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Transcript
Chapter 6: Vitamins and Minerals Introduction 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, classical vitamin deficiency diseases such as scurvy and rickets are rare outside the setting of specific disease states, drugnutrient interactions, or extreme malnutrition due to poverty in the U.S.. On a global basis, vitamin deficiencies still occur in many large countries such as India and China in both rural and urban populations. What can be classified as suboptimal intake of some vitamins such as vitamin D in areas of low sun exposure is a more recently discovered and important area of vitamin deficiency where supplementation is being recommended by authorities in the field. Surveys, Recommendations and State of the Art Health and Nutrition Examination Surveys (HANES) are periodic surveys of the American population that are conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention. Data are obtained through personal interviews and health examinations, and represent some of the best data sets of their kind in the world. NHANES data are used to estimate the prevalence of selected diseases and health risk factors in the U.S. population including the prevalence of overweight, high blood pressure, and elevated serum lipids. National reference values for nutrition and health parameters including food energy and nutrient intakes from dietary sources, nutritional biochemistry values, and body measurement data are produced from NHANES data. NHANES data are also used to examine secular trends in the prevalences of diseases and health risk factors, and to study the etiology of chronic and infectious diseases in the U.S. population. Three national HANES (termed “NHANES”) were completed between 1971 and 1994: NHANES I (1971-75); NHANES II (1976-80); NHANES III (1988-94). Hispanic HANES, a special survey of three Hispanic subgroups, was conducted from 1982-84 to provide comprehensive health and nutrition data on three major Hispanic subgroups living in the United States: Mexican Americans living in the southwest U.S., Cuban Americans in Dade County, FL, and Puerto Ricans in the New York City metropolitan area. The most recent survey, NHANES III, 1988-94, was conducted in two phases. Each three-year phase, as well as the entire 6 years constituted a national sample. The last such survey was conducted between 1976 and 1980, and the NHANES III ran 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. Recent data on the requirements for Vitamin D and how to assess status are included based on recent findings. Despite the uncommon occurrence of vitamin deficiencies sufficient to cause acute disease in healthy individuals, a familiarity with the roles of the various common vitamins and minerals points to directions of research on suboptimal intakes of vitamins and minerals relevant to the reduction of the risk of common age-related chronjc diseases. The Fat Soluble Vitamins A,D, E, and K 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 fatsoluble 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 A Deficient <0.35 umol/L Marginal 0.35-0.70 Satisfactory 0.70-1.75 Excessive 1.75-3.5 Toxic >3.5 Vitamin D Vitamin D is formed from 7-dehydrocholesterol via the action of sunlight in the skin or is taken in from dietary sources, primarily in dairy products. 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 D formed from 25-hydroxyvitamin D in the kidneys. 25hydroxyvitamin D is a large inactive pool formed and stored in the liver. The kidney also has an inactivation enzyme (24 hydroxylase) which converts 25 (OH) D to inactive 24,25 dihydroxyvitamin D. When 1,25 dihydroxyvitamin D acts at the nucleus it turns on the genes necessary to produce the 24 hydroxylase enzyme. Whenever there is such a branch point in the body, there is additional protection from toxicity and it indicates a substance with important metabolic roles (e.g. thyroid hormones). As people age, the skin becomes less effective in forming vitamin D and people are advised to use sunscreens and avoid sun exposure to prevent skin cancer. Vitamin D3 as a supplement is preferable to D2 (found In plants) since D2 is more rapidly cleared and is less biologically active than D3. Taking doses of 800 IU to 2000 IU per day are clearly not t toxic since it translates into small increases in 25OHD levels. For exampole 800 IU results in an increase of only 8 ng/ml (see below, desirable blood levels of vitamin D) Vitamin D beyond vitamin deficiency, rickets, and osteomalacia Vitamin D is not just a vitamin but a hormone that travels to the nucleus to program the