VITAMINS

Water-Soluble and Fat-Soluble Vitamins

Vitamins are among the nutrients found to be essential for life. Unlike other classes of nutrients, vitamins serve no structural function nor do they provide significant energy. Their various uses tend to be highly specific. Common food forms of most vitamins require some metabolic activation into a functional (active) form. Although vitamins share these general characteristics, they show few close chemical or functional similarities. For example, some vitamins function as coenzymes, others function as antioxidants, and two vitamins, A and D, function as hormones.

Fourteen substances are now generally recognized as vitamins. Vitamins are frequently described according to their solubility; they may be either fat-soluble or watersoluble. This method of classification dates back to the history of their discovery as labeled by McCollum as "fatsoluble A" and "water-soluble B."

Other sections in this encyclopedia describe the chemistry, biochemistry, and physiology of the vitamins. This article provides additional information that is focused on dietary requirements, upper levels (to avoid toxicity from supplementation), and food sources. (See sidebar for definition of terms, and see Appendix for a complete chart of vitamins.)

Water-Soluble Vitamins

Thiamin. Thiamin was the first vitamin to be identified. In modern times, thiamin deficiency is seen most commonly in association with chronic alcoholism. Only a small percentage of large doses are absorbed, and elevated serum levels result in its active urinary excretion. After an oral dose of the vitamin, peak excretion occurs in about two hours (Davis et al., 1984). Total body thiamin content in adults is approximately 30 milligrams with a half-life of 9 to 18 days (Ariaey-Nejad et al., 1970).

The recommended dietary allowance (RDA) for thiamin in adult women is 1.1 mg/day and in adult men it is 1.2 mg/day. The RDA for pregnancy and lactation is 1.4 mg/day (FNB, 1998). It should be noted that increased needs exist in persons being treated with hemodialysis or peritoneal dialysis, individuals with malabsorption syndrome, women carrying more than one fetus, and women nursing more than one infant.

There are no reports of adverse effects from the consumption of excess thiamin consumed in food or supplements. No upper level (UL) can be set due to the lack of reported findings associated with adverse effects. Supplements that contain up to 50 mg/day are available over-the-counter with no reported problems.

Food sources from which most of thiamin in the United States is derived include enriched, fortified, or whole-grain products, such as bread, bread products, mixed foods that contain grain, and ready-to-eat cereals. Foods that are especially rich in thiamin include yeast, lean pork, and legumes. Thiamin is absent from fats, oils, and refined sugars. Milk, milk products, seafood, fruits, and vegetables are not good sources.

Riboflavin. The second vitamin discovered was named vitamin B₂ or riboflavin. Most dietary riboflavin is consumed as a complex of food protein. Signs of riboflavin deficiency are sore throat, redness, and edema of the throat and oral mucous membranes, cheilosis (cracking of the skin around the mouth), and glossitis (red tongue). Vitamin B₂ deficiency most often occurs in combination with other nutrient deficiencies. The B vitamins are quite interrelated; for example, niacin requires riboflavin for its formation from the amino acid tryptophan, and vitamin B₆ requires riboflavin for conversion to the active coenzyme form (McCormick, 1989).

The RDA for riboflavin has been set at 1.3 mg/day for men and 1.1 mg/day for women through age seventy years and older. For pregnancy, the RDA for riboflavin is set at 1.4 mg/day and it is 1.6 mg/day for lactation (FNB, 1998).

When riboflavin is absorbed in excess, very little is stored in the body tissues. Excess is excreted via the urine, and the amount varies with intake, metabolic events, and age (McCormick and Greene, 1994). No adverse effects associated with riboflavin consumption from food or supplements have been reported. No adverse effects were reported from a single dose of up to 60 milligrams and 11.6 milligrams of riboflavin given as a single intravenous (IV) dose (Zempleni et al., 1996).

The greatest contribution of riboflavin from the diet comes from milk and milk drinks, followed by bread products and fortified cereals. Especially good food sources of riboflavin are eggs, lean meats, milk, broccoli, and enriched breads and cereals. Recall that riboflavin loss occurs when it is exposed to light, so store milk in opaque containers or away from the light.

Niacin. The term "niacin" refers to nicotinamide and nicotinic acid. The coenzymes, the active form of niacin in the body, are synthesized in all tissues of the body. The amount of niacin in the body is the result of absorbed nicotinic acid and nicotinamide, as well as conversion of the amino acid tryptophan (60 milligrams of tryptophan = 1 milligram of niacin; Horwitt et al., 1981). Excess niacin is excreted through the urine.

Pellagra is the classical manifestation of niacin deficiency. Pellagra has been seen in areas where corn (low in niacin and tryptophan) is the dietary staple. Enrichment and fortification of grain has virtually eliminated pellagra from the United States and Europe.

The RDA for adult men is 16 mg/day of niacin equivalents, and the RDA for women aged nineteen to over seventy is 14 mg/day. In pregnant women the RDA is 18 mg/day of niacin equivalents and in lactating women it is 17 mg/day (FNB, 1998).

Niacin, given as nicotinic acid in doses from 4 to 6 g/day, is one of the oldest drugs used in the treatment of hyperlipidemia, which consists of elevated blood levels of triglycerides and cholesterol. Niacin lowers low-density lipoprotein (LDL) cholesterol and triglyceride concentration. This therapeutic effect is not seen with nicotinamide. Nicotinic acid in therapeutic doses can cause flushing and headache in some people. These side effects are not harmful.

An upper limit for niacin was set at 35 mg/day for adults, if the niacin is obtained from supplements, not foods. Individuals who take over-the-counter niacin to "self-medicate" may exceed the UL on a chronic basis. The UL is not intended to apply to those receiving niacin under medical supervision.

Dietary intake of niacin comes mainly from mixed dishes containing meat, poultry, or fish, followed by enriched and whole-grain breads, and fortified cereals. Significant amounts of niacin are found in red meat, liver, legumes, milk, eggs, alfalfa, cereal grains, yeast, and fish.

Vitamin B _6. Vitamin B₆ is a coenzyme for more than 100 enzymes involved in the metabolism of amino acids, glycogen, and nerve tissues (FNB, 1998). Microcytic anemia, reflecting decreased hemoglobin synthesis, can be seen in deficiency states. The interaction of vitamin B₆ and folate (another B vitamin discussed below) has been shown to reduce the plasma concentrations of homocysteine and decrease the incidence of cardiovascular disease (CVD) risk (Rimm et al., 1998). Subjects with the highest intake of folate and vitamin B₆ had a twofold reduction in CVD as compared to the group with the lowest intake.

In the 1970s there was quite a bit of discussion about the status of vitamin B₆ in women using oral contraceptives. This was probably an artifact of hormonal stimulation of tryptophan catabolism rather than vitamin B₆ deficiency. At the time these studies were conducted, estrogen concentrations were three to five times higher in contraceptive agents than they are today.

The RDA for vitamin B₆ is 1.3 mg/day for adult men and women up to age fifty years. The RDA for people over fifty years of age is 1.7 mg/day for men and 1.5 mg/day for women. For pregnant women the RDA is set at 1.9 mg/day and for lactating women, 2.0 mg/day (FNB, 1998).

No adverse effects have been associated with intakes of vitamin B ₆ from food. However, large doses of pyridoxine used to treat carpal tunnel syndrome and premenstrual syndrome have been associated with sensory neuropathy (Schaumburg and Berger, 1988). These findings were noted with dosages from 2 to 6 g/day. It appears that the risk of developing sensory neuropathy decreases quite rapidly at dosages below 1 g/day. Thus, the UL for adults is set at 100 mg/day of vitamin B₆ as pyridoxine.

Food sources of vitamin B₆ include fortified, ready-to-eat cereals; mixed foods with meat, fish, or poultry as the main ingredient: white potatoes, starchy vegetables, and noncitrus fruits. Vitamin B₆ is widely distributed in foods; good sources are meats, whole-grain products, vegetables, and nuts.

Folate. Folate is a B vitamin that exists in many chemical forms (Wagner, 1996). Folic acid, the most stable form of folate, occurs rarely in food, but is the form used in supplements and fortified food products. Folate coenzymes are involved in numerous reactions that involve DNA synthesis, purine synthesis, and amino acid metabolism. The most well known is the conversion of homocysteine to methionine. It is this reaction that reduces the concentration of homocysteine in the plasma, and may lower the risk of cardiovascular disease (Rasmussen et al., 1996).

The metabolic interrelationship between folate and vitamin B₁₂ may explain why a single deficiency of either vitamin leads to the same hematological changes. In either folate or vitamin B₁₂ deficiency, megaloblastic changes occur in the bone marrow and other replicating cells.

Pregnant women are at risk for developing folate deficiency because of the heightened demands imposed by increased synthesis of DNA. Low folate status is associated with poor pregnancy outcome, low birth weight, and fetal growth retardation (Scholl and Johnson, 2000). Because of the possible incidence of neural tube defects (NTDs) during the preconception period (that is, just before and during the first 28 days of conception), the Food and Nutrition Board recommends that women who are capable of becoming pregnant should consume 400 <g/day of synthetic folic acid, derived from dietary supplements or fortified food, in addition to their usual dietary intake (FNB, 1998). NTDs are the most common major congenital malformations of the central nervous system.

Recommendations for intake of folate are dependent on variation in bioavailability. Supplemental folate is nearly 100 percent absorbed, while absorption of folate found in foods is only about 50 percent. Fortified foods approach the level of bioavailability of folate found in supplements. This has led to the term Dietary Folate Equivalents or DFEs. Thus, dietary recommendations for folate intake are based on "folate equivalents." One <g of folate equivalents = 1 <g of food folate = 0.5 <g of folic acid taken on an empty stomach or = 0.6 <g folic acid with meals. The RDA for women is 320 <g dietary folate equivalents and for men it is 400 <g. During pregnancy 600 <g/day of folate is recommended and 500 <g/day is recommended during lactation (FNB, 1998).

No adverse effects have been associated with the consumption of normal folate-fortified foods. However, the risk of neurological effects that result from vitamin B₁₂ deficiency that are masked with high doses of folate caused the FNB to set a UL. The UL for adults, nineteen years and older, is set at 1,000 <g/day of folate from fortified food or supplements.

Folates are found in nearly all natural foods. Protracted cooking or processing may destroy folate. Foods with the highest folate content include yeast, liver, other organ meats, fresh green vegetables, and some fruits (oranges, for example). Most of the dietary intake of folate in the United States comes from fortified ready-to-eat breakfast cereals followed by a variety of beans and peas, fresh and dried. As of 1 January 1998, all enriched cereal grains, pasta, flour, and rice are required to be fortified with folate at 1.4 mg/kg of grain.

Vitamin B _12. Cyanocobalamin is the compound we call vitamin B₁₂. This is the only vitamin B₁₂ preparation used in supplements. An adequate supply of vitamin B₁₂ is essential for normal blood formation and neurological function. The absorption of vitamin B₁₂ is dependent on several physiological steps. In the stomach, food-bound vitamin B₁₂ is dissociated from proteins in the presence of stomach acid. Vitamin B₁₂ then binds with protein and in the intestine the vitamin B₁₂ binds with intrinsic factor for absorption. If there is a lack of sufficient acid in the stomach or intrinsic factor in the intestine, malabsorption occurs and the resulting condition caused is pernicious anemia.

The anemia of vitamin B₁₂ deficiency (completely reversed by addition of B₁₂) is indistinguishable from that seen with folate deficiency. Because up to 30 percent of people older than fifty are estimated to have atrophic gastritis with low stomach acid secretion, older adults may have decreased absorption of B₁₂ from foods. Thus, it is recommended that most of the vitamin B₁₂ consumed by adults greater than fifty-one years of age be obtained from fortified foods or supplements.

The RDA of vitamin B₁₂ for men and women is 2.4 <g/day, most of that amount coming from fortified foods or supplements in those over fifty years of age. During pregnancy, the RDA is 2.6 <g/day and it is 2.8 <g/day during lactation (FNB, 1998). No adverse effects have been associated with excess B₁₂ intake from food or supplements. After reviewing the literature, the FNB found insufficient evidence for determining a UL.

Vitamin B₁₂ is present in all forms of animal tissues. It is not present in plants and thus does not occur in fruits or vegetables. Because a generous intake of animal foods is customary in the United States, B₁₂ intake from foods is usually adequate. People who avoid eating animal products may obtain most of their requirement through fortified foods.

Vitamin C. Ascorbic acid (the chemical name for vitamin C) is a potent antioxidant in animals and plants. Vitamin C is important in the synthesis of collagen. Some evidence indicates that vitamin C reduces virus activity by inhibiting viral replication (Johnston, 2001). Many anecdotal reports support a role for vitamin C supplementation to reduce the severity of cold symptoms.

Some epidemiological evidence indicates that supplemental vitamin C protects against risk for myocardial infarction. However, large-scale epidemiological studies do not suggest a benefit of vitamin C supplementation on cardiovascular health risks (Kushi et al., 1996).

Non-heme iron absorption from food is enhanced two-to threefold in the presence of 25 to 75 mg of vitamin C, presumably because of the ascorbate-induced reduction of ferric iron to ferrous iron, which is less likely to form insoluble complexes in the intestine. However, vitamin C has no effect on increasing iron absorption from heme iron (Johnston, 2001). Unlike most animal species, humans lack the ability to synthesize ascorbic acid; thus, the diet is the sole source for this vitamin.

The current requirement of vitamin C is 90 mg/day for adult men and 75 mg/day for adult women. During pregnancy the RDA is 85 mg/day, and 120 mg/day during lactation. The UL for vitamin C was set at 2 g/day (FNB, 2000). This level was set as a guideline for people using dietary supplements and was based on reports of gastrointestinal symptoms reported when too much vitamin C was taken.

Almost 90 percent of vitamin C in the diet comes from fruits and vegetables, with citrus fruits, tomatoes, tomato juice, and potatoes being the major contributors. It is also added to some processed foods as an antioxidant.

Pantothenic acid. Pantothenic acid was named after the Greek, meaning "from everywhere," because it is so widespread in foods. Pantothenic acid is essential in the diet because of the inability of animals and humans to synthesize the pantoic acid moiety of the vitamin. Pantothenic acid plays a primary role in many metabolic processes, such as oxidative metabolism, cell membrane formation, cholesterol and bile salt production, energy storage, and activation of some hormones (Miller et al., 2001).

