Hypersensitivity to Vitamins

By Gianfranco Calogiuri

Vitamins are heterogenous bioactive substances required by the human body for its healthy functioning. Vitamins are required through a diet as they are normally not produced by the body. Their deficiency may lead to the development of diseases like scurvy, rickets, pellagra, beri-beri and many others. Vitamins have also been produced synthetically and used in supplements. However, they may induce hypersensitivity reactions, ranging from an allergic contact dermatitis to, urticaria as well as life-threatening anaphylaxis.
Hypersensitivity to Vitamins summarizes knowledge from case reports, studies and investigations on hypersensitivity reactions to all types of vitamins (A, B, C, D, E and K). Chapters explain the identification, diagnosis and management of hypersensitivity reactions to vitamins.

Key Features:
- Provides a general introduction to vitamin allergies
- Covers the major vitamin types: water soluble (B and C) and fat soluble (A, D, E and K) with chapters dedicated to each type
- Provides information about identification, diagnosis and management of the specific hypersensitivity reactions in a clear and concise manner
- Includes a chapter on unusual aspects of vitamin hypersensitivity

Hypersensitivity to Vitamins is an essential handbook for clinicians, nutritionists and pharmacists who want to quickly access information about vitamin allergies. Students of clinical immunology and pharmacology will also be able to learn about the subject.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Feb 14, 2006
• ISBN: 9781681088921

Book preview

Hypersensitivity to Vitamins: General Considerations

Gianfranco Calogiuri

Abstract

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.

Keywords: Allergy, Cosmetics, Fat-Soluble Vitamins, Food Excipients, Food Fortification, Hydrosoluble Vitamins, Hypersensitivity, Hypervitaminosis, Multivitamins, Vitamers, Vitamins, Vitamin Deficiency, Vitamin Toxicity,.

Introduction

With the name of vitamins, a heterogeneous group of biologically active organic substances are indicated. They are essential compounds playing an active role in numerous enzymatic pathways of the human organism [1, 2]. The name derives from the Italian amine [because they were reputed to be amines] della vita [of the life]. However, humans cannot produce vitamins de-novo, so they must absorb vitamins through the diet [1, 2], thus, under the name vitamins there is an highly differentiated family of compounds with various biochemical properties and

chemical structures exhibiting antioxidant, co-enzymatic and hormonal activity, even [1, 2]. Vitamins are essentially divided into two groups [1, 2]:

fat-soluble vitamins (ADEK complex), including

pro-vitamin A and vitamin A,

vitamin D,

vitamin E,

vitamin K;

hydrosoluble vitamins including (mainly B complex)

vitamin B1 (thiamine),

vitamin B2 (riboflavin),

vitamin B3 (niacin, nicotinic acid or nicotinamide),

vitamin B5 (pantothenic acid),

vitamin B6 (pyridoxine),

vitamin B7 or H (biotin),

vitamin B9 (folic acid and folate),

vitamin 12 (cobalamin),

vitamin C (ascorbic acid).

