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 unpublished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