early nutrition programming of long-term...

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EARLY NUTRITION PROGRAMMING OF LONG-TERM HEALTH

Early gluten exposure and celiac disease riskM Luisa Mearin

Warsaw 1st December2014

Gluten Celiac disease

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wheat (gliadin)

rye (secalin)

barley (hordein)

Gluten: storage proteins is some grains

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Puberty & growth

delay, Malignancies

Anemia,Thyroiditis

Diarrhea, vomiting

Distension, pain,

Malnutrition, weight

loss, T1DM, hepatitis, Cholangitis, IBD

Osteoporosis,

Fractures, Arthritis, SjÖgren, Lupus, dental

alt.

Ataxia, Epilepsy,

Depression

Neuropathy

Carditis

Dermatitis H.,Psoriasis, Vitiligo,

Alopecia, Aphtous

stomatitis

Miscarriage,

Infertility

Modified Rewers, Gastroenterology 2005

Celiac disease a multiorgan autoimmune disorder

Husby et al. JPGN 2012

W. K. Dicke (1905-1962)

The gluten free diet

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1%-3% has celiac disease

Chameleon of Medicine

Celiac Disease

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• Your neighbour 1-3

• 1e degree family 5-40

• Non-identical twins 30

• Identical twins 80

Chance CD %

It’s all genes??

DQ2 DQ8

Population

1% CD

HLA-DQ2/DQ8

High Negative Predictive Value

40%

Sensitivity 96%Specificity 54%

Being HLA positive is necessary but NOTsufficient to develop coeliac disease

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/DQ8

Endomysial antibody (EMA)

Transglutaminase 2-specific antibody (anti-TG2)

Deamidated gliadin-specific antibody (anti-DGP)

Anti-TG2

EMA Anti-DGP

ESPGHAN Evidence Report JPGN 2012

Specific celiac disease antibodies

Husby et al. JPGN 2012

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Small bowel biopsies

Friday, December 05, 2014

Genetics

HLA DQ2/ DQ8Non-HLA

Environment

Immunology

GlutenBreastfeedingOthers

Celiac disease

InnateAdaptativeT-cells, CK’s, Ab’sOthers

Primary prevention for CD?

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www.preventcd.comIvarsson A et al.Acta Paediatr. 2000;89:165-71Olsson C, et al Pediatrics 2008;122:528-534

0

50

100

150

200

250

300

1975 1980 1985 1990 1995 2000

Year of diagnosis

Cas

es p

er 1

00 0

00 p

erso

n ye

ars

0-1.9 year

2-4.9 year

5-14.9 year

Larger amounts gluten in infant foods

Gluten introduction from 6 months of age

Gluten introduction from 4 months of age

Celiac disease epidemic in Sweden

Prospective Denver study

1560 children high risk for CD (HLA-DQ2/DQ8)

Significant higher risk for CD whengluten introduced

16Norris et al. 2005

Before 4 months of age

After 6 months of age

"Window of opportunity"

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5-12-2014

Reference Effect

Akobeng 2006 Protective

Ziegler 2003 No effect

Norris 2005 No effect

Roberts 2008 No effect

Welander 2010 No effect

Decker 2010 No effect

Ivarsson 2013 Protective

Størdal 2013 No protective

Duration breastfeeding and CD

Systematic review early feeding and celiac disease

Swajeska et al. AP &T 2012; Schaar and Mearin JPGN 2014

Project PreventCD (Prevention celiac disease)

Friday, 05 December 2014

By introduction of gluten

- In small amounts

4-6 months age

- Preferably breastfeeding

Hypothesis

Childhood coeliac disease may be prevented

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"Window of opportunity"

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Israel

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Project PreventCD

17 partners10 countries

medical centres labs industries

AOECS

PreventCD RCT family intervention study

vrijdag 5 december 2014

HLA DQ2/DQ8 typing

2007-2010

HLA DQ2/DQ8 typingnewborns high risk family

2007-2010

Positive Negative

StopRandomization

100 mg lactosePlacebo

100 mg lactose100 mg gluten

double-blind4-6 Monthsdouble-blind

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PreventCD family study

PreventCD family intervention study

vrijdag 5 december 2014

Symptoms and/or high antibodies

Small bowel

biopsies

Small bowel

biopsies

Coeliac No coeliac

End point frequency CD at 3yPresent analysis closed September 2013

Youngest participant turned 3 years Oldest participants up to 6 years

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Friday, December 05, 2014ML Mearin 23


Randomized feeding intervention in infants at high risk for Celiac Disease

N Engl J Med 2014;371:1304-15

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HLA-typing in 944 children from CD families

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994 Children in the PreventCD cohort

Follow-upMedian: 4 y. 22 days - 6.3 y.

