Harmonisation of

micronutrient

requirements in

Europe

Dr. Nico van Belzen

Executive director

ILSI Europe

Go

ogle

Earth

Netherlands

Belgium Vitamin D

10-15 ug/day

2.5 ug/day

Google Earth

3m 9m 5y 10y 15y 25y 50y 70y

age

0

5

10

15

20

25

ug

_V

itD

5

7,57,5

10 10

5 55

France France

EC, Croatia,

Italy

Belgium

UK, Ireland

WHO, Bulgaria

Netherlands

IcelandIceland, Spain

Slovakia, Nordics, Estonia

Nordics, Estonia

Belgium Belgium

Russia, Netherlands

Russia, Netherlands

UK UK

Need for alignment

Doets et al. Eur J Nutr (2008) 47 (Suppl 1):17–40

Diversity of recommendations, vitamin D - men

Bodies responsible for setting

recommendations

5

Nutrition Society

Ministry of Health

Ministry of health and an advisory committee

Food Safety Authority

Harmonisation of micronutrient

recommendations in Europe

• EURRECA (2007-2012)

• EFSA1 (2009-201x)

1European Food Safety Authority

EFSA’s work on micronutrient

recommendations

• Request from the European Commission (2009)

• Scientific Opinion on principles for deriving and

applying Dietary Reference Values (2010) (http://www.efsa.europa.eu/en/efsajournal/pub/1458.htm)

• Proposes to derive the following DRVs: • Population Reference Intake (PRI) • Average Requirement (AR) • Lower Threshold Intake (LTI) • Adequate Intake (AI)

• EFSA’s DRVs are expected in 201x

Dietary Reference Values

EFSA Journal 2010; 8(3):1458

AR ANR EAR

PRI RDA INLx

LRNI

A Network of Excellence EC-funded (2007-2011)

Harmonising micronutrient recommendations across Europe

with special focus on vulnerable groups

and consumer understanding

EURRECA EURopean RECommendations Aligned

EURRECA’s aim

Produce a framework for use in deriving dietary recommendations that is:

• Transparent • Systematic • Sustainable

EURRECA scope

VitB12 Fol Fe Zn I VitC VitD Ca Se Cu

Intake x x x x x x x x x x

Status x x x x x

Population Groups

• infants (0-12 months)

• children and adolescents (1-18 years)

• adults (19-64 years)

• elderly (65+ years)

• pregnant and lactating women

Micronutrients

EURRECA Micronutrient

Requirement Process

Flow chart: aims to

facilitate the scientific

alignment of micronutrient

requirements

Defining the nutrition related health problem

Identification of which •Health problems •Population groups •Micronutrients

Setting up an infrastructure to identify the specific characteristics of the process to be followed by the committee •Purpose of committee •Composition of committee •Criteria on which to base requirements and/or recommendations

Defining the process

Step 3 – 6

Steps 3-6: Two approaches to derive requirements

Factorials de/repletion,

balance

Bio-availability

Required intake

EAR SD

Intake as measured

Status biomarker

Health measure

EAR SD

‘Classical’

‘Association’

Factorial

approach

Dose response, based on

RCTs and epi-research

Factorial approach

Factorial approach

ANR

“Population groups” / age

Pregnancy & lactation

Birth

Infants Children and adolescents

Adults, postmenopausal women

Older people

Fetal growth

Shape of curve :

scaling issue

(“extrapolation”)

Evidence base is heterogeneous: population groups, designs, methods, micronutrients

Dhonukshe-Rutten et al. 2010

S

H I

Intake-Health relation of primary interest for micronutrient

recommendations

.... but data may be scarce

.... therefore we want to use also data on Intake-Status and Status-

Health relations

Systematic Review steps

SEARCH

data bases

MASTER LIBRARY

2) SELECT:

Full text/papers

3) APPLY:

Eligible criteria

DATA

EXTRACTION

DATA BASE + META-

ANALYSIS

• Abstracts and full text

• 10 languages

• Reviews with full text

references

• Experts & their

organisations

3) Eligible criteria:

Different population groups

definition

Only intervention & observational

studies

Intake methodology in BPG

Biomarkers of status used in BPG

PROTOCOL

1) Sorted by:

Relationship (I-S, S-H, I-H, I-S-H)

Populations (adults & elderly, children,

adolescents, pregnant & lactating

women)

1) SCREEN & SORT:

Title & abstract

S

H I

Health

What functions/endpoints to take into account when

setting micronutrient recommendations?

Vitamin D metabolism and ‘classical’ functions

Thacher and Clarke (2011) Mayo Clin Proc. 86:50

Vitamin D ‘emerging’ functions (example 1)

Zasloff (2006) Nature Medicine 12, 388

Vitamin D ‘emerging’ functions (example 2)

Lamprecht and Lipkin (2003) Nature Reviews Cancer 3: 601

Vitamin D functions

• ‘Classical’ functions (skeletal)

– Intestinal calcium absorption

– Maintenance of calcium homeostasis and skeletal integrity

• ‘Emerging’ functions

– Stimulation of immune function (Zasloff 2006)

– Cell proliferation, differentiation and apoptosis

– Decreased risk of (lung) cancer? (Ramnath et al. 2011;

Weinstein et al. 2011)

– Decreased risk of CVD? (Guessous et al. 2011)

Taking into account the ‘classical’ and ‘emerging’

functions, what is the optimal intake and status

of vitamin D?