transcription of specific proteins. Research over the last three decades has brought to light many additional functions of vitamin D and redefined what is considered optimal Vitamin D nutrition. It is now estimated that approximately 1 billion people worldwide have blood concentrations of vitamin D that are considered suboptimal. Low vitamin D serum concentrations are linked to several types of cancers, cardiovascular disease, diabetes, upper respiratory tract infections, and all-cause mortality. Several observational studies and a few prospectively randomized controlled trials have demonstrated that adequate levels of vitamin D can decrease the risk and improve survival rates for several types of cancers including breast, rectum, ovary, prostate, stomach, bladder, esophagus, kidney, lung, pancreas, uterus, non-Hodgkin lymphoma, and multiple myeloma. Individuals with serum vitamin D concentrations less than 20 ng/mL are considered most at risk, whereas those who achieve levels of 32 to 100 ng/mL are considered to have sufficient serum vitamin D concentrations. Vitamin D can be obtained from exposure to the sun, through dietary intake, and via supplementation. Obtaining a total of approximately 4000 IU/d of vitamin D3 from all sources has been shown to achieve serum concentrations considered to be in the sufficient range. Most individuals will require a dietary supplement of 2000 IU/d of vitamin D3 to achieve sufficient levels as up to 10 000 IU/d is considered safe. Vitamin D3 is available as an over-thecounter product at most pharmacies and is relatively inexpensive, especially when compared with the demonstrated benefits. Serum 25-Hydroxyvitamin D Concentrations by Category Category Deficiency Insufficiency Sufficiency Excess 25-Hydroxyvitamin D Concentrations, ng/mL (nmol/L) <20 (<50) 20-32 (50-80) 32-100 (80-250) >100 (> 250) Intoxication >150 (>325) An individual's 25-hydroxyvitamin D level is determined by many variables, including the amount of solar ultraviolet B (UVB) radiation (determined by the time of day, season, latitude, skin pigmentation, use of sunscreen, and age), dietary habits, and body fat with obese individuals having lower levels than lean indivduals. UVB radiation penetrates the skin and converts vitamin D precursors to vitamin D3. Vitamin D obtained from the skin and diet is metabolized to 25-hydroxyvitamin D. This determines the measured serum level of vitamin D. 25-hydroxyvitamin D is then further metabolized in the kidneys to its active form, 1,25hydroxyvitamin D. Most tissues and cells in the body possess a vitamin D receptor, and many have the ability to convert 25-hydroxyvitamin D to 1,25-hydroxyvitamin D. This discovery is thought to be the reason such a broad range of diseases and conditions, including cancer, have benefited from vitamin D supplementation. Vitamin E A group of fat-soluble substances, the tocopherols and tocotrienols are referred to as vitamin E. There a four forms of tocopherols and tocotrienols called alpha, beta, gamma and delta making a total of eight forms of vitamin E. There is a specific protein for carrying tocopherols to the liver called alpha tocopherol transfer protein (alpha-TTP) A neurological disease called Friedrich’s Ataxia occurs in individuals with a genetic absence of functioning alpha-TTP indicating that it has some important function in the body that is as yet poorly understood. The tocotrienols have oneseventh the affinity for alpha-TTP as alpha tocopherol. The gamma-tocopherol is carried on triglycerides in the blood to the various tissues in the body. Vitamin E was discovered in 1922 by Herbert Evans and isolated from green leafy vegetables as a fertility factor in rats. Vitamin E was synthesized in 1938 and alpha-D-tocopherol was found to be is biologically active in rodents where a Vitamin E deficiency can cause infertility. This deficiency has never been demonstrated in humans, but an RDA value was set for humans based on the data in rodents. The tocotrienols were isolated in 1964 at the University of Wisconsin from wheat germ oil, but are also found in palm oil, rice bran oil, barley oil, and oat bran. The refined forms of rice and oats do not contain tocotrienols. Gamma tocotrienol has been found to be the most protective against radiation, and both gamma and delta tocotrienols inhibit the rate limiting enzyme in cholesterol synthesis. Alpha tocotrienol is present in the blood at concentrations ten times less than alpha tocopherol and so has been ignored by researchers until recent work demonstrating that in animal models alpha-tocotrienol can reduce the amount of brain tissue destroyed after blocking a blood vessel to recreate the damage that would occur with a stroke. Alpha-tocotrienol prevents nerve cell death in test tube experiments and gets into the brain independent of alpha-TTP. Recently a tocotrienol-rich fraction of palm oil obtained GRAS (Generally Recognized as Safe Status) from the US Food and Drug Administration. Toctotrienol supplements are sold commercially as extracts of palm oil. The emerging science on tocotrienols is growing rapidly. 