Further substances have been indicated like the missing vitamins, such as vitamin B4 (also known as adenine), vitamin B8 (also known as inositol), vitamin B10 (paraamino benzoic acid – PABA), vitamin B11 (carnitine), but not all the nutritionists accept these compounds may be included in the group of the hydrosoluble vitamins because they are not so essential or alternatively they are so widespread and common in nature, thus their deficiency is extremely rare. Moreover, PABA, for instance, is included in the chemical structure of folic acid, so it can be absorbed with folates too. (see: Chapter 8: Vitamin B9). Vitamin deficiency may be caused by the inadequate absorption of one or more of these compounds as a consequence of both insufficient dietary intake and malnutrition [1, 2]. In Table 1, the main diseases associated with each vitamin deficiency are reported. Vitamins act as cofactors in several cellular enzymatic pathways [1, 2], and it has been suggested that, due to their antioxidant properties, an increased daily consumption of vitamins, taken as megadoses, might protect against ageing and degenerative diseases [1, 2]. For every vitamin, nutritionists have tried to establish the dietary reference intakes (DRIs), which are a set of reference values including the estimated average requirement [EAR], recommended dietary allowance [RDA], adequate intake [AI], and tolerable upper intake level [UL]. These values are changing according to the age and health status of the patient [1]. Then, in 1988, in an eight-month double-blind clinical trial, both multivitamin and multimineral supplements were reported to improve the performance of 30 school children in Wrexham [UK] who were administered non-verbal intelligence tests as part of an 8-month double-blind clinical trial [3]. Although the British nutrition establishment found many weaknesses in the trial, and some attempts to confirm the results failed, the myth of unnecessary intake of vitamins at high doses had started; thus, nowadays, it has become increasingly popular to consume vitamins either as multivitamin formulations or vitamin megadoses. For instance, the Myers cocktail, which is often intravenously injected to treat or prevent various chronic diseases, contains high doses of hydroxycobalamin, pyridoxine, dexpanthenol, ascorbic acid, magnesium, and calcium gluconate [4]. Unfortunately, such empirical do-it-yourself multivitamin treatments may cause serious adverse effects, including accidental intoxication and hypervitaminosis [5, 6], rather than supposed benefits to the body. Moreover, vitamins and multivitamin consumption has turned to represent a business. It has been estimated that more than 90,000 dietary supplementation products, containing vitamins and minerals available on the USA market, foster an industry of about 30 bilion USD, although the real beneficial effects on the patients' health status induced by vitamins megadoses are doubtfully demonstrated [7]. From a National Health and Nutrition Examination Survey [NHANES] data survey, it has been recorded that from 2003 to 2006, 53% of the United States population aged 1 year and older took a multivitamin supplement in a given month in front of a previous survey [1988-1994] reporting consumption of only about 44% of general population [8] while in 2009, 56% of USA consumers said they comsumed vitamins or other supplements, and 44% of them told to take such compounds daily [8]. In Europe and Latin America, vitamin and supplement usage is lower with a 30% and 28%, and France, Italy and Spain bringing up the bottom with only 13-17 percent and of consumers saying that they take vitamins and supplements. The primary reason for not taking vitamins was that their diets were already balanced, so there was no need to take them [8], while 90% of the American population do not follow vitamin E intake recommendations because of the scarce consumption of green leafy vegetables in the country [9]. For that reason, in 1995, vitamin E supplements have been taken daily by more than 35 million people only in the United States [9], although 10 years later, many clinicians alerted about the potential adverse effects of vitamin E excessive consumption [10]. A report published in 2005 found no clear evidence that men and women who had vascular disease or diabetes and who took 400 I.U. of vitamin E daily for seven years reduced their risk of cancer compared to others with these conditions who took a placebo [10]. However, vitamins and multivitamin supplements are perceived as beneficial and natural substances required by the human body, but commercial vitamins rarely are natural products. Firstly, it is necessary to distinguish between vitamins, which naturally occur in foodstuffs, and their semi-synthetic analogues, obtained by chemical procedures, as in the case of thiamine. Naturally occurring vitamin B1 or thiamine, is a water-soluble vitamin found in plants and animals usually bound to phosphates. However, synthetic vitamin B1 (i.e., thiamine hydrochloride) is obtained from coal tar, ammonia, acetone, and hydrochloric acid [11]. For that reason, it is necessary to consider that the refined vitamin is usually a compound not completely identical to the naturally occurring form, because often it is an ester or a salt unconjugated instead of the original phosphate moiety [11]. Then most of the substances known as vitamins (A, D, E, K, B6 and others) are constituted by groups of minor molecules named vitamers with a variable biological activity that can be influenced by their isomeric shape, so the efforts of researchers were made to identify among them, the most biologically active component performing properly its biochemical and nutritional effects on the organism, viz the vitamer whose lack generates severe hypovitaminosis. Vitamin E, for instance, is a mixture of compounds derived by plants designated as tocotrienols and tocopherols. Among the latter group, it is possible to distinguish alpha-,beta-, gamma- and delta-tocopherols, but only alpha-tocopherol was identified as the form that greatly fits with vitamin E requirements by human beings (see: Vitamin E chapter). Yet, some vitamins are present in foodstuff as provitamin, such as vitamin A or vitamin D, needing to be processed by hydrolysis or other metabolic pathways for their conversion in a biologically active form, such as the beta-carotene [pro-vitaminA] needs to be converted in vitamin A [retinol] or calcitriol or vitamin D (see: Vitamin A – Vitamin D chapters), whereas the ultimate active metabolite may be produced synthetically with biochemical procedures. Anyway, synthetic vitamins show many advantages compared with the naturally occurring vitamins because they can be administered not only orally, but also intramuscularly or intravenously, thus to achieve quickly a therapeutic dosage for the treatment of a severe vitamin deficiency as in Wernicke Korsakoff syndrome (see: Vitamin B1 chapter), or when they are used as an antidote, such as vitamin K given to contrast a coumarin overdose or hydoxy-cobalamin, a vitamin B12, whose high doses are administered in cyanide intoxication (see: Vitamin B12 chapter). Furthermore, synthetically obtained vitamins can be easily stored for long periods, and they are not conditioned by food deterioration, although light and temperature may influence certain vitamins storage, causing a decline in their biological strength. On the other hand, clinical practitioners and nutritionists have emphasized the importance of vitamins in specific groups of people at risk for vitamin deficiency, such as newborns and infants who specifically need vitamin K, and pregnant women who are recommended to take folic acid, to avoid neural tube defects to the newborn [12, 13]. Moreover, vitamin D may be essential for children living in northern European countries during the winter, while alcohol-addicted patients are recommended to take supplemental thiamine [12]. Multivitamin supplements may also be useful in treating patients with low caloric intake caused by an inappropriate diet or decreased appetite, as well as emotionally disturbed patients, i.e. anorexics, and patients receiving total parental nutrition preparations. In developing countries, there is increasing evidence that vitamin deficiencies are associated with individual increased susceptibility to infections and with a higher incidence of mortality [13]. The identification and synthesis of each vitamin has allowed to pursue a procedure to increase vitamin consumption in general population, represented by food fortification. Food fortification is the process of adding micronutrients like vitamins or minerals to foods to increase its overall nutritional content, thus preventing vitamin deficiency [14]. Food fortification has been safely and effectively employed in developed countries for well over a century. Food fortification has been recognized by many national governments and world agencies like the World Health Organization [WHO] and Food Agriculture Organization [FAO] as an important strategy to help and improve the health and nutrition status of millions of people because it does not require either change in the customary diet of a population or in individual compliance [14]. For example, vitamin A-fortified margarine was introduced in Denmark in 1918; and in the 1930s, vitamin A-fortified milk and flour supplemented with iron and vitamin B complex was introduced in several developed countries [15]. A wide variety of foods have been fortified with different nutritional ingredients, and vitamin enriched foods may be grouped into three broad categories:

