ARTICLE
ejd.2010.1248
Auteur(s) : Johanna STOEVESANDT Stoevesandt_J@klinik.uni-wuerzburg.de,
Eva-B. BRÖCKER, Axel TRAUTMANN
Department of Dermatology, Venereology, and Allergology,
University of Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg,
Germany
Folate is the generic term for a group of related B-vitamins
acting as single-carbon-transfer co-enzymes. As deficiency is a
cause of infant neural tube defects, and the daily reference intake
of 400 μg of folate equivalent is not easily achieved on an
average diet, pharmaceutical folic acid (FA) preparations are
available for substitution. Moreover, FA is added to a variety of
convenience foods, and FA-fortification of cereal grain products is
mandatory in some countries, including the US and Canada
[1, 2].
Allergic anaphylaxis is a rare, but potentially dangerous side
effect of FA-preparations [3-5]. Recently, an IgE-mediated
mechanism could be demonstrated by IgE binding to folate-albumin
[3]. Naturally occurring folates are tolerated by sensitised
patients who are generally advised to avoid all artificially added
FA [3-5]. Total abstention however is getting increasingly
difficult due to substitution in every day food. The question
arises whether sensitised individuals are really at risk of
developing anaphylaxis when consuming FA-fortified products.
We report a 45-year old woman who developed generalised
urticaria and angioedema, accompanied by difficulty in swallowing
30 minutes after ingestion of a 5 mg FA-tablet. Intake of the
same supplement had been well tolerated during a pregnancy some 10
years before. Her diet included vitamin-enriched products, such as
ready-to-eat breakfast cereals. This was her first episode of
hives.
Prick tests were performed using the FA-tablet, an intravenous
FA-preparation, folinic acid (5-formyltetrahydrofolic acid), and
tetrahydrofolic acid (THF). Intradermal tests were carried out
using intravenous FA and folinic acid-preparation, diluted up to
1:1 000. While skin tests with folinic acid and THF were negative,
prick and intradermal tests with FA were strongly and unequivocally
positive. Three healthy volunteers showed no skin reactions with
the FA-preparations. Graded oral provocation with FA up to a single
dose of 400 μg (the cumulative dose being 660 μg) was
well tolerated by our patient, defining an individual with no
observed adverse effect level (NOAEL). She denied further increment
of provocation doses to establish the lowest observed adverse
effect level (LOAEL). Her blood levels of folate, vitamin B12, and
a full blood count were normal.
Tolerance of low FA doses is supported by documentation of
reactions provoked following intake of several hundred μg [4],
while there are no reported episodes of anaphylaxis due to
ingestion of FA-fortified foods. Synthetic FA, correctly referred
to as pteroylmonoglutamic acid, does not occur naturally. It
represents the most oxidised form of folate. Skin tests with
naturally occurring, reduced folates (THF and
5-formyltetrahydrofolic acid) were negative in our patient. This is
consistent with most reports [4], though different patterns of skin
test cross-reactivity have been described [3].
Upon ingestion, FA is absorbed in the intestine and transferred
to the liver via the portal vein (figure 1). A
considerable amount is released into the bile, entering
enterohepatic recirculation. Generally, FA is reduced by
dihydrofolate reductase (DHFR) [2, 6] thereby becoming
indistinguishable from natural folates that are stored in the liver
as polyglutamates and may be released to systemic circulation,
linked to folate binding proteins. Upon intake of high doses of FA,
DHFR may become saturated and bypassed by unmetabolised FA. We
hypothesise that high doses of FA lead to significant amounts of
unreduced FA circulating, which produces the anaphylaxis-triggering
allergen. Our patient's NOAEL of 660 μg exceeds the daily
reference intake of 400 μg and is hardly achievable by the
consumption of a single FA-fortified meal. However, DHFR activity
significantly differs among patients [6] resulting in an individual
NOAEL which might be as low as 110 μg [5]. Our findings
underline the need for an individualised allergological work-up,
not only to the establish FA-allergy diagnosis but also to enable
detailed recommendations, preventing unnecessary dietary
restrictions.
Disclosure
Financial support: none. Conflict of interest: none.
References
1 M Eichholzer, O Tönz, R. Zimmermann Folic acid: a
public-health challenge Lancet 2006; 367: 1352-1361.
2 AJ Wright, JR Dainty, P.M. Finglas Folic acid metabolism in
human subjects revisited: potential implications for proposed
mandatory folic acid fortification in the UK Br J Nutr 2007;
98: 667-675.
3 MS Dykewicz, NA Orfan, W. Sun In vitro demonstration of IgE
antibody to folate-albumin in anaphylaxis from folic acid J
Allergy Clin Immunol 2000; 106: 386-389.
4 N Nishitani, A Adachi, T Fukumoto et al. Folic
acid-induced anaphylaxis showing cross-reactivity with
methotrexate: a case report and review of the literature Int J
Dermatol 2009; 48: 522-524.
5 F Pfab, R Willi, A Albert et al. Anaphylactic reaction
to folic acid verified by provocational testing Allergy
2007; 62: 823-824.
6 SW Bailey, J.E. Ayling The extremely slow and variable
activity of dihydrofolate reductase in human liver and its
implications for high folic acid intake Proc Natl Acad Sci
USA 2009; 106: 15424-15429.
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