Vitamins, Minerals
and the RDA

Vitamins and the RDA
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Vitamin and mineral deficiency diseases in the United States were relatively common prior to World War II. Today, with the fortification of the food supply, true vitamin deficiency states are rare outside the setting of specific disease states ,drug-nutrient interactions, or extreme malnutrition. The US Dept of Agriculture conducts regular surveys (The National Health and Nutrition Examination Survey) of the U.S. population. The last such survey was conducted between 1976 and 1980, and the current survey runs from 1988 to 1994. The 1976 to 1980 survey indicated that the most common vitamin deficiencies in the U.S. population in good health were iron and calcium, in women only. The intake of most B vitamins, vitamin C, D, E and others were at or above the Recommended Dietary Allowances (RDA). The RDA are normally issued every ten years by the National Academy of Science Food and Nutrition Board to help guide healthy individuals and help in planning various national nutrition programs for infant feeding and school nutrition. The RDA levels are normally set above the threshold needed to prevent deficiency diseases, but in some cases the levels are below those some experts would like to see for the prevention of disease. In fact, in 1980 the guidelines were not issued due to a philosophical difference of opinion among the expert members of the group as to whether the RDA should be raised to encourage intake of Vitamin A (carotenoid)-rich and Vitamin C rich foods such as fruits and vegetables. The controversy was finally settled with the issuance of the 1989 guidelines which reverted to the original aim of averting nutritional deficiency states through public policy recommendations.

The following discussion deals specifically with nutrient deficiencies and only alludes briefly to the preventive potential of micronutrients including carotenoids, vitamin C, vitamin E and folate. Despite the uncommon occurrence of these deficiencies in healthy individuals, a familiarity with the roles of the various common vitamins and minerals, and some knowledge of their assessment in the clinical laboratory will aid in the assessment of the hospitalized or ambulatory patient with suspected nutritional deficiency.

Vitamin A
Night blindness was well-recognized in ancient Egypt where it was treated with juice from cooked liver or by including liver in the diet. The active agent, vitamin A, was discovered as a fat-soluble growth factor necessary for the rat in 1914 and structurally analyzed in 1930 (1). The parent compound of the vitamin A family is all-trans retinol. Its aldehyde and acid forms are retinal and retinoic acid. The active form of vitamin A for vision is 11-cis retinal. The most common clinical manifestations of vitamin A deficiency are night blindness and xerophthalmia (a thickening of the conjunctiva of the eye). In young children, Bitot's spots (foamy white accumulations of sloughed cells on the conjunctiva) can be useful in diagnosing vitamin A deficiency. A second active function for vitamin A is cellular differentiation. The recent discovery of four retinoic acid receptors (termed RAR-alpha through RAR-gamma) in the nucleus of cells has begun to elucidate the molecular mechanisms by which vitamin A induces differentiation of many types of cells (2). A number of retinoids or synthetic vitamin A analogs (the best known is 13-cis retinoic acid or Accutane) are used to treat acne and have been studied for their differentiating activities in the prevention and treatment of premalignant lesions of the mouth, trachea, and cervix (3). Retinol, retinal and retinoic acid are bound to specific retinol-binding proteins in plasma. Tissue cells contain a retinol binding protein (CRBP,types I and II, the latter an intestinal form) and a retinoic acid binding protein (CRABP) (4). In the eye, retinol is bound by interphotoreceptor interstitial-binding protein (IRBP) (5). All of these proteins have been sequenced and cloned, and much is known about their structure and ligand binding sites.

Given the importance of vitamin A, it is fortunate that it can be formed from provitamin A carotenoids found in carrots, yellow squash, dark-green leafy vegetables, corn, tomatoes, papaya, and oranges. Preformed vitamin A is found as retinyl palmitate in liver, various dairy products including milk, cheese, butter, and ice cream, and fish such as herring, sardines, and tuna. In the U.S., about 75% of vitamin A is obtained from preformed dietary sources and 25% from provitamin A carotenoids (6).