staples such as wheat, rice, and oils, condiments including soy and sauces, and processed commercial foods such as noodles, cereals,

infant complementary foods,

dairy products.

Table 1 Main vitamins, sources and deficiency diseases [1, 2].

*mcg: microgram

These categories of products have been proposed because they meet three food fortification policies: mass fortification involving widely consumed foods, targeted approaches allowing the fortification of foods consumed by specific age groups like infant complementary foods; and lastly, market-driven approach occurs when a food manufacturer fortifies a specific brand for a particular consumer area. Although actually most nutritional interventions are focused on enriching foodstuff with vitamins like folic acid, vitamin D and vitamin A [15], there is a growing interest to enrich the first group of foods with other vitamins as shown in Table 2.

Table 2 Vitamins in Food Fortification (Cereals).

Furthermore, it has been observed that certain vitamins may be used as therapeutic agents to attenuate the toxic effects or to improve the clinical efficacy of some chemotherapeutic alkylates used to treat cancer patients. Folinic acid or leucovorin is the reduced form of folic acid: it can be administered as an antidote for folic acid antagonists such as methotrexate or given intravenously with 5-fluorouracil [5-FU] to enhances the cytotoxic effects of chemotherapy in resected colon cancer patients [16]. Using vitamins as drugs has increased the attention towards the development of vitamin-derived drugs, starting from the first anti-folate agent like methotrexate [see: Vitamin B9 chapter], or vitamin A whose derivatives such as isotretinoin, acitretin, etretinate are used to treat recalcitrant acne [see: vitamin A chapter] and lastly, some vitamin D derivatives like calcitriol and calcipotriol are applied topically to treat severe psoriasis [see: Vitamin D chapter]. Some vitamins like vitamin A, E, B3, B6 and C and their derivatives, are used for their antioxidant and anti-aging properties in cosmetics [17] but also as excipients, conservants or dyes in foods, juices and drinks. Riboflavin [vitamin B2], and carotenoids [provitamin A] are permitted as colorants by USA and European authorities as well as vitamin C esters like sodium and calcium ascorbate and vitamin E are allowed as antioxidants in foods, and industrial beverages, including alcoholic drinks [18]. For that reason, the widespread and undervalued presence of vitamins in many dairy consumer products may represent an occult source of exposure to these substances, able to induce a sensitization or to elicit hypersensitivity symptoms, beyond the voluntary intake of multivitamins.

Hypersensitivity to Vitamins: Pathomechanisms, Diagnosis and Management

Like any drug, even vitamins may induce hypersensitivity reactions and that kind of reaction are conventionally conformed to the four classes of immune pathomechanism proposed by Gell and Coombs [19], thus they are distinguished in,

Type I reactions, which are characterized by a large release of histamine and other vasoactive mediators by specific inflammatory cells such as mast cells and basophilic granulocytes. Symptoms include, urticaria, angioedema, bronchospasm or asthma and anaphylactic shock which is the most dangerous and life-threatening condition. The reaction usually is genuinely IgE-mediated [immunologic hypersensitivity], however pseudoallergic or anaphylactoid reactions are also possible [20], caused by the direct degranulation of mast cells by physical stimuli [hyperosmolar drugs] or by complement activation-related pseudoallergy, caused by complement anaphylatoxin C3 and C5 [non-immologic hypersensitivity]. Clinically both the manifestations are very difficult to distinguish;

Type II reactions [i.e., cytotoxic hypersensitivity reactions] are identified by the presence of two antibody isotypes such as immunoglobulin G [IgG] or immunoglobulin M [IgM] that bind to the antigen on the cellular membrane. As a consequence, this interaction causes complement fixation and activation with consequent cellular lysis as, for instance, in hematologic cytopenia

Type III reactions are also defined as reactions mediated by immune complexes because they are characterized by the deposition in postcapillary venules of antigen-antibody complexes resulting in complement fixation. Neutrophlis are attracted and activated, thus inducing damage in vessels and subsequently in highly vascularized organs like kidneys, lungs and eyes. Vasculitis and serum-sickness are the result of this process with symptoms like skin rash, glomerulonephritis, arthralgiae and fever

Type IV reactions [i.e., delayed hypersensitivity reactions, cell-mediated immunity] are distinguished from the other categories of reactions because there is the involvement of T cells. Contact dermatitis and maculopapular exanthema are