Transcript Serology in Children: How Reliable?

Celiac Disease:
Exploring the Iceberg
Stefano Guandalini, M.D.
Professor of Pediatrics
Chief, Section of Gastroenterology,
Hepatology and Nutrition
University of Chicago
We’ll talk about...
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How we define celiac disease
Who gets it and how?
How common it is
What are its clinical manifestations
What conditions can accompany it
Complications
How it is diagnosed and treated
Definition
Celiac disease is a permanent condition affecting
primarily the intestine and caused by an abnormal
reaction to gluten occurring in the immune (defense)
system of the gut of individuals who possess
certain genes.
It leads to gastrointestinal and non-gastrointestinal
symptoms, but it my as well be asymptomatic.
Indeed, celiac disease occurs more often in
people who have few or no symptoms!
Flattened villi
Malabsorption
Gluten
Normal villi
Absorption
Where is gluten found?
Where is gluten found?
The Grass Family - (GRAMINEAE)
Subfamily
Festucoideae
Tribe
Zizaneae
wild rice
Oryzeae
Hordeae
rice
wheat
Aveneae
oat
Festuceaea
finger millet
(ragi)
rye
I’m Innocent!!
barley
Chlorideae
teff
And what exactly is it?
Gluten is
made up
by Gliadin
and
Glutenin
A (huge!)
grain of
Some well-identified pieces (called “peptides”)
wheat
of gliadin are Gliadin
resistant
to digestion
Glutenin
Starch in the gut
and are toxic for celiac patients
We’ll talk about...
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How we define celiac disease
Who gets it and how?
How common it is
What are its clinical manifestations
What conditions can accompany it
Complications
How it is diagnosed and treated
Who gets celiac disease?
Gluten
HLA is not
DQ2, DQ8
Nothing....
Who gets Celiac Disease?
Gluten
Other necessary
Risk Factors
Infant
feeding
Infections...
HLA is either
DQ2 or DQ8
Celiac Disease
Breast feeding and celiac disease
Odds ratios (95% CI) of effect of breast feeding at the time of
gluten introduction on development of CD.
Akobeng AK et al., Arch Dis Child 2006
Timing of gluten introduction and
risk of celiac disease autoimmunity
- A prospective study on 1560 children at risk
1307 children followed from birth:
996 for cord blood HLA-DR3
311 for FH of IDDM
253 children enrolled at age 2-3
for FH of IDDM
Interviews with telephone questionnaire
At age 3, 6, 9, 12, 15 months
Same dietary information
collected retrospectively
Blood drawn for celiac serology (TG2)
at 9, 15, 24 m and then annually
Blood drawn for celiac serology (TG2)
at enrollment and then annually
Norris JM et al., JAMA 2005
Timing of gluten introduction and
risk of celiac disease autoimmunity
- A prospective study on 1560 children at risk
Norris JM et al., JAMA 2005
Does the amount of gluten
matter?
Amount of gluten at weaning
and celiac disease
The Swedish experience
Ivarsson A et al., Eur J Epidemiol 2003
“The rise in incidence was preceded by a
twofold increase in the average daily
consumption of gluten, and later the
decline in incidence coincided with a
consumption decrease by one third.”
Hernell O et al., Celiac Disease: Effect of Weaning on Disease Risk, 2005
Take-home message:
celiac disease can be prevented!
Does the timing of gluten
introduction influence the timing of
appearance and/or the presenting
symptoms of celiac disease?
Breast feeding at time of gluten introduction
influences the presenting symptoms
of celiac disease
90
80
%
P<0.01
70
60
50
40
30
Non breastfed when
gluten
introduced
20
10
0
Breast-fed
when gluten
introduced
GI
Non-GI
Symptoms at diagnosis
Guandalini S., UCCDP – n=92 pts., in press
Changing pattern of celiac disease
according to age at presentation
100
90
80
70
% 60
50
40
30
20
10
0
<15 mos
16-36mos
4-7 yrs
>8yrs
GI
Extra-GI
Guandalini S., UCCDP – n=92 pts., in press
In summary, the role of environmental
factors in celiac disease
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Breast feeding reduces the risk of celiac disease and/or at
least delays its onset.
Introducing gluten at 4-6 months seems to be associated with
the lowest risk of celiac disease.
Infants non breast-fed at the time of gluten introduction seem
to be more likely to develop typical (GI) celiac disease.
To reduce risk of celiac disease, gluten should be introduced
in small amounts.
Intestinal infections – especially by Rotavirus – increase the
risk of developing celiac disease
We’ll talk about...
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How we define celiac disease
Who gets it and how?
How common it is
What are its clinical manifestations
What conditions can accompany it
Complications
How it is diagnosed and treated
How common is celiac disease?
Geographic Area
Prevalence on clinical
diagnosis
Prevalence on screening data
Brasil
?
1:400
Denmark
1:10,000
1:500
Finland
1:1,000
1:130
Germany
1:2,300
1:500
Italy
1:1,000
1:184
1:4,500
Currently accepted
worldwide
Norway Prevalence (in1:675
Caucasians):
1:198
Sahara
?
