1. No category

New ESPGHAN guidelines for the
diagnosis of Coeliac Disease in
Children and Adolescents
Steffen Husby
Hans Christian Andersen Children’s Hospital
Odense University Hospital, Denmark
Agenda
•
•
•
•
Change in clinical paradigm
Definitions of coeliac disease
New diagnostic guidelines
Algorithms
Interlaken ESPGHAN criteria (1979)
1.
2.
3.
4.
5.
Small intestinal biopsy: villous atrophy
Gluten free diet for 1-2 years
Biopsy: normal.
Re-introduction of gluten
Biopsy: villous atrophy
McNeish et al. Arch Dis Childh 1979;54:783
Revised ESPGHAN criteria 1990
1. Small intestinal biopsy: villous atrophy
2. Clinical and serological improvement
after 2-3 months
•
•
No further biopsy
Provided age > 2 years
Walker‐Smith et al. Arch Dis Child 1990;65:99 Celiac disease as a multiorgan autoimmune disease
General:
Puberty & growth delay
Malignancies
Anemia
CNS:
Ataxia, seizures
Depression
Heart:
Carditis
GI system:
Diarrhea, vomiting
Distension, pain
Malnutrition, weight loss
Hepatitis, cholangitis
Bone:
Osteoporosis, fractures
Arthritis
Dental anomalies
Skin & mucosa:
Dermatitis herpetiformis
Aphtous stomatitis
Hair loss
Reproductive system:
Miscarriage
Infertility
Modified from
Rewers, Gastroenterology 2005
Patient
Adrenal antibodies
Type 1 Diabetes
Coeliac disease
Dermatitis
herpetiformis
Autoimmune hypothyroidism
Hansen et al. unpublished
Towards a new definition of
coeliac disease
 Chronic
 Multi-organ
 Small intestinal inflammation
 Transglutaminase-related
ESPGHAN working group, 2011
Suggestion: New definition
 an immune-mediated systemic disorder
 elicited by gluten and related prolamines
 in genetically (mainly HLA) susceptible individuals
 characterized by a combination of:
• gluten dependent clinical manifestations
• anti-tissue transglutaminase (TG2) antibodies
• enteropathy
Husby et al. JPGN 2012
ESPGHAN classification
 Silent CD: positive CD antibodies and biopsy
findings, not sufficient symptoms to warrant
clinical suspicion of CD
 Latent CD: positive CD antibodies, no villous
atrophy. The patient has had a glutendependent enteropathy. Patient may/may not
have symptoms
 Potential CD: positive antibodies, but no villous
atrophy. Patient may/may not have symptoms.
CD may or may not develop
The Oslo Definitions
 Coeliac disease is a chronic small intestinal
immune-mediated enteropathy precipitated by
exposure to dietary gluten in genetically
predisposed individuals.
 Discourage the use of classical vs. non-classical,
typical vs. atypical
 Discourage the use of the term latent CD
Ludvigsson et al. Gut 2012
ESGPHAN member Questionnaire
85 % of those who are compliant to the 1990
criteria want them to be changed
• challenge policy: 100 %
• HLA should be included for DX 80%
C.Ribes et al. JPGN 2012
Previous evidence-based
guidelines for CD diagnosis
 AHRQ (USA, 2004)
 Adults and children
 NICE guidelines (UK, 2009)
 Adults and children
 For GP’s and general paediatricians
 None questioned the biopsy
Rostom A, et al.. Celiac Disease. EvidenceReport/ Technology Assessment
No. 104. AHRQ Publication No. 04-E029-2, 2004
NICE Clinical Guidelines 86. Coeliac Disease:
Recognition and assessment of coeliac disease. UK, May 2009
Guidelines: AHRQ (USA, 2004)
Main issues
1.
2.
3.
4.
5.
Sensitivity/specificity of
serological tests
Prevalence / incidence
of CD
CD associated
lymphoma
Consequences of testing
for CD
Interventions for
adherence to a glutenfree diet
Conclusions
Sensitivity and specificity
of EMA and TG2 ab quite
high
2. CD common, prevalence
in the general population
likely close to 1:100
3. Education/participation in
coeliac societies improves
compliance with a GFD
1.