Pantothenic acid deficiency in humans is rare because of its ubiquitous distribution in foods. Many health claims are made regarding the role of pantothenic acid in ameliorating rheumatoid arthritis, lowering cholesterol, enhancing athletic performance, and preventing graying of hair (Miller et al., 2001). However, sufficient information is lacking at this time and so firm recommendations may not be made. No reports of adverse effects of oral pantothenic acid in humans have been reported.

The Food and Nutrition Board (1998) established an adequate intake level (AI) for pantothenic acid of 5.0 mg/day for adult men and women, 6.0 mg/day during pregnancy, and 7.0 mg/day during lactation. As mentioned above, pantothenic acid is found in a wide variety of both plant and animal foods. Because of its thermal lability and susceptibility to oxidation, significant amounts are lost during processing. Rich food sources include chicken, beef, liver, and other organ meats, whole grains, potatoes, and tomato products.

Biotin. In mammals, biotin serves as a coenzyme for reactions that control such important functions as fatty acid metabolism and gluconeogenesis. Biotin is recycled upon degradation of enzymes to which it is bound. Biotin from pharmaceutical sources is 100 percent bioavailable. Deficiency is rare but has been seen in patients on parenteral nutrition without biotin supplementation (Zempleni and Mock, 1999). Lipoic acid and biotin have structural similarities, thus competition potentially exists for intestinal or cellular uptake. This may be of concern in settings where large doses of lipoic acid are administered or taken as supplements (Zempleni et al., 1997).

The Food and Nutrition Board established an AI for biotin due to insufficient data to set an RDA. Adult men and women have an AI of 30 <g/day (FNB, 1998). It is the same for pregnancy and increases to 35 <g/day during lactation. No adverse effects of biotin have been reported. Toxicity has not been reported in patients receiving up to 200 mg orally daily or up to 20 mg intravenously.

Biotin is distributed widely in natural foods. Those rich in biotin include egg yolk, liver, and some vegetables. It is estimated that individuals in the United States consume between 35 and 70 <g/day.

Choline. Choline has been considered a nonessential nutrient because humans can synthesize sufficient quantities. However, when hepatic function is compromised, hepatic choline synthesis is decreased and thus choline is now considered "conditionally" essential. In a 1998 report from the Food and Nutrition Board, choline is considered an essential nutrient (FNB, 1998). The Food and Nutrition Board noted that additional studies on the essentiality for human nutrition are needed. Specifically, the 1998 Food and Nutrition Board study suggested that graded doses of choline intake be studied regarding their effects on organ function, plasma cholesterol, and homocysteine levels.

Choline functions as a precursor for phospholipids and acetylcholine, and betaine. The AI for adult men was set at 550 mg/day and for women at 425 mg/day. For pregnancy, the AI was increased to 450 mg/day and during lactation, to 550 mg/day (FNB, 1998). Due to reports of hypotension (low blood pressure) from excess intake, a UL was set at 3.5 g/day for persons nineteen years and older. Choline and choline-containing lipids, mainly phosphatidylcholine, are abundant in foods of both plant and animal origin. Rich sources include muscle and organ meats and eggs. To date there are no nationally representative estimates of choline intake from food or supplements.

Fat-Soluble Vitamins

Vitamin A. The active forms of vitamin A participate in three essential functions: visual perception, cellular differentiation, and immune function. A number of food sources are available for vitamin A. Preformed vitamin A is abundant in animal foods and provitamin A carotenoids are abundant in dark-colored fruits and vegetables. With a 2001 report from the Food and Nutrition Board (FNB 2001), there has been recognition of a change in equivalency values of various carotenoids to vitamin A. Retinol activity equivalents (RAEs) for dietary provitamin A carotenoids—beta-carotene, alpha-carotene, and betacryptoxanthin—have been set at 12, 24, and 24 <g, respectively (see Table 1, below). This decision is based on an extensive review of studies, which are summarized in the FNB report (2001) (see Table 1).

A number of factors affect the bioavailability of carotenoids (Castenmiller and West, 1998). Percent absorption

decreases as the amount of dietary carotenoids increases, and the relative carotene concentration absorbed increases when consumed with oil or associated with plant matrix material. That is part of the plant vitamin source, not separated out as a supplement. The presence of dietary fat stimulates the secretion of bile acids and improves the absorption of carotenoids.

Recommended dietary allowance for men is 900 <g/day of vitamin A and for women 700 <g/day. During pregnancy, RDA is set at 770 <g/day and 1,300 <g/day during lactation. Human infants consume about 400 <g/day of vitamin A in the first six months of life (FNB, 2001).

Based on the literature review, the FNB used liver abnormalities as the critical adverse effect for setting the UL for adults. Issues of carcinogenicity were considered for women of childbearing age. The UL varies slightly with age between 2,800 and 3,000 <g/day of preformed vitamin A in food or supplements for adolescents and adults. Note that alcohol intake enhances the toxicity of vitamin A.

The richest sources of vitamin A are fish oils, liver, and other organ meats. Whole milk, butter, and fortified margarine and low-fat milks are also rich in the vitamin. In the United States carrots, fortified spreads, and dairy products are the leading contributors of vitamin A to the diet.

Vitamin D. Vitamin D is essential for life in higher animals. It is one of the most important regulators of calcium homeostasis and was historically considered the "anitrachitic" factor. The biological effects of vitamin D are achieved only by its hormonal metabolites, including two key kidney-produced metabolites: 1,25(OH)₂ vitamin D and 24,25(OH) vitamin D. In addition to its role in calcium metabolism, research has identified that vitamin D plays an important role in cell differentiation and growth of keratinocytes and cancer cells and has shown that it participates in the process of parathyroid hormone and insulin secretion (Bouillon et al. 1995).

Vitamin D₃, the naturally occurring form of the vitamin, is produced from the provitamin, 7-dehydrocholesterol, found in the skin under the stimulation of ultraviolet (UV) irradiation or UV light. Vitamin D₂ is a synthetic form of vitamin D that is produced by irradiation of the plant steroid ergosterol. A requirement for vitamin D has never been precisely defined because vitamin D is produced in the skin after exposure to sunlight. Therefore, humans do not have a requirement for vitamin D when sufficient sunlight is available. The fact that humans wear clothes, live in cities where tall buildings block the sunlight, use synthetic sunscreens that block UV rays, and live in geographical regions of the world that do not receive adequate sunlight contributes to the inability of the skin to synthesize sufficient vitamin D (Holick, 1995). Exposure to the sun sufficient for humans to obtain enough UV radiation to synthesize adequate vitamin D can be as little as three weekly exposures of the face and hands to ambient sunlight for 20 minutes (Adams et al., 1982).

A substantial proportion of the U.S. population is exposed to suboptimal levels of sunlight during the winter months. Under these conditions, vitamin D becomes a true vitamin and must be supplied regularly in the diet. The Food and Nutrition Board recommend an AI or adequate intake of vitamin D at 200 IU/day (5 <g) for adults up to fifty years of age (FNB, 1997). For adults over fiftyone, the AI is set at 400 IU/day (10 <g).

To prevent life-threatening hypercalcemia, an upper level (UL) for vitamin D has been set at 2,000 IU/day (50 <g) for adults over age eighteen. The use of 1,25 (OH)₂ vitamin D for treatment of hypoparathyroidism, vitamin D–resistant rickets, renal osteodystrophy, osteoporosis, and psoriasis opens the door for potential toxicity because this form of the vitamin is much more toxic and the body's metabolic controls are bypassed. When this medication is being used, careful monitoring of plasma calcium concentrations is required.

Salt-water fish are good unfortified sources of vitamin D. Small quantities are derived from eggs, beef, butter, and vegetable oils. Fortification of milk, butter, margarine, cereals, and chocolate mixes help in meeting the dietary requirements. Excessive amounts of vitamin D are not available in usual dietary sources. However, excessive amounts can be obtained through supplements that result in high plasma levels of 25(OH) vitamin D.

Vitamin E. Vitamin E (also called tocopherol) is found in cell membranes and fat depots. Because of their chemical structure, there are eight stereoisomers of each of the tocopherols. In addition to each of the stereoisomers, each occur in alpha, beta, gamma, and delta forms (FNB, 2000).

Its most recognized function is to protect polyunsaturated fatty acids (PUFA) from oxidation. PUFAs are particularly sensitive to oxidative damage, and the protective role of vitamin E is supported by a similar antioxidant protection from vitamin C and selenium. One tocopherol molecule can protect 100 or more PUFA molecules from autoxidative damage (Pryor, 2001).

The various forms of vitamin E have different biological activity, with the natural source isomer—R,R,R,-alpha-tocopherol—being the most active. In supplements you may see this isomer called by its former name, d -alpha-tocopherol. Synthetic vitamin E is called all -rac -alpha-tocopherol or dl -alpha-tocopherol in supplements. Biological activities of vitamin E are given in the older international units (IU) or alpha-tocopherol equivalents (alpha-TE). Because of the many forms of vitamin E in plants and available synthetically, the relative activities of each form is complex. Current evidence indicates that vitamin E from natural sources has approximately twice the bioactivity in humans that the all-rac (synthetic) vitamin does (Burton et al., 1998).

Based on the literature review, FNB used hemorrhagic (bleeding) effects for the criteria to set the UL. For adults nineteen years and older the UL is 1,000 mg (2,326 mol)/day of any form of supplementary alpha-tocopherol. There is no evidence of adverse effects from intake of vitamin E naturally occurring in foods.

The RDA for vitamin E is 15 mg/day of naturally occurring alpha-tocopherol for adults above nineteen years of age (FNB, 2000). During pregnancy 15 mg/day is recommended and 19 mg/day for lactation.

The tocopherol content of foods varies widely depending on storage, processing, and preparation. The best sources of vitamin E are the common vegetable oils and products made from them. However, most of the tocopherols may be removed in processing. Wheat germ and walnuts also have high amounts of tocopherols.

Vitamin K. Vitamin K was named after the first letter of the German word Koagulation. For many years blood coagulation was assumed to be the sole physiological role for vitamin K. We now know that vitamin K plays an essential role in the synthesis of proteins including prothrombin and the bone-forming protein, osteocalcin (Vermeer et. al., 1995).

Dietary vitamin K absorption is enhanced by dietary fat and is dependent on bile and pancreatic enzymes. The human gut contains large amount of bacterially produced vitamin K, but its contribution to the maintenance of vitamin K status has been difficult to assess (Suttie, 1995). The vitamin K produced by bacteria in the gut is less biologically active even though it is stored in the liver and present in blood. Current understanding supports the view that this vitamin K source may partially satisfy the human requirement but that the contribution is much less than previously thought.

The drug warfarin, widely prescribed as an anticoagulant, functions through inhibition of vitamin K. As a result, alterations in vitamin K intake can influence the efficacy of warfarin. The effective dose of warfarin varies from individual to individual, as does the dietary intake of vitamin K. The best solution appears to be to establish the necessary dose of warfarin and urge patients to maintain a constant intake of foods high in vitamin K in their diets. Only a small number of food items contribute substantially to the dietary vitamin K.

The recommended intake is based on an AI or adequate intake of 120 <g/day for men, 90 <g/day for women, and 90 <g/day during pregnancy and lactation (FNB, 2001). No adverse effects have been associated with vitamin K intake in humans from food or supplements. Thus, no UL is set for vitamin K.

Collards, spinach, and salad greens are high in vitamin K. Broccoli, Brussels sprouts, cabbage, and Bib lettuce contain about two-thirds as much, and other green vegetables contain even less. Vitamin K is also found in plant oils and margarine, with soybean and canola oils having the highest amounts. U.S. food intake surveys indicate that spinach, collards, broccoli, and iceberg lettuce are the major contributors of vitamin K in the diet.

See also Additives ; Assessment of Nutritional Status ; Dietary Guidelines ; Immune System Regulation and Nutrients ; Microbiology ; Nutrient Bioavailability ; Nutrient–Drug Interactions ; Nutritional Biochemistry ; Appendix: Dietary Reference Intakes .

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Zempleni, J., J. R. Galloway, and D. B. McCormick. "Pharmacokinetics of Orally and Intravenously Administered Riboflavin in Healthy Humans." American Journal of Clinical Nutrition 63 (1996): 54–66.

Zempleni, J., and D. M. Mock. "Biotin Biochemistry and Human Requirements." Journal of Nutritional Biochemistry 10 (1999): 128–138.

Ann M. Coulston

Dietary Reference Intakes

See Appendix for full chart of Dietary Reference Intakes.

Recommended Dietary Allowance (RDA) —the dietary intake level that is sufficient to meet the nutrient requirement of nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group.

Adequate Intake (AI) —a recommended intake value based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of healthy people that are assumed to be adequate—used when an RDA cannot be determined.

Tolerable Upper Intake Level (UL) —the highest level of nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals in the general population. As intake increases above the UL, the risk of adverse effects increases.

SOURCE: Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes (FNB, 2000, p. 3).

VITAMINS

CONCEPT

Most of us have been told to take our vitamins, but few people know why, and despite all the talk about them in modern culture, vitamins remain something of a mystery. Vitamins are organic substances, essential for maintaining life functions and preventing disease among humans and animals and even some plants. They are found in very small quantities in food; certain health specialists recommend taking vitamin supplements to augment the supplies in food, while others insist that a well-balanced diet provides all the vitamins that an ordinary person needs. Some vitamins, such as vitamin C and the B complex, are water-soluble, which means that they are excreted easily and must be ingested every day. Others, such as vitamins A, D, E, and K, are fat-soluble and therefore are retained in the body's fatty tissues. With such vitamins, there may be a danger of taking too much, but in the case of most vitamins, the greatest harm comes from not receiving enough. Vitamin deficiencies can be the cause of rickets, pellagra, and other diseases that have plagued the poor in the Western world and the third world in the past and in the present.

HOW IT WORKS

An Introduction to Vitamins

Once they were called vitamines, but for reasons that we address later, the "e" was dropped, and they became known as vitamins. There is also a reason for the strange alphabet of vitamins (A, B, C, D, E, K), which, like the change in spelling, came out of the early days of scientific research into the subject during the first third of the twentieth century. Though people did not know about vitamins per se until that time, folk wisdom certainly had taken account of the fact that certain foods are essential to the health and well-being of humans and animals.

