Celiac disease

Gluten Sensitivity and
Celiac disease
Dr. Mohamed Naguib, MD
Associate professor of Int. Medicine
Hepatology and gastroenterology
GLUTEN SENSITIVITY
• MEETING POINT FOR GENETICS, PROTEIN
CHEMISTRY AND IMMUNOLOGY
 Western societies: 1% of the population
• Coeliac disease: caused by a genetically determined, specific immune
response to antigens present in wheat gluten, focused on a limited region of
the α-gliadin.
The antigenic 33-mer peptide generated by digestion with intestinal
enzymes produce a highly stimulatory antigen for CD4+ T cells. Moreover,
this peptide is resistant to further digestion by intestinal brush border
enzymes, because of it’s high proline and glutamine content.
•
The epitopes’ recognition by CD4+ T cells previously requires the
deamination of the glutamine residues by the tissue Transglutaminase
(TTG).
• Most to all patients with celiac disease express
human leukocyte antigen (HLA)-DQ2 or HLADQ8, which facilitate the immune response
against gluten proteins
What Is Gluten?
• A protein found in wheat, barley, rye, and
several other grains.
• After absorption in the small intestine these
proteins interact with the antigen-presenting
cells in the lamina propria causing an
inflammatory reaction that targets the
mucosa of the small intestine.
Gluten Intolerance Does Not Have to
Mean Celiac Disease.
• Many people know or suspect that there exist
non-celiac forms of gluten intolerance.
• Patients test negative on blood work and
biopsy for celiac disease, yet they know that
wheat and gluten trigger their symptoms.
What Is Villous Atrophy?
Villous atrophy is damage to the surface of
the small intestine.
This damage is a sign of gluten intolerance.
It occurs in symptomatic subjects with gastrointestinal
and non-gastrointestinal symptoms, and in some
asymptomatic individuals, including subjects affected
by
• Type 1 diabetes
• Williams syndrome
• Down syndrome
• Selective IgA deficiency
• Turner syndrome
• First degree relatives of individuals with celiac disease
Today’s World View of Celiac Disease
Common & Not Limited to Europeans
Finland:
~2.5%
North America
& Europe
0.6 to 2.5%
Northern India
?3%
SouthEast
Asia
CD Rare
Subsaharan
Africa
CD Rare
8
Celiac disease
An expanded perspective
 Who?
 Common in many ethnic
backgrounds
 When?
 Any age after gluten ingestion
 Average age at diagnosis ~45 yrs
 How?
 Highly diverse presentations.
 Average 11 years of symptoms
prior to diagnosis
Celiac Disease Foundation
Green AJG 2001, Cranney DDS 2007
9
Rising incidence of auto-immune
& allergic conditions
Type I
Diabetes
CD in
Finland
CD in
United States
Bach JF, NEJM 2002, Lohi et al. APT 2007, Rubio-Tapia Gastro 2009
10
Pathogenesis:
1 A component of gluten,
gliaden, interacts with a specific
genetic form of HLA receptor on
an antigen presenting cell.
2. Tissue transglutaminase
converts glutamine residues to
glutamic acid residues making
an even more potent antigen.
3. T helper cells are activated
and, in turn, activate B and
killer T cells.
4. Plasma cell antibodies bind to
gliadin bound to enterocytes,
tissue transglutaminase and
reticular fibers surrounding gut
smooth muscle (endomysial
ab’s).
5. T cells release (inappropriate)
inflammatory cytokines as well
as inflict tissue damage.
Source:NEJM 346:180, 2002
Biopsy of the intestine in a patient with no active disease following challenge
with gluten (~ 1 week). What is particularly notable is the infiltration of the
epithelium by lymphocytes (you can see the increased number of nuclei but it’s
hard to determine specific cell types!) Enterocytes also show damage.
Progress of the disease is shown on the next slide.
Normal intestinal biopsy
Small intestinal biopsy
in a patient with active
celiac disease
Source:NEJM
Normal intestinal surgical specimen
with distinct villi
Source: Pathology of the Gastrointestinal Tract, 2nd Ed.,
1998, Ed. by Ming and Goldman
Celiac disease specimen with
total loss of villi, the arrows
indicate crypt openings
Arrows indicate intraepithelial lymphocytes which, in
this disease, are destructive.