Rostom A, et al.. Celiac Disease. EvidenceReport/Technology Assessment No. 104. AHRQ Publication No. 04‐E029‐2, 2004
Evidence-based criteria for
clinical decisions
1.
2.
3.
Formulate an answerable
question
Track down the best evidence
Critically appraise the evidence
for
• Validity
• Impact (size of the benefit)
• Applicability
4.
5.
Integrate with clinical
expertise and patient values
Evaluate our effectiveness and
efficiency
Clinical
circumstances
Evidence-based
medicine
Patient preferences
and values
• keep a record/improve the
process
Devereaux 2004
Literature search
Search 1: n=1,418
EMBASE, Medline
01.01.2004-15.07.2007
Search 2: n=402
Medline
17.07.07-15.09.2008
Search 3: n=778
Embase 15.07.2007-01.09.2009
Medline 15.09.2008-01.09.2009
n=2,598
Entering Level 1 screening
n=2,242 + 22 no full text
excluded
n=334 Full text
Entering Level 2 screening
n=247
excluded
n=87
Entering Level 3 screening
n = 16 publications
Included in data synthesis
N = 71 excluded based on E1-8:
No biopsy
Age
Quality etc.
Giersiepen et al. 2010
Grading Evidence
Type of study: Diagnosis
Study Quality
Level 1: Good quality patient-oriented
evidence
 Validated clinical decision rule
 Systematic Review(SR)/meta-
Level 2: Limited quality patientoriented evidence
 Unvalidated clinical decision rule
 SR/meta-analysis of lower quality
Level 3: Other evidence
Consensus guidelines, extrapolations
from bench research, usual practice,
opinion, disease-oriented evidence,
case series etc.
analysis of high quality studies
 High quality diagnostic cohort study
studies or studies
 Lower quality diagnostic cohort study
or diagnostic case control study
Ebell MH et al. JABFP 2004
Example statement:
Increased prevalence of CD in children with
%
•
•
•
•
•
•
•
•
Type 1 diabetes
Down’s syndrome
Autoimmune thyroid disease
Turner syndrome
Williams’ syndrome
IgA deficiency
Autoimmune liver disease
First degree relatives with CD
2–12
5-12
up to 7
2-5
up to 9
2-8
12-13
10-20
Recommendation: (↑↑) offer testing for CD
of children and adolescents with the
following conditions:








Type 1 diabetes
Down’s syndrome
Autoimmune thyroid disease
Turner syndrome
Williams’ syndrome
IgA deficiency
Autoimmune liver disease
1st degree relatives with CD
Coeliac Antibodies
• IgA Anti-TG2 antibody
• IgA Endomysial antibody (EMA)
• IgA and IgG Deamidated Gliadin Peptide (DPG)
antibody
• NOT: IgA and IgG anti-gliadin antibodies
DISEASE PREDICTION BY ANTIBODIES
(pooled estimates with 95% confidence values; § indicates high hetereog neity)
EMA /IgA
Anti-TG2 /IgA
Anti-DGP /IgG
Anti-DGP /IgA
AGA /IgA
Positive
likelihood ratio
Negative
likelihood ratio
Odd’s
ratio
31.8
0.067§
553
(18.6-54.3)
(0.038-0.118)
(218-1402)
21.8§
0.060§
469§
(12.9-36.8)
(0.040-0.090)
(250-880)
13.6
0.061§
234
(8.1-22.8)
(0.017-0.221)
(100-546)
9.4
0.121§
86.1
(6.8-13.1)
(0.072-0.203)
(56-132)
7.3§
0.186§
40.6§
(4.5-11.8)
(0.095-0.362)
(14-117)
Giersiepen, Evidence report, JPGN 2012
Development of symptomatic coeliac
disease in EMA positive subjects
3654
3617
3644
9
2001
1994
Diagnosed
celiac: 0
56
1.5%
10
27
1:99
Mäki, N Engl J Med 2003
Predictive values for TG2 antibody
Positive predict. value
Toftedal et al. JCLM 2010
Median ELISA values in 14
commercial anti-TG2 assays
(data kindly provided by UK NEQAS)
1000
AU
100
10
10
20
30
AU in Varelisa [Celikey]
‘High’
sample xULN
Aesku
135
9.0
Binding Site
33.3
8.3
BMD Luminex
43
DiaSorin
57
Euroimmun
200
10.0
Eurospital*
95
13.6
Generic Assays
89
4.5
Genesis
69
9.9
Immco
48.3
2.4
Inova*
95.5
4.8
Orgentec
65.5
9.9
Phadia ELIA
69.0
9.9
Phadia ImmunoCAP
73.9
10.6
Phadia Varelisa
30.1
10.0
40
*logarithmic assays
Child / Adolescent with Symptoms suggestive of CD
Anti-TG2 IgA & total IgA*
Anti-TG2
positive
Transfer to Paediatric GI
Anti-TG2 < 10 x normal
EMA & HLA DQ8/DQ2
EMA pos.
