Folic Acid A case for personalised preventive nutrition

Abstract

Fortification of food with folic acid has resulted in significant declines in the occurrence of Neural Tube defect affected pregnancies; however, growing scientific evidence in the field suggests a possible association between high intake levels of folic acid and risks of cancer and other harmful effects. This article discusses the need to translate new epigenetic evidence into a more personalized folic acid supplementation approach

Full text

FOLIC ACID
A case for personalized preventive nutrition?
Fortification of food with folic
acid has resulted in significant
declines in the occurrence of
Neural Tube defect affected
pregnancies; however, growing
scientific evidence in the field
suggests a possible association
between high intake levels of
folic acid and risks of cancer and
other harmful effects. This article
discusses the need to translate
new epigenetic evidence into a
more personalized folic acid sup-
plementation approach.
Verhagen, M.C.M. 1 ; Brand, A 1;
Ambrosino, E 1; Haslberger, A.G. 2
FOLATE DEFICIENCY AND NTDS
The relationship between folate deficien-
cy and Neural Tube Defects (NTDs) occur-
rence was hypothesized as early as 1965
(Crider, Bailey, & Berry, 2011). Evidence
from scientific studies has since then
conclusively demonstrated that folic acid
supplementation can prevent the occur-
rence of NTDs (EFSA, 2009); supplemen-
tation of >400µg/day is found to prevent
as much as 70% of these defects (Van
den Veyver, 2002). This has led many
countries to recommend women plan-
ning to become pregnant to supplement
their diet with folic acid (synthetic form of
folate). In the EU, the recommended ref-
erence intake for folate is set by SCF (Sci-
entific Committee on Foods, EC) : 200μg
folate/day for adults, 400μg folate/day
for pregnancy (EFSA, 2009). Yet, Public
Health campaigns by countries to pro-
mote the awareness of this message and
promote voluntary supplement intake by
pregnant women have been unsuccessful
in most countries (EUROCAT, 2005); the
fact that the former target group needs
to consume folic acid in the 4 weeks be-
fore and 8 weeks after conception, makes
a voluntary intervention hard to imple-
ment effectively. This problem, together
with the discovery of another important
suspected effect of folic acid in the early
1990s: protection against cardiovascular
diseases later in life (Cornel, de Smit, &
de Jong-van den Berg, 2005), lead Public
Health prevention policies to develop in
two ways: some American and developing
countries choose to implement mandato-
ry fortification of staple foods (Cornel,de
Smit, & de Jong-van den Berg, 2005), like
flour, while voluntary fortification of food
with folic acid is permitted and obligated
in most European countries. Currently
no EU country has implemented manda-
tory fortification (EFSA, 2009). Manda-
tory folic acid food fortification has since
then resulted in significant declines in the
occurrence of NTD affected pregnan-
cies (EFSA, 2009). The percent declines
range from 28% to 46% in the USA and
Canada respectively (EFSA, 2009). Many
(European) countries are therefore con-
sidering whether to adopt this mandatory
fortification policy. American biomarker
studies postfortification showed dramatic
increases in population blood measure-
ments of folate, this raised concerns that
fortification exceeded the original daily
intake target by
as much as 2-fold
(Ulrich & Potter,
2006). At the
same time an ad-
vertising hyper-
bole of proactive
fortified health
foods market
seems to have
occurred, “where
a muddying of
waters can oc-
cur regarding the
ideal between too
little or too much
of any given nutrient” (Lucock & Yates,
2009). This is of concern, taking into ac-
count the growing scientific evidence that
has recently emerged suggesting a pos-
sible association between high intake lev-
els of folic acid and risks of cancer (EFSA,
2009) and various other harmful effects.
RESULTS FROM CLINICAL STUDIES
Effects of folic acid supplementation are
reviewed by Lucock & Yates (2009); the
main positive effects described are low-
ering of the risk for birth defects, lower
vasculotoxic, embryotoxic and neurotoxic
homocysteine with benefit to a range
of vascular conditions and Alzheimer’s
disease. Evidence from in vitro, animal,
and human studies has shown that fo-
late supplementation can act to prevent
tumour initiation (Smith, Kim, & Refsum,
2008), yet it seems to facilitate progres-
sion of precancerous lesions (Lucock &
Yates, 2009). A similar effect has also
been shown in vascular patients, where
supraphysiologic vitamins B6 and B12
along with folic acid did not lower recur-
rent cardiovascular disease after acute
myocardial infarction, with the authors
indicating a possible harmful effect of
combined vitamin B therapy (Reviewed
in: Lucock & Yates, 2009). Furthermore,
it now seems that synthetic folate satu-
rates human dihydrofolate reductase
(DHFR) leading to unmetabolized folate
in the circulation, and possibly masks the
irreversible pernicious anaemia of B12
deficiency, the former increasing risk for
cognitive impairment, while during preg-
nancy the same folate-B12 disposition
may increase insulin resistance and obe-
sity in offspring (Reviewed in: Lucock &
Yates, 2009). Folic acid also reduces natu-
ral killer cell cytotoxicity, may increase the
prevalence of positional plagiocephaly,
and increases multiple births after IVF
(Reviewed in: Lucock & Yates, 2009).
