Celiac Disease, Gluten Sensitivity_Dr. Scot Lewey

Celiac & Gluten Sensitivity

Scot Michael Lewey, DO, FACG, FASGE, AGAF, FACOI, FACP, FAAP, FACOP
Gastroenterologist
Peak Gastroenterology Associates
Clinical Professor of Medicine
Rocky Vista University-College of Osteopathic Medicine
&
Kansas City University of Medicine and Bioscience
www.thefooddoc.com www.peakgastro.com
@thefoodgutdoc
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Facebook.com/thefooddoc
Gastroenterology Associates,

Differential Diagnosis of Abdominal Pain, Diarrhea &
Bloating
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Inflammatory Bowel Disease (IBD)
– Ulcerative Colitis (UC), Crohn’s Disease (CD), Diverticular
Associated Colitis (DAC)
– Microscopic Colitides
• Lymphocytic Colitis (LC), Collagenous Colitis (CC), & Mastocytic
Enterocolitis (MCE)
Celiac Disease-Celiac Sprue (CS)
– Non-Celiac Gluten Sensitivity (NCGS)
Diarrhea Predominant Irritable Bowel Syndrome (IBS-D)
Carbohydrate Intolerances
– Lactose Intolerance (LI)
– Fructose Intolerance (FI)
Dysbiosis/Altered Gut Flora
Gastroenterology

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 Scot M.
result
Copyright (c) 2014

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
Gastroenterology

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 diet (c) 2014 Scot M.
Copyright
Gastroenterology

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

Gastroenterology

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
Gastroenterology

“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 “not specific” for Celiac disease
•40% of U.S. HLA DQ2 or DQ8+, the major genes
predisposing to CD
Gastroenterology

Clues that celiac should be
considered-screen

Gastroenterology

Celiac is frequently missed by primary care physicians
Primary Care Physician Awareness

Percentage

Wheat intolerance
Onset of symptoms in adults existed

95%
32%

Diarrhea as a symptom
IBS symptoms are common
Chronic abdominal pain common
Fatigue is common
Depression & irritability common
Associated with diabetes
Associated with anemia
Associated with osteoporosis
Diagnosed by blood tests

90%
71%
67%
54%
24%
13%
45%
45%
44%

Copyright (c) Med. 2005;
Zipser et.al J Gen Intern 2014 Scot M. 20(7):644-6

Celiac & IBS Link Recognized
Increasingly


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Historically, it has been reported that patients with undetected celiac
disease (CD) may present with irritable bowel syndrome (IBS) type
symptoms.
This has led to the recommendation by the American College of
Gastroenterology Task force that patients presenting with diarrhea
predominant IBS type symptoms should be serologically tested for CD.
Concurrently speculative media data suggest that the US general public
have increased their uptake of a gluten-free diet (GFD) far in excess of the
known prevalence of CD.
This may suggest that individuals with gastrointestinal symptoms are
deriving benefit from a GFD even if they do not have CD. This has led to
the scientific community considering the evidence for an emerging concept
of non-celiac wheat sensitivity.
There is a significant disparity in our views about what this phenomenon
may be. There is also confusion about the nomenclature for this entity and
indeed whether patients are suffering due to symptoms related to gluten or
perhaps other components of wheat, for example fructans….we see
evidence to support the clinical concept of wheat sensitivity or intolerance..
Am. J. Gastroenterol. 2012 (12):1908-12
Gastroenterology

Popularity of Gluten Sensitivity
& Celiac online


HLA Genetics
• All of us have “white blood cell types” based on
inherited HLA genes Just like we have a red
blood cell types (I’m A positive) we have white
blood cell types (I’m DQ2/DQ7)
• Our HLA “white blood cell types” are
inherited
• Our HLA protein types determine our risk for
certain diseases, especially autoimmune diseases
like Celiac disease & type I Diabetes

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
Gastroenterology

Ancient & Early Celiac History
• Aretaeus of
Cappadocia 250 A.D.
• Described “koiliakos”
which meant “suffering in
the bowels”
• Francis Adams translated
Aretaeus observations
from Greek to English for
the Sydenham Society of
England in 1856
• “Koiliakos” became
Celiac or Coeliac

Gastroenterology

Dr. Samuel Gee
• 1888 Dr. Samuel Gee of the
Great Ormond Street Hospital
for Children in the U.K.
• Published “On the Coelic
Affliction”
• Recognized dietary cause
but mistakenly advised
gluten containing foods
• Presented accounts of both
children & adults with Coeliac

