Hypersensitivity to Vitamins

Vitamins include a wide range of biochemical compounds, very different from each other, whose presence is essential for the wellness and health of a human organism, given their importance in many enzymatic pathways of cell and tissue biology. However, the body cannot produce them. For that reason, their intake must be granted by a rich and highly differentiated diet which should include large amount of fresh vegetables and fruits, but also meats, wheat and natural vegetable oils from different seeds. During the years, every vitamin has been identified and produced synthetically, so allowing to treat pharmacologically the diseases related to their deficiency. The large amount of vitamin derivatives has led to development strategies of food fortification enriching common aliments and dairy products with specific vitamins but also to discover particular vitamin derived drugs, whose properties recall the original vitamin, allowing to increase their therapeutic effects or decrease the potential vitamin toxicity or their use through topical or mucosal routes even. Because of the antioxidant properties of some vitamins as vitamin C, for instance, some vitamins have been developed as food preservatives or food dyes. The increased attention and fashion for body wellness has brought to an augmented consumption of multivitamin, above all, in Western societies, believing that consumption of vitamin megadoses could be a protective factor from degenerative disease. On the contrary, vitamins may induce toxic effects as hypervitaminosis, but also, more rarely, hypersensitivity reaction.

Vitamin B1 or thiamine was the first water-soluble vitamin to be isolated. Thiamine deficiency leads to the onset of beri-beri and Wernicke encephalopathy, often associated with Korsakoff psicosis, above all, in chronic alcohol addicted patients. The necessity to administer quickly intravenous thiamine hydrochloride to restore blood thiamine level caused in some patients the onset of a severe immediate type reaction like anaphylactic shock, sometimes with lethal outcomes. The pathomechanism of hypersensitivity reaction seems to be genuinely IgE mediated and thiamine hydrochloride, that is the synthetic pharmaceutical form of thiamine, probably is a sensitizing hapten able to conjugate with azoproteins. Furthermore, patients with immediate-type hypersensitivity to parenteral thiamine may tolerate that vitamin when assumed orally. On the contrary, few cases of allergic contact dermatitis to thiamine are reported in literature, mainly following an occupational exposure and the oral intake of vitamin B1 is always associated with a flare-up of dermatitis.

Riboflavin or vitamin B2 is rarely responsible for allergic reactions and few cases mainly immediate-type reactions are reported in literature. Despite that riboflavin is used as a coloring excipient in drinks and industrial foods in the form of sodium phosphate salt, it does not seem to cause occult sensitization or cross-reactivity with natural riboflavin naturally occurring in foodstuffs.

Niacin is an essential nutrient necessary to the human body for numerous enzymatic pathways requiring nicotinamide adenine dinucleotide (NAD) and its derivatives for redox metabolism. Niacin can be deficient despite its fortification in flour and cereal products. Niacin deficiency can present in several different forms, although the most known and recognized is pellagra disease. Immediate type hypersensitivity to nicotinic acid is rare and it was reported with intravenous administration only. Even allergic contact dermatitis are reported exceptionally and it occurs mainly with the topical use of nicotinic acid derivatives more than vitamin B3 itself.

Pantothenic acid is widely distributed in numerous foodstuffs and it is essential for normal epithelial function and as a component of coenzyme A, which serves as a cofactor for a variety of enzyme-catalyzed reactions highly important in the metabolism of carbohydrates, fatty acids, proteins, steroid hormones, and many others. However, panthotenic acid is chemically unstable, thus the stereoisomer of the alcoholic analog, dexpathenol is truly used in cosmetics or multivitamins. Although it is a hydrosoluble vitamin, its derivatives are largely used in cosmetics, moistures, hair products and regenerative emulsions for skincare, for that reason the risk of skin irritancy or sensitization is stronger than other hydrosoluble vitamins and allergic contact dermatitis to panthotenic acid and its derivatives are described in literature, whereas immediate-type reactions like anaphylaxis and contact urticaria occur less frequently.

The name of Vitamin B6 refers to a group of vitamers based on a core pyridine structure from which a synthetic homolog, pyridoxine hydrochloride, has been obtained, for pharmaceutical purposes. However, that synthetic compound is responsible for different allergic reactions, mainly delayed, cell-mediated-type. Because of the vitamin B6 photosensitivity, various cases of adverse cutaneous reactions, above all photoallergic, are described in the literature following the use of systemic assumption of vitamin B6 or its skin application from vitamin enriched topical products like creams and cosmetics.