Vitamins may be defined as organic substances, found in food, that are essential in very small quantities for the health of most animals and some plants. Organic substances, discussed in The Biosphere, are compounds (substances in which atoms of more than one element are chemically bonded to one another) containing hydrogen and carbon. Primarily, vitamins work with enzymes (protein materials that speed up chemical reactions in the bodies of plants and animals) in regulating metabolic processes—that is, processes that convert food to energy. They do not in themselves provide energy, however, and thus vitamins alone do not qualify as a form of nutrition.

Organisms require vitamins only in very small amounts: the total amount of vitamin mass a person needs in one day, for instance, is only about 0.0011 lb. (0.5 g). Yet vitamins are absolutely essential to the maintenance of health and for disease prevention, and most animals are not capable of synthesizing or manufacturing vitamins on their own. Nonetheless, most animals can produce vitamin C, though there are exceptions—humans included.

Animals depend on plants for their nutrition, either directly or indirectly (i.e., either by consuming the plant or by consuming an animal that has consumed the plant). Plants, on the other hand, are autotrophs, meaning that they can meet their nutritional needs with only sunlight, water, and a few chemical compounds. Among the nutrients plants produce are vitamins, which they pass on to animals that consume them directly or indirectly. (See Food Webs for more about autotrophs and the relationship of animal consumers to them.)

Classifying Vitamins

Numerous vitamin groups are necessary for the nutritional needs of humans, and though only minute amounts of each are required to achieve their purpose, without them life could not be maintained. Some vitamins, including A, D, E, and K, are fat-soluble, meaning that they are found in fattier foods and in body fat. Thus, they can be stored in the body; for this reason, it is not necessary to include them in the diet every day. In fact, it could be dangerous to do so, since it is possible that they would build up to toxic levels in the tissues. Other vitamins, the most notable of which are vitamin C and the many vitamins in what is known as the "B complex," are water-soluble. They are found in the watery parts of food and body tissue, and because they are excreted regularly in the urine, they cannot be stored by the body. Instead, they must be consumed on a daily basis. This difference in solubility is extremely important to the way the vitamins function within an organism and in the ways and amounts in which they are consumed.

THE NAMES OF VITAMINS.

Vitamins originally were classified in terms of their solubility in water or in fat, and these distinctions remain important for the reasons outlined above. Today, vitamins are known primarily by letters of the alphabet, a fact that harks back to a naming system developed as more and more vitamins were discovered in the early years of the twentieth century.

As scientists detected the existence of more vitamins, or what they thought were vitamins, they assigned to them successive letters of the alphabet: A, B, C, and so on. Eventually, however, they discovered that some substances originally thought to be vitamins were not vitamins, and they removed them from the roster. For example, what used to be called vitamin F is simply an essential fatty acid, a necessary component of the diet of a mammal but not the same thing as a vitamin. In other cases, what were once believed to be individual vitamins later were subsumed into the B complex. Among these substances are riboflavin, formerly termed vitamin G, and biotin, once called vitamin H. The result is that today the only alphabetical vitamin names are A, the B complex, C, D, E, and K.

REAL-LIFE APPLICATIONS

Fat-Soluble Vitamins

We are accustomed in modern life to being told that fat is bad for us, but to quote a much-cited line from the American composer George Gershwin's opera Porgy and Bess, "It ain't necessarily so." Fat is not inherently bad for people; in fact, a certain amount in the diet is essential. The problem in America today is the type of fat that people consume. There is a big difference between the healthy, natural, unsaturated fats one might find, say, in fresh salmon, and the highly processed and saturated fats in a bag of potato chips. (The term saturated means that every gap in which a hydrogen atom could fit in a string of carbon and hydrogen atoms has been filled. This helps make fats firm, for use in such products as shortening.)

Such fat is extremely harmful, because the body is not able to process it; even so, a certain amount of natural fat in the diet can be highly beneficial. This is true in large part because fat can serve as a medium for the fat-soluble vitamins A, D, E, and K, which are deposited in the body's fat cells. But as we noted earlier, it is important not to overdose on fat-soluble vitamins, because then what is inherently healthy can become extremely unhealthy.

VITAMIN A.

In 1596 the Dutch explorer Willem Barents (1550-1597) and his shipwrecked crew spent a grueling winter on the island of Novaya Zemlya in the Arctic Ocean north of Russia. They had sailed from Holland in search of the Northeast Passage, which, like the more famous Northwest Passage above Canada, offered the prospect of a short, relatively direct sea route from Europe to Asia and the Americas. The problem was that the ice made sailing the northern seas virtually impossible. It would be almost three centuries before a crew managed to negotiate the Northeast Passage, by which time the European powers had long since given up all hopes of using it as a viable sailing route. (The same was true of the Northwest Passage, which was not traversed until 1906.)

Barents and his men knew none of that, nor would they have cared in that miserable winter of 1596-1597. All they cared about was survival, the chances for which seemed slim—and not just because of the almost inhuman cold or the fact that their ship had been cracked to pieces by the ice. Men were dying of scurvy, a vitamin-deficiency disease we discuss later in the context of vitamin C, as well as from the cold. Yet there were a few blessings, mainly in the form of available wood for fuel and animals for food. The men killed polar bears and ate their meat, and no doubt they were thankful just to stay alive. They could not have guessed, however, that they were actually killing themselves with an overdose of vitamin A.

Just 1 lb. (0.454 kg) of polar bear liver contains about 450 times the recommended daily dose of vitamin A, and the men in Barents's expedition were absorbing far more of the vitamin than they should have. In time, they began to experience the effects of vitamin A poisoning: painful joints, bone thickening, peeling of the skin over the entire body, and chronic liver disease. When spring came, the men managed to make it off the island, but many of them—Barents included—never lived to see Holland again, in part because the side effects of vitamin A toxicity had weakened them.

So why take vitamin A at all? Because it is necessary for proper growth of bones and teeth, for the maintenance and functioning of skin and mucous membranes, and for the ability to see in dim light. There is some evidence that it can help prevent cataracts (a clouding of the lens in the eye) and cardiovascular disease, a condition of the heart and circulatory system. Furthermore, when taken at the onset of a cold, vitamin A can ward off the illness and fight its symptoms.

One of the first signs of vitamin A deficiency is "night blindness," in which the rods of the eye (necessary for night vision) fail to function normally. Extreme cases of vitamin A deficiency can lead to total blindness. Other symptoms include dry and scaly skin, problems with the mucous linings of the digestive tract and urinary system, and abnormal growth of teeth and bones. The bodies of healthy adults who have an adequate diet can store several years' supply of this vitamin, but young children, who have not had time to build up such a large reserve, suffer from deprivation much more quickly if they do not consume enough.

Vitamin A is present in meats (mainly liver), fish oil, egg yolks, butter, and cheese. Although plants do not have vitamin A, dark green leafy vegetables and yellow fruits and vegetables (e.g., carrots, sweet potatoes, cantaloupe, corn, and peaches) contain a substance called beta-carotene, which is converted to vitamin A in the intestine and then absorbed by the body. It is nearly impossible to ingest beta-carotene in toxic amounts, unlike vitamin A from animal sources, since the body will not convert excess amounts to toxic levels of vitamin A.

VITAMIN D.

Vitamin D is actually two different substances, D₂ and D₃. (There was no D_1, since the substance designated thus at one time turned out to be a mixture of several compounds, including calciferol, or D₂) Both forms of vitamin D are activated, or made effective, by sunlight, and for this reason vitamin D often is called the sunshine vitamin. It is hard to suffer a vitamin D deficiency if one gets enough sunshine in combination with consuming such foods as eggs (specifically, the yolk), such fatty fish as salmon, and enriched milk. (Milk does not naturally contain vitamin D, but the vitamin is sometimes included as an additive.)

Vitamin D lets the body utilize calcium and phosphorus in bone and tooth formation, and a deficiency causes a bone disease called rickets. Under the influence of this physically debilitating and disfiguring disease, legs become bowed by the weight of the body, and the wrists and ankles thicken. The teeth are badly affected and, for a young child, take much longer to mature. Infants and children are most likely to suffer the effects of rickets, but since all milk and infant formulas have vitamin D added to them, the condition is seen rarely in the industrialized world today. In the brutal early days of the Industrial Revolution, however (i.e., in England ca. 1760-1830), crowded slum conditions in areas where there was little or no sunlight made possible many cases of rickets.

Whereas rickets primarily affects children, adults may suffer from a disease called osteomalacia, caused by a deficiency of vitamin D, calcium, and phosphorous. Sometimes seen in the Middle East and other parts of Asia, osteomalacia brings with it rheumatic pain and causes the bones to become soft and deformed. As with rickets, the treatment for osteomalacia is a combination of calcium, phosphorous, and vitamin D. On the other hand, as with all fat-soluble vitamins, a person may take in excessive amounts of vitamin D, which has its own ill effects: nausea, diarrhea, weight loss, and pain in the bones and joints. Damage to the kidneys and blood vessels also can occur as calcium deposits build up in these tissues.

VITAMIN E.

Composed of at least seven similar chemicals called the tocopherols, vitamin E is found in green leafy vegetables, wheat germ and other plant oils, egg yolks, and meat. The main function of this vitamin is to act as an antioxidant, to counteract the harmful effects oxygen can have on tissues. It may seem strange to speak of oxygen causing harm, since it is essential to life, but oxidation is an extremely powerful chemical reaction that, under various conditions, can manifest as rotting or putrefaction, rusting, or even combustion and explosion. When an apple turns brown a few minutes after you have cut it open, it is the result of oxidation.

Oxidation also may be linked to the effects of aging in humans as well as to other conditions, such as cancer, hardening of the arteries, and rheumatoid arthritis. It appears that oxygen molecules, which draw electrons to them, extract these electrons from the membranes in human cells. Over time, this can cause a gradual breakdown in the body's immune system. Antioxidants, such as vitamin E or beta carotene, therefore may be important in preserving human health and well-being.

Vitamin E is particularly important for counteracting oxidation in fats. When they are oxidized, fats form a highly reactive substance called peroxide, which is often very damaging to cells. Vitamin E is more reactive (i.e., more likely to form or break chemical bonds) than the fatty acid molecule, and, therefore, the vitamin reacts instead of the fat. Because cell membranes are composed partly of fat molecules, vitamin E is vitally important in maintaining the nervous, circulatory, and reproductive systems and in protecting the kidneys, lungs, and liver.

Because vitamin E is so common in foods, it is very difficult to suffer from a deficiency of this vitamin unless a person avoids consuming fats altogether—another example of why a no-fat diet is not a healthy one. The effects of vitamin E deficiency, all of which are apparently linked to the loss of its antioxidant protection, include cramping in the legs, fibrocystic breast disease (a condition that involves the formation of lumps and cysts in the breasts), and even muscular dystrophy. The seriousness of the latter two diseases only serves to highlight the importance of vitamin E to the body.

VITAMIN K.

Like vitamin D, vitamin K is composed of two groups of compounds, vitamins K₁ and K₂. There is also a substance called K₃, but this vitamin is actually menadione, a synthetic compound from which the other forms of K are derived. You can find vitamin K in many plants, especially green leafy ones such as spinach, and in liver. Vitamin K is also made by the bacteria that live in the intestine—the "good" bacteria that help make possible the processing of food through the body.

Vitamin K appears to be critical to blood clotting, thanks to its role in assisting the formation of a chemical called prothrombin in the liver. Deficiencies of this vitamin rarely occur as the result of an incomplete diet; instead, it is usually a consequence of liver damage and the blood's inability to process the vitamin. The deficiency manifests in unusual bleeding or large bruises under the skin or in the muscles. Adults in the West seldom experience vitamin K deficiencies, but newborn infants have been known to suffer from brain hemorrhage owing to a lack of this vitamin.

Water-Soluble Vitamins

B VITAMINS.

The two water-soluble vitamins, as we shall see, have played a major part in medical history. Actually, there are more than two water-soluble vitamins, because vitamin B is really a complex of about a dozen vitamins—hence, the name B complex. Among them are vitamin B₁ (thiamine), vitamin B₂ (riboflavin), vitamin B₆ (pyridoxine), and vitamin B₁₂ (cobalamin). A few others—for example, niacin (vitamin B₇) and pantothenic acid (vitamin B₃), are known better by names other than their "B names," while biotin and folate, or folic acid, are not known by "B names" at all.

Vitamin B₁, present in whole grains, nuts, legumes (e.g., peas), pork, and liver, helps the body release energy from carbohydrates. More than 4,000 years ago, the Chinese described a disease we know today as beriberi, which affects the nervous and gastrointestinal systems and causes nausea, fatigue, and mental confusion. The cause of beriberi is a deficiency of thiamine, or B₁, found in the husks or bran of rice and grains. White rice, which most people find more pleasing to the palate than brown rice, is the result of a milling and polishing process in which the husks—and along with them, this important nutrient—are removed. Manufacturers today produce "enriched" rice, flour, and other grain products by adding thiamine back in, but until scientists discovered the importance of thiamin in grain husks, many people, especially in the Far East, suffered the effects of beriberi. (Early research on beriberi will be discussed later.)

Vitamin B₂ helps the body release energy from fats, proteins, and carbohydrates. It can be obtained from whole grains, organ meats (e.g., liver), and green leafy vegetables. Lack of this vitamin causes severe skin problems. Vitamin B₆ is important in the building of body tissue as well as in protein metabolism and the synthesis of hemoglobin (an iron-containing pigment in red blood cells that is responsible for transporting oxygen to the tissues and removing carbon dioxide). A deficiency can cause depression, nausea, and vomiting. Vitamin B₁₂ is necessary for the proper functioning of the nervous system and in the formation of red blood cells. It can be obtained from meat, fish, and dairy products. Anemia (a lack of red blood cells, which produces a lethargic condition), nervousness, fatigue, and even brain degeneration, can result from vitamin B₁₂ deficiency.

Niacin is also highly important to human health, as we explain later in the context of the disease pellagra. Pantothenic acid helps release energy from fats and carbohydrates and is found in large quantities in egg yolks, liver, eggs, nuts, and whole grains. Deficiency of this vitamin causes anemia. Biotin, widely available from grains, legumes, and liver, plays a part in the release of energy from carbohydrates and in the formation of fatty acids. A lack of biotin causes dermatitis, or skin inflammation.

VITAMIN C.