• “to regulate food is the main
part of treatment. The
allowance of farinaceous foods
must be small, but if the patient
can be cured at all, it must be
by means of diet”

Dr Hass & the “Banana Diet”
• 1924 NY Pediatrician Sidney Valentine Haas
described treatment banana diet, excluded bread,
crackers, potatoes & cereals, later published
“The Management of Celiac Disease” in 1951
• Described cures of Celiac with diet
• Led to many individuals now with untreated
Celiac

Gastroenterology

Dr. Dicke linked gluten to Celiac
• Dutch pediatrician Willem K.
Dicke Netherlands suspected
grain as cause
• During WWII scarcity of
cereals & breads & noted
Celiac Sprue diminished
remarkably during this
shortage
• Observed relapse after air lift
bread by Swedish planes into
Netherlands
• He then found that alcohol
soluble fraction of wheat gluten
known as gliadin was toxic
portion of wheat
• Published his thesis
Gastroenterology

Celiac History- Role of Intestinal Biopsy
• 1954 Pauley reported abnormal
appearance of jejunal mucosa obtained
at operation
• Shiner & Royal independently
developed biopsy method
• Crosby developed suction capsule
“Crosby capsule” swallowed by
patients

Elaine Gottschall & SCD
• Elaine Gottschall
housewife with
daughter with IBD
“cured”
• Becomes PhD
• Publishes “Breaking
the Vicious Cycle”
• Specific
Carbohydrate Diet
“SCD”

Gastroenterology

History of the Celiac Blood Tests
• 1971 reticulin antibodies described,
specific but not sensitive
• Gliadin antibodies
• Endomysial antibodies
• 1997 tissue transglutaminase antibody
(tTG) established as autoantigen for
endomysial antibody
• HLA DQ genetic testing in past several
years

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, intraepithelial lymphocytes
 Patchy distribution, multiple biopsies needed

 Symptom improvement on a gluten-free diet &
normalization of serologies and/or biopsy
Gastroenterology

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
 “Normal” individuals, probably NCGS/latent
Celiacs; cow’s milk allergy and post-viral enteritis
Gastroenterology

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
Gastroenterology

“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 “normal”
individuals, cow’s milk allergy, post-viral
infection, Crohn’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
Gastroenterology

“Normal biopsies” do not
exclude Celiac disease
• Positive endomysial antibody
with “normal” biopsy but
abnormal immuhistochemistry
stains
• All became EMA negative on
gluten free diet who tried GFD

Gastroenterology

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


Scalloped Folds & Mosaic Mucosal
Pattern


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, cow’s milk allergy, post-viral
Gastroenterology

Definitive Diagnosis of Celiac
Disease
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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
Gastroenterology

What about patient started glutenfree 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

History of the Small Bowel
Biopsy
1954 Pauley reported abnormal
appearance of jejunal mucosa
obtained at operation
Shiner & Royal independently
developed biopsy method
Crosby developed suction capsule
“Crosby capsule” swallowed by
patients

Close-up of Crosby Capsule


X-ray of Crosby-Kugler Capsule

Gastroenterology

Assessing Duodenal Biopsies


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


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 IEL’s
with normal villi is earliest abnormality with
gluten challenge
Gastroenterology

Intraepithelial Lymphocytosis
“Marsh I Lesion”

• Increased lymphocytes or IEL’s in tips of villi is
highly suggestive of gluten sensitivity
• But may also be seen in other conditions like
giardiasis, H. pylori infection, cow’s milk protein
allergy (CMPA) or intolerance (CMPI)

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
IEL’s
• Increased IEL’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 gluten
in their diet.

Normal biopsies may not be
normal

• Pathologists reading the intestinal
biopsies have varying degree of
experience

• They also may have a negative bias
towards “over diagnosing” Celiac
disease
Biopsies that are “normal” under
routine light microscope have been
shown to be abnormal when examined
with special stains and research based
electron microscopyFACG - Peak
Lewey, DO, FACP,

Normal biopsies may not be
normal
• Pathologists reading the intestinal
biopsies have varying degree of
experience
• They also may have a negative bias
towards “over diagnosing” Celiac
disease
• Biopsies that are “normal” under
routine light microscope have been shown
to be abnormal when examined with
(c) 2014 Scot M.
special stainsCopyrightFACP, FACG - Peakbased
and research
Lewey, DO,
electron microscopy
Gastroenterology

