
• Normalization of biopsy no longer required
for definitive diagnosis though supports
• Older standard required challenge with
documentation of return symptoms and
abnormal biopsy
 What about patient started gluten-
free diet without testing?
• Cannot confirm or exclude diagnosis
• Recommend gluten-challenge followed by
– Serologic testing
• If positive, then biopsy to confirm diagnosis
• If negative or individual declines to undergo gluten
challenge then HLA DQ2, DQ8 testing an option
– If negative, extremely unlikely Celiac
– If positive, as already noted, repeat serology and/or
biopsy after additional interval on gluten
containing diet
• Resolution of symptoms on gluten-free diet not sufficient
to diagnose Celiac, though no adverse nutritional effects
from careful gluten-free diet
 Further Diagnosis
• Normal biopsy after gluten
avoidance
• Symptoms & abnormal biopsy
return with gluten challenge
• HLA DQ2 &/or HLA DQ8 positive
supportive
Assessing Duodenal Biopsies
Marsh Classification
 Celiac disease pathology

Normal slender finger like villi

3-5:1 villous to crypt ratio
No increased intraepithelial
lymphocytes
Abnormal is blunted to flat,
villous to crypt ratio <3:1,
increased IELs
Celiac Disease-Subtotal Villous
Atrophy
 Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
 Intraepithelial Lymphocytosis
“Marsh I Lesion”

• Immune active white blood cells (lymphocytes)

are normally present in villi but not
excessively in tips

• Increased numbers of lymphocytes or I E L ’ s

with normal villi is earliest abnormality with
gluten challenge
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
 Intraepithelial Lymphocytosis
“Marsh I Lesion”

• Increased lymphocytes or I E L ’ s in tips of villi is

highly suggestive of gluten sensitivity
• But may also be seen in other conditions like
giardiasis, H. pylori infection, c o w ’ s milk
protein allergy (CMPA) or intolerance (CMPI)

Copyright (c) 2014 Scot M.

Lewey, DO, FACP, FACG - Peak
Gastroenterology
 Immunohistochemical staining
makes it easier to see early changes
• Immune staining
using antibodies that
are specific for the
lymphocytes cells
makes it easier to see
and count numbers
of I E L ’ s

• Increased I E L ’ s in
villous tip show up as
reddish brown cells
Immunohistochemical
staining
• Stains are very accurate

• Reproducible

• Reduces subjective
reading error.

• But these stains are not

routinely performed and
have to be requested.
This can be important in
early Celiac disease or
in those who have
already restricted GFD.
t
Whether to take biopsy in
normal looking mucosa ??
• Biopsies can confirm Celiac disease
type changes and assess their severity.

• Biopsies may suggest Celiac disease

by early changes that may only be seen
on special stains especially if gluten
has been restricted.

• Biopsies may reveal another diagnosis

or abnormality not otherwise detectable
without a biopsy.
Routine biopsies of duodenum strongly encouraged

Prevalence of Celiac disease is 1% in general population but much higher in

patients presenting for EGD for symptoms

Histological changes may be present with “ n o r m a l ” appearing mucosa or

subtle mucosal abnormalities not appreciated by endoscopist

Duodenal biopsy rates during EGD varied from 30%-74% per CORI
4 biopsies should be done of
duodenum
No excuse for failure to obtain
duodenal biopsies
 What about patient started gluten-
free diet without testing?
• Cannot confirm or exclude diagnosis
• Recommend gluten-challenge followed by
– Serologic testing
• If positive, then biopsy to confirm diagnosis
• If negative or individual declines to undergo gluten
challenge then HLA DQ2, DQ8 testing an option
– If negative, extremely unlikely Celiac
– If positive, as already noted, repeat serology and/or
biopsy after additional interval on gluten
containing diet
• Resolution of symptoms on gluten-free diet not sufficient
to diagnose Celiac, though no adverse nutritional effects
from careful gluten-free diet
Non-Celiac gluten sensitivity diarrhea
reverses with gluten free diet
• Girls with chronic severe diarrhea
• Explosive watery diarrhea also
occurring at night
• Symptoms included loss of appetite,
malaise, weight loss & abdominal pain
• Normal blood tests
• Duodenal biopsies: “ n o r m a l ” except
intra-epithelial lymphocytes
• Therefore were note Celiac Disease
using strict criteria for diagnosis
Non-celiac gluten sensitivity (NCGS)
• Duodenal biopsies “ n o r m a l ” except
intraepithelial lymphocytes
• However, with gluten-free diet chronic
diarrhea resolved
• Increased I E L ’ s resolved
• Gluten challenge & diarrhea recurred
• Gluten causes inflammation of gut that
causes of diarrhea even if biopsy
“ n o r m a l ” or non-diagnostic and
blood tests are normal
• NCGS exists
Old belief = Celiac disease
Celiac disease is rare
1/2000-5000 people world wide
EMA or tTG specific Celiac
blood tests positive 1/250 to
1/100
Duodenal biopsy is “ g o l d
standard” for diagnosis
95-99% Celiac disease are
DQ2 &/or DQ8 positive
New paradigm gluten sensitive
Celiac disease common
1/100 1/3 to 1/10 gluten
sensitivity
1/8 positive blood gliadin
1/3 positive stool gliadin +/- tTG
Biopsy not gold standard
Increase IELs, EM studies
1/1.6 DQ risk for gluten sensitivity
 How is Celiac treated?
• Lifelong gluten free diet
• Exclude wheat, rye, & barley
• Oats safe in most but cross
contamination
• 70% with symptoms @ diagnosis notice
improvement in intestinal symptoms
within 2 weeks of beginning gluten-free
diet
• Even small amounts of gluten can cause
disease & symptoms.
 CONCLUSIONS
Regarding Celiac Disease
• Celiac disease is common but non-celiac
gluten sensitivity is much more common
• Though abnormal specific blood tests and an
abnormal biopsy can confirm celiac disease,
normal biopsies neither exclude celiac nor
gluten sensitivity
• Abnormal specific blood tests likely confirm
celiac disease even if biopsy is
“normal”
 CONCLUSIONS
Regarding Non-Celiac Gluten
Sensitivity
• Abnormal gliadin antibodies or non-specific blood
tests likely indicate gluten sensitivity
• Elevated gliadin antibodies may be earliest sign of
celiac disease before specific blood tests or biopsy
are abnormal
• Symptoms that respond to a gluten-free diet indicate
gluten sensitivity
• The presence of stool gliadin antibodies predict
response to gluten free diet and support diagnosis of
non-celiac gluten sensitivity
Celiac disease Algorithm
Thank you..