The American chemist and peace activist Linus Pauling (1901-1994), winner of the Nobel Prize in chemistry (1954) and peace (1962), helped popularize vitamin C, also known as ascorbic acid. It was Pauling who originated the idea, now widespread in society, that massive doses of vitamin C can ward off the common cold. Pauling went further, by maintaining that vitamin C offers protection against some forms of cancer. While scientific studies have been unable to prove this theory, they do suggest that the vitamin can at least reduce the severity of the symptoms associated with colds.

Most animals can synthesize this vitamin in the liver, where glucose (a type of sugar that occurs widely in nature) is converted to ascorbic acid. This is not the case with at least four types of animal: monkeys, guinea pigs, Indian fruit bats, and humans, all of which must obtain vitamin C from their diets. Citrus fruits, berries, and some vegetables (e.g., tomatoes and peppers) are good sources of vitamin C. It is a fragile vitamin, one that is oxidized or destroyed easily. Food storage or food processing can render it ineffective; so, too, can soaking vitamin C-containing fruits and vegetables in water for long periods.

Vitamin Deficiencies and History

Most of the early history in the study of vitamins centered around what are now known as the water-soluble vitamins. Although vitamins as such were not discovered until early in the twentieth century, it was common knowledge long before that time that substances in certain foods were necessary for good health. An important turning point came in the mid-eighteenth century, with the work of the Scottish physician James Lind (1716-1794) on a vitamin deficiency condition that jeopardized England's vast merchant and military navies.

At a time when England had emerged as the world's leading sea power, even Her Majesty's sailing crews were at the mercy of a condition known as scurvy. Common among crews who had been at sea too long, scurvy could result in swollen joints, bleeding gums, loose teeth, and an inability to recover from wounds. Scientists today recognize scurvy as resulting from a deficiency of vitamin C, available in such citrus fruits as oranges. At the time, however, the concept of vitamins was unknown, and sailors at sea continued to live on a diet that consisted primarily of salted meats and hard biscuits—items that could be stored easily without spoilage in an era before refrigeration.

In 1746, Lind, a ship's doctor, observed that 80 of 350 seamen aboard his ship came down with scurvy during a 10-week cruise. Conducting a controlled experiment, he took 12 of the sailors in whom scurvy had developed and divided them into six groups. He gave each pair different substances, such as nutmeg, cider, seawater, and vinegar; the final pair was given lemons or oranges. The two men given the oranges and lemons both completely recovered in about a week. Not only was this a milestone in the history of vitamin research, but it also was the first example of a clinical trial, or the testing of a medication by careful and well-documented experimentation in which other variables or factors are kept unchanged.

It would be another half-century before the British navy adopted Lind's techniques. Another Scottish physician, Sir Gilbert Blane (1749-1834), had long fought for the adoption of Lind's methods, and finally, in 1796, he persuaded the navy to give each sailor a daily ration of lemons. At that time, the term lime was common for both lemons and limes, and, as a result, British sailors became known as limeys. Eventually, the treatment spread to the population as a whole, but outbreaks of scurvy continued until after World War I, when doctors isolated vitamin C as the controlling factor in scurvy prevention.

BERIBERI IN THE DUTCH EAST INDIES.

In 1897 the Dutch government sent the physician Christiaan Eijkman (1858-1930) as part of a government commission to the Dutch East Indies (now Indonesia), which had been long afflicted by a condition known as beriberi. There are various forms of this disease, including infant beriberi, which can kill a breast-feeding baby after the fifth month, as well as various juvenile and adult forms. In the childhood and adult versions of the disease, there is a preliminary condition of fatigue, loss of appetite, and a numb, tingling feeling in the legs. This condition can lead to either wet beriberi, characterized by the accumulation of fluid throughout the body and a rapid heart rate that can bring about sudden death, or dry beriberi, which is marked by a loss of sensation and weakness in the legs. The patient first needs to walk with the aid of a stick and then becomes bedridden and easy prey to infectious diseases.

Experimenting with birds, Eijkman noticed that some of the fowl experienced paralysis and polyneuritis (a disorder affecting several nerves at once), as in the dry form of beriberi. The director of the hospital had told Eijkman that he could not feed the birds with table scraps from the dining hall, where the diet was heavy in polished rice. The doctor thus was forced to feed his birds whole rice, and something amazing happened: the birds began to regain their ability to move and experienced no recurrence of paralysis.

Eijkman's colleagues rejected his claim that the birds had contracted some form of beriberi, though, in fact, he was correct. He was incorrect, however, in his supposition that the polished rice contained a toxin that was missing from the whole, unpolished rice. After Eijkman and the rest of the medical commission left the East Indies, another Dutch physician, Gerrit Grijns (1865-1944), stayed on to study the disease. He discovered that when the chickens were taken off the rice diet completely and fed meat instead, they did not show signs of the characteristic paralysis; if the meat was overcooked, however, the condition reappeared. In 1901, Grijns showed that beriberi could be cured by putting the rice polishings back into the rice. As it turned out, the husks and the meat contained vitamin B₁, also present in wheat germ, whole grain and enriched bread, legumes, peanuts, and nuts.

PELLAGRA IN THE AMERICAS.

A vitamin-deficiency disease often associated with poverty, pellagra produces symptoms known as the "three Ds": diarrhea, dermatitis, and dementia, or mental deterioration. It was first identified in 1762 by the Spanish physician Gaspar Casal (ca. 1680-1759), who wrote about the "mal de la rosa"—so called because of the reddened dermatitis that appeared around the back of the victim's neck—that afflicted sufferers in one particular region of Spain.

Casal was far ahead of his time in maintaining that inadequate nutrition caused pellagra, but for many centuries the belief persisted that the disease resulted from infection. The breakthrough came with the work of the American physician Joseph Goldberger (1874-1929), a member of the U.S. Public Health Service who studied the high numbers of pellagra cases among poor blacks and whites in the southern United States. Goldberger established that pellagra stems from insufficient niacin, which is required to release energy from glucose.

Niacin is present in whole grains, meat, fish, and dairy products. One of the foods from which niacin is not easily available is corn, and it so happened that corn products constituted a major part of the diet in areas suffering from high rates of pellagra. The poor of Spain and Latin America subsisted on a diet heavy in corn products, such as tortillas and polenta, while their counterparts in the southern United States survived on cornbread, grits, hominy, and other variants of corn. Although such foods made it possible to fill the stomach cheaply, this diet was killing people in large numbers because it was not delivering the essential B vitamin niacin.

MODERN KNOWLEDGE OF VITAMINS.

As it turned out, corn, in fact, does contain niacin, but to release the niacin from the large, fibrous molecules in corn, it is necessary to treat the corn with an alkaline solution, such as limewater. This is just one example of the vast knowledge that has accumulated since the time when the Polish-American biochemist Casimir Funk (1884-1967) coined the term vitamine in 1912. The first half of the word came from the Latin vita, or "life," and the second half reflected Funk's belief that all these substances belonged to a group of chemicals known as amines. Scientists later dropped the "e" when they discovered that not all vitamins contain an amine group.

In the director Stephen Spielberg's acclaimed 1987 film Empire of the Sun, one of the characters asks another, "Do you believe in vitamins?" The question reflects the relative newness of vitamins as an idea at the time when the movie was set, during World War II. After the war, interest in commercially produced vitamin supplements exploded, particularly among America's middle classes. Pauling's promotion of vitamin C, coming in the 1950s and 1960s, found a willing audience.

Although vitamin supplements remain a big business today, opinions vary as to the importance of enhancing one's diet with them. Many nutritionists insist that eating a well-balanced diet, consisting of the major food substances, is an effective and economical way to obtain nutrients for health. On the other hand, advocates of health foods and alternative medicine (medical practices that are not recognized officially by groups of university-trained and state-licensed medical doctors) insist that the recommended daily allowances established by the U.S. Food and Drug Administration do not provide sufficient vitamins for an average person.

The American Dietetic Association (ADA) recommends that nutrient needs come from a variety of foods taken from different dietary sources rather than from self-prescribed vitamin supplements. The organization makes allowances, however, for supplement usage by people who need extra doses of key vitamins and minerals. Examples include the use of iron supplements by women experiencing heavy menstrual bleeding as well as supplements of iron, folic acid, and calcium by pregnant women.

WHERE TO LEARN MORE

Apple, Rima D. Vitamania: Vitamins in American Culture. New Brunswick, NJ: Rutgers University Press, 1996.

Brody, Jane E., and Denise Grady. The New York Times Guide to Alternative Health: A Consumer Reference. New York: Times Books/Henry Holt, 2001.

Duyff, Roberta Larson. The American Dietetic Association's Complete Food and Nutrition Guide. Minneapolis, MN: Chronimed Publishing, 1998.

Kiple, Kenneth F., and Kriemhild Coneé Ornelas. T he Cambridge World History of Food. New York: Cambridge University Press, 2000.

Nardo, Don. Vitamins and Minerals. New York: Chelsea House Publishers, 1994.

Reference Guide for Vitamins (Web site). <http://www.realtime.net/anr/vitamins.html>.

Snyder, Carl H. The Extraordinary Chemistry of Ordinary Things. New York: John Wiley and Sons, 1998.

Vitamins and Coenzymes. Indiana State University (Web site). <http://www.indstate.edu/thcme/mwking/vitamins.html>.

The Vitamin Collection. Molecular Expressions: Exploring the World of Optics and Microscopy, Florida State University (Web site). <http://micro.magnet.fsu.edu/vitamins/>.

Vitamin-Deficiency Diseases. Medic Planet (Web site). <http://www.medic-planet.com/MP_article/internal_reference/Vitamin-deficiency_diseases>.

Vitamins and Minerals Topic Page. Food and Nutrition Information Center National Agricultural Library, U.S. Department of Agriculture (Web site). <http://www.nal.usda.gov/fnic/etext/000068.html>.

KEY TERMS

AMINO ACIDS:

Organic compounds made of carbon, hydrogen, oxygen, nitrogen, and (in some cases) sulfur bonded in characteristic formations. Strings of amino acids make up proteins.

ANEMIA:

A condition marked by a lack of red blood cells or hemoglobin or a shortage in total blood volume, any one of which can produce a lethargic condition.

ANTIOXIDANT:

An enzyme, or some other organic substance, that is capable of counteracting the negative impact of oxygen (which draws electrons to it) on living tissue.

CARBOHYDRATES:

Naturally occurring compounds, consisting of carbon, hydrogen, and oxygen, whose primary function in the body is to supply energy. Included in the carbohydrate group aresugars, starches, cellulose, and various other substances.

COMPOUND:

A substance in which atoms of more than one element are bonded chemically to one another.

ENZYME:

A protein material that speeds up chemical reactions in the bodies of plants and animals.

GLUCOSE:

A type of sugar that occurs widely in nature. Glucose is the form in which animals usually receive carbohydrates.

HEMOGLOBIN:

An iron-containing pigment in red blood cells that is responsible for transporting oxygen to the tissues and removing carbon dioxide.

METABOLISM:

The chemical process by which nutrients are broken down and converted into energy or used in the construction of new tissue or other material in the body.

MINERALS:

Inorganic substances that, in a nutritional context, serve a function similar to that of vitamins. Minerals may include chemical elements, particularly metallic ones, such as calcium or iron, as well as some compounds.

ORGANIC:

At one time chemists used the term organic only in reference to living things. Now the word is applied to compounds containing carbon and hydrogen.

PROTEINS:

Large molecules built from long chains of amino acids. Proteins serve the functions of promoting normal growth, repairing damaged tissue, contributing to the body's immune system, and making enzymes.

TISSUE:

A group of cells, along with the substances that join them, that form part of the structural materials in plants oranimals.

VITAMINS:

Organic substances that, in extremely small quantities, are essential to the nutrition of most animals and some plants. In particular, vitamins work with enzymes in regulating metabolic processes; however, they do not in themselves provide energy, and thus vitamins alone do not qualify as a form of nutrition.

VITAMINS

Overview

The word "vitamin" came from the term vita mines (vital amines), which was introduced by Casimir Funk, who, in 1912, isolated a growth factor from rice polishings that contained an amine (a compound incorporating a nitrogen atom with two hydrogen atoms) and could cure the disease beriberi. Several other growth factors were identified early in the twentieth century as well, and these substances were also called vitamins even though they did not contain an amine. Vitamins are classified into two major groups: fat-soluble and water-soluble. (See the Appendix for a complete chart of vitamins.)

Fat-Soluble Vitamins

Vitamin A. In the early 1900s, Sir Frederick Hopkins demonstrated that animals would not grow if lard was provided as a sole dietary lipid. When a small quantity of milk containing fat was added to the diet, the animals thrived. The fat-soluble factor was isolated and designated as vitamin A, later called retinol or retinal; these and similar compounds are referred to as retinoids. Carotenoids, which are essentially two retinoids joined tail to tail, are inactive forms of vitamin A and are called provitamin A. They are converted to vitamin A in the intestine and liver. Vitamin A and carotenoids are absorbed in the chylomicron (a lipoprotein particle that transports lipids from the intestine) fraction and stored in the liver. Some foods such as milk are fortified with vitamin A. Rich sources of carotenoids include carrots, leafy green vegetables, and pink grapefruit.

Vitamin A is, chemically, a subgroup of retinoids, which are defined as a class of compounds that consist of a six-membered ring and a side chain with four conjugated double bonds (four isoprenoid units). The term vitamin A is used to describe retinoids exhibiting qualitatively the biologic activity of the retinoid, retinol.

Vitamin A binds to a retinol-binding protein that transports the light-sensitive vitamin to various target tissues, including the eyes, skin, and gastrointestinal track. The major functions of vitamin A include vision and regulation of cellular proliferation and differentiation. Vitamin A functions on vision by interacting with the rod and cone cells in the retina. It is responsible for absorbing light. The 11-cis form of vitamin A (retinal) combines with the protein opsin to form rhodopsin in the rod cells and iodopsins in the cone cells. The rhodopsin and iodopsins absorb light at various wavelengths and trigger a nerve impulse to the visual cortex in the brain that is ultimately perceived as black-and-white and color vision, respectively.

Vitamin A's other major physiologic function is to maintain the health of skin and mucous-secreting cells by regulating their cellular activity and maturation. The dietary requirements depend on age.