Electron Microscopy of Villi

 Electron microscopy abnormalities may be
seen on intestine biopsies when biopsy
appears normal
 Gluten injury may be (c) 2014 Scot M. when biopsy
Copyright present
Lewey, DO, FACP, FACG
appears normal Gastroenterology - Peak

“Normal biopsies” not always
normal
• People with a positive celiac blood test positive
had a “normal” biopsies have been studied
using research electron microscopy (EM)
• Majority have abnormal electron microscopy
studies of biopsies
• Therefore normal biopsies may not be normal
and do not exclude Celiac disease especially
when blood tests are positive

Conclusions
• 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 “normal” appearing mucosa or
subtle mucosal abnormalities not appreciated by endoscopist
Duodenal biopsy rates during EGD varied from 30%-74% per CORI

Gastroenterology

4 biopsies should be done of
duodenum

Gastroenterology

No excuse for failure to obtain
duodenal biopsies

Gastroenterology

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: “normal” except
intra-epithelial lymphocytes
• Therefore were note Celiac Disease
using strict criteria for diagnosis


Non-celiac gluten sensitivity (NCGS)
• Duodenal biopsies “normal” except
intraepithelial lymphocytes
• However, with gluten-free diet chronic
diarrhea resolved
• Increased IEL’s resolved
• Gluten challenge & diarrhea recurred
• Gluten causes inflammation of gut that
causes of diarrhea even if biopsy
“normal” or non-diagnostic and
blood tests are normal
• NCGS exists

Elevated stool gliadin antibodies
Population (Number)

Positivity Rate (%)

Untreated Celiac (20)

100%

Microscopic colitis (63)

75%

Chronic diarrhea (182)

49%

Normal (37)

32%

“Symptomatic” (14)

57%

Treated Celiacs (11)

9%


The “iceberg” or “hidden epidemic”
of Non-Celiac gluten sensitivity
• >60% those tested had one of HLA DQ
types predisposing to gluten sensitivity
• All untreated Celiacs had elevated stool
antibodies to gluten
• >50% of high risk & symptomatic
individuals had elevated stool AGA IgA with
or without + fecal tTG IgA)
• 35% of normal individuals tested had
elevated stool antibodies to gluten

Gastroenterology

Old belief = Celiac disease

New paradigm gluten sensitive

Celiac disease is rare
1/2000-5000 people world wide

Celiac disease common 1/100
1/3 to 1/10 gluten sensitivity

EMA or tTG specific Celiac
blood tests positive 1/250 to
1/100

1/8 positive blood gliadin
1/3 positive stool gliadin +/- tTG

Duodenal biopsy is “gold
standard” for diagnosis

Biopsy not gold standard
Increase IELs, EM studies

95-99% Celiac disease are DQ2
&/or DQ8 positive

1/1.6 DQ risk for gluten sensitivity


New Paradigm: Gluten sensitivity not just a gut disease
• Gluten Sensitivity, Celiac Disease, & Celiac Sprue
used synonymously for years but to quote
Hadjivassiliou in 2004:
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“the systemic nature of this disease, the
overwhelming evidence of an immune pathogenesis
and the accumulating evidence of diverse
manifestations involving organs other than the
gut, such as the skin (dermatitis herpetiformis) and
the nervous system (gluten ataxia, gluten
neuropathy), necessitates a re-evaluation of the
belief that gluten sensitivity is solely a disease of the
gut.”

• Hadjivassiliou et.al. in Trends in Immunology 2004
Nov; 25(11):578-582
Gastroenterology

Diagnosis and classification of celiac disease and gluten sensitivity.
Autoimmun Rev 2014
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Celiac disease is a complex disorder, the development of which is controlled by a
combination of genetic (HLA alleles) and environmental (gluten ingestion) factors.
New diagnostic guidelines developed by ESPGHAN emphasize the crucial role of
serological tests in the diagnostic process of symptomatic subjects, and of the detection
of HLA DQ2/DQ8 alleles in defining a diagnosis in asymptomatic subjects belonging to
at-risk groups.
The serological diagnosis of CD is based on the detection of class IgA anti-tissue
transglutaminase (anti-tTG) and anti-endomysial antibodies. In patients with IgA
deficiency, anti-tTG or anti-deamidated gliadin peptide antibody assays of the IgG class
are used.
When anti-tTG antibody levels are very high, antibody specificity is absolute and CD can
be diagnosed without performing a duodenum biopsy.
Non-celiac gluten sensitivity is a gluten reaction in which both allergic and autoimmune
mechanisms have been ruled out.
Diagnostic criteria for NCGS include the presence of symptoms similar to those of celiac
or allergic patients; negative allergological tests and absence of anti-tTG and EMA
antibodies; normal duodenal histology; evidence of disappearance of the symptoms with
a gluten-free diet; relapse of the symptoms when gluten is reintroduced.