(and other micronutrients)

S

H I

Intake

Micronutrient intake work from ILSI

Europe’s Addition of Nutrients task force

Mensink et al. in preparation

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20

40

60

80

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120

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Denmark France Germany Poland Spain NL 19-30 NL 31-60 UK

P5 Intake

Mean Intake

LRNI

EAR

% <LRNI

% < EAR

Vitamin D intakes in men from base diet

Mensink et al. in preparation

Vitamin D intakes in men from fortif. diet + suppl.

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20

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Denmark France Germany Spain NL 19-30 UK

P5 Intake

Mean Intake

LRNI

EAR

% <LRNI

% < EAR

Vitamin D intakes in men

in selected EU countries With the base diet

• >50% of men in all countries have intakes < EAR

• Men with lowest 5% intake are <LRNI in all countries

• France and Spain have main intakes < LRNI

• Only Poland has a mean intake > EAR

• Intake men > women (not shown)

With the fortified diet (base+fortified+supplements):

• Denmark’s mean intake now reaches EAR

• France and Spain still have main intakes < LRNI

• Men with lowest 5% intake remain < LRNI in all

countries

• Intake men ≥ women (not shown)

S

H I

Status

Biomarkers to assess adequacy of

micronutrient status

Biomarkers can be used to validate intake or identify deficiency

EURRECA Systematic Reviews (AJCN supplement)

EURRECA Eminence-based Reviews (BJN supplement)

EURRECA Best Practice Guidelines (web-based)

Limited number of useful biomarkers

Usually invasive (e.g. blood samples)

Cut-offs for ‘normal’ range may be uncertain

Particular issues with measuring iron status in the presence of infection/inflammation (disregard ferritin if CRP high)

Micronutrient 3* biomarkers (as rated by EURRECA)

Iron Serum/plasma ferritin, sTfR, ‘Body iron’ (Cook method) ratio sTfr:ferritin, bone marrow examination

Iodine Iodine excretion in 24hr or spot urine samples, serum thyroid-stimulating hormone (neonates only)

Selenium None (2* plasma/serum/platelet/erythrocyte/urinary /toenail/hair selenium, selenoprotein P, GPx activity)

Zinc None (2* serum/plasma zinc, prevalence of stunting, prevalence of inadequate intakes (suggested by iZiNCG))

Copper None (Copper chaperone for SOD a potential 2* marker)

Calcium None (2* skeletal mineral content & neutron activation)

Vitamin D Serum 25-hydroxyvitamin D

Vitamin C Serum/plasma ascorbic acid, leukocyte ascorbic acid

Folate Erythrocyte folate

Vitamin B12 None (2* serum/plasma total B12, methylmalonic acid, HoloTC)

Biomarkers for measuring nutrient status

Recommended dietary intake of vitB12

How to use the meta-analysis

VitB12 intake (μg/day)

Se

rum

/p

lasm

a v

itB

12

(p

mo

l/L)

Intake-Status relationship

Optimal vitB12 status, based on S-H meta-

analysis

Highlights of results on Vitamin B12 Association approach (RA3.1) - RCT’s

Intake-Status (RCT’s)

Adults & Elderly

Study-specific (grey) and overall pooled regression lines

(black) between vitB12 intake and serum/plasma vitB12 status

(24 RCT’s)

Highlights of results on Vitamin B12 Association approach (RA3.1) - Observational

Intake-Status (Observational)

Adults & Elderly

Steps 3-6: Main findings

• Current Recommendations

– Lack of transparency

– Different methodologies and terminologies used

among countries.

– Reference values are often extrapolated from adults or

infant data.

• Available data

– Scarcity of clinical studies (children and adolescents)

– When studies available - large heterogeneity

– Often moderate/high risk of bias

EURRECA Micronutrient

Requirement Process

Flow chart: aims to

facilitate the scientific

alignment of micronutrient

requirements

Eurreca’s output (so far)

Scientific publications

• About 65 presentations at key events in 2010

• ~50 databases soon online

• Data (Access)

• Literature (EndNote)

Tools developed by EURRECA

• Nutri-RecQuest (www.serbianfood.info/eurreca/)

• Micronutrient Wiki (http://www.eurreca.org/everyone/1431/5/0/32)

• NutPlan: nutrition planning, e.g. recipes, intake ass.

• Nutritional phenotypes database

• E-learning tools (www.eurreca.org/Courses/demo/index.html)

– Reproducibility and validation studies within nutritional research

• Validation of a 24-hour recall

• Validation of FFQ

Cavelaars et al. 2010

Take home messages • Setting recommendations in a transparent, systematic way is

still difficult - in most cases, there is a distinct lack of high quality

studies

• EURRECA developed the Micronutrient Requirement Process

Flow Chart for deriving reference values

• EURRECA is unique by:

1. Integration of association (I-S-H) and factorial approach

(including bioavailability)

2. Policy aspects

3. Multiple micronutrients/health space

• EURRECA generated several tools, such as Nutri-RecQuest

• EURRECA established key collaborations to ensure its legacy

B O N

D

Thanks to all partners