The major consequence of vitamin A deficiency, which continues to be a serious nutritional problem among millions of schoolchildren in southern and southeastern Asia and parts of Africa and South America, is night blindness. Vitamin A deficiency can lead to complete blindness and severe damage to the outer covering of the eye (the cornea), often causing it to perforate, with loss of the fluid from inside the eye (keratomalacia). Vitamin A deficiency also produces changes in the skin that are related to the inability of the skin cells to mature and produce keratin properly. This leads to follicular hyperkeratosis and phrynoderma (a condition characterized by rough, dry skin). Vitamin A deficiency has also been linked to increased mortality in early childhood.

Acute and chronic ingestion of excessive amounts of vitamin A can cause a multitude of symptoms and consequences. The most serious is that it can cause severe birth defects, spontaneous abortions and learning defects, and skin and epithelial-cell exfoliation. Inexperienced white explorers of the Arctic who ate polar-bear liver in excess developed severe vitamin A intoxication that caused a total sloughing of their skin and mucoussecreting cells in the upper airway and esophagus, bringing on painful death. (This is in contrast to the indigenous Inuit, who specifically avoid eating polar-bear liver.)

Vitamin D. One of the consequences of the industrial revolution was the high incidence of the bone-deforming disease rickets. It was estimated, at the turn of the twentieth century, that more than ninety percent of children living in the industrialized cities of northern Europe and the northeastern United States had rickets. It had been known that cod-liver oil possessed a factor that had antirachitic activity. Originally, it was thought that the antirachitic factor was vitamin A. However, Hopkins heated cod-liver oil to destroy the vitamin A activity and demonstrated that it still possessed antirachitic activity. This new fat-soluble vitamin was labeled vitamin D. It was also recognized that exposure of food, animals, and humans to ultraviolet radiation also prevented and cured rickets.

There are two principal forms of vitamin D: Vitamin D ₂ comes from the precursor ergosterol found in yeast and plants, and vitamin D ₃ comes from the cholesterol precursor 7-dehydrocholesterol that is found in the skin of reptiles, birds, mammals, and humans. Vitamin D ₂ and vitamin D ₃ are essentially equally active in most birds and in most mammals, including humans. Chickens and New World monkeys, however, cannot utilize vitamin D ₂. There are very few foods that naturally contain vitamin D. Fatty fish, such as salmon and mackerel, and fish-liver oils, such as cod-liver oil are good sources of vitamin D. Cow's milk and human milk have very little vitamin D. However, in the United States and Canada, milk and some breads and cereals are fortified with vitamin D. In Europe, fortification of foods with vitamin D was outlawed when sporadic cases of vitamin D intoxication were observed in children in the 1950s. Today some margarine and cereals are fortified with vitamin D in Europe, but milk is not.

Vitamin D ₃ is made by the action of sunlight on the skin. Provitamin D ₃ (7-Dehydrocholesterol) absorbs solar ultraviolet B radiation (wavelengths 290–315 nm) and is transformed into previtamin D ₃. Previtamin D ₃ is unstable at body temperature and isomerizes (rotates its double bonds) to vitamin D ₃. Once formed, vitamin D ₃ leaves the skin and enters the circulation, bound to the vitamin D binding protein. It travels to the liver where it is activated to 25-hydroxyvitamin D [25(OH)D]. This form, however, is biologically inert at physiologic concentrations and is the major circulating form of vitamin D. It is, nevertheless, the form that is measured to determine the vitamin D status of an individual, because it represents a summation of dietary and skin sources of vitamin D. 25(OH)D is transported on the vitamin D binding protein to the kidney, where it undergoes its final activation on carbon 1 to form 1,25-dihydroxyvitamin D [1,25(OH) ₂D], the biologically active form of vitamin D.

The principal function of vitamin D is to maintain blood calcium and phosphorus in the normal range in order to promote neuromuscular function and to maintain metabolic activities. It accomplishes this by enhancing the efficiency of intestinal calcium transport in the small intestine and by stimulating precursor cells of osteoclasts to become mature osteoclasts. Among the functions of osteoclasts is to remove calcium from bone. Serum calcium and phosphorus are in the form of Ca _x(PO ₄). When these compounds are in the normal range, they are in a supersaturated state that can thus be deposited in the skeletal matrix as calcium hydroxyapatite.

1,25(OH) ₂D interacts with a receptor in the nucleus of cells, known as the VDR (vitamin D receptor). It also complexes with the "retinoic acid x" receptor in that cellular structure. These receptor-activated vitamin D complexes find their way to genes that have responsive elements known as the vitamin D-responsive element. These elements in turn unlock genetic information that is responsible for various biologic functions in intestine and bone. It is recognized that a wide variety of tissues including the brain, parathyroid glands, breast, pro state, stomach, and skin also have VDR. Although the exact physiologic function of 1,25(OH) ₂D in these non-calcium-regulating tissues is not well understood, 1,25(OH) ₂D inhibits cellular proliferation and induces terminal differentiation of a wide variety of cells, including bone, skin, skeletal muscle, breast, and prostate. The dietary requirement depends on age.

Vitamin D deficiency results in a decrease in the efficiency of intestinal calcium absorption that in turn leads to a decrease in unbound or free calcium concentrations in the circulation. This is recognized by the parathyroid gland and results in an increase in the production and secretion of parathyroid hormone (PTH). PTH enhances calcium reabsorption by the kidney and causes increased output of phosphate in the urine. PTH also stimulates the kidney to produce more 1,25(OH) ₂D. The net effect of vitamin D deficiency is a low-normal serum calcium and a low serum phosphorus (due to the PTH-induced phosphate wasting in the kidney). Thus calcium and phosphorus concentrations fall below supersaturating levels, thereby resulting in poorly mineralized bone. In children, this causes rickets and, in adults, osteomalacia. In addition, vitamin D deficiency in adults can precipitate and exacerbate osteoporosis. In winter, little if any vitamin D can be made in the skin of people who live above 40° north or below 40° south of the equator. An increase in the zenith angle of the sun due to latitude, time of day, and season of the year will dramatically reduce the production of vitamin D ₃ in the skin. Moreover, aging and sunscreen use can markedly reduce the production of vitamin D by more than 60 percent and 99 percent, respectively. Rickets due to vitamin D deficiency in children may include bowlegs or knock-knees, widening of the ends of the long bones, growth retardation, and muscle weakness. In adults, in addition to osteomalacia and increased risk of osteoporosis, it causes bone pain, muscle weakness, and fractures.

The safe upper limit for Vitamin D is 2,000 units a day. Although it is difficult to ingest enough to cause vitamin D intoxication, it can occur. Usually, oral ingestion of 10,000 units a day and greater will cause vitamin D intoxication. This intoxication causes an elevation in the blood levels of calcium and phosphorus, which results in the calcification of soft tissues, including the kidney and major blood vessels, and may also cause the formation of kidney stones.

Vitamin E. The discovery of vitamin E (tocopherols—from toc- meaning 'childbirth', phero- meaning 'bringing forth', and -ol representing the alcohol portion of the molecule) was due to the observation that supplementation of the diet with vitamin E prevented fetal death in animals that were fed a diet containing rancid lard. There are eight naturally occurring vitamin E compounds. Four of them are known as tocopherols and four are known as tocotrienols. The most abundant form of vitamin E is alpha-tocopherol. One of the major functions of vitamin E is to act as a biologic antioxidant to protect the sensitive cellular membranes from oxidative destruction. The major sources of vitamin E consumed by Americans are vegetables and seed oils, such as corn oil, soybean oil, and safflower oil. Wheat germ is a rich source of vitamin E. Although butter contains very little vitamin E, American margarine contains a significant amount of this antioxidant vitamin.

Vitamin E, like the other fat-soluble vitamins, is absorbed in the chylomicron fraction into the lymphatic system and is transported into the venous blood. The dietary requirements depend on age.

There have been difficulties in defining a clinical syndrome that correlates with vitamin E deficiency in humans. Vitamin E deficiency is associated with anemia in newborns.

Toxicity from excess vitamin E has been associated with increased bleeding tendency in adults and impaired immune function, decreased levels of vitamin K-dependent clotting factors, and impairment of leukocyte function.

Vitamin K. Vitamin K was discovered by Henrik Dam in Copenhagen in 1929. He observed that chicks fed a fat-free diet developed severe bleeding under the skin and in the muscle and other tissues. He named this new fatsoluble vitamin, vitamin K (for "Koagulation vitamin"). Vitamin K is distributed widely in both animal and vegetable foods as well as in milk. It comes in several forms: vitamin K ₁ comes from plants and is known as phylloquinone, and vitamin K ₂, first isolated from fish meal and in animal foods, comprises a group of compounds known as menaquinones. In addition, bacterial flora in the intestine synthesize menaquinones that are bioavailable.

Vitamin K, like other fat-soluble vitamins, is absorbed in the chylomicron fraction and then appears in the lymph and subsequently in the venous circulation. The major physiologic function of vitamin K is to activate blood-clotting proteins. This is accomplished by the modification of a substance, glutamate, found in several precoagulant factors, including factors II, VII, VIIII, and X, that are produced in the liver. Vitamin K is also re sponsible for the modification of other proteins, including the major noncollagenous protein in bone. The dietary requirements depend on age.

Vitamin K deficiency is rare because of the widespread distribution of the vitamin in plant and animal foods and because microbiotic flora in the normal gut synthesize menaquinones. However, vitamin K deficiency in breast-fed newborns remains a major worldwide cause of infant morbidity and mortality. Infants have very little stored vitamin K at birth, and the gut is nearly sterile during the first few days of life. As a result, infants can develop a severe bleeding condition known as hemorrhagic disease of the newborn if they do not obtain vitamin K during the first few days of life from an exogenous source, particularly since mother's milk contains little vitamin K and few bacteria other than those it picks up from maternal skin as an infant suckles. Adults who have intestinal malabsorption syndrome and who are taking antibiotics can become severely vitamin K-deficient. This can lead to generalized bleeding from all orifices.

There are no reported cases of intoxication due to excessive ingestion of phylloquinone. Ingestion of excessive amounts of menadione, a vitamin K precursor, can cause anemia secondary to the destruction of red blood cells, and an alteration in bilirubin metabolism causing hyperbilirubinemia in infants (kernicterus).

Water-Soluble Vitamins

Thiamine (vitamin B ₁). Beriberi is a disease with a constellation of systems affecting the nervous and cardiovascular systems. It was first described by the Chinese in 2697 b.c.e. In 1926, B. C. P. Jansen and W. F. Donath identified a factor from rice-bran extracts that prevented beriberi. The antiberiberi factor was identified chemically and called thiamine (vitamin B₁). Thiamine is found in yeast, lean pork, and legumes. It serves as a receptor for high-energy pyrophosphate. It is this form of the vitamin that provides its chemical function. Pyrophosphate is extremely important for the generation of energy in the cell. However, it cannot enter the cell unless it is attached to thiamine. Thiamine is absorbed by the small intestine and transported to the liver. The major biochemical function of thiamine is to act as a coenzyme (that is, to provide a transfer site) in the alpha-keto acid carboxylation pathway. The dietary requirements depend on age.

Thiamine deficiency causes beriberi. Anorexia, neuritis, gastrointestinal dysfunction, cardiac irregularities, and muscle atrophy are present. There are three types of this disorder: wet, dry, and infantile. Wet beriberi is associated with body fluid retention (edema). Dry beriberi is related to neurologic abnormalities. It is recognized that alcoholics who have poor nutrition and thiamine deficiency, when receiving intravenous fluids, for example in the emergency room of a hospital, can develop severe altered mental states known Wernicke's and Korsakoff's syndromes. Wet beriberi is associated with heart abnormalities; dry beriberi is associated with neurological abnormalities that can cause permanent confusion if not treated in a timely manner.

Excessive ingestion of thiamine is cleared by the kidneys. There is no evidence that ingesting excessive amounts causes toxicity.

Riboflavin. In the 1920s, another water-soluble vitamin was discovered; it exhibited antipellagra activity and was termed vitamin B₂. The substance was found to be yellow in color and was identified as a coenzyme, riboflavin 5'-phosphate (flavin mononucleotide or FMN).

The more abundant form of this vitamin is a complex flavin-adenine dinucleotide (FAD) that also participates as a coenzyme. Usually, the FMN and FAD are associated loosely with proteins and are released in the acidic gastrointestinal juices. The vitamin is absorbed by the proximal small intestine. Sources of riboflavin include eggs, lean meats, milk, broccoli, and enriched breads and cereals.

The physiologic function of riboflavin is to participate in oxidation-reduction reactions in numerous metabolic pathways and in energy production via the respiratory chain in the mitochondria. The dietary requirements depend on age.

Riboflavin is distributed widely in foodstuffs, and therefore deficiency is not common. However, there are reported cases of deficiency that are characterized by sore throat, hyperemia and edema of the pharyngeal and oral mucosal membranes, cheilosis (abnormal scaling and fissuring of the lips), angular stomatitis (surface inflammation of the mouth), glossitis (inflammation of the tongue), seborrheic dermatitis (an inflammation of the skin involving oversecretion by the oil-producing cutaneous glands), and anemia. Severe riboflavin deficiency can affect the conversion of vitamin B₆ to its coenzyme and reduce the conversion of tryptophan, an amino acid found in proteins of animal and plant origin, to niacin (see next section). Deficiency is principally due to abnormal digestion, abnormal absorption, or both. People who are lactose-intolerant—a condition that is most common among blacks and Asians—often limit consumption of milk (as noted above, an excellent source of riboflavin); they may therefore be at increased risk for riboflavin deficiency. Intestinal malabsorption syndromes, including tropical sprue celiac disease, small bowel resection, and gastrointestinal and biliary obstruction can lead to riboflavin deficiency.

There is no evidence that toxicity can occur as a result of excessive ingestion of riboflavin. The most likely reason for this is that riboflavin is cleared rapidly by the kidney and is not stored in the body.

Niacin. In the mid-1700s, a Spanish physician, Gaspar Casal, recognized a disease known as pellagra that caused diarrhea, dementia, and dermatitis in maize-eating (corneating) populations throughout the world. In 1937, Conrad Elvehjem and his colleagues observed that nicotinic acid was an effective treatment for pellagra. Nicotinic acid is synonymous with both niacin and nicotinamide. It is associated with ribose lyphosphate to form nicotinamide adenine dinucleotide (NAD) and NAD phosphate. Most niacin in food is present as a component of NAD or NADP and is relatively stable to cooking and storage. Good sources of niacin include meats (especially liver), fish, legumes such as peanuts, some nuts, and some cereals. Both coffee and tea also contain reasonable amounts of this vitamin. Niacin is unique among the B vitamins because its precursor amino acid, tryptophan, can help meet the daily niacin requirement.