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 Scot M.
Copyright (c) 2014
Gastroenterology

New Paradigm: Gluten Sensitivity Is
Not Just a Disease of the Gut
“the systemic nature of this disease, the
overwhelming evidence of an immune
pathogenesis and the accumulating
evidence of diverse manifestations
involving organs other than the gut, such
as the skin (dermatitis herpetiformis) and
the nervous system (gluten ataxia, gluten
neuropathy), necessitates a re-evaluation
of the belief that gluten sensitivity is
solely a disease of the gut.”
Dr. M Hadjivassiliou, 2004
Gastroenterology

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

Gliadin does not induce mucosal inflammation or basophil activation in patients with
nonceliac gluten sensitivity. Clin. Gastroenterol. Hepatol. 2013
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Nonceliac gluten-sensitive (NCGS) patients report intestinal and extra-intestinal symptoms shortly
after ingesting gluten; these symptoms disappear on gluten-free diets, although these patients have
no serologic markers of celiac disease or intestinal damage.
There is no evidence for mucosal or serologic modifications in those individuals.
Investigation of immunologic responses of duodenal mucosa samples and peripheral blood
basophils, isolated from NCGS patients, after exposure to gliadin. Participants underwent a complete
clinical evaluation to exclude celiac disease while on a gluten-containing diet, a skin prick test to
exclude wheat allergy, and upper endoscopy (n = 119) at 2 tertiary medical centers in Italy.
Patients were considered to have NCGS based on their symptoms and the current definition of the
disorder.
Subjects were assigned to the following groups: patients with celiac disease on gluten-free diets (n =
34), untreated patients with celiac disease (n = 35), patients with NCGS (n = 16), or controls (n = 34)
Duodenal mucosa samples collected from 69 patients with celiac disease showed markers of
inflammation after incubation with gliadin. Some, but not all, markers of inflammation were detected
weakly in biopsy samples from 3 controls and 3 NCGS patients (P = .00 for all markers).
There were no significant increases in the levels of CD63 and CD203c in NCGS patients.
Unlike the duodenal mucosa from patients with celiac disease, upon incubation with gliadin, mucosa
from patients with NCGS does not express markers of inflammation, and their basophils are not
activated by gliadin.
In vitro gliadin challenge therefore should not be used to diagnose NCGS.

Gastroenterology

Non-coeliac gluten sensitivity: hype, or new epidemic?
Ned Tijdschr Geneeskd 2013 (21)
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Coeliac disease is an immune-mediated inflammation of the small
intestine caused by sensitivity to dietary gluten and related proteins in
genetically sensitive individuals.
Recently, a novel gluten-related disorder has gained significant interest
from the scientific community and mass media. This condition, known
as non-coeliac gluten sensitivity, is characterised by gastrointestinal or
extra-intestinal symptoms that respond to gluten withdrawal without
evidence of underlying coeliac disease.
Its symptoms overlap considerably with those of irritable bowel
syndrome and the number of individuals embracing a gluten-free diet is
rapidly growing.
No discriminative markers to support a diagnosis of gluten sensitivity
have been identified; the perceived response to a gluten-free diet after
exclusion of coeliac disease is currently the best diagnostic and
therapeutic marker.
Its pathogenesis remains obscure but may be related to non-gliadin
molecules in grains that stimulate the innate immune system of the
intestine.

Prevalence of gluten-free diet adherence among individuals without celiac disease in the
USA: results from the Continuous National Health and Nutrition Examination Survey
2009-2010
Scand. J. Gastroenterol. 2013
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Clinical inference suggests the prevalence of non-celiac gluten sensitivity is substantially higher than
that of celiac disease in the USA.
Unfortunately, there are currently no data supporting these claims. The authors analyzed nationally
representative data to estimate the prevalence of adherence to a gluten-free diet among participants
without celiac disease and also to characterize the demographics and general health status of these
participants.
The Continuous National Health and Nutrition Examination Survey (NHANES) 2009-2010 enrolled
7762 individuals representing the civilian, non-institutionalized, US population free of celiac disease.
Participants responded to interviewer administered questionnaires regarding current adherence to a
gluten-free diet. Prevalence estimates were computed using SAS survey procedures.
There were 49 individuals who reported current adherence to a gluten-free diet reflecting a weighted
prevalence of 0.548% (95% CI 0.206-0.889).
The prevalence of a gluten-free diet was higher in females (0.58%) than males (0.37%), although this
was not statistically significant (p = 0.34).
Participants reporting a gluten-free diet were older (46.6 vs. 40.5 years, p = 0.005), had higher highdensity lipoprotein, lower iron and lower body mass index
The estimated national prevalence of non-celiac gluten sensitivity is 0.548%, approximately half that
of celiac disease.
Future studies are merited in order to better understand the population burden of non-celiac gluten
sensitivity

