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. Small intestinal biopsy: villous atrophy
2. Gluten free diet for 1-2 years
3. Biopsy: normal.
4. Re-introduction of gluten
5. 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
CNS:
General: Ataxia, seizures
Puberty & growth delay Depression
Malignancies
Anemia
Heart:
Carditis
GI system:
Diarrhea, vomiting
Distension, pain Skin & mucosa:
Malnutrition, weight loss Dermatitis herpetiformis
Hepatitis, cholangitis Aphtous stomatitis
Hair loss

Bone:
Osteoporosis, fractures Reproductive system:
Arthritis Miscarriage
Dental anomalies 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 unpublished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 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

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 Conclusions
1. Sensitivity/specificity of 1. Sensitivity and specificity
serological tests of EMA and TG2 ab quite
2. Prevalence / incidence high
of CD 2. CD common, prevalence
3. CD associated in the general population
lymphoma
4. Consequences of testing likely close to 1:100
for CD 3. Education/participation in
5. Interventions for coeliac societies improves
adherence to a gluten- compliance with a GFD
free diet
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. Formulate an answerable
question Clinical Evidence-based
2. Track down the best evidence circumstances medicine
3. Critically appraise the evidence
for
• Validity
• Impact (size of the benefit)
• Applicability Patient preferences
4. Integrate with clinical and values
expertise and patient values
5. Evaluate our effectiveness and
efficiency
• keep a record/improve the
process Devereaux 2004
 Literature search
Search 1: n=1,418 Search 2: n=402 Search 3: n=778
EMBASE, Medline Medline Embase 15.07.2007-01.09.2009
01.01.2004-15.07.2007 17.07.07-15.09.2008 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 = 71 excluded based on E1-8:
No biopsy
Age
n = 16 publications Quality etc.
Included in data synthesis
Giersiepen et al. 2010
 Grading Evidence
Type of study: Diagnosis
Study Quality
Level 1: Good quality patient-oriented  Validated clinical decision rule
evidence  Systematic Review(SR)/meta-
analysis of high quality studies
 High quality diagnostic cohort study
Level 2: Limited quality patient-  Unvalidated clinical decision rule
oriented evidence  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 Negative Odd’s
likelihood ratio likelihood ratio ratio
EMA /IgA 31.8 0.067§ 553
(18.6-54.3) (0.038-0.118) (218-1402)
Anti-TG2 /IgA 21.8§ 0.060§ 469§
(12.9-36.8) (0.040-0.090) (250-880)
Anti-DGP /IgG 13.6 0.061§ 234
(8.1-22.8) (0.017-0.221) (100-546)
Anti-DGP /IgA 9.4 0.121§ 86.1
(6.8-13.1) (0.072-0.203) (56-132)
AGA /IgA 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 3644 3617

9
2001
1994
56
Diagnosed 1.5% 10 27
celiac: 0

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) ‘High’
1000
sample xULN
Aesku 135 9.0
AU
Binding Site 33.3 8.3
BMD Luminex 43
DiaSorin 57
Euroimmun 200 10.0
Eurospital* 95 13.6
Generic Assays 89 4.5
100
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
10
10 20 30 40
AU in Varelisa [Celikey] *logarithmic assays
 Child / Adolescent with Symptoms suggestive of CD

Anti-TG2 IgA & total IgA*

Anti-TG2 Anti-TG2
Not CD
positive negative

Transfer to Paediatric GI Consider further diagnostic testing if:

IgA deficiency
Paed. GI discusses with family the 2 diagnostic pathways and Age: < 2 years
consequences considering patient’s history & anti-TG2 titers History: - 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

EMA pos. EMA pos. EMA neg. EMA neg. Marsh 0-1 Marsh 2 or 3
HLA pos. HLA neg. HLA neg. HLA pos.

Unclear case
CD+ Consider false Consider false
Consider: CD+
neg. HLA test. pos. anti-TG2
false pos. serology
Consider biopsies false neg. biopsy or
potential CD
 Child / Adolescent with Symptoms suggestive of CD

Anti-TG2 IgA & total IgA*

Anti-TG2 Anti-TG2
Not CD
positive negative

Transfer to Paediatric GI Consider further diagnostic testing if:

IgA deficiency
Paed. GI discusses with family the 2 diagnostic pathways and Age: < 2 years
consequences considering patient’s history & anti-TG2 titers History: - 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

EMA pos. EMA pos. EMA neg. EMA neg. Marsh 0-1 Marsh 2 or 3
HLA pos. HLA neg. HLA neg. HLA pos.