Niacin has a multitude of physiologic functions in a wide variety of metabolic pathways that are related to energy production and biosynthetic processes. At least two hundred enzymes are dependent on NAD and NADP. Both of these substances act as electron acceptors or hydrogen donors. Most NAD-dependent enzymes are involved in catabolic reactions, whereas NADP is used more commonly for reductive biosyntheses of fatty acids and steroids, for example. The dietary requirements depend on age.

Niacin deficiency causes pellagra. This condition is associated with diarrhea, dementia, and dermatitis. It is endemic in India and in parts of China and Africa. The classic appearance of pellagra is a pigmented rash that develops symmetrically in areas of the skin exposed to sunlight. The tongue can become bright red and there is often vomiting and diarrhea. Patients can also exhibit anxiety or sleeplessness, and can become disoriented and delusional.

Nicotinic acid is now used to treat hypercholesterolemia. Side effects of large amounts of nicotinic acid include flushing of the skin, abnormalities in liver function, and hyperglycemia. At extremely high ingestion levels, nicotinamide causes death in rats.

Pyridoxine (vitamin B ₆ ). Vitamin B₆ was identified in the 1930s. Like many of the water-soluble B vitamins, vitamin B₆ includes a group of compounds that act as a coenzyme phosphate donor. These include pyridoxal 5>-phosphate (PLP), and pyridoxamine 5>-phosphate (PMP). Plants foods contain predominantly pyridoxine, whereas animal products contain primarily pyridoxal and pyridoxamine. Vitamin B₆ is absorbed mainly by the lower small intestine (jejunum).

Like many of the other coenzyme B vitamins, vitamin B₆ has numerous biologic functions that are related to metabolism. B₆ is critically important for the production of glucose. PLP is also necessary for the conversion of tryptophan to niacin, which is why the two are often associated. The dietary requirements depend on age.

As with many of the other B vitamins, there are a wide variety of clinical symptoms associated with vitamin B₆ deficiency including an abnormal electroencephalogram, convulsions, stomatitis, cheilosis, glossitis, irritability, depression, and confusion.

High doses of pyridoxine have been used to treat premenstrual syndrome and other neurological diseases. Such uses have resulted in neurotoxicity and photosensitivity.

Pantothenic acid. Pantothenic acid was one of the more difficult vitamins to isolate and separate from the other water-soluble B vitamins. Finally in the 1940s, it was synthesized and was found to be associated with coenzyme A (CoA). CoA is an essential cofactor for biologic acetylation reactions and participates in the respiratory tricarboxcylic acid cycle, fatty-acid synthesis and degradation, and a wide variety of other metabolic and regulatory processes. The dietary requirements depend on age.

Pantothenic acid deficiency affects the adrenal gland, nervous system, skin, and hair adversely. Pantothenic acid deficiency in humans is rare, but has been associated with fatigue and depression.

High doses of calcium pantothenate have not been found to be toxic in humans.

Folic acid and cobalamin (vitamin B ₁₂ ). In the mid-1800s, several physicians recognized that a severe form of anemia was associated with disorders of the digestive system. In 1934, William Castle and his associates observed that normal human gastric juice contained an intrinsic factor (IF) that combines with an extrinsic factor in animalprotein food, resulting in the absorption of a vitamin that prevents anemia. Vitamin B₁₂ was isolated in 1948 and was shown to be the extrinsic antianemia factor.

Vitamin B₁₂ absorption is unique among the B vitamins, in requiring an IF to help its absorption. Folate, on the other hand, is absorbed directly by the upper (proximal) small intestine.

Whereas vitamin B₁₂ is found only in animal protein, folates are common in nature and present in nearly all natural foods. The dietary requirements depend on age.

Vitamin B₁₂ deficiency can occur either because of inadequate vitamin B₁₂ ingestion or because of the loss or inadequacy of production of intrinsic factor in the stomach. The two most notable clinical signs of vitamin B₁₂ deficiency include megaloblastic anemia and neurological deficits. Vitamin B₁₂ deficiency can cause paresthesia (especially numbness and tingling in the hands and feet); the diminution of vibration and position sense; unsteadiness; poor muscular coordination with ataxia (loss of muscular coordination); moodiness; mental slowness; poor memory; confusion; agitation; depression; and central visual loss. Delusions, overt psychosis, and paranoid ideas may occur in severe deficiency.

Folate deficiency also causes megaloblastic anemia and can cause neurological abnormalities as well, including irritability, forgetfulness, and hostile and paranoid behavior. For adults, ingestion of ten thousand times the minimum requirement for B₁₂ and several hundred times that for folic acid has not been associated with toxicity.

Biotin. Biotin was identified in the 1940s. It, like many of the other B vitamins, acts as a coenzyme. Biotin is plentiful in foods such as liver, egg yolk, soybeans, yeast, cereals, legumes, and nuts. With the exception of cauliflower and mushrooms, vegetables, fruits, and meats, however, are poor sources of biotin. Biotin is also present in human and cow's milk. The major physiologic functions of biotin are related to carbohydrate and lipid metabolism. The dietary requirements depend on age.

Biotin deficiency causes mental-status changes, myalgia (muscle pain), hyperesthesia (abnormal sensitivity to pain, touch, cold, etc.), localized paresthesia, and anorexia with nausea. Dermatitis can also be associated with deficiency. The immune system is impaired in biotin-deficient animals. Neurological disorders including seizures and developmental delays have been reported in children. There have been no reports of intoxication due to excessive biotin ingestion.

Vitamin C. Scurvy is recognized as a deficiency disease that has taken a high toll in human suffering and death. The disease, which is caused by vitamin C deficiency, was recognized in ancient times by the Egyptians, Greeks, and Romans. It was especially prevalent among sea explorers of the sixteenth to eighteenth centuries. Typically, sailors developed bleeding and rotting gums, swollen and inflamed joints, dark blotches on the skin, and muscle weakness that occurred within months when at sea. It was the loss of 1,051 sailors in 1774 that prompted the British Admiralty to seek a cure for this devastating disease. They found that lemon or lime juice could prevent the disease. In the late 1920s, Albert Szent-Györgyi and Glenn King isolated vitamin C and identified it as hexuronic acid. Vitamin C is water-soluble and is absorbed efficiently by the small intestine. Its major physiologic function is to provide reducing activity for a wide variety of metabolic steps. It is important for the modification of lysine and proline—two amino acids that are common components of collagen. These modifications result in the cross-linking of collagen strands providing structural support for this essential component of bone and fibrous tissues. The dietary requirements depend on age.

As noted, vitamin C deficiency causes scurvy, which is associated with a wide variety of abnormalities, including hemorrhages under the skin, black-and-blue marks, hyperkeratosis, joint discomfort, edema, weakness, fatigue, lassitude, depression, and hysteria.

It was suggested by the Nobel Prize Laureate Linus Pauling that extremely high doses of vitamin C could prevent cancer. With the exception of excessive amounts of vitamin C causing bowel impaction via a large number of vitamin C tablets ingested, there are very few serious consequences from an overingestion of vitamin C, though it can increase the risk of kidney stones and other renal diseases.

Other nutrients. Other nutrients that are essential could be considered vitamins. These include choline, carnitine, inositol, and taurine.

See also Beriberi ; Choline, Inositol, and Related Nutrients ; Inuit ; Maize ; Niacin Deficiency (Pellagra) ; Nutrients ; Vitamin C ; Vitamins: Water-soluble and Fat-soluble Vitamins ; Appendix: Dietary Reference Intakes .

BIBLIOGRAPHY

Frisell, W. R., ed. Human Biochemistry. New York: Macmillan, 1982.

Holick, Michael F. "Vitamin D: New Horizons for the 21st Century" (McCollum Award Lecture, 1994). The American Journal of Clinical Nutrition 60 (1994): 619–630.

Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, D.C.: National Academy Press, 2001.

Institute of Medicine. "Vitamin D." In Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, pp. 250–287. Washington, D.C.: National Academy Press, 1997.

Shils, M. E., J. A. Olson, and M. Shike, eds. Modern Nutrition in Health and Diseases. 8th ed. Philadelphia: Lea and Febiger, 1994.

Michael Holick

Vitamin/nutritional deficiency

Definition

Vitamins are substances that the human body requires but is unable to synthesize and therefore, must obtain externally. Deficiencies in three B vitamins, B1 or thiamine, B3 or niacin and B12 or cobalamin are known to cause neurological disorders. Thiamine deficiencies result in a disease called beriberi , which causes peripheral neurological dysfunction and cerebral neuropathy. Niacin deficiencies cause a wasting disease known as pellagra, which affects the skin, mucous membranes, gastrointestinal tract as well as the brain, spinal cord and peripheral nerves. Cobalamin deficiencies most often result in the disease pernicious anemia. Neurological symptoms of pernicious anemia include numbness in the extremities, impaired coordination and a ringing in the ears.

Description

Thiamine deficiency

Thiamine was the first water-soluble vitamin to be discovered, and is therefore, also known as vitamin B1. Thiamine deficiency, or beriberi, manifests itself as both wet beriberi, which affects the cardiovascular system, and dry beriberi, which causes neurological dysfunction. People suffering from beriberi exhibit muscle atrophy or wasting (especially in the legs), edema (swelling), mental confusion, intestinal discomfort and an enlarged heart. Severe cases of dry beriberi may result in Wernicke-Korsakoff syndrome and acute cases of wet beriberi may cause shoshin beriberi. Both of these extreme forms of the disease are sometimes fatal. In most cases, administering thiamine successfully reverses symptoms associated with thiamine deficiencies.

Niacin deficiency

Niacin deficiency results in a disease called pellagra. The major symptoms of pellagra include dermatitis, dementia (loss of intellectual functions) and diarrhea. Pellagra means rough skin in Italian and it was named because of the characteristic roughened skin of people who have the disease. Skin lesions generally appear on both sides of the body (bilaterally) and are found in regions exposed to sunlight. The disease also affects mucous membranes of the mouth, vagina, and urethra. Gastrointestinal discomfort is an early symptom, followed by nausea, vomiting, and diarrhea, often bloody. Neurological dysfunctions associated with niacin deficiencies include memory loss, confusion and confabulation (imagined memory). Although treatment with niacin usually reverses all of the symptoms, untreated niacin deficiencies can result in multiple organ failure.

Vitamin B12 deficiency

Vitamin B12, also called cobalamin or cyanocobalamin, has the most complex chemical structure of all vitamins. It is unique in that it contains a cobalt atom embedded in a ring, similar to the iron atom in hemoglobin. The cobalt gives the molecule a dark red color. Vitamin B12 is found bound to animal protein and is very rare in vegetables. A deficiency of vitamin B12 results in a blood disorder, also called an anemia, which enlarges red blood cells so that the immune system destroys them at an increased rate. Because the blood cells are enlarged, the disease is characterized as a macrocytic anemia. Vitamin B12 functions in many important cellular processes including synthesis of red blood cells, DNA synthesis and the formation of the myelin sheath that acts as insulation around nerve cells. One of the most common causes of vitamin B12 deficiency is pernicious anemia. Pernicious anemia is caused by a lack of a glycoprotein called intrinsic factor that is required for absorption of vitamin B12. Intrinsic factor is secreted by the stomach, where it binds to the vitamin and transports it to the small intestine for absorption. Symptoms of vitamin B12 deficiency progress from weakness and fatigue to neurological disorders including numbness in the extremities, poor coordination, and eventually, to hallucinations and psychosis. Vitamin B12 deficiencies are usually treated with intramuscular injections of vitamin B12 initially and oral vitamin B12 supplements on an ongoing basis.

Demographics

Thiamine deficiency

Thiamine deficiencies have no sex or racial predilection. Thiamine deficiency is more common in developing countries where poor nutrition occurs frequently, although no accurate statistics on its occurrence are available. In many of these countries, cassava or milled rice acts as a major staple of the diet. While cassava does contain some thiamine, it contains so much carbohydrate relative to the thiamine that eating cassava actually consumes thiamine. Most of the thiamine in rice is found in the husk. When the husk is removed from the rice during milling, the result is a diet staple that is an extremely poor source of thiamine.

Beriberi is often associated with alcoholism, likely because of low thiamine intake, impaired ability to absorb and store thiamine, and acceleration in the reduction of thiamine diphosphate. People who strictly follow fad diets, people undergoing starvation, and people receiving large amounts of intravenous fluids are all susceptible to beriberi. Some physical conditions such as hyperthyroidism, pregnancy, or severe illness may cause a person to require more thiamine than normal and may put a person at risk for deficiency.

A form of beriberi specific to infants known as infantile beriberi can occur in babies between two and four months old that are fed only breast milk from mothers who are thiamine deficient.

Niacin deficiency

Pellagra is most common when maize is a major part of the diet. Although maize does contain niacin, it is not biologically available unless it is treated with basic compounds, such as lime. This process occurs in the making of tortillas, so populations in Mexico and Central America do not usually suffer from pellagra. Maize is also deficient in tryptophan, a precursor to niacin.

In the early 1900s, pellagra was epidemic in the southern United States because of the large amount of corn in the diet. After niacin was discovered to prevent pellagra in 1937, flour was fortified with niacin and reports of pellagra decreased dramatically. Currently, incidence rates of pellagra in the United States are unknown. People at risk for pellagra include alcoholics, people on fad diets, and people with gastrointestinal absorption dysfunction.

The group of people who most commonly suffer from pellagra live in the Deccan Plateau of India. Their diet is rich in millet or sorghum, which contains tryptophan, but also large concentrations of another amino acid, leucine. It is thought that leucine inhibits the conversion of tryptophan to niacin.

Vitamin B12 deficiency

Pernicious anemia is most common in patients of northern European descent and African Americans and less frequent in people of southern European descent and Asians. There is no sex predilection. Vitamin B12 deficiency occurs in 3–43% of people over the age of 65. A form of pernicious anemia is also found in children under the age of ten. It is more frequent in patients with other immune disorders such as Grave's disease or Crohn's disease. There is some evidence that relatives of people who have pernicious anemia are more likely to get the disorder, indicating some genetic component to the disease. Because vitamin B12 only occurs in animal proteins, vegetarians are susceptible to the disease and should take vitamin B12 supplements.