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. A recent analysis of multiple studies found that above 330 IU per day there was a 5 percent increase in overall mortality from cardiovascular disease. These results remain highly controversial. One of the effects of taking alpha tocoperol is to reduce the amounts of gamma tocopherol in the blood. In the laboratory gamma tocopherol is a more potent antioxidant than alpha-tocopherol. 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 oxygeninduced 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. Vitamin K Vitamin K is a fat-soluble vitamin. The "K" is derived from the German word "koagulation". Coagulation refers to blood clotting, because vitamin K is essential for the functioning of several proteins involved in blood clotting. A deficiency of this vitamin in newborn babies results in hemorrhagic disease, as well as postoperative bleeding and hematuria while muscle hematomas and inter-cranial hemorrhages have been reported. A shortage of this vitamin may manifest itself in nosebleeds or internal hemorrhaging. Individuals taking coumadin® (warfarin) must regulate their vitamin K intake since taking in large amounts of vitamin K from foods or supplements will affect the ability of this blood thinning drug to work. The small amounts of vitamin K found in some multivitamins are not a problem (around 100 micrograms) and may even smooth out variations in blood clotting due to minor changes in dietary vitamin K consumption. Patients taking blood thinners are given a list of foods to avoid which are rich in vitamin K and include spinach, green leafy vegetables, cabbage, potatoes, cereals, and liver. Half of vitamin K comes from the diet, and the other half is synthesized from precursors by intestinal bacteria .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. There are two naturally occurring forms of vitamin K. Plants synthesize phylloquinone, also known as vitamin K1. Bacteria synthesize a range of vitamin K forms, using repeating 5carbon units in the side chain of the molecule. These forms of vitamin K are designated menaquinone-n (MK-n), where n stands for the number of 5-carbon units. MK-n are collectively referred to as vitamin K2. MK-4 is not produced in significant amounts by bacteria, but appears to be synthesized by animals (including humans) from phylloquinone. MK-4 is found in a number of organs other than the liver at higher concentrations than phylloquinone. This fact, along with the existence of a unique pathway for its synthesis, suggests there is some unique function of MK-4 that is yet to be discovered. Vitamin K deficiency has been shown to be a risk factor for hip fracture in the elderly and vitamin K2 supplementation increases serum levels of osteocalcin ( a bone forming hormone) and has a modest effect on bone mineral density. The Water Soluble Vitamins Unlike fat-soluble vitamins which can be stored after a single administration for long periods of time, water soluble vitamins need to be supplied in foods and supplements on a regular basis to avoid deficiency. Industrialized societies have few cases of water-soluble vitamin deficiency except in homeless or alcoholic individuals. The recent increase in obesity surgeries which lead to malabsorption of vitamin B12 by bypassing the stomach have led to a new group of individuals at risk of vitamin deficiencies. Strict vegans, individuals with food intolerances, and raw food enthusiasts can also develop vitamin deficiencies if their choices of foods are narrowed significantly. 