HLA pos.
CD+
EMA pos.
HLA neg.
Consider false
neg. HLA test.
Consider biopsies
Not CD
Consider further diagnostic testing if:
IgA deficiency
Age: < 2 years
History: - low gluten intake
- drug pretreatment
- severe symptoms
- associated diseases
Paed. GI discusses with family the 2 diagnostic pathways and
consequences considering patient’s history & anti-TG2 titers
Anti-TG2 > 10 x normal
Anti-TG2
negative
EMA neg.
HLA neg.
Consider false
pos. anti-TG2
Not available
EMA neg.
HLA pos.
OEGD & biopsies
Marsh 0-1
Unclear case
Consider:
false pos. serology
false neg. biopsy or
potential CD
Marsh 2 or 3
CD+
Child / Adolescent with Symptoms suggestive of CD
Anti-TG2 IgA & total IgA*
Anti-TG2
positive
Transfer to Paediatric GI
Anti-TG2 < 10 x normal
EMA & HLA DQ8/DQ2
EMA pos.
HLA pos.
CD+
GFD
& F/u
EMA pos.
HLA neg.
Consider false
neg. HLA test.
Consider biopsies
Not CD
Consider further diagnostic testing if:
IgA deficiency
Age: < 2 years
History: - low gluten intake
- drug pretreatment
- severe symptoms
- associated diseases
Paed. GI discusses with family the 2 diagnostic pathways and
consequences considering patient’s history & anti-TG2 titers
Anti-TG2 > 10 x normal
Anti-TG2
negative
EMA neg.
HLA neg.
Consider false
pos. anti-TG2
Not available
EMA neg.
HLA pos.
OEGD & biopsies
Marsh 0-1
Unclear case
Consider:
false pos. serology
false neg. biopsy or
potential CD
Extended evaluation of
HLA/serology/biopsies
Marsh 2 or 3
CD+
GFD
& F/u
Child / Adolescent with Symptoms Suggestive of CD
Anti‐TG2 & total IgA* Anti‐TG2
positive
Anti‐TG2
negative
Transfer to Paediatric Gastroenterologist
Paed. GI discusses with family the 2 diagnostic pathways and consequences considering patient’s history & anti‐TG2 titers
Positive Anti‐TG2
> 10 x normal Positive Anti‐TG2
< 10 x normal EMA & HLA testing for DQ2/DQ8
EMA pos.
HLA pos.
CD+
EMA pos.
HLA neg.
EMA neg.
HLA neg.
Consider false
neg. HLA test
Consider biopsies Consider false
pos. Anti‐TG2 GFD
& F/u
*or specific IgG based tests
Not available
EMA neg.
HLA pos.
Not CD
Consider further diagnostic testing if:
IgA deficient
Age: < 2 years
History: ‐ low gluten intake
‐ drug pretreatment
‐ severe symptoms
‐ associated diseases
OEGD & biopsies
Marsh 0‐1
Unclear case
Consider:
false pos. serology
false neg. biopsy or
potential CD
Extended evaluation of
HLA/serology/biopsies
Marsh 2 or 3
CD+
GFD
& F/u
*
Rationale for omitting biopsies
in selected cases
 Serological tests improved over last years
 Histology not as perfect as thought 20 yrs ago
(lower sensitivity and specificity than serology)
 Risk-benefit ratio has changed:
risk and cost of invasive procedure (OEGD,
histological work-up) versus risk of false positive
diagnosis
Asymptomatic person at genetic risk for CD
Explain implication of positive test result(s) and get consent for testning
HLA DQ2 / DQ8 (+/- TG2)
HLA positive
DQ2 and/or DQ8
Consider retesting in intervals or if
symptomatic
TG2 & total IgA*
Titer > 3 x normal
OEGD & biopsies
From bulbus & 4 pars
descendens, proper
histological work up
Marsh 2 or 3
CD+
GFD
& F/u
No CD,
no risk for CD
HLA negative
DQ2 and/or DQ8
Titer < 3 x normal
TG2 negative
Not CD
EMA
EMA positive
EMA negative
Consider:
False neg. Results, exclude
IgA deficiency and history of
low gluten intake or drugs
Marsh 0-1
Unclear case
F/u on normal diet.
