New ESPGHAN guidelines for the diagnosis of Coeliac Disease in
Children and Adolescents
Steffen HusbyHans 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. Small intestinal biopsy: villous atrophy 2. Gluten free diet for 1-2 years3. Biopsy: normal. 4. Re-introduction of gluten 5. Biopsy: villous atrophy
McNeish et al. Arch Dis Childh 1979;54:783
Revised ESPGHAN criteria 19901. Small intestinal biopsy: villous atrophy2. 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
General:Puberty & growth delayMalignancies
Anemia
GI system:Diarrhea, vomiting
Distension, painMalnutrition, weight lossHepatitis, cholangitis
Bone:Osteoporosis, fracturesArthritisDental anomalies
CNS:Ataxia, seizuresDepression
Heart:Carditis
Skin & mucosa:Dermatitis herpetiformisAphtous stomatitis
Hair loss
Reproductive system:MiscarriageInfertility
Modified fromRewers, Gastroenterology 2005
Celiac disease as a multiorgan autoimmune disease
Coeliac disease
Type 1 Diabetes
Dermatitis herpetiformis
Autoimmune hypothyroidism
Adrenal antibodies
Hansen et al. unpublished
Patient
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 gluten-dependent 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
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%
ESGPHAN member Questionnaire
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 biopsyRostom 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)
1. Sensitivity/specificity of serological tests
2. Prevalence / incidence of CD
3. CD associated lymphoma
4. Consequences of testing for CD
5. Interventions for adherence to a gluten-free diet
1. 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
Rostom A, et al.. Celiac Disease. EvidenceReport/Technology Assessment No. 104. AHRQ Publication No. 04‐E029‐2, 2004
Main issues Conclusions
Evidence-based criteria for clinical decisions
1. Formulate an answerable question
2. Track down the best evidence 3. Critically appraise the evidence
for• Validity• Impact (size of the benefit)• Applicability
4. Integrate with clinical expertise and patient values
5. Evaluate our effectiveness and efficiency
• keep a record/improve the process
Evidence-based medicine
Patient preferencesand values
Devereaux 2004
Clinical circumstances
Literature searchSearch 1: n=1,418EMBASE, Medline01.01.2004-15.07.2007
Search 2: n=402Medline17.07.07-15.09.2008
Search 3: n=778Embase 15.07.2007-01.09.2009Medline 15.09.2008-01.09.2009
n=2,598Entering Level 1 screening
n=2,242 + 22 no full textexcluded
n=334 Full textEntering Level 2 screening
n=247excluded
n=87Entering Level 3 screening
n = 16 publicationsIncluded in data synthesis
N = 71 excluded based on E1-8:No biopsyAgeQuality etc.
Giersiepen et al. 2010
Grading EvidenceType of study: DiagnosisStudy Quality
Level 1: Good quality patient-oriented evidence
Validated clinical decision rule Systematic Review(SR)/meta-
analysis of high quality studies High quality diagnostic cohort study
Level 2: Limited quality patient-oriented evidence
Unvalidated clinical decision rule SR/meta-analysis of lower quality
studies or studies Lower quality diagnostic cohort study
or diagnostic case control study
Level 3: Other evidence Consensus guidelines, extrapolations from bench research, usual practice, opinion, disease-oriented evidence, case series etc.
Ebell MH et al. JABFP 2004
Example statement: Increased prevalence of CD in children with
• Type 1 diabetes 2–12• Down’s syndrome 5-12• Autoimmune thyroid disease up to 7 • Turner syndrome 2-5• Williams’ syndrome up to 9• IgA deficiency 2-8 • Autoimmune liver disease 12-13• First degree relatives with CD 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)
Positive likelihood ratio
Negative likelihood ratio
Odd’sratio
EMA /IgA 31.8(18.6-54.3)
0.067§
(0.038-0.118)553
(218-1402)Anti-TG2 /IgA 21.8§
(12.9-36.8)0.060§
(0.040-0.090)469§
(250-880)Anti-DGP /IgG 13.6
(8.1-22.8)0.061§
(0.017-0.221)234
(100-546)Anti-DGP /IgA 9.4
(6.8-13.1)0.121§
(0.072-0.203)86.1
(56-132)AGA /IgA 7.3§
(4.5-11.8)0.186§
(0.095-0.362)40.6§
(14-117)Giersiepen, Evidence report, JPGN 2012
19942001
3654 3644
Diagnosedceliac: 0
10
3617
27
Mäki, N Engl J Med 2003
1:99
561.5%
9
Development of symptomatic coeliac disease in EMA positive subjects
Predictive values for TG2 antibodyPositive predict. value
Toftedal et al. JCLM 2010
10
100
1000
10 20 30 40
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
AU in Varelisa [Celikey]
Median ELISA values in 14 commercial anti-TG2 assays
(data kindly provided by UK NEQAS)
AU
‘High’sample xULN
*logarithmic assays
Child / Adolescent with Symptoms suggestive of CD
Anti-TG2 IgA & total IgA*
Anti-TG2positive Not CD
Transfer to Paediatric GIPaed. GI discusses with family the 2 diagnostic pathways and consequences considering patient’s history & anti-TG2 titers
Consider further diagnostic testing if:IgA deficiencyAge: < 2 yearsHistory: - low gluten intake
- drug pretreatment- severe symptoms- associated diseases
Anti-TG2 > 10 x normal Anti-TG2 < 10 x normal
EMA & HLA DQ8/DQ2
EMA pos.HLA pos.
Not available OEGD & biopsies
Anti-TG2negative
EMA pos.HLA neg.
EMA neg.HLA neg.
EMA neg.HLA pos.