From a biochemistry point of view, Biotin or vitamin B7, previously also known as vitamin H, possesses a simple chemical structure; thus it is quickly metabolized and addressed to its biological tasks. For that reason, probably, no case report of immediate- and delayed-type reactions are described in the literature. Just two cases of occupational allergic contact dermatitis to biotin and biotin precursors have been reported.

Folic acid is the synthetic form of vitamin B9 or folate and it is not found in nature. Folate conversion to the active form requires reduction to tetrahydrofolate, a reaction that is catalyzed by dihydro-folate reductase, which is expressed in the intestine and other peripheral tissues. Folic acid is the lonely vitamin able to induce severe anaphylactic shock following its oral assumption or through any route of administration, i.e. intravenously or intramuscularly. The sensitizing strength of the folic acid might be due to its accumulation in blood, caused by its property to exhaust the enzymatic pathways responsible for its metabolism. Specific IgE to folic acid has been isolated by different research groups, thus suggesting immediate-type reactions to folic acid have genuinely a reaginic pathomechanism. Furthermore, derivative drugs like folinic acid or antifolate drugs like methotrexate have been produced and they may show an allergic cross-reactivity with folic acid. Isolated cases of folic acid desensitization have been performed but poorly described in literature whereas a wellelaborated desensitization protocol would be desirable, given the importance of folic acid during pregnancy to prevent neural tube malformations in the newborn.

Vitamin B12, also known as cobalamin, is one of the few organo-metallic compounds occurring in nature and was the last hydro-soluble vitamin to be identified. The cobalamin biochemical structure and its metabolism are highly complex, and diseases related to its deficiency are associated with hematological and neurological alterations. The complex chemical structure of cobalamin gives it a high molecular weight, making cobalamin an immunogenic molecule. Moreover, the presence of the cobalt atom in the corrin ring of cobalamin may cause an allergic contact dermatitis flare-up in patients previously sensitized to cobalt. Immediate-type reactions induced by the parental administration of vitamin B12 have been reported in the literature, and they are linked to the used cobalamin moiety or its delivery route. They are reputed to be genuinely IgE mediated. Two “time patterns” of sensitization have been evidenced and probably two patterns of immune recognition also exist. Desensitization protocols have been used as an alternative method to administer vitamin B12 in patients needing it when all the other strategies fail.

Vitamin C, (ascorbic acid), is a water-soluble, highly labile compound, easily lost during food processing. It is one of the most common and essential vitamins, involved in numerous metabolic pathways in the human body and has a protective and preventive role against the damages of free radicals. Vitamin C deficiency is responsible for the onset of scurvy. Ascorbic acid has a high tolerability, due to its short half-life and rarely induces hypersensitivity reactions. Because of its antioxidant properties, ascorbate salts and other ascorbic acid derivatives are largely used as food preservatives in industrial beverages or more recently like whitening agents in cosmetics, thus the first case reports involving products like 3-O-ethyl-L-ascorbic acid or ascorbyl tetraisopalmitate, have been described in the literature. Such allergic contact dermatitis seems to be caused by the side chains of these compounds rather than the ascorbic acid core structure.

The name of vitamin A designates the group of retinoids, i.e., some lipophilic substances, which include carotenoids, retinol, retinal and retinoic acid and their synthetic derivatives. Carotenoids and retinoids have several similar biological activities such as antioxidant properties, beneficial effects on the skin, the inhibition of malignant tumor growth and the induction of apoptosis. Retinoic acid [RA] is the active form of the retinol isoform of vitamin A, while retinol is its vitamer form found in food and is converted in the body to 11-trans-retinal by an oxidative process where the hydroxyl group is converted into an aldehyde. 11-trans-retinal is subsequently isomerized into 11-cis-retinal, the functional isomer of the vitamin important in the physiology of vision. Among carotenoids, beta carotene is the pro-vitamin A form obtained from vegetables. Hypervitaminosis A and the relative toxicity usually occur as a consequence of the administration of large amounts of vitamin A preparations, usually for therapeutic purposes. Many esters of vitamin A have been isolated and produced and following their topical use in cosmetics, allergic contact dermatitis has been reported. Furthermore, from retinoic acid, a new class of drugs largely used in dermatology have been produced and the first representant was the cis-retinoic acid or isotretinoin and many others which can be assumed orally to treat severe acne. Such drugs have induced contact dermatitis, photodermatitis, but also urticaria/angioedema with a pseudoallergic mechanism due to the imbalance of inflammatory prostaglandins. On the contrary, true allergic reactions like anaphylaxis from these vitamin A derivative drugs are attributed to their emulsifier, the soybean oil, able to induce severe reactions in peanut allergic patients.