Arrowheads indicate plasma cells which are secreting ab’s against
gliadin bound to enterocytes as well against reticulin and tissue
transglutaminase resulting in tissue destruction. Source:NEJM
•Biopsy from which
the previous high
power micrograph
was taken.
•Villous atrophy,
crypt hyperplasia (it
almost looks like the
colon) are evident.
•From what region of
the small intestine
was this biopsy
taken?
Duodenum  see
Brunner’s glands?
Source:NEJM
‘Classic’ Presentation of Celiac Disease
• Starts around 6 - 24 months old, after gluten
introduced into diet
• “Malabsorption” Symptoms
–
–
–
–
–
–
Diarrhea
Vomiting
Abdominal pain
Loss of appetite
Failure to thrive
Irritability
CDHNF/NASPGHAN
Dermatitis herpetiformis
Major Complications of
Celiac Disease
•
•
•
•
•
Short stature
• Osteoporosis
Dermatitis herpetiformis • Gluten ataxia and other
Dental enamel hypoplasia neurological
disturbances
Recurrent stomatitis
• Thyroid dysfunctiom
Fertility problems
• Refractory celiac
disease and related
disorders
• Intestinal lymphoma
Other Signs and Symptoms
Associated With Celiac Disease and
Gluten Intolerance
What are all of the signs and symptoms
associated with celiac disease and gluten
intolerance?
Gluten Intolerance
Celiac
Disease
Signs and Symptoms Associated with
Gluten Intolerance
Digestive
Diarrhea
Constipation
Abdominal pain
Cramping
Dyspepsia
Gas
Bloating
Steatorrhea (fatty stools)
Encopresis
Enamel defects in teeth
Heartburn
Gastroparesis
GERD
Reflux
IBS (irritable bowel syndrome)
Esophagitis
Eosinophilic gastroenteritis
Eosinophilic esophagitis
Canker sores
Apthous ulcers
Vomiting
Nausea
Intestinal bleeding
Liver enzymes, elevated (ALT, ALK, ALP)
Liver disease
Pancreatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Colon cancer
Lactose intolerance
Fructose intolerance
Occult blood in stool
Hepatitis, autoimmune
Hepatic steatosis
Hepatic t-cell lymphoma
Pancreatic exocrine function may
be impaired
Villous atrophy (celiac
disease)
Skin
Acne
Eczema
Dermatitis
Dermatitis herpetiformis
Dry skin
Follicular keratosis
Hives
Rashes
Itchiness
Welts
Redness
Dark circles under eyes
Physical well-being
Fatigue
Weight loss
Weight gain
Poor endurance
Inability to gain weight
Chronic fatigue
Failure to thrive
Short stature
Emotional
Anxiety
Irritability
Depression
Ups and downs
Mind/neurological
Autism
ADHD
Difficulty concentrating
Cerebellar atrophy
Mental fog
Brain white-matter lesions
Insomnia/difficulty sleeping
Schizophrenia
Ataxia/difficulty with balance
Epilepsy (with or
without brain calcifications)
Multifocal axonal polyneuropathy
Neuropathy, peripheral (numbness or
tingling of hands or feet)
Musculoskeletal
Arthritis
Fibromyalgia
Rheumatoid arthritis
Muscle aches
Joint pain
Osteoporosis
Osteopenia
Osteomalacia
Polymyositis
Dental enamel defects
Loss of strength
Short stature
MS (multiple sclerosis)
Myasthenia gravis
Chromosomal defects
Respiratory system
Down syndrome
Wheezing
Sinusitis, chronic
Shortness of breath
Asthma
Miscellaneous
Women’s health
Irregular cycle
Infertility (also male infertility)
Delayed menarche
Premature menopause
Spontaneous abortion/miscarriage
Head
Headaches
Migraines
Alopecia (hair loss)
Fatigue
Anemia
Iron deficiency
Vitamin B12 deficiency
(pernicious anemia)
Vitamin K deficiency
Folate deficiency
Impotency
Raynaud’s
Eosinophils elevated (in blood
test)
Cystic fibrosis
Pulmonary hemosiderosis
Vasculitis
Autoimmune disorders
Addison’s disease
Autoimmune chronic hepatitis
Alopecia areata
Diabetes, type 1
Graves disease
Hyperparathyroidism, secondary
Hypoparathyroidism,
idiopathic autoimmune
Lupus (SLE)
Myasthenia gravis
Sarcoidosis
Scleroderma
Sjogrens syndrome
Hypothyroidism
Villous atrophy
Thyroiditis
ITP (idiopathic thrombocytopenic
purpurea)
Malignancies
Small bowel adenocarcinoma
Esophageal and oro-pharyngeal
carcinoma
Melanoma
Non-Hodgkin’s lymphoma
Over 130 Problems!