Non-celiac gluten sensitivity: questions still to be answered despite
increasing awareness
Cell. Mol. Immunol. 2013
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Recently, the increasing number of patients worldwide who are sensitive to dietary gluten without
evidence of celiac disease or wheat allergy has contributed to the identification of a new gluten-related
syndrome defined as non-celiac gluten sensitivity.
Our knowledge regarding this syndrome is still lacking, and many aspects of this syndrome remain
unknown. Its pathogenesis is heterogeneous, with a recognized pivotal role for innate immunity; many
other factors also contribute, including low-grade intestinal inflammation, increased intestinal barrier
function and changes in the intestinal microbiota.
Gluten and other wheat proteins, such as amylase trypsin inhibitors, are the primary triggers of this
syndrome, but it has also been hypothesized that a diet rich in fermentable monosaccharides and polyols
may elicit its functional gastrointestinal symptoms. The epidemiology of this condition is far from
established; its prevalence in the general population is highly variable, ranging from 0.63% to 6%.
From a clinical point of view, non-celiac gluten sensitivity is characterized by a wide array of
gastrointestinal and extraintestinal symptoms that occur shortly after the ingestion of gluten and improve
or disappear when gluten is withdrawn from the diet. These symptoms recur when gluten is reintroduced.
Because diagnostic biomarkers have not yet been identified, a double-blind placebo-controlled gluten
challenge is currently the diagnostic method with the highest accuracy.
Future research is needed to generate more knowledge regarding non-celiac gluten sensitivity, a
condition that has global acceptance but has only a few certainties and many unresolved issues.


Mucosal cytokine response after short-term gluten challenge in celiac disease and
non-celiac gluten sensitivity.Am. J. Gastroenterol. 2013 (5):842-50
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Celiac disease (CD), gluten induces both adaptive and innate immune responses.
Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the
immune response is less characterized.
Comparison of early mucosal immunological events in CD and NCGS by challenging
30 HLA-DQ2(+) NCGS and 15 CD patients, all on a gluten-free diet, with four slices
of gluten-containing bread daily for 3 days. Duodenal biopsy specimens were
collected before and after challenge.
In CD patients, tumor necrosis factor alpha (P=0.02) and interleukin 8 (P=0.002)
mRNA increased after in vivo gluten challenge. The interferon gamma (IFN-γ) level
of treated CD patients was high both before and after challenge and did not increase
significantly (P=0.06). Four IFN-γ-related genes increased significantly.
Treated and untreated CD patients had comparable levels of IFN-γ. Increased
expression of MxA in treated CD patients after challenge suggested that IFN-α was
activated on gluten challenge. In NCGS patients only IFN-γ increased significantly
(P=0.03)
Importantly, we found that the density of IELs was higher in NCGS patients
compared with disease controls, independent of challenge, although lower than the
level for treated CD patients.CD patients mounted a concomitant innate and adaptive
immune response to gluten challenge.
NCGS patients had increased density of intraepithelial CD3(+) T cells before
challenge compared with disease Copyrightand 2014 Scot M.
controls (c) increased IFN-γ mRNA after
challenge.
Gastroenterology

Non-celiac gluten sensitivity: clinical relevance and
recommendations for future research.
Neurogastroenterol. Motil. 2013
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There has been increasing interest in the entity of Non-Celiac Gluten Sensitivity
(NCGS) in recent years; however, it still remains a controversial topic and its
pathogenesis is not well understood.
Celiac Disease, in contrast, is a well-studied condition that has become increasingly
recognized as a prevalent condition arising from a heightened immunological
response to gluten
Wheat allergy is an IgE-mediated condition capable of causing a variety of
gastrointestinal symptoms.
However, the number of patients who have neither celiac disease nor wheat
allergy, but appear to derive benefit from a gluten-free diet, is also increasing
substantially.
The use of the term NCGS as a way of describing this condition has become
increasingly prevalent in recent years.
There is evidence for the condition but it’s putative pathogenesis is in dispute.
There are areas of controversy and areas for potential future research.
Gastroenterology