Causes and symptoms

Thiamine deficiency

Thiamine deficiencies are caused by an inadequate intake of thiamine. In most developed countries, getting enough thiamine is not a problem since it is found in all vegetables, especially the outer layer of grains. It is not present in refined sugars or fats and is not found in animal tissue. Diets rich in foods that contain thiaminases, enzymes that break down thiamine, such as milled rice, shrimp, mussels, clams, fresh fish and raw meat may be associated with thiamine deficiencies.

Thiamine is absorbed through the digestive tract by a combination of active and passive absorption. It is stored in the body as thiamine diphosphate, also called thiamine pyrophosphate, and thiamine triphosphate. Thiamine diphosphate is the active form and it is used as a coenzyme in several steps in cellular respiration. Thiamine may also have an important role in the function of nerve cells independent of cellular respiration. It is found in the cell membranes of nerve axons, and electrical stimulation of nerve cells causes a release of thiamine.

Early thiamine deficiency produces fatigue, abdominal pain , constipation, irritation, loss of memory, chest pain, anorexia and sleep disturbance. As the deficiency progresses, it can be classified as dry beriberi or wet beriberi depending on the activity of the patient. Many persons experience a mixture of the two types of beriberi, although pure forms do occur.

When caloric intake and physical activity are low, thiamine deficiency produces neurological dysfunction termed dry beriberi. Symptoms occur with equal intensity on both sides of the body and usually start in the legs. Impaired motor and reflex function coupled with pain, numbness and cramps are symptomatic of the disease. As the disease advances, ankle and knee jerk reactions will be lost, muscle tone in the calf and thigh will atrophy and eventually the patient will suffer from foot drop and toe drop. The arms may begin to show symptoms of neurological dysfunction after the legs are already symptomatic. Histological (tissue) tests may indicate patchy degradation of myelin in muscle tissues.

Wernicke-Korsadoff syndrome, also called cerebral beriberi, occurs in extreme cases of dry beriberi. The early stage is called Korsakoff's syndrome and it is characterized by confusion, the inability to learn, amnesia and telling stories that bear no relation to reality. Wernicke's encephalopathy follows with symptoms of vomiting, nystagmus (rapid horizontal or vertical eye movement), opthalmoplegia (inability to move the eye outwards) and ptosis (eyelid droop). If untreated, Wernicke's encephalopathy may progress to coma and, eventually death.

If a person has a high caloric intake and reasonable levels of activity, but has a diet with insufficient thiamine, myocardial dysfunction termed wet beriberi may result. This disease consists of vasodilatation and high cardiac output, retention of salt and water, and eventual damage to the heart muscle. A person suffering from wet beriberi will exhibit rapid heartbeat (tachycardia), swelling (edema), high blood pressure, and chest pain.

Shoshin beriberi is a more acute form of wet beriberi and it is characterized by damage to the heart muscle accompanied by anxiety and restlessness. If no treatment is received, the damage to the heart may be fatal.

Niacin deficiency

Niacin, also called vitamin B3, is a general term for two molecules: nicotinic acid and nicotinamine. Nicotinic acid is very easily converted into biologically important molecules including nicotinamide adenine dinucleotide (NAD or coenzyme I) and nicotinaminamide adenine dinucleotide phosphate (NADP or coenzyme II), both of which are crucial to oxidation-reduction reactions in cellular metabolism. These reactions play key roles in glycololysis, the generation of high-energy phosphate bonds, and metabolism of fatty acids, proteins, glycerol, and pyruvate. Because niacin plays such an important role in so many different cellular functions, the effect of niacin deficiencies on the body is extremely broad.

The amino acid, tryptophan is a precursor to niacin, and therefore, niacin deficiency can be averted if tryptophan is included in the diet. Some of the psychological symptoms of pellagra are thought to be related to decreased conversion rates of tryptophan to serotonin (a neurotransmitter) in the brain.

Causes of pellagra include diets that are deficient in niacin or its precursor, tryptophan. These diets often rely heavily on unprocessed maize. Other diets that may cause pellagra contain amino acid imbalances. For example, diets that rely on sorghum as a staple contain excessive amounts of the amino acid leucine, which interferes with tryptophan metabolism. Other causes of pellagra include alcoholism, fad diets, diabetes, cirrhosis of the liver, and digestive disorders that prevent proper absorption of niacin or tryptophan. One such disorder is called Hartnup disease, which is a congenital defect that interferes with tryptophan metabolism.

Symptoms of pellagra occur in the skin, in mucous membranes, the gastrointestinal tract, and the central nervous system . Skin symptoms are usually bilaterally symmetric. They include lesions characterized by redness and crusting, thickening of the skin and skin inelasticity. Secondary infections are common, especially after exposure to the sun. Mucus membranes are also affected by pellagra. Typically, the tongue becomes bright red first and then the mouth becomes sore, coupled with increased salivation and edema of the tongue. Eventually, ulcers may appear throughout the mouth. Gastrointestinal symptoms include burning of the mouth, esophagus and abdominal pain. Later symptoms include vomiting and diarrhea, often bloody.

The central nervous system is also affected by niacin deficiencies. Early symptoms include memory loss, disorientation, confusion, hallucination . More severe symptoms are characterized by loss of consciousness, rigidity in the extremities, and uncontrolled sucking and grasping.

Vitamin B12 deficiency

Vitamin B12 is required for the biochemical reaction that converts homocysteine to methionine, one of the essential amino acids required to synthesize proteins. Because vitamin B12 impairs DNA translation, cell division is slow, but the cytoplasm of the cell develops normally. This leads to enlarged cells, especially in cells that usually divide quickly, like red blood cells. In addition, there is usually a high ration of RNA to DNA in these cells. Enlarged red blood cells are more likely to be destroyed by the immune system in the bone marrow, causing a deficit of red blood cells in the blood. Methionine is also required to produce choline and choline-containing phospholipids. Choline and choline-containing phospholipids are a major component of cell membranes and acetocholine, which is crucial to nerve function.

Vitamin B12 requires several binding proteins in order to be absorbed properly. After ingestion into the stomach, it forms a complex with R binding protein, which moves into the small intestine. The stomach secretes another protein, intrinsic factor, which binds with vitamin B12 after R binding factor is digested in the small intestine. Intrinsic factor bound with vitamin B12 adheres to specialized receptors in the ileum, where it is brought inside of cells that line the intestinal wall. Vitamin B12 is then transferred to another protein, transcobalamin II, which circulates through the blood plasma to all parts of the body. Another protein, transcobalamin I, is found bound to vitamin B12; however its function is not well understood.

Because of the complexity of the steps required for vitamin B12 absorption, there are many different ways that deficiencies could arise. First, a person could have inadequate intake of vitamin B12. This is extremely rare, since it is found in most animal proteins, but it does occur in some strict vegetarians. If any of the proteins that usher vitamin B12 through the body are unavailable or damaged, vitamin B12 deficiencies could arise. The most common such problem is associated with inadequate production of intrinsic factor, which results in pernicious anemia. Inadequate production of intrinsic factor can occur because of atrophy (wasting) of the stomach lining, the removal of the part of the stomach that produces intrinsic factor, or in rare cases, because of a congenital defect. Rare cases of intestinal parasites such as a fish tapeworm and bacterial infections may also result in vitamin B12 deficiencies. Finally, acid is often required to hydrolyze vitamin B12 from animal proteins in the stomach. If the stomach is not sufficiently acidic, for example in the presence of antacid medicines, quantities of vitamin B12 available for absorption may be deficient.

The liver stores large amounts of vitamin B12. It is estimated that if vitamin B12 uptake is suddenly stopped, it would take three to five years to completely deplete the stores in a typical adult. As a result, vitamin B12 deficiencies develop over many years. Initial symptoms include weakness, fatigue, lightheadedness, weight loss, diarrhea, abdominal pain, shortness of breath, sore mouth and loss of taste, and tingling in the fingers and toes.

As the disease progresses, neurological symptoms begin to appear. These include forgetfulness, depression , confusion, difficulty thinking, and impaired judgment. Eventually, a person with vitamin B12 deficiency will have numbness in the fingers and toes, impaired balance and poor coordination, ringing in the ears, changes in reflexes, hallucinations, and psychosis.

Diagnosis

Thiamine deficiency

A patient with bilateral symmetric neurological symptoms, especially in the lower extremities may be suffering from thiamine deficiency, especially if there is an indication that the diet may be poor. Some diseases with symptoms that are similar to beriberi include diabetes and alcoholism. Other neuropathies, such as sciatica , are often not symmetric and are not usually associated with beriberi.

Laboratory tests may show high concentrations of pyruvate and lactate in the blood and low concentrations of thiamine in the urine. Because the disease responds so well to thiamine, it is often used as a diagnostic tool. After administration of thiamine diphosphate, an increase in certain enzyme activity in red blood cells is an excellent indicator of thiamine deficiency.

Niacin deficiency

There are no diagnostic tests currently available to detect niacin deficiencies. Concentrations of niacin and tryptophan in the urine of patients suffering from pellagra are low, but not lower than other patients with malnutrition. Diagnosis must be made given a patient's symptoms and dietary history. Because replacement of niacin is so effective, it may be used as a diagnostic tool.

Vitamin B12 deficiency

A person suspected of suffering from vitamin B12 deficiency will be subjected to a physical examination along with blood tests. These blood tests will include a complete blood count (CBC). If blood analyses indicate that the red blood cells are enlarged, vitamin B12 deficiency may be diagnosed. Other disorders that exhibit enlarged red blood cells (macrocytes) include alcoholism, hypthyroidism, and other forms of anemia. White blood cells with segmented nuclei also indicate vitamin B12 deficiency. Other blood tests include a vitamin B12 test and folic acid tests. Low concentrations of both may indicate vitamin B12 deficiencies. Elevated levels of homocysteine, methylmalonic acid (MMA) or lactate dehydrogenase (LDH) indicate vitamin B12 deficiencies. Finally tests that indicate the presence of antibodies against intrinsic factor may indicate pernicious anemia.

Once a vitamin B12 deficiency has been established in a patient, the severity of the disease can be evaluated using a Schilling test. The patient is orally administered radioactive cobalamin and then an injection of unlabeled cobalamin is given intramuscularly. The ratio of radioactive to unlabeled cobalamin in the urine during the next 24 hours gives information on the absorption rate of cobalamin by the patient. If the rates are abnormal, pernicious anemia is diagnosed. As a final check, the patient is given cobalamin bound to intrinsic factor. With this, the patient's absorption rates should become normal if pernicious anemia is the cause of the symptoms.

Treatment

Thiamine deficiency

In most cases, rapid administration of intravenous thiamine will reduce symptoms of thiamine deficiency. Continued dosages of the vitamin should be continued for several weeks accompanied by a nutritious diet. Following recovery, a diet containing one to two times the recommended daily allowance of thiamine (1-1.5 mg per day) should be maintained. Shoshin beriberi requires cardiac support as well. Thiamine has not been found to be toxic for people with normal kidney function, even at high doses.

Niacin deficiency

Niacin deficiency can be treated effectively with replacement of niacin in the diet. In the case of Hartnup disease, large quantities of niacin may be required for effective reversal of symptoms.

Vitamin B12 deficiency

Vitamin B12 deficiency responds well to administration of cobalamin. Because absorption in the small intestine is often part of the problem, the best way to administer cobalamin is by intramuscular injection on a daily basis. After 6 weeks, the injections can be decreased to monthly for the rest of the patient's life. Usually, response to this treatment alleviates all symptoms of the disease. In severe cases, a blood transfusion may be needed and neurological conditions may not be completely reversed.

Resources

BOOKS

Garrison, Robert H., Jr. and Elizabeth Somer. The Nutrition Desk Reference. Keats Publising, Inc., 1985.

Peckenpaugh, Nancy J. and Charlotte M. Poleman. Nutrition: Essentials and Diet Therapy. Philadelphia: W. B. Saunders Company, 1999.

OTHER

Lovinger, Sarah Pressman. "Beriberi" MEDLINE plus. National Library of Medicine. (February, 8 2004). <http://www.nlm.nih.gov/medlineplus/ency/article/000339.htm#Symptoms>.

"Niacin deficiency." The Merck Manual. (January 16, 2004). <http://www.merck.com/mrkshared/mmanual/section1/chapter3/3l.jsp>.

"Thiamine deficiency and dependency." The Merk Manual. (January 16, 2004). <http://www.merck.com/mrkshared/mmanual/section1/chapter3/3j.jsp>.

ORGANIZATIONS

NIH/National Digestive Diseases Information Clearinghouse. 2 Information Way, Bethesda, MD 20892-3570. (301) 654-3810 or (800) 891-5389; Fax: (301) 907-8906. [email protected]. <http://www.niddk.nih.gov>.

National Heart, Lung, and Blood Institute (NHLBI). P. O. Box 30105, Bethesda, MD 20824-0105. (301) 592-8573; Fax: (301) 592-8563. [email protected]. <http://www.nhlbi.nih.gov>.

Juli M. Berwald, PhD

Vitamin

Vitamins are complex organic compounds that occur naturally in plants and animals. People and other animals need these compounds in order to maintain life functions and prevent diseases. About 15 different vitamins are necessary for the nutritional needs of humans. Only minute amounts are required to achieve their purpose, yet without them life cannot be maintained. Some vitamins, including vitamins A, D, E, and K, are fat soluble and are found in the fatty parts of food and body tissue. As such they can be stored in the body. Others, the most notable of which are vitamin C and all the B-complex vitamins, are water soluble. These vitamins are found in the watery parts of food and body tissue and cannot be stored by the body. They are excreted in urine and must be consumed on a daily basis.

History

Vitamins were not discovered until early in the twentieth century. Yet it was common knowledge long before that time that substances in certain foods were necessary for good health. Information about which foods were necessary developed by trial and error—with no understanding of why they promoted health. Scurvy, for example, had long been a dreaded disease of sailors. They often spent months at sea and, due to limited ways of preserving food without refrigeration, their diet consisted of dried foods and salted meats. In 1746, English naval captain and surgeon James Lind (1716–1794) observed that 80 out of his 350 seamen came down with scurvy during a 10-week cruise. He demonstrated that this disease could be prevented by eating fresh fruits and vegetables during these long periods at sea. Because they lasted a long time, limes became the fruit of choice. In 1795, lemon juice was officially ordered as part of the seaman's diet. The vitamin C found in both limes and lemons prevented scurvy in sailors.