Age

Median 4.9 y.

Range 3.1 – 6.6

Male 52%

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www.preventcd.com Friday, December 05, 2014ML Mearin 27


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Age at diagnosis of CD in 80 children

Mean = 2.8 y; SD = 1.1 y

Girls: 59%

55% TG2A +

Symptoms –

43%

Most frequent symptoms:

- Abdominal distension (N=20)

- Diarrhea (N=19)

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Cumulative incidence of CD (%)

3 y. 5.2 4 y. 8.85 y. 12.1

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•Country of origin

•Family characteristics

•Rotavirus vaccination

•Gastrointestinal infections

•Respiratory infections

•Mean daily gluten intake

Development of CD NOT related to

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Duration of breastfeeding

Breastfeeding not related to CD

Breastfeeding Exclusive breastfeeding


Italian Baby study on weaning and CD

Prospective, multicentre, intervention trial in a cohort of 707 children at family risk for CD, followed from birth and randomized to gluten introduction at 6 months or at 12 months of age.

Breastfeeding duration was irrelevant for the development of CD

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Cumulative incidence of CD by gender in 80 children

p=0.04

girls boys 3 y. 7.2 3.44 y. 11.8 6.1 5 y. 14.5 9.9

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Cumulative incidence of CDby HLA-type (n=911)

P<0.0001

P<0.0001

Homozygous DQ2

(DR3-DQ2/DR3-DQ2 or

DR3-DQ2/DR7-DQ2)

4 y 23.9

5 y 26.9

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Cumulative incidence of CDby HLA-type according to gender


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Cumulative incidence of CDGluten versus placebo

3 y. (95% CI) 5.9% (3.7-8.1) v.s.4.5% (2.5-6.5)


Cumulative incidence of CD gluten v.s. placebo in girls and in boys

3y. glu. plac.G 8.9 5.5 B 3.6 3.2

due to chance?to higher nr.

HLA-DQ2 homozygous girls randomized to gluten?

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Female only factorto favor placeboP=0.02

Effect of gluten or placebo at 4 months on development of CD in 994 children from high risk families

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Conclusions

• Early introduction of small quantities of gluten did not reduce the risk of CD at 3 y. in genetically predisposed children from high-risk families

• Our results do not support the protective effect that we had hypothesized

• Breast feeding does not protect against the development of CD in young children from high risk families

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Conclusions

In high risk families CD

• Develops at a very young age

• Significantly more often in girls

• Significantly associated with DQ2 homozygosity

• Good predictive value of anti-TG2 positivity

• Prospective cohorts long follow-up necessary to

explore prevention extrategies

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SL VriezingaCE Hogen EschYW Wijkhuisen

E StoopmanF Koning

Y KooyV Monserrate

J MugicoProMISeR BrandH Putter

R TronconeR AuricchioA Ivarsson

A RosenA Myleus

H SzajewskaA Chmielewska

G PiescikC WijmengaJ Romanos

I PolancoE Martinez

C RibesP Crespo

J BindelsT KoltaiC Scerri

E MummertE Bravi

R ShamirC Hartman

L SollidM Raki

S KolacekZ Misak

I KorponayJ Gymesi

G Castillejo

S KoletzkoK Werkstetter

G OsianderV Villanacci

M Berant

Etc,etc...

All participating children and parents

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Thanks!

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• Prevent CD has been funded by the European Commission

FP6-2005-FOOD-4B-36383

Further sponsors

Azrieli Foundation, Israel; Deutsche Zöliakie Gesellschaft BV,

Eurospital SpA; Fondazione Celiachia, Italy; Instituto de Salud

Carlos III, Spain; Komitet Badań Naukowych

(1715/B/P01/2008/34); Fundacja Nutricia 1W44/FNUT3/2013;

Hungarian Scientific Research Funds (OTKA101788 and TAMOP

2.2.11/1/KONV-2012-0023); Stichting STICOON, the Netherlands;

Thermo Fischer, Germany; ESPGHAN; Fria Bröd, Sweden;

Fondazione Celiachia, Italy.


International Symposium

Baby Feeding and Disease Prevention

What we learn from prospective studies

April 17, 2015Leiden University Medical Center

Leiden, the Netherlands

Information and registration

[email protected]

[email protected]

0031. (0)71.5262806

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