Consider:
False pos. serology, false
neg. biopsy or potential CD
Consider:
Transient/false pos. antiTG2
F/u on normal diet with
further
serological testing
*Or
specific IgG based tests
Asymptomatic person at genetic risk for CD
Explain implication of positive test result(s) and get consent for testning
HLA DQ2 / DQ8 (+/- TG2)
HLA positive
DQ2 and/or DQ8
Consider retesting in intervals or if
symptomatic
TG2 & total IgA*
Titer > 3 x normal
OEGD & biopsies
From bulbus & 4 pars
descendens, proper
histological work up
Marsh 2 or 3
CD+
GFD
& F/u
Titer < 3 x normal
Not CD,
no risk for CD
HLA negative
DQ2 and/or DQ8
TG2 negative
Not CD
EMA
EMA positive
EMA negative
Consider:
False neg. Results, exclude
IgA deficiency and history of
low gluten intake or drugs
Marsh 0-1
Unclear case
F/u on normal diet. Consider:
False pos. serology, false
neg. biopsy or potential CD
Consider:
Transient/false pos. anti-TG2
F/u on normal diet with further
serological testing
*Or
specific IgG based tests
Asymptomatic Person at Genetic Risk for CD
Explain implication of positive test result(s) and get consent for testing
HLA DQ testing (+/‐Anti‐TG2)
HLA positive for
DQ2 and/or DQ8
Positive Anti‐TG2 < 3x normal
no risk for CD
Consider retesting in intervals or if symptomatic
Anti‐TG2 & total IgA*
Positive Anti‐TG2 > 3x normal
Not CD,
HLA negative for
DQ2 and/or DQ8
Not CD
Anti‐TG2 negative
EMA
OEGD & biopsies: 1 x bulbus & 4 x pars descendens, proper EMA positive
histological work up Marsh 2 or 3
CD+
GFD
& F/u
EMA negative
Consider: age, false neg. results, exclude IgA deficiency and history of low gluten intake or drugs Marsh 0‐1
-
Unclear case
F/u on normal diet Consider: false pos. serology, false neg. biopsy or potential CD
Consider: Transient / false pos. anti‐TG2
F/u on normal diet with further serological testing *or specific IgG based tests
*
Why different algorithms for symptomatic and
asymptomatic (at risk) patients?
1.
2.
3.
False positive or transient TG2 antibody levels more
frequent in genetically at risk persons than symptomatic
cases
TG2 titres with normal histology (Marsh 0) are often of low
titre (<3 x upper limit of normal)
In asymptomatic patients with low antibody levels there no
urgency to perform biopsies compared to symptomatic
patients with the same low levels.
Conclusions
1. The new guidelines will offer the option of omitting biopsies
in selected cases with symptoms suggestive of CD without
increasing the risk of misclassification.
2. Preconditions are
•
•
•
•
high quality serology including EMA
taking quantitative antibody levels into account
HLA typing
full information to parents/patient on consequences
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ESPGHAN Working Group on Celiac
David Branski
Disease Diagnosis
Carlo Catassi
Steffen Husby
Sibylle Koletzko
Ilma Korbonay-Szabo
Luisa Mearin
Markku Maki
Alan Phillips
Carmen Ribes
Luca Ronfani
Raanan Shamir
Riccardo Troncone
Alessandro Ventura
Klaus Peter Zimmer
Tunde Koltai
Klaus Giersiepen
Monika Lelgemann
Hans Christian Andersen