Is gluten a cause of gastrointestinal symptoms in people without
celiac disease?
Curr Allergy Asthma Rep 2013
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The avoidance of wheat- and gluten-containing products is a worldwide
phenomenon.
While celiac disease is a well-established entity, the evidence base for gluten
as a trigger of symptoms in patients without celiac disease (so-called 'nonceliac gluten sensitivity' or NCGS) is limited.
The problems lie in the complexity of wheat and the ability of its carbohydrate
as well as protein components to trigger gastrointestinal symptoms, the
potentially false assumption that response to a gluten-free diet equates to an
effect of gluten withdrawal, and diagnostic criteria for coeliac disease.
Recent randomized controlled re-challenge trials have suggested that gluten
may worsen gastrointestinal symptoms, but failed to confirm patients with selfperceived NCGS have specific gluten sensitivity.
Furthermore, mechanisms by which gluten triggers symptoms have yet to be
identified but there is recent scientific evidence supporting the entity of NCGS.


Non-Celiac Gluten sensitivity: the new frontier of gluten related
disorders.
Nutrients 2013
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Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a
"re-discovered" disorder characterized by intestinal and extra-intestinal symptoms
related to the ingestion of gluten-containing food, in subjects that are not affected with
either celiac disease (CD) or wheat allergy (WA).
Although NCGS frequency is still unclear, epidemiological data have been generated
that can help establishing the magnitude of the problem.
Clinical studies further defined the identity of NCGS and implications in human disease.
An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected,
requiring even more stringent diagnostic criteria.
Several studies suggest a relationship between NCGS and neuropsychiatric disorders,
particularly autism and schizophrenia.
The first case reports of NCGS in children have been described.
Lack of biomarkers is still a major limitation of clinical studies, making it difficult to
differentiate NCGS from other gluten related disorders.
Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin
inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can
contribute to symptoms (at least those related to IBS) experienced by NCGS patients.
Gastroenterology

A UK study assessing the population prevalence of self-reported
gluten sensitivity and referral characteristics to secondary care.
Eur J Gastroenterol Hepatol 2014
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Reports suggest that gluten sensitivity (GS) exists in the absence of coeliac disease (CD).
This clinical entity has been termed noncoeliac gluten sensitivity (NCGS).
To determine the population prevalence of self-reported GS and referral characteristics to secondary
care.A UK population-based questionnaire screened for GS and related symptoms.
Diagnostic outcomes were also analyzed in patients referred to secondary care with GS. CD
diagnosis entailed a positive coeliac serology (endomysial and/or tissue transglutaminase antibodies)
plus Marsh 1-3 on duodenal biopsies. NCGS diagnosis was based on exclusion of CD.
Clinical comparisons were made between NCGS and CD.A total of 1002 adults in the population
(female 55%, mean age 39 years).
The self-reported prevalence for GS was 13% (female 79%, mean age 39.5 years, P<0.0001), with
3.7% consuming a gluten-free diet and 0.8% known to have a doctor diagnosis of CD. Individuals
with GS had an increased prevalence of fulfilling the Rome III criteria for irritable bowel syndrome, in
comparison with those without GS (20 vs. 3.89%, odds ratio 6.23, P<0.0001).
In secondary care 200 GS patients (female 84%, mean age 39.6 years) were investigated, in whom
7% were found to have CD and 93% to have NCGS. All CD patients were human leucocyte antigen
DQ2 or DQ8 positive compared with 53% of NCGS cases (P=0.0003).
Nutritional deficiencies (P≤0.003), autoimmune disorders (23.1 vs. 9.7%, P=0.0001) and a lower
mean BMI (23.7 vs. 25.8, P=0.001) were significantly associated with CD compared with NCGS.
GS is commonly self-reported with symptoms suggesting an association with irritable bowel
syndrome. The majority of patients have NCGS, an entity which demonstrates clinical and
immunologic difference to CD.