Villous Atrophy Is
Only One of These.
Villous atrophy is only one possible end product
of gluten intolerance.
Celiac disease = villous atrophy.
Celiac disease (villous atrophy) is a
gluten intolerance, but
Gluten intolerance is not
always celiac disease
(villous atrophy)
What If You Don’t Have
Villous Atrophy?
Most of these are also signs and symptoms
that can be associated with gluten
intolerance even when villous atrophy is
not present.
Gluten Intolerance
Celiac
Disease
THE CELIAC ICEBERG
CLASSIC
ATYPICAL
SILENT
LATENT
THE CELIAC ICEBERG
CLASSIC
ATYPICAL
SILENT
LATENT
How Do We Know This?
• People tell us
• Clinical results tell us
• Blood tests tell us
• Medical Studies tell us
The Free Market Tells Us
• The University of Chicago Celiac Disease
Center states that 97% of celiacs have not
been diagnosed. (Only about 70,000 dx.)
• The market for gluten free products is now
known to be over $1 billion per year (USDA
estimates $3.7 bill by 2015).
• That’s $14,200 per person, per year.
What do the lab results look like
for non-celiac gluten
intolerance?
Negative Celiac, Positive Gluten
Intolerance
• Tissue Transglutaminase antibody negative
and
• Biopsy negative
• Gliadin antibody positive (IgA or IgG)
• Total IgA normal
Some Studies on NonCeliac Gluten Intolerance
Small-bowel mucosal inflammation in reticulin or
gliadin antibody-positive patients without villous
atrophy. Scandinavian Journal of
Gastroenterology, 33, 944–949. Kaukinen, K., et al.
(1998).
“CONCLUSIONS: IgA-class … antigliadin antibody-
positive patients with normal small-bowel
mucosal morphology … implies that they may be
gluten-sensitive.”
Intolerance to cereals is not specific for coeliac
disease.
Scand J Gastroenterol. 2000 Sep;35(9):942-6.
Kaukinen K, et al.
“Allergy to cereals [other than celiac disease]
should be considered even in adults.”
Celiac disease without villous atrophy:
Revision of criteria called for.
Digestive Diseases and Sciences, 46, 879–887.
Kaukinen, K., et al. (2001).
“10 adults suspected to have celiac disease,
but evincing only minor mucosal
inflammation … showed a clinical,
histological, and serological recovery on (a
gluten free) diet.”
Common Blood Tests for Non-Celiac
Gluten Intolerance
Gliadin antibodies
• Gliadin IgA
• Gliadin IgG
Non-Celiac Gluten Intolerance
is Not Less Severe Than Celiac
Disease
• Nor is there any evidence that celiac
disease is the end stage of gluten
intolerance.
Emerging new clinical patterns in the
presentation of celiac disease. Arch Pediatr
Adolesc Med. 2008 Feb;162(2):164-8.
Telega G, Bennet TR, Werlin S
[A review of] the medical records of all patients
diagnosed with celiac disease at the Children's
Hospital of Wisconsin between 1986 and
2003…[demonstrated that patients] with celiac
disease usually do not present with classic
symptoms; they are more likely to be
asymptomatic…”
Non-Celiac Gluten Sensitivity
Theories:
•
Imaginary?