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. Minerals Macro-Minerals The macro-minerals are inorganic substances derived from soil and water and incorporated into our diet in significant amounts. Those that are required in large amounts in the diet are called macro-minerals and include calcium, magnesium, and phosphorus. Calcium Calcium is vital component of a healthy diet The blood levels of calcium are carefully regulated by a number of hormones since elevated levels of calcium in the blood could lead to kidney malfunction and decreased absorption of other minerals. On the other hand, loss of body calcium can lead to decreased bone health and dental health as calcium together with phosphate as the mineral hydroxyapatite is the mineral supporting the function of bones and teeth. Therefore, calcium is essential for the normal growth and maintenance of bones and teeth, and calcium requirements must be met throughout life. Vitamin D is also needed to absorb calcium. Supplementation of calcium with vitamin D is recommended at a level of 1500 milligrams per day from food and supplements for postmenopausal women and at a level of 1000 milligrams per day for women before menopause and for men. Vitamin D supplementation has been increasing in recent years as the functions of vitamin D beyond bone health have been discovered. Dairy products, especially in the U.S. and Europe are the primary dietary source of calcium often in forms fortified with vitamins A and D. This fortification which became common in the 1950’s accounts for the decrease in bone diseases observed in the U.S. and Europe by comparison to the early part of the twentieth century. There are many good sources of calcium beyond dairy products. These include seaweeds such as kelp, wakame and hijiki; nuts and seeds (like almonds and sesame); blackstrap molasses; beans; oranges; amaranth; collard greens; okra; rutabaga; broccoli; dandelion leaves; kale; sardines; and fortified products such as orange juice and soy milk. Individuals throughout the world are allergic to dairy products and even more people, particularly those of non Indo-European descent, are lactose-intolerant, leaving them unable to consume dairy products. Moreover, strict vegans avoid dairy products for ethical and health reasons. Magnesium Magnesium ions are essential to the basic DNA chemistry of life, and thus are essential to all cells of all known living organisms. Many enzymes require the presence of magnesium ions for their catalytic action, especially enzymes utilizing ATP, or those which use other nucleotides to synthesize DNA and RNA. Magnesium is a vital component of a healthy human diet and deficiency has been implicated in a number of human diseases. Magnesium is readily available in many common foods but studies indicate that many Americans are magnesium deficient. Supplemental magnesium is readily available and it is also difficult to overdose on magnesium. General failure of the kidneys may also lead to magnesium imbalance. Magnesium deficiency in humans was first described in the medical literature in 1934. The adult human daily nutritional requirement, which is affected by various factors including gender, weight and size, is 300-400 mg/day. Inadequate magnesium intake frequently causes muscle spasms, and has been associated with cardiovascular disease, diabetes, high blood pressure, anxiety disorders, migraines and osteoporosis. Acute deficiency (called hypomagnesemia) is rare, and is more common as a drug side effect (such as chronic alcohol or diuretic use) than from low food intake per se, but it can also occur within people are fed intravenously for extended periods of time. The incidence of chronic deficiency resulting in less than optimal health is debated. The DRI upper tolerated limit for supplemental magnesium is 350 mg/day calculated as mg of Mg elemental in the salt. The best dietary source is Brazil nuts which have 150 mg in one ounce followed by pumpkin seeds, fortified bran cereals, halibut, spinach, almonds, soy nuts, and other seeds and nuts. Magnesium is widely distributed in plant foods so that vegetarian-like diets are rarely deficient in Magnesium. Dietary deficiencies are only seen in extreme situations as with homeless people on restricted diets or alcoholics. Supplements based on Amino Acid Chelates, Glycinate, Lysinate etc. are much better tolerated by the digestive system and do not have the side effects of the older compounds used. The most common symptom of excess oral magnesium intake is diarrhea. Since the kidneys of adult humans excrete excess magnesium efficiently, oral magnesium poisoning in adults with normal renal function is very rare. Infants, which have less ability to excrete excess magnesium even when healthy, should not be given magnesium supplements, except under a physician's care. Phosphorus Phosphorus is an essential mineral that is found inside cells where it plays a key role in maintaining the energy needed by cells. It is linked to adenosine by a high energy bond so that as the number of phosphates linked to adenosine is reduced from three to two (i.e. ATP going to ADP or adenosine triphosphate to adenosine diphosphate) chemical energy is released in the cell that can be used to drive the