1:70
?
1:550
Sweden
1:330
1:190
United Kingdom
1:300
1:112
USA
1:10,000
1:133
Netherlands
Slovenia
1%
1:250
Projected number of celiacs in North America: about 3,000,000
Actual number of known celiacs: about 50,000
For each known celiac there are 53 undiagnosed patients.
The Celiac Iceberg
Symptomatic
Celiac Disease
Intestine
is damaged
Silent Celiac
Disease
Latent Celiac Disease
Genetic susceptibility: - DQ2, DQ8
Positive serology
Intestine
appears normal
We’ll talk about...
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How we define celiac disease
Who gets it and how?
How common it is
What are its clinical manifestations
What conditions can accompany it
Complications
How it is diagnosed and treated
Clinical Manifestations
Symptomatic
Celiac disease
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Gastrointestinal symptoms/signs
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Non-gastrointestinal symptoms/signs
(“typical”)
(“atypical”)
Celiac Disease may also be associated with other conditions,
and mostly with:
• Autoimmune disorders
• Some syndromes
Gastrointestinal symptoms
Most common age of presentation: 6-24
months
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Chronic or recurrent diarrhea
Constipation
Anorexia
Failure to thrive or weight loss
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Abdominal pain,
bloating
Vomiting
Typical Celiac Disease
London, 1938
Children with Celiac Disease
Non Gastrointestinal symptoms
Most common age of presentation: older child to adult
•
•
•
•
•
•
Dermatitis Herpetiformis •
Dental enamel hypoplasia •
•
of permanent teeth
Osteopenia/Osteoporosis •
•
Short Stature
Delayed Puberty
Iron-deficient anemia
resistant to oral Fe
Liver disease
Arthritis
Neurological problems
Psychiatric Disorders
Women Sub-In-fertility
and/or miscarriages
and/or low birth babies
The list keeps growing
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Idiopathic dilated cardiomyopathy
Pancreatitis (ESPGHAN 2007)
Cardiac valves involvement (ESPGHAN
2007)
Dermatitis Herpetiformis
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Erythematous macules >
urticarial papules > tense
vesicles
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Severe itching
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Most have no GI symptoms
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75% Gluten dependent
villous atrophy
Serology positive in only
30-40%
It’s not just DH!
Other skin disorders possibly
associated with celiac disease
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Urticaria
Hereditary angioneurotic edema
Cutaneous vasculitis
Erythema nodosum
Psoriasis
Vitiligo
Dermatomyositis
Alopecia aerata…
Abenavoli L et al., World J Gastroenterol 2006
Dental Enamel Defects
Involve the permanent teeth and
can be the only presenting sign of Celiac Disease
Low bone density
(Osteoporosis)
Normal Peak Bone Mass can be achieved at puberty
by celiac children on a GFD, but only if the diet is
strict!
Short Stature/Delayed
Puberty
Can anyone guess how many children who are short
have
of their
reduced height?
 celiac
Short disease
stature as
in cause
children
/ teens:
~10% of short children and teens are celiacs
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Delayed onset of menstrual periods:
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Not uncommon in teen girls with untreated
Celiac Disease
Anemia
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Considered the most common non-GI
manifestation in older teenagers and adults
5-8% of adults with unexplained iron
deficiency anemia have Celiac Disease
In children with newly diagnosed Celiac
Disease:
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Anemia is very common
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However, in children presenting with anemia only,
celiac disease is not very frequent
Liver disease: A study on 14,000 CD
patients and 67,000 controls
Highly statistically (p<0.001) increased risk for the
following conditions in celiac disease (occurring
before and after diagnosis) is shown for:
 Acute and chronic hepatitis
 Primary sclerosing cholangitis
 Fatty liver
 Liver failure
 Liver cirrhosis or fibrosis
 Primary biliary cirrhosis
Ludvigsson JF et al. Clin Gastroenterol Hepatol 2007
Arthritis and Neurological
Problems
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Arthritis in adults
– Fairly common, including those on gluten-free diets
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Juvenile chronic arthritis
– Up to 3% have Celiac Disease
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Neurological problems in teenagers and adults
– Cerebellar ataxia (abnormal gait)
– Peripheral neuropathies
– Epilepsy with cranial calcifications
Asymptomatic
Silent
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Silent:
No symptoms
Damaged mucosa
Positive serology
(=elevated celiac
antibodies in the blood)
Latent
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Latent:
No symptoms
Normal mucosa
Positive Serology
(=elevated celiac
antibodies in the blood)
We’ll talk about...



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


How we define celiac disease
Who gets it and how?
How common it is
What are its clinical manifestations
What conditions can accompany it
Complications
How it is diagnosed and treated
Other conditions can be
associated with celiac disease
The prevalence of Celiac Disease is
higher in patients who have the
following:
–
Relative of a celiac person
–
Certain genetic disorders or syndromes
–
Other autoimmune conditions
Associated Conditions
20
percentage
16
12
8
4
General
Population
0
Relatives
IDDM
Thyroiditis
Down
syndrome
Celiac Disease and
Autoimmunity
The Prevalence Of Autoimmune Disorders Increases As Diagnosis Is Delayed
34%
35.00%
30.00%
p = 0.000001
27%
25.00%
20.00%
16.70%
15.00%
10.50%
10.00%
5.00%
5.10%
0.00%
<2
2 to 4
4 to 12
12 to 20
Age at diagnosis (years)
Ventura A et al., Gastroenterology 1999
>20
We’ll talk about...