Marsh 0-1 Marsh 2 or 3
Consider false neg. HLA test. Consider biopsies
Unclear caseConsider:
false pos. serologyfalse neg. biopsy or
potential CD
Consider false pos. anti-TG2
CD+ CD+
EMA pos.HLA pos.
EMA pos.HLA neg.
EMA neg.HLA neg.
EMA neg.HLA pos.
Marsh 0-1 Marsh 2 or 3
Consider false neg. HLA test. Consider biopsies
Unclear caseConsider:
false pos. serologyfalse neg. biopsy or
potential CDExtended evaluation of HLA/serology/biopsies
Consider false pos. anti-TG2
CD+
GFD& F/u
CD+
GFD& F/u
Child / Adolescent with Symptoms suggestive of CD
Anti-TG2 IgA & total IgA*
Anti-TG2positive Not CD
Transfer to Paediatric GIPaed. GI discusses with family the 2 diagnostic pathways and consequences considering patient’s history & anti-TG2 titers
Consider further diagnostic testing if:IgA deficiencyAge: < 2 yearsHistory: - low gluten intake
- drug pretreatment- severe symptoms- associated diseases
Anti-TG2 > 10 x normal Anti-TG2 < 10 x normal
EMA & HLA DQ8/DQ2 Not available OEGD & biopsies
Anti-TG2negative
Child / Adolescent with Symptoms Suggestive of CD
Anti‐TG2 & total IgA*
Anti‐TG2positive Not CD
Transfer to Paediatric GastroenterologistPaed. GI discusses with family the 2 diagnostic pathways and consequences considering patient’s history & anti‐TG2 titers-
Consider further diagnostic testing if:IgA deficientAge: < 2 yearsHistory: ‐ low gluten intake
‐ drug pretreatment‐ severe symptoms‐ associated diseasesPositive Anti‐TG2
>10xnormal
EMA & HLA testing for DQ2/DQ8
EMA pos.HLA pos.
Not available
OEGD & biopsies
Anti‐TG2negative
EMA pos.HLA neg.
EMA neg.HLA neg.
EMA neg.HLA pos. Marsh 0‐1 Marsh2or3
Consider falseneg. HLA testConsider biopsies
Unclear caseConsider:
false pos. serologyfalse neg. biopsy or
potential CDExtended evaluation ofHLA/serology/biopsies
Consider falsepos. Anti‐TG2
CD+
GFD& F/u
CD+
GFD& F/u
**or specific IgG based tests
Positive Anti‐TG2<10xnormal
Rationale for omitting biopsiesin 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
EMA
Marsh 0-1Marsh 2 or 3
*Or specific IgG based tests
EMA positive EMA negative
OEGD & biopsiesFrom bulbus & 4 pars descendens, proper histological work up
CD+
GFD& F/u
Unclear caseF/u on normal diet.
Consider:False pos. serology, false
neg. biopsy or potential CD
Consider:Transient/false pos. anti-
TG2F/u on normal diet with
furtherserological testing
Consider:False neg. Results, exclude IgA deficiency and history of low gluten intake or drugs
Asymptomatic person at genetic risk for CDExplain implication of positive test result(s) and get consent for testning
HLA DQ2 / DQ8 (+/- TG2)
HLA positiveDQ2 and/or DQ8
No CD,no risk for CD
TG2 & total IgA* Consider retesting in intervals or if symptomatic
Titer > 3 x normal
HLA negativeDQ2 and/or DQ8
Titer < 3 x normal TG2 negative Not CD
*Or specific IgG based tests
CD+
GFD& F/u
Unclear caseF/u on normal diet. Consider:
False pos. serology, false neg. biopsy or potential CD
Consider:Transient/false pos. anti-TG2F/u on normal diet with further
serological testing
Asymptomatic person at genetic risk for CDExplain implication of positive test result(s) and get consent for testning
HLA DQ2 / DQ8 (+/- TG2)
HLA positiveDQ2 and/or DQ8
Not CD,no risk for CD
TG2 & total IgA* Consider retesting in intervals or if symptomatic
Titer > 3 x normal
EMA
Marsh 0-1Marsh 2 or 3
HLA negativeDQ2 and/or DQ8
Titer < 3 x normal TG2 negative Not CD
EMA positive EMA negative
OEGD & biopsiesFrom bulbus & 4 pars descendens, proper histological work up
Consider:False neg. Results, exclude IgA deficiency and history of low gluten intake or drugs
Asymptomatic Person at Genetic Risk for CDExplain implication of positive test result(s) and get consent for testing
HLA DQ testing (+/‐Anti‐TG2)
HLA positive forDQ2 and/or DQ8
Not CD,no risk for CD
Anti‐TG2 & total IgA* Consider retesting in intervals or if symptomatic
EMA
Marsh 0‐1-Marsh 2 or 3
*
*or specific IgG based tests
HLA negative forDQ2 and/or DQ8
Positive Anti‐TG2 < 3x normal Anti‐TG2 negative Not CD
EMA positive EMA negative
OEGD & biopsies: 1 x bulbus & 4 x pars descendens, proper histological work up
CD+
GFD& F/u
Unclear caseF/u on normal diet Consider: false pos. serology, false neg. biopsy or potential CD
Consider: age, false neg. results, exclude IgA deficiency and history of low gluten intake or drugs
Positive Anti‐TG2 > 3x normal
Consider: Transient / false pos.
anti‐TG2F/u on normal diet with further serological testing
Why different algorithms for symptomatic and asymptomatic (at risk) patients?
1. False positive or transient TG2 antibody levels more frequent in genetically at risk persons than symptomatic cases
2. TG2 titres with normal histology (Marsh 0) are often of low titre (<3 x upper limit of normal)
3. 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 Disease Diagnosis• David Branski
• 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