Low plasma concentrations of retinol (<0.35 umol/L) are associated with clinical symptoms of vitamin A deficiency (7). The Recommended Dietary Allowance for vitamin A is 5000 IU (800 to 1000 mcg retinol equivalents, or RE) per day, and toxicity has been reported at intakes of 25,000 IU per day. This makes vitamin A one of the most toxic vitamins known. The plasma levels of vitamin A can be used to assess status as follows (8):

Vitamin D
Vitamin D is formed from 7-dehydrocholesterol via the action of sunlight in the skin or is taken in from dietary sources. Since dairy products have been fortified with vitamins A and D, dietary rickets has become rare in the U.S. Vitamin D acts to enhance calcium absorption from the intestine and has been shown to have differentiating effects on a number of different cell types including white blood cells and prostate cancer cells. The active form of vitamin D is 1,25 dihydroxyvitamin D3 formed from 25-hydroxyvitamin D in the kidneys. 25-hydroxyvitamin D is a large inactive pool formed and stored in the liver. The Recommended Dietary Allowance for adults is between 5 and 10 micrograms per day.

Vitamin E
A group of fat-soluble substances, the tocopherols are referred to as vitamin E. One of these substances, alpha-D-tocopherol, is biologically active in rodents where a deficiency can cause infertility. This deficiency has never been demonstrated in humans, but tocopherols have antioxidant properties protecting tissues and substances from the effects of oxygen. For example, these compounds can prevent oxidation of cholesterol, polyunsaturated fats, and other membrane lipids and proteins. The antioxidant effects of vitamin E have been demonstrated only at doses that cannot be derived from usual diets but can only be achieved using supplement capsules. The use of vitamin E supplements has been associated with lower cardiovascular disease risk in males, and has also been used effectively to retard the oxygen-induced damage to the eye in infants given 100% oxygen known as retrolental fibroplasia. There is increased interest in using vitamin E as an antioxidant for prevention of cardiovascular disease and common forms of cancer. The Recommended Dietary Allowance for vitamin E is between 8 and 12 mcg retinol equivalents per day to prevent vitamin E deficiency (infertility seen only in animals), but many individuals take 400 to 800 IU supplements without ill effects.

Vitamin K
Vitamin K is a co-factor for the synthesis of clotting proteins in the liver, and has been proposed to play a role in proper bone metabolism. Half of vitamin K comes from the diet, and the other half is synthesized from precursors by intestinal bacteria. Spinach, green leafy vegetables, cabbage, potatoes, cereals, and liver are good sources. Since vitamin K is found in so many foods and is also formed by intestinal bacteria, deficiency is rare. Individuals receiving prolonged antibiotic therapy destroying intestinal bacteria, and individuals with fat malabsorption are at risk for vitamin K deficiency. The Recommended Dietary Allowance for adults ranges between 45 and 80 micrograms per day.

Vitamin B1 (Thiamin)
Thiamin deficiency disease, still seen today in alcoholics, is known as beriberi (9). This disease, which damages the nervous and cardiovascular systems, is found in two forms, wet beriberi with edema and congestive heart failure, and dry beriberi characterized by muscle atrophy due to nerve damage. In alcoholics, Wernicke-Korsakoff syndrome, characterized by mental confusion, memory disturbances, ataxia, opthalmoplegia, and nystagmus, can be fatal if not treated with intravenous thiamin (10). The dietary vitamin is phosphorylated to form thiamin pyrophosphate in the intestine. Its primary function is to act as a coenzyme for the oxidative decarboxylation of alpha-keto-acids to carboxylic acids (e.g. pyruvate to acetyl CoA) and the transketolase reaction of the pentose phosphate shunt. The latter pathway is important for nucleic acid synthesis and the formation of NADPH for fatty acid synthesis and other reactions. Decreased transketolase activity in red cells can be detected early in the course of thiamin deficiency.

The Recommended Dietary Allowance of thiamin is 0.5 mg/1000 kcal and this is four times the intake at which deficiency signs are observed.

Vitamin B2 (riboflavin)
Riboflavin is a yellow fluorescent compound found throughout the animal and plant kingdoms. Humans and other mammals cannot synthesize these compounds which function in numerous enzyme complexes (including flavin mononucleotide and flavin adenine dinucleotide) involved in electron transport oxidation-reduction reactions (11). Flavins are transported in the blood by albumin and by immunoglobulins. Uncomplicated riboflavin deficiency is uncommon, but dietary lack of the vitamin can lead to a deficit, not only in flavin coenzyme functions, but also in the conversion of vitamin B-6 to pyridoxal phosphate. The recommended dietary allowance for riboflavin ranges between 1.2 and 1.8 mg per day for adults.