Since the 1940s antifolate drugs are being
used in cancer chemotherapy (Ulrich &
Potter, 2006), because removal of folate
or a blockade of its metabolism causes in-
hibition of tumor growth (Smith, Kim, &
Refsum, 2008). Recent evidence showed
that excess folic acid alters the efficacy
of antifolate drugs (Reviewed in: Lucock
& Yates, 2009). In general, “intervention
studies using folic acid have produced a
range of different results including ad-
verse effects; overall they do not support
the hypothesis that folic acid supplemen-
tation of human populations reduces the
chronic disease risk” (EFSA, 2009). It is
clear that disruptions in folate metabolism
increase risk for a variety of pathologies
(Stover & Caudill, 2008), yet while folate
supplementation can reduce the risk of
some disorders developing (Stover & Cau-
dill, 2008), it can itself likely disrupt the
folate metabolism as well. So far, the pre-
cise biochemical mechanisms underlying
folate-related pathologies have remained
elusive despite intensive investigation
(Stover & Caudill, 2008), yet new system
biological evidence is rapidly emerging.
NUTRIGENETIC AND
EPIGENETIC ASPECTS
Adequate folate status is essential for
DNA synthesis and cell division and low
folate status in humans is associated
with an increase in DNA strand breaks,
impaired DNA repair and increased mu-
tations (Smith, Kim, & Refsum, 2008).
Folate also plays a major role in the fo-
late-mediated one-carbon metabolism;
with a main function in the provision of
methyl-groups for the conversion of ho-
mocysteine to methionine (Smith, Kim, &
Refsum, 2008), which in turn can be ad-
enosylated to form S-adenosylmethionine
(SAM) (Stover & Caudill, 2008). SAM is
a molecule with many functions, includ-
ing methylation of cytosine residues in
DNA and of arginine and lysine residues
in histones, both of which are involved in
regulating gene expression (Smith, Kim,
& Refsum, 2008). By example, meth-
ylation of promoter related CpG islands
can suppress gene expression by caus-
ing chromatin condensation (“silencing”),
and could, for instance, silence tumor
supressor as well as a tumor oncogenes.
Therefore, folate plays a major role in epi-
genetic mechanisms; “any processs that
alters gene activity without changes of
the DNA sequence” (Haslberger, Varga,
& Karlic, 2006). Gene variants that en-
code folate-dependent enzymes and al-
ter the efficiency of nucleotide and SAM
biosynthesis can confer both, protection
and risk for specific pathologies; exam-
ples are the common SNPs in the methy-
lenetetrahydrofolate dehydrogenase
gene (MTHFD1), 1958G>A and methy-
lenetetrahydrofolate reductase gene
(MTHFR), 677C>T, which increases the
risk for NTDs (Stover & Caudill, 2008).
It is described that periconceptual expo-
sure to folic acid might genetically select
the latter gene,
and lead to
an increase
in prevalence
of individuals
with MTHFR,
677C>T. This
SNP is also as-
sociated with
d e ge ne r at iv e
disorders (Lu-
cock & Yates,
2009), however,
seems protec-
tive against co-
lon cancer in
folate-replete individuals (Stover & Cau-
dill, 2008). So far, “The functional role
of these polymorphisms in the etiology
of NTDs and cancer is unknown but is
likely related to DNA synthesis, repair,
and/or methylation mechanisms (Stover
& Caudill, 2008)”. “Low folate status
is often associated with impairment of
DNA methylation, but sometimes it leads
to hypermethylation and thus could af-
fect gene expression in complex ways. It
is not known whether an excess of fo-
late might have any adverse effects on
these functions (Smith, Kim, & Refsum,
2008)”. Changing the folate status in hu-
mans has been shown to influence DNA
methylation, but, it is not yet established
whether alterations in DNA methylation
after changes in folate status are harm-
ful in humans, for example, by regulating
the expression of oncogenes or tumor
suppressorgenes (Smith, Kim, & Refsum,
2008) and studies published have shown
many contradicting results. However,
animal studies on colorectal cancer have
shown that the timing and dose of folate
intervention are critical: If folate supple-
mentation is started before the establish-
ment of neoplastic foci, the development
and progression of the tumor is sup-
pressed, if started after, it enhances their
growth and progression (Smith, Kim, &
Refsum, 2008). This dichotomy has been
consistently shown for colorectal adeno-
mas, colorectal cancer rates, breast and
prostate cancers (Lucock & Yates, 2009).