•
Psycho-somatic?
•
Irritable bowel syndrome variant?
•
A result of gluten’s:
•
Indigestibility
• Ability to activate “innate” immunity
•
versus activation of adaptive immunity in celiac disease
45
Non-celiac gluten sensitivity
Similar & significant differences for: Abdominal pain, bloating,
tiredness & satisfaction with stool consistency
1. NCGS is a real phenomenon
2. Celiac disease cannot be diagnosed by a GFD trial
Some Studies on Signs and
Symptoms Associated with
Non-Celiac Gluten Intolerance
Dietary treatment of gluten neuropathy. Muscle Nerve. 2006
Dec;34(6):762-6.
Hadjivassiliou M, et al.
“We studied the effect of a gluten-free diet in patients with idiopathic
sensorimotor axonal neuropathy and circulating antigliadin antibodies. A
total of 35 patients participated in the study, with 25 patients going on the
diet and 10 not doing so. There was a significant difference … with
evidence of improvement in the [treatment] group and deterioration in
the control group.”
Myopathy associated with gluten sensitivity. Muscle Nerve. 2007
Apr;35(4):443-50. Hadjivassiliou M, et al.
“Among seven patients not on immunosuppressive
treatment, four showed clinical improvement of the
myopathy with a gluten-free diet. The myopathy
progressed in one patient who refused the gluten-free
diet. Myopathy may be another manifestation of gluten
sensitivity and is likely to have an immune-mediated
pathogenesis.”
Gluten sensitivity masquerading as systemic lupus
erythematosus. Ann Rheum Dis. 2004 Nov;63(11):1501-3.
Hadjivassiliou M, Sanders DS, Grünewald RA, Akil M.
“Three patients are described whose original presentation and
immunological profile led to the erroneous diagnosis of systemic
lupus erythematosus. The correct diagnosis of gluten sensitivity was
made after years of treatment…The presence of an enteropathy is no
longer a prerequisite for the diagnosis of gluten sensitivity, which
can solely present with extraintestinal symptoms and signs.
Knowledge of the diverse manifestations of gluten sensitivity is
essential in avoiding such misdiagnosis.”
Dietary treatment of gluten ataxia. J Neurol Neurosurg
Psychiatry. 2003 Sep;74(9):1221-4. Hadjivassiliou M,
Davies-Jones GA, Sanders DS, Grünewald RA.
“Gluten ataxia is an immune mediated disease, part of the
spectrum of gluten sensitivity, and accounts for up to 40%
of cases of idiopathic sporadic ataxia. Twenty six patients
(treatment group) adhered to the gluten-free diet and had
evidence of elimination of antigliadin antibodies by one
year. CONCLUSIONS: Gluten ataxia responds to a strict
gluten-free diet even in the absence of an enteropathy.”
Antibodies Against Foods Other
Than Gluten
• In the same way, you can also test for
antibodies to wheat, barley, rye, spelt, etc.
• Typically IgG antibodies.
• If gliadin antibodies are elevated, these will
also be elevated.
(Visit www.IBSTreatmentCenter.com for more info).
A Few Studies on IgG Food
Antibodies (other than gluten)
The clinical significance of food specific IgE/IgG4 in
food specific atopic dermatitis. Pediatric Allergy and
Immunology, 18(1), 63–70. Noh, G., et al. (2007).
“Specific IgE and IgG4 concentration were measured ...
Double blinded placebo controlled food challenge test
(DBPCFC) was performed. Mean IgE/IgG4 levels in DBPCFC
(+) subjects is higher than those in DBPCFC (-) subjects in
all food items studied. Allergen-specific IgE/IgG4 may
provide one of the clues to understand the mechanism of
food allergy in atopic dermatitis.”
Food-specific IgG4 antibody-guided exclusion diet
improves symptoms and rectal compliance in irritable
bowel syndrome. Scandinavian Journal of
Gastroenterology, 40, 800–807. Zars, S., et al. (2005).
