Anaphylactic reaction to folic acid verified by provocational testing

Folic acid (pteroylmonoglutamic acid; Fig. 1A) – the synthetic and unconjugated form of folate B vitamins in foods – is widely used in vitamin supplements. It is essential for DNA synthesis and other metabolic processes. The recommended daily intake of folic acid is 400 lg; deficiency may lead to impaired growth, neural tube defects and megaloblastic anemia amongst others. Due to its importance and frequent lack in the diet food manufacturers are more and more required to add folic acid to enriched grain products such as breakfast cereals, bread, pasta and rice (1). Although a few cases (2–4) of presumed folic acid allergy have already been published the proof of an allergy to folic acid in double-blind placebocontrolled oral challenge with folic acid as single substance has so far been lacking. We present the first case of an anaphylactic reaction to folic acid itself proven by oral provocational testing. A 44-year-old Caucasian woman had suffered from an anaphylactic reaction with tachycardia, generalized skin eruption and dyspnea 10 min after intake of a multivitamin tablet. Four similar reactions had occurred within 20 min after intake of various multivitamin products from different sources, such as multivitamin juices, tablets and sweets in the last 5 years. As ingredients common to all suspected multivitamin agents vitamin B6, B12 and folic acid were found. The patient was otherwise healthy and did not take any medication; there was no personal or family history of atopy or other allergic diseases. Skin prick tests revealed positive reactions to only one of the suspected multivitamin tablets vaso-loges (Dr Loges und Co. GmbH, Winsen, Germany; consisting of vitamin B6, B12, folic acid, gelatine, titandioxide, ferrum oxide, magnesium stearate) as well as Dreisafol (GRY-Pharma GmbH, Kirchzarten, Germany; consisting of folic acid, magnesium stearate, cellulose, lactose and silicium dioxide). Three healthy control subjects showed no reactions when tested with vaso-loges and Dreisafol . Other multivitamin agents, vitamin B6 and B12 showed no reaction. Additive substances (titandioxide 100 mg, magnesium stearate 5 g, colors (E127, E131, E132, E151, E172) 5 mg and gelatine 10 g) were also negative on oral challenge (5). Vaso-loges did not show reactions when labially and lingually challenged. However, after oral provocation with 1/4 tablet vaso-loges (one whole tablet contains 440 lg folic acid, 4.4 mg vitamin B6 and 8.8 lg vitamin B12) the patient developed a generalized urticarial eruption and mild laryngeal dyspnea. Symptoms resolved gradually upon treatment with intravenous H1 – Antagonist dimetindene (4 ml) and prednisolone (250 mg) together with fenoterol aerosol (two puffs). After a resting period of more than 4 weeks the patient was challenged with vitamin B6 and B12 which was well tolerated. After negative labial and lingual challenge also Dreisafol was orally challenged. At the dose of 500 lg folic acid (1⁄41/10 tablet) the patient reacted with a generalized urticarial eruption, conjunctival injection, dyspnea, tachycardia and blood pressure decrease (90/ 50 mmHg; Fig. 1B). Upon treatment with dimetindene, prednisolone and hydroxyethyle starch solution intravenously and fenoterol as aerosol the patient recovered quickly, without any symptoms in the overnight inpatient observation. As a consequence of the strong reactions after oral challenge the patient was advised to avoid synthetically produced folic acid and enriched Folic acid is an essential vitamin needed for DNA synthesis and metabolic processes. We present the first verified clinical anaphylactic reaction to folic acid.