Clinical, Serologic, and Histologic Features of Gluten Sensitivity in Children.
J. Pediatr. 2013
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Study to describe the clinical, serologic, and histologic characteristics of children with gluten sensitivity
(GS).
15 children (10 males and 5 females; mean age, 9.6 ± 3.9 years) with GS who were diagnosed based
on a clear-cut relationship between wheat consumption and development of symptoms, after excluding
celiac disease (CD) and wheat allergy, along with 15 children with active CD (5 males and 10 females;
mean age, 9.1 ± 3.1 years) and 15 controls with a functional gastrointestinal disorder (6 males and 9
females; mean age, 8.6 ± 2.7 years).
All children underwent CD panel testing (native antigliadin antibodies IgG and IgA, anti-tissue
transglutaminase antibody IgA and IgG, and anti-endomysial antibody IgA), hematologic assessment
(hemoglobin, iron, ferritin, aspartate aminotransferase, erythrocyte sedimentation rate),
HLA typing, and small intestinal biopsy (on a voluntary basis in the children with GS).Abdominal pain
was the most prevalent symptom in the children with GS (80%), followed by chronic diarrhea in (73%),
tiredness (33%), bloating (26%), limb pain, vomiting, constipation, headache (20%), and failure to
thrive (13%).
Native antigliadin antibodies IgG was positive in 66% of the children with GS. No differences in
nutritional, biochemical, or inflammatory markers were found between the children with GS and
controls. HLA-DQ2 was found in 7 children with GS.
Histology revealed normal to mildly inflamed mucosa (Marsh stage 0-1) in the children with GS.
Our findings support the existence of GS in children across all ages with clinical, serologic, genetic,
and histologic features similar to those of adults.
Gastroenterology

Seroreactive marker for inflammatory bowel disease and associations with
antibodies to dietary proteins in bipolar disorder.
Bipolar Disord 2013
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Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar
disorder.
Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through
action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food
antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with
bipolar disorder.
We measured a marker of GI inflammation, anti-Saccharomyces cerevisiae antibodies (ASCA), in non-psychiatric
controls (n = 207), in patients with bipolar disorder without a recent onset of psychosis (n = 226), and in patients
with bipolar disorder with a recent onset of psychosis (n = 38).
We compared ASCA levels to antibodies against gluten, casein, Epstein-Barr virus (EBV), herpes simplex virus 1
(HSV-1), influenza A, influenza B, measles, and Toxoplasma gondii.
Elevated ASCA conferred a 3.5-4.4-fold increased odds ratio of disease association (age-, race-, and gendercorrected multinomial logistic regressions, p ≤ 0.00001) that was independent of type of medication received.
ASCA correlated with food antibodies in both bipolar disorder groups (R(2) = 0.29-0.59, p ≤ 0.0005), and with
measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group (R(2) = 0.310.36, p ≤ 0.004-0.01)
Elevated seropositivity of a GI-related marker and its association with antibodies to food-derived proteins and
self-reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder.
Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this
mood disorder.

Gastroenterology

Reactivity to dietary gluten: new insights into differential diagnosis
among gluten-related gastrointestinal disorders.
Pol. Arch. Med. Wewn. 2013
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The ingestion of dietary gluten sometimes may trigger allergic, autoimmune
or nonallergic and nonautoimmune response.
The typical gluten-related allergic disorder is the wheat allergy (WA).
Celiac disease (CD) is a well-known gluten-related autoimmune condition.
The clinical expression of a gluten-related nonallergic and nonautoimmune
response is nonceliac gluten sensitivity (NCGS), an emerging condition
whose framework is yet unclear and whose diagnosis is suggested only by
demonstration of gluten-dependency in patient' symptoms after exclusion of
WA and CD.
This review discusses the current tools to identify patients suffering from
WA, CD, and NCGS, as well as the most recent insights in the differential
diagnosis among these gluten-related gastrointestinal disorders .


Biomarkers of gluten sensitivity in patients with non-affective
psychosis: A meta-analysis.
Schizophr. Res. 2013
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Dohan first proposed that there may be an association between gluten sensitivity and schizophrenia
in the 1950s.
Since then, this association has been measured using several different serum biomarkers of gluten
sensitivity.
At this point, it is unclear which serum biomarkers of gluten sensitivity are elevated in patients with
schizophrenia.
However, evidence suggests that the immune response in this group is different from the immune
response to gluten found in patients with Celiac disease.
A systematic literature review was performed to identify all original articles that measured biomarkers
of gluten sensitivity in patients with schizophrenia and non-affective psychoses compared to a control
group. Three databases were used dating back to 1946 and a meta-analysis was performed of
specific biomarkers and reported according to MOOSE guidelines.
17 relevant original articles were identified, and 12 met criteria for the meta-analysis.
Five biomarkers of gluten sensitivity were found to be significantly elevated in patients with nonaffective psychoses compared to controls.
The pooled odds ratio and 95% confidence intervals were Anti-Gliadin IgG OR=2.31 [1.16, 4.58],
Anti-Gliadin IgA OR=2.57 [1.13, 5.82], Anti-TTG2 IgA OR=5.86 [2.88, 11.95], Anti-Gliadin
(unspecified isotype) OR=7.68 [2.07, 28.42], and Anti-Wheat OR=2.74 [1.06, 7.08]. Four biomarkers
for gluten sensitivity, Anti-EMA IgA, Anti-TTG2 IgG, Anti-DGP IgG, and Anti-Gluten were not found to
be associated with schizophrenia.
Not all serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia.
Copyright in 2014 Scot M.
However, the specific immune response to gluten (c)this population differs from that found in patients
with Celiac disease.
Gastroenterology