Unclear case
CD+ Consider false Consider false
Consider: CD+
neg. HLA test. pos. anti-TG2
false pos. serology
Consider biopsies false neg. biopsy or
potential CD
GFD Extended evaluation of GFD
HLA/serology/biopsies
& F/u & F/u
 Child / Adolescent with Symptoms Suggestive of CD

Anti‐TG2 & total IgA* 

Anti‐TG2 Anti‐TG2 Not CD

positive negative

Consider further diagnostic testing if:
Transfer to Paediatric Gastroenterologist IgA deficient
Paed. GI discusses with family the 2 diagnostic pathways and  Age: < 2 years
consequences considering patient’s history & anti‐TG2 titers
-
History:   ‐ low gluten intake
‐ drug pretreatment
‐ severe symptoms
Positive Anti‐TG2 Positive Anti‐TG2 ‐ associated diseases
> 10 x normal  < 10 x normal 
Not  OEGD & biopsies
EMA & HLA testing for DQ2/DQ8 available

EMA pos. EMA pos. EMA neg. EMA neg. Marsh 0‐1 Marsh 2 or 3

HLA pos. HLA neg. HLA neg. HLA pos.

Unclear case
CD+ Consider false Consider false Consider: CD+
neg. HLA test pos. Anti‐TG2  false pos. serology
Consider biopsies  false neg. biopsy or
potential CD
GFD Extended evaluation of GFD
& F/u HLA/serology/biopsies & F/u

*or specific IgG based tests *
 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 HLA negative No CD,

DQ2 and/or DQ8 DQ2 and/or DQ8 no risk for CD

Consider retesting in intervals or if

TG2 & total IgA* symptomatic

Titer > 3 x normal Titer < 3 x normal TG2 negative Not CD

EMA
OEGD & biopsies
From bulbus & 4 pars Consider:
descendens, proper EMA positive EMA negative False neg. Results, exclude
histological work up IgA deficiency and history of
low gluten intake or drugs

Marsh 2 or 3 Marsh 0-1

CD+ Unclear case Consider:

F/u on normal diet. Transient/false pos. anti-
Consider: TG2
False pos. serology, false F/u on normal diet with
GFD neg. biopsy or potential CD further
serological testing
& F/u *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 HLA negative Not CD,

DQ2 and/or DQ8 DQ2 and/or DQ8 no risk for CD

Consider retesting in intervals or if

TG2 & total IgA* symptomatic

Titer > 3 x normal Titer < 3 x normal TG2 negative Not CD

EMA
OEGD & biopsies
From bulbus & 4 pars Consider:
descendens, proper EMA positive EMA negative False neg. Results, exclude
histological work up IgA deficiency and history of
low gluten intake or drugs

Marsh 2 or 3 Marsh 0-1

CD+ Unclear case Consider:

F/u on normal diet. Consider:
False pos. serology, false
neg. biopsy or potential CD
GFD
& F/u
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 HLA negative for Not CD,

DQ2 and/or DQ8 DQ2 and/or DQ8 no risk for CD

Consider retesting in intervals or 
Anti‐TG2 & total IgA* if  symptomatic

Positive Anti‐TG2  Positive Anti‐TG2 
< 3x normal Anti‐TG2 negative Not CD
> 3x normal

EMA
OEGD & biopsies:              
1 x bulbus & 4 x pars 
Consider: age, false neg. results, 
descendens, proper   EMA positive EMA negative exclude IgA deficiency and history 
histological work up  
of low gluten intake or drugs 

Marsh 2 or 3 Marsh 0‐1
-

CD+ Unclear case Consider: 

F/u on normal diet  Transient / false pos. 
Consider: false pos.  anti‐TG2
serology, false neg.  F/u on normal diet with  *or specific IgG based tests
GFD biopsy or potential CD further serological testing 
& F/u *
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
• 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
Hans Christian Andersen
• Klaus Giersiepen
• Monika Lelgemann