Furthermore, a recent study by Berner, et
al. (2010) found that exposure to a high
concentration of folic acid enhanced
cancer cell growth, and concomitant in-
creased methylation of estrogen recep-
tor and tumor suppressor promotors was
observed, while a lower concentration of
folic acid decreased cell growth. Aber-
rant promotor hypermethylation that is
associated with inappropriate gene si-
lencing of tumor suppressor genes is hy-
pothesised to affect virtually every step
in tumor progression (Haslberger, Varga,
& Karlic, 2006).
It is important to note that Smith, Kim,
& Refsum (2008) stated that additional
biological explanations for contradictions
in study outcomes are also likely: “For ex-
ample, it is biologically plausible that any
effect of folate on carcinogenesis will in-
teract with a large number of other risk
factors and that the patterns of these
risk factors will differ between individu-
als. Observational studies have identified
many factors, apart from age and sex, that
might interact with folate in cancer risk,
including vitamin B-12, alcohol, smoking,
and polymorphisms in genes coding for
enzymes related to one-carbon metabo-
lism (Smith, Kim, & Refsum, 2008)”. Fur-
thermore, the influence of folate status
on DNA methylation in both animals and
humans is hypothesised to be tissue-, site-
, and gene-specific (Smith, Kim, & Ref-
sum, 2008). Overall, studies reviewed by
Smith, Kim, & Refsum (2008) show that it
is not justified to assume that the finding
of a protective effect of high folate in a
whole population necessarily applies to all
people within that population, moreover,
evidence provides cause for concern that
increasing folate levels in an entire popu-
lation may, in some people, increase the
risk of cancer.
A NEED FOR AN
INDIVIDUALIZED APPROACH?
Because the interactions between the
epigenome and folic acid methylation-
diets are complex and the fact that un-
derlying biochemical mechanisms remain
elusive, a population-based prevention
method like folic acid food fortification
is hazardous. “The highly complex and
critical biological importance of folic ac-
id-related molecular nutrition makes it a
difficult micronutrient to deploy as a sim-
ple intervention at a population level – it
has far too many biochemical spheres of
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Bericht & Report

influence to predict effects in a general-
ized way” (Lucock & Yates, 2009). It re-
mains unclear whether the possible harm
of high folic acid levels outweighs the
known and potential benefits. Further-
more, this harm-benefit balance may dif-
fer across individuals and populations, by
genetic characteristics and by life stage
(Ulrich & Potter, 2006). Therefore, rec-
ommended folic acid supplementation
may need to be adapted to individual
genotypes (Van den Veyver, 2002), and
epigenetic DNA methylation profiles.
Yet, to individualize folic acid dietary
recommendations it seems necessary
to have a detailed understanding of all
genetic and physiological variables that
influence the interaction of folate with
the genome and their relationship to the
disease process (Stover & Garza, 2002).
Moreover, a thorough understanding of
the role of epigenetic variables in this in-
teraction seems crucial.
1 Institute for Public Health Genomics,
Maastricht University
2 Department for Nutritional Sciences,
University of Vienna, alexander.haslberg-
er@univie.ac.at
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LCPUFAs IN SCHWANGER-
SCHAFT UND STILLZEIT
– Auswirkungen auf Kind und BMI
Publiziert & Kommentiert Muhlhausler B.S., Gibson R.A.,
Makrides M. Eect of long-
chain polyunsaturated fatty
acid supplementation during
pregnancy or lactation on
infant and child body com-
position: a systematic review.
American Journal of Clinical
Nutrition 2010: 92:857-863
EINFÜHRUNG
Langkettige, mehrfach ungesättigte Fett-
säuren (LCPUFAs) können die Zelldiffe-
renzierung und Fettspeicherung beim Er-
wachsenen hemmen. Es ergibt sich daraus
die Hypothese, dass eine LCPUFAs-Sup-
plementierung bei der schwangeren Mut-
ter die Fettmasse des Kindes im späteren
Leben reduzieren kann. Es gibt bereits ei-
nige randomisierte Studien, die den Effekt
von Omega-3-LCPUFAs-Supplementen
während Schwangerschaft und Stillzeit
auf die Körperzusammensetzung im
Säuglings- und Kindesalter untersuchten.