production of proteins, carbohydrates, and lipids to be used in the structure of the cell or as intermediates in various chemical reactions essential to cell function. Similarly, when ADP goes to ATP, energy has been stored for future use. In the cell the ratio of ATP to ADP is a marker of the energy status of the cell and these compounds recycle back and forth at a very high rate. Phosphorus is also utilized when glucose or fructose sugars enter cells. The first step in their chemical processing for energy is the addition of a phosphate to either glucose or fructose which then leads to other modifications. In all, there are over 5000 different proteins in the cell involved in phosphate chemistry. Despite the important intracellular roles of phosphates, on a weight basis, 85% of the body's phosphorus is found in bone as calcium phosphate or hydroxyapatite. Phospholipids (e.g., phosphatidylcholine) are major structural components of cell membranes. All energy production and storage are dependent on phosphorylated compounds, such as adenosine triphosphate (ATP) and creatine phosphate. Nucleic acids (DNA and RNA), which are responsible for the storage and transmission of genetic information, are long chains of phosphate-containing molecules. Phosphorus is absorbed in the small intestine, and excess phosphorus is excreted by the kidneys. The blood levels of phosphorus are regulated together with blood calcium by parathyroid hormone (PTH) and vitamin D. PTH causes decreased urinary excretion of calcium and increased urinary excretion of phosphorus. In turn high levels of phosphate in the blood suppress conversion of vitamin D to its active form in the kidneys serving as a control on calcium absorption. Increased intakes of phosphates in the diet result from the phosphoric acid in soft drinks and phosphate additives in a number of commercially prepared foods such as instant puddings. As long as calcium intake is adequate, increased phosphate intake does decrease bone density. However, reducing the intake of milk and other calcium rich foods often coincides with an increased in soft drink consumption and this decrease in calcium intake without supplementation can lead to decreases in bone density and bone health. All cells in plant and animal food sources containg phosphorus, so that dietary phosphorus deficiency is only seen in cases of near-total starvation as can occur in patients with eating disorders such as anorexia nervosa. Refeeding patients in prison camps has led to phosphorus deficiency as glucose going into cells rapidly depletes body phosphorus in already deficient individuals further. There are specific methods for providing minerals and vitamins together with gradual refeeding in starved patients to avoid this condition. Trace Minerals There are also a number of trace minerals which serve critical roles in body metabolism but are required in much smaller amounts. These trace minerals and their roles include: Iron: Iron is needed for red cell formation and is also a pro-oxidant used in catalase and other peroxidase-type enzymes. The use of oral iron cannot lead to overload but parenteral iron can be toxic. Iron is commonly deficient in menstruating females, and should be replaced when anemia is identified, or as a preventive in individuals with low range hematocrits. The Recommended Dietary Allowance for iron is between 10 and 15 mg per day. Selenium: This is a structural component of enzymes including glutathione peroxidase and type I iodothyronine monodeiodinase. The Recommended Dietary Allowance is between 40 and 70 micrograms per day in adults. Zinc: Zinc is an essential component of many different enzymes and is necessary for a variety of metabolic processes. Zinc deficiency was first observed in adolescent boys in Egypt who were eating unleavened whole grain bread containing phytate which bound to zinc in the intestinal tract preventing its absorption. The boys demonstrated growth retardation and delayed puberty. Zinc supplements have been marketed as a cure for impotence without any substantiation of that claim. The daily requirements are comparable to those for iron and range between 12 and 15 mg per day in adults. The major sites of potential losses are in semen and from the gastrointestinal tract with severe diarrhea or fistula. Zinc should not be administered in the absence of any copper and should not be consumed as a separate supplement except in individuals with a demonstrated zinc deficiency. Copper: The elevation of serum copper seen in Wilson's Disease is due to a deficiency of ceruloplasmin, the copper-binding protein. This leads to a syndrome of