“IgG4 antibodies to common food antigens are elevated in IBS. The aim
of this article was to evaluate the effect of exclusion diet based on
IgG4 titres… CONCLUSIONS: Food-specific IgG4 antibody-guided
exclusion diet improves symptoms in IBS and is associated with an
improvement in rectal compliance.”
Food-specific serum IgG4 and IgE titers to common food
antigens in irritable bowel syndrome. American Journal of
Gastroenterology, 100, 1550–1557. Zars, S., et al. (2005).
“No significant difference in IgE titers was observed between IBS and
controls. Serum IgG4 antibodies to common foods like wheat, beef,
pork, and lamb are elevated in IBS patients. In keeping with the
observation in other atopic conditions, this finding suggests the
possibility of a similar pathophysiological role for IgG4 antibodies in
IBS.”
Food elimination based on IgG antibodies in irritable
bowel syndrome: a randomised controlled trial. Gut.
2004 Oct;53(10):1459-64.
Atkinson W, et al.
“150 outpatients with IBS were randomised to receive, for three months,
either a diet excluding all foods to which they had raised IgG
antibodies (enzyme linked immunosorbant assay test) or a sham diet
excluding the same number of foods but not those to which they had
antibodies.
CONCLUSION: Food elimination based on IgG antibodies may be effective
in reducing IBS symptoms and is worthy of further biomedical
research. (The compliant patients experienced significant benefit).”
The therapeutic effects of eliminating allergic foods
according to food-specific IgG antibodies in irritable
bowel syndrome. Zhonghua Nei Ke Za Zhi. 2007
Aug;46(8):641-3. Yang CM, Li YQ.
“CONCLUSIONS: Abnormal immune reactions
mediated by IgG antibodies coexisted in patients
with IBS. It is of great significance in treating IBS
by eliminating the allergic foods according to the
serum level of food-specific IgG antibodies.”
How to diagnose
Serological Tests
Role of serological tests:
• Identify symptomatic individuals who need a biopsy
• Screening of asymptomatic “at risk” individuals
• Supportive evidence for the diagnosis
• Monitoring dietary compliance
Serological Tests
• Antiendomysial antibodies (EMA)
• Anti tissue transglutaminase antibodies (TTG)
–first generation (guinea pig protein)
–second generation (human recombinant)
• HLA typing
• Serum immunoglobulin A (IgA) endomysial
antibodies and IgA tissue transglutaminase
(tTG) antibodies have sensitivity and
specificity > 95%.
• The tTG antibody test is less costly because it
uses an enzyme-linked immunosorbent assay;
it is the recommended single serologic test for
celiac disease screening in the primary care
setting.
• Testing for gliadin antibodies is no longer
recommended because of the low sensitivity and
specificity for celiac disease.
SMALL BOWEL BIOPSY
• Required to confirm the diagnosis of celiac disease for most
patients.
• Should also be considered in patients with negative serologic test
results who are at high risk or in whom the physician strongly
suspects celiac disease.
• Mucosal changes may vary from partial to total villous
atrophy, or may be characterized by subtle crypt lengthening or
increased epithelial lymphocytes.
• To avoid false-negative results on endoscopic biopsy, most
authorities recommend obtaining at least four tissue samples,
which increases the sensitivity of the test.
Intestinal damage in Celiac disease
& healing on the Gluten Free Diet
Flat Villi
Healthy Villi
65
Histological Features
Normal 0
Infiltrative 1
Partial atrophy 3a
Subtotal atrophy 3b
Hyperplastic 2
Total atrophy 3c
68
Horvath K. Recent Advances in Pediatrics, 2002.
Evaluation for Celiac
Disease
Patient presents with symptoms of celiac disease
Perform serologic IgA tTG
antibody testing
Positive
Negative
Small bowel biopsy
Positive
High clinical suspicion?
No
Yes
Negative
Small bowel biopsy
Dx confirmed,
Gluten-free diet
F/U and consider
Other dx, consider
Repeat bx
Positive
Negative
Tx and monitor
Celiac ruled out,
Look for other cause
Improvement?