Vitamin D has many benefits for body and human health. Vitamin D is involved in calcium homeostasis and bone metabolism, and it can be obtained from food, but it is produced by the human body too. Vitamin D from foodstuffs is available in two forms; vitamin D2 [ergocalciferol,] is contained in plants, and vitamin D3 [cholecalciferol] is contained in animals. Furthermore, the vitamin D produced by human body, is synthesized mainly in the skin. The synthesis of vitamin D in the skin starts with the conversion of 7-dehydrocholesterol [provitamin D3] to previtamin D by UVB. Some of the formed vitamin D3 in the skin is transported to the liver and metabolized to become 25(OH)D3 (calcidiol), then furtherly converted in two steps to 1,25(OH)2D3 (calcitriol), i.e., the biologically active form of vitamin D. Being produced by the organism, vitamin D shows a high tolerability; thus hypersensitivity reactions to vitamin D are rarely reported in the literature. From vitamin D, many analogs have been used successfully to treat secondary hyperparathyroidism or other derivatives synthetically produced like calcipotriol, calcitriol and maxcalcitol that are used in dermatologic field as topical therapeutic agents for psoriasis. For this last class of compounds, given the external use on the skin, cases of allergic contact dermatitis are described.

Vitamin E refers to a family of compounds that function as lipid-soluble antioxidants capable of preventing lipid peroxidation. Naturally occurring forms of vitamin E include tocopherols and tocotrienols. The form of vitamin E most studied is natural alpha-tocopherol, which is the form more adapted for humanorganism requirements. It is possible to distinguish two isomers, the D-alpha tocopherol, the natural form and the synthetic form of vitamin E, DL-alpha-tocopherol, which has allowed the synthesis of various esters like the alpha-tocopheryl acetate, succinate, nicotinate and many others to increase vitamin E hydrosolubilty and its penetration throughthe skin in cosmetic applications as antioxidant and anti-aging agent. Consecutively, allergic contact dermatitis represents the most common form of hypersensitivity induced by vitamin E and its derivatives and vitamin E is the third most frequent contact allergen found in moisturizers. Despite the first cases of contact allergy to vitamin E were described in the 60ies, concentrations, and vehicles for the diagnostic patch tets to vitamin E are very far from being well standardized.

Vitamin K is a fat soluble vitamin used to treat or prevent certain coagulation disorders, because it is strongly required by the human organism for the production of the coagulation factors II, VII and X, and the dietary intake of the daily doses are strongly recommended to avoid the onset of bleeding and haemostasis disorders. However, Vitamin K is surely the vitamin for which majority of hypersensitivity reactions have been described for, either immediate or delayed-type, and sometimes the clinical manifestations do not allow the certain identification of the immune pathomechanism. Furthermore, the excipient like Cremophor EL i.e., polyoxyl 35-hydrogenated castor oil, plays a role in eliciting immediate type reactions, which can be pseudo allergic or IgE mediated even. Crempopor EL is in fact used as a suspending agent in many hydrophobic drugs like cyclosporine, tacrolimus, paclitaxel, teniposide and many others. On the other hand, vitamin K-induced delayed type reactions exhibit a wide range of morphological clinical pictures, mainly cutaneous. Patch tests and intradermal tests are very useful in delayed type reactions to diagnose such a hypersensitivity, while immediate reading skin tests have resulted doubtful or poorly helpful in the diagnosis of the immediate type reactions.

Although immediate-type hypersensitivity and allergic contact dermatitis have been mainly reported following vitamins or multivitamins intake and exposure respectively, more rarely unusual immune-mediated adverse reactions such as fixed drug eruption and other more serious hypersensitivity syndrome are described in the literature, but their diagnostic approach is more difficult because skin tests in severe cutaneous adverse reactions are validated for few drugs as anti-convulsivant agents.