New ESPGHAN guidelines for the diagnosis of Coeliac Disease in Children and Adolescents pptx

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...

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

• Change in clinical paradigm

• Definitions of coeliac disease

• New diagnostic guidelines

• Algorithms

Interlaken ESPGHAN criteria (1979)

McNeish et al Arch Dis Childh 1979;54:783

Revised ESPGHAN criteria 1990

after 2-3 months

• No further biopsy

• Provided age > 2 years

Walker‐Smith et al. Arch Dis Child 1990;65:99 

Carditis

Skin & mucosa:

Dermatitis herpetiformis Aphtous stomatitis

Hair loss

Reproductive system:

Miscarriage Infertility

Modified from Rewers, 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Hansen et al unpublished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

Suggestion: New definition

• gluten dependent clinical manifestations

• anti-tissue transglutaminase (TG2) antibodies

• enteropathy

Husby et al JPGN 2012

ESPGHAN classification

findings, not sufficient symptoms to warrant

clinical suspicion of CD

atrophy The patient has had a

gluten-dependent enteropathy Patient may/may not have symptoms

atrophy Patient may/may not have symptoms

CD may or may not develop

The Oslo Definitions

immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically

predisposed individuals

typical vs atypical

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

 Adults and children

 Adults and children

 For GP’s and general paediatricians

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)

1 Sensitivity and specificity

of EMA and TG2 ab quite high

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

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 ruleSystematic

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

from bench research, usual practice, opinion, disease-oriented evidence, case series etc.

Ebell MH et al JABFP 2004

%

Recommendation: (↑↑) offer testing for CD

of children and adolescents with the

Coeliac Antibodies

antibody

DISEASE PREDICTION BY ANTIBODIES

(pooled estimates with 95% confidence values; § indicates high hetereog neity)

Positive likelihood ratio

Negative likelihood ratio

Odd’s ratio EMA /IgA 31.8

Development of symptomatic coeliac

disease in EMA positive subjects

Predictive values for TG2 antibody

Positive predict value

Toftedal et al JCLM 2010

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

Child / Adolescent with Symptoms suggestive of CD

Anti-TG2 IgA & total IgA *

Anti-TG2

Transfer to Paediatric GI

Paed GI discusses with family the 2 diagnostic pathways and

consequences considering patient’s history & anti-TG2 titers

Consider further diagnostic testing if: IgA deficiency

Age: < 2 years History: - 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-TG2 negative

Consider false pos anti-TG2

Consider false pos anti-TG2

Child / Adolescent with Symptoms suggestive of CD

Anti-TG2 IgA & total IgA *

Anti-TG2

Transfer to Paediatric GI

Paed GI discusses with family the 2 diagnostic pathways and

consequences considering patient’s history & anti-TG2 titers

Consider further diagnostic testing if: IgA deficiency

Age: < 2 years History: - low gluten intake

- drug pretreatment

- severe symptoms

- associated diseases

Anti-TG2 > 10 x normal Anti-TG2 < 10 x normal

Anti-TG2 negative

Age: < 2 years History:   ‐ low gluten intake

Anti‐TG2 negative

Consider false pos. Anti‐TG2 

Rationale for omitting biopsies

in selected cases

(lower sensitivity and specificity than serology)

risk and cost of invasive procedure (OEGD,

histological work-up) versus risk of false positive

diagnosis

Marsh 0-1

Marsh 2 or 3

* Or specific IgG based tests

EMA positive EMA negative

OEGD & biopsies

From bulbus & 4 pars

further serological testing

Consider:

False neg Results, exclude IgA deficiency and history of low gluten intake or drugs

Asymptomatic person at genetic risk for CD Explain implication of positive test result(s) and get consent for testning

* Or specific IgG based tests

CD+

GFD

& F/u

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

Asymptomatic person at genetic risk for CD Explain implication of positive test result(s) and get consent for testning

EMA positive EMA negative

OEGD & biopsies

From bulbus & 4 pars

Explain implication of positive test result(s) and get consent for testing

HLA DQ testing (+/‐Anti‐TG2)

HLA positive  for DQ2 and/or DQ8

-*

*or specific IgG based tests

HLA negative  for DQ2 and/or DQ8

serology, false neg. 

biopsy or potential CD

Consider: age, false neg. results,  exclude IgA deficiency and history 

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

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