In 1897, Dutch physician Christian Eijkman (1858–1930) found that something in the hulls of rice (thiamine, a B vitamin) not present in the polished grains prevented the disease beriberi (a disease that affects the nerves, the digestive system, and the heart). Soon after, British biochemist Frederick G. Hopkins (1861–1947) fed a synthetic diet of fats, carbohydrates, proteins, and minerals (but no vitamins) to experimental rats. The rats showed poor growth and became ill, leading Hopkins to conclude that there were some "accessory food factors" necessary in the diet. Eijkman and Hopkins shared the 1929 Nobel Prize in physiology and medicine for their important work on vitamins.

Words to Know

Antioxidant: A substance that can counteract the effects of oxidation.

Beriberi: A disease caused by a deficiency of thiamine and characterized by nerve and gastrointestinal disorders.

Carbohydrate: A compound consisting of carbon, hydrogen, and oxygen found in plants and used as a food by humans and other animals.

Deficiency diseases: Diseases caused by inadequate amounts in the diet of some substance necessary for good health and the prevention of disease.

Fat-soluble vitamins: Vitamins such as A, D, E, and K that are soluble in the fatty parts of plants and animals.

Pellagra: A disease caused by a deficiency of niacin and characterized by severe skin problems and diarrhea.

Proteins: Large molecules that are essential to the structure and functioning of all living cells.

Scurvy: A disease caused by a deficiency of vitamin C, which causes a weakening of connective tissue in bone and muscle.

Water-soluble vitamins: Vitamins such as C and the B-complex vitamins that are soluble in the watery parts of plant and animal tissues.

Finally, in 1912, Polish American biochemist Casimir Funk (1884–1967) published a paper on vitamin-deficiency diseases. He coined the word vitamine from the Latin vita, for "life," and amine, because he thought that all of these substances belonged to a group of chemicals known as amines. The e was later dropped when it was found that not all vitamins contained an amine group. Funk identified four vitamins (B₁ or thiamine, B₂, C, and D) as substances necessary for good health and the prevention of disease.

Since that time additional vitamins have been isolated from foods, and their relationship to specific diseases have been identified. All of these accessory food factors have been successfully synthesized in the laboratory. There is no difference in the chemical nature of the natural vitamins and those that are made synthetically, even though advertisements sometimes try to promote natural sources (such as vitamin C from rose hips) as having special properties not present in the synthesized form.

Nature of vitamins

Vitamins belong to a group of organic compounds required in the diets of humans and other animals in order to maintain good health: normal growth, sustenance, reproduction, and disease prevention. In spite of their importance to life, they are necessary in only very small quantities. The total amount of vitamins required for one day weigh about one-fifth of a gram. Vitamins have no caloric value and are not a source of energy.

Vitamins cannot be synthesized by the cells of an animal but are vital for normal cell function. Certain plants manufacture these substances, and they are passed on when the plants are eaten as food. Not all vitamins are required in the diets of all animals. For example, vitamin C is necessary for humans, monkeys, and guinea pigs but not for animals able to produce it in their cells from other chemical substances. Nevertheless, all higher animals require vitamin C, and its function within organisms is always the same.

Vitamins were originally classified into two broad categories according to their solubilities in water or in fat. As more vitamins were discovered, they were named after letters of the alphabet. Some substances once thought to be vitamins were later removed from the category when it was found that they were unnecessary or that they could be produced by an animal. Four of the better known vitamins, A, D, E, and K, are fat soluble. Other vitamins such as vitamin C and the B-complex vitamins are water soluble.

This difference in solubility is extremely important to the way the vitamins function within an organism and in the way they are consumed. Fat-soluble vitamins lodge in the fatty tissues of the body and can be stored there. It is, therefore, not necessary to include them in the diet every day. Because these vitamins can be stored, it also is possible (when consumed in excess) for them to build up to dangerous levels in the tissues and cause poisoning.

The Food and Drug Administration publishes a set of nutritional recommendations called the U.S. Recommended Dietary Allowances (USRDA) patterned on the needs of the average adult. These recommendations are based on the best information available but are less than perfect; most of the research upon which they are determined is done on experimental animals. Because the amounts of vitamins required are so small, precise work is very difficult.

A person who eats a balanced diet with plenty of fresh fruits and vegetables should receive adequate amounts of all the vitamins. Many vitamins, however, are very sensitive to heat, pressure cooking, cold, and other aspects of food preparation and storage and can be inactivated or destroyed.

A controversy about vitamins exists among experts regarding the dose needed to fight off some common diseases. According to these experts, the USRDA are really minimum requirements, and higher doses will keep a person healthier. Thus, many people worldwide take vitamin supplements as insurance that they are getting all they need. Overdosage on vitamins, especially the fat-soluble ones, can cause serious side effects, however, and in some cases they even interfere with the proper function of other nutrients.

Vitamin A

Vitamin A is present in animal tissue, mainly in liver, fish oil, egg yolks, butter, and cheese. Plants do not contain vitamin A, but they do contain beta carotene, which is converted to vitamin A in the intestine and then absorbed by the body. Beta carotene occurs most commonly in dark green leafy vegetables and in yellowish fruits and vegetables such as carrots, sweet potatoes, cantaloupe, corn, and peaches. The bodies of healthy adults who have an adequate diet can store several years' supply of this vitamin. But young children, who have not had time to build up such a large reserve, suffer from deprivation more quickly if they do not consume enough of the vitamin.

Vitamin A is necessary for proper growth of bones and teeth, for the maintenance and functioning of skin and mucous membranes, and for the ability to see in dim light. There is some evidence that it can help prevent cataracts and cardiovascular disease and, when taken at the onset of a cold, can ward it off and fight its symptoms. One of the first signs of a deficiency of this vitamin is night blindness, in which the rods of the eye (necessary for night vision) fail to function normally. Extreme cases of vitamin A deficiency can lead to total blindness. Other symptoms include dry and scaly skin, problems with the mucous linings of the digestive tract and urinary system, and abnormal growth of teeth and bones.

Vitamin A is stored in the fatty tissues of the body and is toxic in high doses. As early as 1596, Arctic explorers experienced vitamin A poisoning. In this region of extreme conditions, the polar bear was a major source of their food supply, and a quarter pound of polar bear liver contains about 450 times the recommended daily dose of vitamin A. Excessive amounts of vitamin A cause chronic liver disease, peeling of the skin of the entire body, bone thickening, and painful joints. However, it is nearly impossible to ingest beta carotene in toxic amounts since the body will not convert excess amounts to toxic levels of vitamin A.

Vitamin D

Vitamin D is often called the sunshine vitamin. It is produced when compounds that occur naturally in animal bodies are exposed to sunlight. Thus, it is difficult to suffer a vitamin D deficiency if one gets enough sunshine. One form of vitamin D is often added to milk as an additive. Storage and food preparation do not seem to affect this vitamin.

Vitamin D lets the body utilize calcium and phosphorus in bone and tooth formation. Deficiency of this vitamin causes a bone disease called rickets. This disease is characterized by bone deformities (such as bowlegs, pigeon breast, and knobby bone growths on the ribs where they join the breastbone) and tooth abnormalities. In adults, bones become soft and porous as calcium is lost.

Excessive amounts of vitamin D cause nausea, diarrhea, weight loss, and pain in the bones and joints. Damage to the kidneys and blood vessels can occur as calcium deposits build up in these tissues.

Vitamin E

Vitamin E is present in green leafy vegetables, wheat germ and other plant oils, egg yolks, and meat. The main function of this vitamin is to act as an antioxidant, particularly for fats. (When oxidized, fats form a very reactive substance called peroxide, which is often very damaging to cells. Vitamin E is more reactive than the fatty acid molecule and, therefore, takes its place in the oxidizing process.) Because cell membranes are partially composed of fat molecules, vitamin E is vitally important in maintaining the nervous, circulatory, and reproductive systems and in protecting the kidneys, lungs, and liver.

All of the symptoms of vitamin E deficiency are believed to be due to the loss of the antioxidant protection it offers to cells. This protective effect also keeps vitamin A from oxidizing to an inactive form. And when vitamin E is lacking, vitamin A deficiency also frequently occurs. However, because vitamin E is so prevalent in foods, it is very difficult to suffer from a deficiency of this vitamin unless no fats are consumed in the diet. When it does occur, the symptoms include cramping in the legs, muscular dystrophy, and fibrocystic breast disease.

According to some current theories, many of the effects of aging are caused by the oxidation of fat molecules in cells. If this is true, then consuming extra vitamin E might counteract these effects because of its antioxidant properties.

Vitamin K

Vitamin K is found in many plants (especially green leafy ones like spinach), in liver, and in the bacteria of the intestine. Nearly all higher animals must obtain the vitamin K they need from these sources. Although the exact method by which vitamin K works in the body is not understood, it is known that vitamin K is vital to the formation of prothrombin—one of the chemicals necessary for blood clotting—found in the liver.

When vitamin K deficiency develops, it is rarely due to an incomplete diet. Instead, it results from liver damage and the blood's inability to process the vitamin. The deficiency is characterized by the inability of the blood to clot, and it manifests in unusual bleeding or large bruises under the skin or in the muscles. Newborn infants sometimes suffer from brain hemorrhage due to a deficiency of vitamin K.

Vitamin B

What was once thought to be vitamin B was later found to be only one of many B vitamins. Today, more than a dozen B vitamins are known, and they are frequently referred to as vitamin B-complex. Thiamine was the first of these vitamins to be identified. All of the B vitamins are water soluble.

Each of the B vitamins acts by combining with another molecule to form an organic compound known as a coenzyme. A coenzyme then works with an enzyme to perform vital activities within the cell. The function of enzymes within a cell vary, but all are somehow related to the release of energy. The most common members of this group of vitamins include vitamin B₁ (thiamine), vitamin B₂ (riboflavin), vitamin B₆ (pyridoxine), vitamin B₁₂ (cobalamin), biotin, folate (also folacin or folic acid), niacin, and pantothenic acid.

Vitamin B₁ is present in whole grains, nuts, legumes, pork, and liver. It helps the body release energy from carbohydrates. More than 4,000 years ago, the Chinese described a disease we know today as beriberi, which is caused by a deficiency of thiamine. The disease affects the nervous and gastrointestinal system and causes nausea, fatigue, and mental confusion. Thiamine is found in the husks or bran of rice and grains. Once the grain is milled and the husks removed, rice is no longer a source of this vitamin. Manufacturers today produce enriched rice and flour by adding thiamine back into the milled products.

Vitamin B₂ helps the body release energy from fats, proteins, and carbohydrates. It can be obtained from whole grains, organ meats, and green leafy vegetables. Lack of this vitamin causes severe skin problems. Vitamin B₆ is important in the building of body tissue as well as in protein metabolism and the synthesis of hemoglobin. A deficiency can cause depression, nausea, and vomiting. Vitamin B₁₂ is necessary for the proper functioning of the nervous system and in the formation of red blood cells. It can be obtained from meat, fish, and dairy products. Anemia, nervousness, fatigue, and even brain degeneration can result from vitamin B₁₂ deficiency.

Niacin is required to release energy from glucose. It is present in whole grains (but not corn), meat, fish, and dairy products. Inadequate amounts of this vitamin cause a disease called pellagra, which is characterized by skin disorders, weak muscles, diarrhea, and loss of appetite. Pellagra was once common in Spain, Mexico, and the southeastern United States, where a large component of the diet consisted of corn and corn products. The niacin in corn exists as part of a large, fibrous molecule that cannot be absorbed by the blood or used by the body. However, after it was discovered that treating corn with an alkaline solution (such as lime water) releases the niacin from the larger molecule and makes it available for the body to use, pellagra became much less common.

Pantothenic acid helps release energy from fats and carbohydrates and is found in large quantities in egg yolk, liver, eggs, nuts, and whole grains. Deficiency of this vitamin causes anemia. Biotin is involved in the release of energy from carbohydrates and in the formation of fatty acids. It is widely available from grains, legumes (peas or beans), egg yolk, and liver. A lack of biotin causes dermatitis (skin inflammation).

Vitamin C

Because of its association with the common cold, vitamin C (also known as ascorbic acid) is probably the best known of all the vitamins. Most animals can synthesize this vitamin in the liver, where glucose is converted to ascorbic acid. Humans, monkeys, guinea pigs, and the Indian fruit bat are exceptions and must obtain the vitamin from their diets. The vitamin is easily oxidized, and food storage or food processing and preparation frequently destroy its activity. Soaking fruits and vegetables in water for long periods also removes most of the vitamin C. Citrus fruits, berries, and some vegetables like tomatoes and peppers are good sources of vitamin C.

The exact function of vitamin C in the body is still not well understood, but it is believed to be necessary for the formation of collagen, an important protein in skin, cartilage, ligaments, tendons, and bone. It also plays a role in the body's absorption, use, and storage of iron. Vitamin C is an antioxidant and is therefore believed to offer protection to cells much as vitamin E does. An increasing body of evidence suggests that a greatly increased amount of vitamin C in the diet lessens the risk of heart disease and cancer.

A deficiency of vitamin C causes a disease called scurvy. Scurvy weakens the connective tissue in bones and muscles, causing bones to become very porous and brittle and muscles to weaken. As the walls of the circulatory system become affected, sore and bleeding gums and bruises result from internal bleeding. Anemia can occur because iron, which is critical to the transport of oxygen in the blood, cannot be utilized. Vitamin C is metabolized (broken down) very slowly by the body, and deficiency diseases do not usually manifest themselves for several months.

Linus Pauling (1901–1994), the winner of two Nobel Prizes (one for chemistry and one for peace), believed that massive doses of vitamin C could ward off the common cold and offer protection against some forms of cancer. While scientific studies have been unable to confirm this theory, they do suggest that vitamin C can at least reduce the severity of the symptoms of a cold. Some studies also suggest that vitamin C can lessen the incidence of heart disease and cancer. If this is true, it could be that the antioxidant properties of the vitamin help protect cells from weakening and breaking down much as vitamin E does. In fact, vitamins A, C, and E all play similar roles in the body, and it is difficult to distinguish among their effects.

[See also Malnutrition; Nutrition ]