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
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How we define celiac disease
Who gets it and how?
How common it is
What are its clinical manifestations
What conditions can accompany it
Complications
How it is diagnosed and treated
Major Complications of
Celiac Disease
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Refractory celiac
disease and related
disorders
Intestinal lymphoma
Reduced life expectancy
(if not on the diet!)
Effects of Diagnostic Delay and Adherence to
GFD on Mortality in Celiac Patients
Diagnostic delay
Patients
340
Observ.
Deaths
19
Expected
deaths
12.7
 12 months
12-119 mos.
320
19
7.3
 120 mos.
273
15
3.9
Adherence to
GFD
Likely
627
5
10.5
Not likely
155
26
4.3
Uncertain
290
22
11.1
SMR
(95% CI)
1. 5
( 0.9-2.3)
2. 6
(1.6-4.1)
3. 8
(2.2-6.4)
p
0. 5
(0.2-1.1)
6. 0
(4.0-8.8)
2. 0
(12-3.0)
0.16
Corrao et al., Lancet Aug 2001
0.12
0.0004
<0.0001
<0.0001
0.005
‘‘The most important diagnostic test in CD is
the suspicion of the disease.’’
NIH consensus 2004
The role of serology
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Gliadin antibodies
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Gliadin is the alcohol soluble fraction of gluten
Elicits a strong humoral response in CD
Anti-food protein antibodies, IgG and IgA
Known to be also often positive in:
•
•
•
•
•
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Milk protein allergy
Crohn’s disease
Post-gastroenteritis
GERD
Etc……………
Anti-Reticulin, Anti-Endomysium, Anti-tissue
Transglutaminase Antibodies
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IgA and IgG auto-antibodies
Anti-gliadin IgG
Sensitivity
Specificity
83-100%
47-94%
Average 93%
Average 71%
Anti-gliadin IgA
Sensitivity
Specificity
51-100%
71-100%
Average 79%
Average 89%
Anti-Endomysium Antibodies (EMA)
Sensitivity
88-100%
Average 95%
Specificity
98-100%
Average 99%
Anti-Tissue Transglutaminase Antibodies (TTG)
Sensitivity
78-100%
Average 94%
Specificity
96-100%
Average 98%
IgA Deficiency: a common problem
in celiac patients
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5-7% of celiac patients are IgA-deficient, thus
unable to produce any IgA autoantibodies (either
EMA or TTG).
 In this subset of patients, research shows that
IgG-EMA and IgG-TTG can be detected and are
as sensitive and as specific for the diagnosis of
celiac disease.
Corollary: always test for total serum IgA when looking for celiac disease
Cataldo F et al., Gut 2000
Korponay-Szabo, Gut 2003
Dahlbom I, Clin Diagn Lab Immunol. 2005
CD Antibodies in other biological fluids?
Stools
AGA
TTG
Kappler M et al., BMJ 2006
Normal
Celiac
Celiac
Histological Features
Normal 0
Infiltrative 1
Partial atrophy 3a Subtotal atrophy 3b
Hyperplastic 2
Total atrophy 3c
Suggested Diagnostic Strategy: I
Strong suspicion of CD?
(“Typical” GI presentation)
Do NOT initiate a gluten-free diet!
Refer to Pediatric GI for EGD with biopsies
Suggested Diagnostic Strategy: II
Signs of possible extra-intestinal CD and/or
associated conditions
 Dental enamel
hypoplasia
Patient
in a group at risk?
 Recurrent aphtous stomatitis
 Any autoimmune disorder (Diabetes, Hashimoto, SLE, etc.)
 Short Stature/Delayed Puberty
 Persistently Elevated AST/ALT
 Epilepsy or Ataxia
 Fe-resistant anemia
 Weakness, fatigue, lethargy
CheckDown,
tTG, Turner,
total serum
 Syndromes:
Williams IgA
 Total IgA Deficiency
 First-degree relative of a celiac or of a type 1 diabetic
 History
of recurrent miscarriages
Negative
Positive
No CD
Refer to Pediatric GI for EGD with biopsies
Efficacy of the case-finding strategy
“By applying simple and well-established criteria for CD case finding
on a sample of adults, we achieved a 32- to 43-fold increase
in the diagnosis rate of this condition.”
After diagnosis, use serology to monitor
the dietetic compliance of celiac patients
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In adults, TTG and EMA are poor predictors of
dietary transgressions
 In children, TTG and AGA can both be used to
monitor compliance: AGA disappear before TTG
 Periodic monitoring of serology is an integral
component of proper follow-up in children with
celiac disease
Vahedi Y et al., Am J Gastroenterol 2003
Cataldo F et al., Acta Pediatr 1995
NASPGHAN guideline, JPGN 2005