Bei den Studien zeigten sich sehr deutliche
Unterschiede bezüglich Studienqualität
und Studiendesign. Auch die Ergebnisse
waren sehr unterschiedlich. Dieser Review
soll auf die mangelhafte und fehlende Da-
tenlage in diesem Zusammenhang hin-
weisen. Kindliche Adipositas ist ein glo-
bales Problem. Zahlreiche Faktoren haben
einen zentralen Einfluss auf die Entwick-
lung. Vor allem das Ernährungsverhalten
der Mutter während der letzten Wochen
der Schwangerschaft sowie die Ernährung
des Säuglings nach der Geburt können die
Entstehung von Übergewicht und Adipo-
sitas signifikant beeinflussen. So spielt vor
allem die Zusammensetzung der Fettsäu-
ren in der Ernährung der Frau während
Schwangerschaft und Stillzeit für
die Körperzusammensetzung
des Säuglings eine entscheidende Rolle. In
dem vorliegenden Review wird der aktu-
elle Stand der Literatur zum Thema LCPU-
FAs-Supplemente während Schwanger-
schaft und Stillzeit und ihr Einfluss auf die
spätere Entwicklung und Körperzusam-
mensetzung des Säuglings besprochen.
METHODEN
In diversen Datenbanken wurde nach Hu-
manstudien zu diesem Thema gesucht.
Unter den passenden Artikeln wurden
sieben relevante Studien ausgewählt.
Wichtige Auswahlkriterien waren dabei:
maternale LCPUFAs-Supplementierung
für mindestens zwei Wochen, sowie Mes-
sungen von BMI und Prozent an Körper-
fett. Die Studien wurden aussortiert und
es blieben drei Studien übrig, die in die-
sem Review aufgenommen wurden.
RESULTATE
Es wurden drei Studien zusammengefasst.
In der ersten Studie wurde Olivenöl sup-
plementiert, in der zweiten Studie Mais-
keimöl und in der dritten Studie wurden
probiotische Supplemente und Vitamin-
tabletten mit LCPUFAs verabreicht. Die
LCPUFAs-Dosen lagen zwischen 0,2
und 1,18g pro Tag. Der Zeitpunkt der
Intervention lag zwischen der 18. und
21. Schwangerschaftswoche bis
zum dritten Lebensmonat.
Als Outcome wurden BMI,
BMI Z-Score und Haut-
faltendicke bestimmt.
Die Messungen er-
Dieser Review untersucht die Effekte
einer hohen Aufnahme von LCPUFAs-
Supplementen während Schwanger-
schaft und Stillzeit auf die Körperzusam-
mensetzung des Säuglings und Kindes.
Er weist auf einen Mangel an Studien
hin, die sich mit diesem Thema ausei-
nandersetzen. Es konnten nur drei Hu-
manstudien gefunden werden, die den
Auswahlkriterien entsprachen. Innerhalb
dieser drei Studien bestehen deutliche
Unterschiede bezüglich Studiendesign,
Studienqualität, Dauer und Zeitpunkt
der Intervention, sowie Outcome-Mes-
sungen. So waren auch die Ergebnisse
sehr unterschiedlich. Es kam zu einem
positiven, einem negativen und einem
neutralen Ergebnis. Derzeit ist es nicht
möglich, definitive Aussagen zu treffen
und die Empfehlung einer LCPUFAs-
Supplementierung während Schwan-
gerschaft und Stillzeit kann momentan
nicht ausgesprochen werden. Es besteht
ein deutlicher Mangel an gehaltvollen
Daten aus Humanstudien. Um das
bestehende Loch an aussagekräftigen
Informationen zu füllen, sind weitere
Langzeitstudien notwendig, und diese
sollten besser aufgebaut werden.
Conclusio
*Mag. Karin Gatternig, Univ.-Prof. Dr. Kurt
Widhalm, Österreichisches Akademisches
Institut für Ernährungsmedizin, Alserstraße
14/4a, 1090 Wien, E-Mail office@oeaie.org
folgten jeweils im 21. Lebensmonat, mit
2,5 Jahren und im 7. Lebensjahr. In al-
len drei Studien war die Drop-Out-Rate
sehr hoch. In der ersten Studie war der
BMI der Kinder im 21. Lebensmonat bei
gesteigerter Aufnahme von LCPUFAs
deutlich reduziert. In der zweiten Studie
zeigte sich kein Effekt durch die mater-
nale LCPUFAs-Supplementierung. Die
dritte Studie zeigte sogar ein negatives
Ergebnis, da eine maternale LCPUFAs-
Supplementierung während der Stillzeit
eine Erhöhung des BMI und Bauchum-
fangs mit 2,5 Jahren bedeutete.
LCPUFAs: Derzeit
noch keine defi-
nitiven Aussagen
möglich.
© Foto: Fotol ia/Anatoliy Samar a
30 JEM Dezember 2011
Bericht & Report
31 JEM Dezember 2011
Publiziert & Kommentiert