Vitamin B6 (Pyridoxine)
The active form of vitamin B6 is pyridoxal 5'- phosphate (PLP), and this coenzyme is involved in over 60 different enzymatic reactions in the body including such common reactions as decarboxylation and aminotransferase reactions (12). Isolated deficiencies of vitamin B-6 are rare, and it is most common to see deficiencies of multiple B vitamins. The best measure of vitamin B-6 status is plasma PLP which can be measured by HPLC. An intake of 2 mg per day is recommended in the RDA, and doses greater than 1 mg must be given to change PLP levels. At intakes of greater than 25 mg, PLP levels do not change further with the excess vitamin B-6 excreted in the urine as pyridoxal and pyridoxic acid. Very large doses (e.g. 500 mg/day) can cause peripheral neuropathy by inducing a conditioned deficiency of other B-vitamins catabolized in a manner similar to the excess vitamin B-6 ingested.

Niacin
Niacin refers to both nicotinic acid and nicotinamide which are converted to the Nicotinamide Adenine Dinucleotide cofactors (NAD and NADH) esssential for a number of enzymatic reactions. The deficiency disease, pellagra, was observed to occur in populations consuming a maize-based diet deficient in the amino acid tryptophan, which is the precursor for endogenous niacin formation. Large doses of nicotinic acid (1.5 to 3 gm/day) but not nicotinamide will lower cholesterol and triglyceride levels and raise HDL levels in subgroups of hypercholesterolemic individuals. However, long-acting forms of niacin in large doses have been associated with liver damage, facial flushing and worsening of hyperglycemia in diabetics. The recommended dietary allowance for niacin ranges between 13 and 20 mg per day for adults.

Folic Acid
Folate is a micronutrient which frequently is deficient in American diets since it is derived from dark green, leafy vegetables. Folic acid acts in cell maturation and differentiates epithelial tissues. In the lung and the cervical epithelium pro-differentiation effects have been demonstrated. Folic acid has also been associated with the prevention of neural tube defects such as spina bifida. It is included in all prenatal vitamins at an enhanced level. It is restricted by law to 400 mcg per tablet in over the counter vitamins. Folate given to patients with pernicious anemia can lead to subacute combined spinal degeneration.

Vitamin B12
Vitamin B12 is needed to make all red blood cells and is necessary for the synthesis of nerve sheaths, fatty acids, and DNA. Since this vitamin is stored in the liver, nutritional deficiency usually takes years to develop. It is much more common to see metabolic deficiencies. Most commonly an anemia due to B12 deficiency results from an autoimmune disease which destroys the cells in the stomach that make a binding protein (intrinsic factor) necessary for B12 absorption. The individuals most at risk of a dietary vitamin B12 deficiency are vegetarians, since there is no B12 in any plant product. There is also a decreased capability for absorption in the elderly. Vitamin B12 levels need to measured in individuals at risk, since folate administered to an individual with B12 deficiency will result in subacute combined degeneration of the spine and paralysis. The Recommended Dietary Allowance for adults is only 2 to 2.6 micrograms per day.

Vitamin C
Vitamin C is an antioxidant and a vitamin necessary for the synthesis of collagen. In scurvy there is a failure in collagen synthesis leading to the loss of teeth, and poor wound healing. Since vitamin C is found in fruits, scurvy is rare today except in alcoholics who take in no natural sources of vitamin C. It enhances the absorption of iron from the gastrointestinal tract, and has been proposed as an effective means of increasing absorption of iron from supplements in areas of endemic iron deficiency such as Egypt. The body stores of vitamin C approximate 1500 mg. and 3% per day is excreted leading to an calculated requirement of 45 mg for the prevention of scurvy. The current Recommended Dietary Allowance for adults is between 50 and 95 mg/day. However, there are many Americans who take 500 mg. or more of this vitamin. It has been estimated that paleolithic man ate enough fruit to provide about 500 mg. per day, and that the ability to synthesize vitamin C was not essential to ancient man. This amount of vitamin C can be obtained by eating five servings/day of fruits and vegetables or through vitamin supplementation. Vitamin C exists both as ascorbate and in a reduced form as dihydroascorbate. There are ongoing studies of vitamin C as an antioxidant, and it has been implicated in the prevention of gastric cancer through its inhibition of nitrosamine formation.

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