Non-celiac gluten sensitivity. Is it in the gluten or the grain?
J Gastrointestin Liver Dis 2013
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Celiac disease is an immune-mediated inflammatory disorder of the small
intestine caused by sensitivity to dietary gluten and related proteins in
genetically predisposed individuals.
Over the past several years, the concept of non-celiac gluten sensitivity
(NCGS) has gained significant interest from the scientific community and
mass media and the number of individuals embracing a gluten-free diet is
rapidly growing.
This condition is characterized by gastrointestinal or extraintestinal
symptoms that respond to gluten withdrawal without evidence for
underlying celiac disease or wheat allergy.
Symptoms display significant overlap with the irritable bowel syndrome.
Many important factors regarding this relatively novel condition remain to
be elucidated; no discriminative markers to support a diagnosis of gluten
sensitivity have been identified yet and its pathogenesis remains obscure.
Here we review the current knowledge on NCGS, and outline potential
pathogenic pathways of different gluten related disorders in order to gain
clues about the pathophysiology of this(c) 2014 condition.
Copyright novel Scot M.

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Leonardo da Vinci's face symmetry derives from 3 equal craniofacial segments
It has been reported that adult subjects with celiac disease (CD) can be
identified on the basis of a greater extension of the forehead in comparison to
the medium third of the face.
126 biopsy-proven patients with CD (76 children and 50 adults) and 102 healthy
controls (43 children and 59 adults). Their faces were photographed; the
pictures were edited using a software program to calculate the facial segments.
The tn length was significantly different between adult celiac and adult controls
(7.43 ± 1.46 cm vs 6.38 ± 1.73 cm, P = 0.001)
43 of 50 patients (sensitivity 86%), but 34 of 59 controls were positive
(specificity 54.2%). The positive predictive value was 56%. Neither the tn length
nor the tn/ns ratio in celiacs correlated to the time of gluten exposure.
Adults, but not children, with celiac disease show a forehead extension
significantly greater than controls, but this test's specificity appears too low to be
used in the screening of CD.
Leonardo da Vinci meets celiac disease.J. Pediatr. Gastroenterol. Nutr. 2013
(2):206-10Chiara Zanchi, Giovanna Ventura, Grazia Di Leo, Nicoletta Orzes,
Luca Ronfani, Tarcisio Not, Alessandro


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Food intolerance is a common complaint amongst patients with functional
gastrointestinal (GI) disorders (FGIDs), including those with irritable bowel
syndrome (IBS), functional dyspepsia, as well as gastroesophageal reflux
disease.
Although there has been a longstanding interest in the possible role of food
allergy in IBS, there are limited data supporting the association.
However, the prevalence of food allergy is sufficiently high that patients with
FGID may also have food allergies or hypersensitivities.
Food intolerances or sensitivities are reactions to foods, which are not due
to immunological mechanisms. Lactose intolerance is common in the
general population and can mimic symptoms of FGID or coexist with FGID.
Other carbohydrate intolerances may be responsible for symptom
generation in patients with IBS and perhaps other FGIDs.
There is a great interest in the role of a major dietary protein, gluten, in the
production of symptoms that are very similar to those of patients with celiac
disease without the enteropathy that characterizes celiac disease.
Emerging research into a syndrome known as nonceliac gluten sensitivity
suggests a heterogeneous condition with some features of celiac disease
but often categorized as FGIDs, including IBS..
Dietary proteins and functional gastrointestinal disorders.Am. J.
Gastroenterol. 2013 (5):728-36 DO, FACP, FACG - Peak
Lewey,

Celiac Disease, Gluten Sensitivity_Dr. Scot Lewey

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