Yes
Dx confirmed
Low probability of celiac
disease; consider total
IgA test to R/O IgA
deficiency
No
Evaluate for possible secondary
cause of symptoms
Already on a Gluten Free Diet
but no formal diagnosis
Do I have celiac disease (or NCGS)?
Gluten challenge: aka Gluten free diet holiday:
V
 Typical regimen:


Full gluten diet for 8 weeks
Small intestinal biopsy & celiac antibody tests
 Why bother?

Certainty re diagnosis





Celiac disease versus non-celiac gluten sensitivity
Certainty re need for lifelong, strict GFD
Certainty re family risk
Certainty re potential for celiac complications & associations
Can “cure” celiac disease!
70
Gluten challenge: making it easier
Improvements:
1. Genetic test before
challenge – if negative no
challenge
1.
3.
2.
2.
Lower dose of gluten
(3g versus 10-15g)
3.
Option for 2 week dropout
(>90% accuracy)
4.
4.
Late blood work to increase
sensitivity further
Next steps?
• Gluten challenge of biopsy
• Gluten reaction “biomarkers”
in blood
2013 American College of Gastroenterology Guidelines for Gluten Challenge in Celiac disease diagnosis (Am J Gastro in press)
71
Celiac Disease and gluten sensitivity
Treatment:
• Only treatment is a
gluten free diet (GFD)
• Celiac: Strict, lifelong diet
• Gluten Sensitivity: Remove
gluten as much as possible to
avoid symptoms
– Avoid:
• Wheat
• Rye
• Barley
Management of CELIAC Disease
C
E
L
I
A
C
= Consultation with a skilled dietitian
= Education about celiac disease
= Lifelong adherence to GF diet
= Identification/treatment of nutritional
deficiencies
= Advocacy group
= Continuous long-term follow-up
NIH Consensus Development Conference Statement,
• It is essential that the diagnosis be confirmed before submitting patients
to this therapy.
• Key elements to successful treatment include the motivation of the
patient, the attentiveness of the physician to comorbidities that need to
be addressed.
• Formal consultation with a trained dietitian is necessary.
• The dietitian plays a vital role in helping the patient successfully adapt to
the necessary behavioral changes and may provide much of the required
follow-up.
• National celiac disease support organizations can provide patients
invaluable resources for information and support.
Follow-up
• Serologic markers (serum IgA tTG) used to monitor
compliance with a gluten-free diet.
• Antibody levels return to normal within three to 12
months of starting a gluten-free diet.
• A repeat small bowel biopsy three to four months after
initiation of a gluten-free diet is not necessary if the
patient responds appropriately to therapy.
• If the patient does not respond as expected despite
adherence to a gluten-free diet, the physician should
consider diseases that may mimic celiac disease
Screening
• Screening an asymptomatic patient for celiac disease must be
weighed against the psychological, emotional, and economic
impact of a false positive result.
• Also, it would necessitate further evaluation with small bowel
biopsy.
• The need to follow a strict diet indefinitely can adversely
affect the patient's perceived quality of life.
• Routine screening of the general population is not
recommended.
• Persons at high risk for celiac disease who exhibit any level of
symptoms, appropriate testing is indicated.
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Key clinical recommendation
Evidence rating
IgA tissue transglutaminase antibodies
and IgA endomysial antibodies are appropriate
first-line serologic tests to rule in celiac disease.
C
Because IgA deficiency can cause false-negative
results, total IgA levels should be measured in
patients at high risk for celiac disease who have
negative results on serologic testing.
C
Small bowel biopsy should be performed
to confirm the diagnosis of celiac disease
in patients with abnormal results on serologic testing.
C
A gluten-free diet is recommended as the primary
A
treatment for celiac disease.
Discovery is to see what everyone
else has seen and to think what no
one else has thought.
Albert Szent Gyorgyi
1937 Nobel Prize in Medicine
Resources
• National Foundation for Celiac Awareness:
http://www.celiaccentral.org/
• Gluten Intolerance Group: http://www.gluten.net/
• Celiac Disease Foundation:
http://www.celiac.org/
• Celiac Sprue Association:
http://www.csaceliacs.info/
Thank you