hepatolenticular degeneration. As mentioned above a copper deficiency can be induced with megadoses of zinc. There is no Recommended Dietary Allowance for copper but an Estimated Safe and Adequate Dietary Daily Intake of 3 mg per day in adults was issued by the National Research Council of the National Academy of Sciences in 1980. Iodine: The only major role of iodine is to serve as an essential part of the basic structure of thyroid hormones. Iodine deficiency in areas away from sea water (e.g. highlands around Mexico City, inland areas of Southeast Asia) can lead to goiter formation. Since the late 1950's iodine has been used as a bleaching agent for white flour and iodine deficiency in this country is rare. It is not unusual for individuals immigrating to the U.S. to develop thyroid disease due to the increase in dietary iodine compared to their country of origin. Iodine supplementation in areas that are normally iodine deficient has led to an increase in various types of thyroid diseases including Grave's Disease, Hashimoto's Thyroiditis, and thyroid nodules. It is possible for susceptible individuals to develop thyroid nodules after taking kelp tablets which are rich in iodine. Chromium : Chromium is also called glucose tolerance factor, but its effectiveness in enhancing glucose tolerance is unproven. A recent study demonstrated enhanced lifespan in small number of rats given chromium picolinate. The increased interest in this trace mineral based on this small study is probably not justified. A natural source of chromium is brewer's yeast. There is no evidence that it enhances muscle building or fat loss in humans. There is no Recommended Dietary Allowance for humans. Many other trace minerals including arsenic, cobalt, manganese, molybdenum, nickel, silicon, tin, and vanadium have a variety of metabolic functions. Some of these are not yet well understood. The combination of taking a multimineral/multivitamin containing these trace minerals and eating fruits and vegetables will likely provide adequate amounts of these trace elements. Taking individual supplements of arsenic is not recommended since this is a poison at higher doses and required as an essential trace element in very low amounts. Nutritional Adequacy Despite the epidemic of overnutrition in the United States today, there are still some groups at risk for nutritional deficiencies. These groups include: 1) pregnant women 2) the elderly, 3) individuals who smoke, drink excess amounts of alcohol, or abuse drugs. The laboratory assessment of possible deficiencies in these groups is summarized in Table 2. Nutritional Optimization - Future Directions While classical vitamin deficiency diseases are rare today in the U.S. except in certain high risk groups (e.g. alcoholics, pregnant teenagers, institutionalized elderly), there are a variety of individuals whose dietary intake is inadequate to maintain optimal health. For instance, it is recommended that Americans eat 25 grams of fiber per day, but the average intake is only about 10 grams. In California, only about one in five people consumes five servings a day of fruits and vegetables as recommended by the US Department of Agriculture. As a result there are a number of micronutrient vitamins and minerals which are deficient but not at levels that would cause disease. Examples include: carotenoids, vitamin E, vitamin C, folate, and selenium. While it is established what nutrient levels constitute deficiency, there is little information on what is suboptimal or what types of responses can be expected following nutritional intervention. It is also unclear why there are individual variations in the absorption of a beta-carotene oral load, the effects of dietary fiber eaten at the same time, or the effects of various fats in the diet on absorption. TABLE ONE Recommended Dietary Allowances, Revised 1989 National Academy of Sciences Food and Nutrition Board for Fat-Soluble Vitamins Group Vit A Vit D Vit E Vit K (mcg RE) (mcg) (mg) (mcg) Infants 0-6m 375 7.5 3 5 6mo-1yr 375 10 4 10 Children 1-3 400 10 6 15 4-6 500 10 7 20 7-10 700 10 7 30 Males 11-14 1000 10 10 45 15-18 1000 10 10 65 19-24 1000 10 10 70 25-50 1000 5 10 80 51 + 1000 5 10 80 11-14 800 10 8 45 15-18 800 10 8 55 19-24 800 10 8 60 25-50 800 5 8 65 51 + 800 5 8 65 800 10 10 65 1st 6mo 1,300 10 12 65 2nd 6mo 1,200 10 11 65 Females Pregnant Lactating TABLE ONE (CONT'D.) Recommended Dietary Allowances, Revised 1989 for Water Soluble Vitamins Group Vit C (mg) Thiamine (mg) Riboflavin (mg) Niacin (mg) B6 (mg) Folate (mcg) B12 (mcg) Infants 0-6m 6mo-1yr 30 35 0.3 0.4 0.4 0.5 5 6 0.3 0.6 25 35 0.3 0.5 Children 1-3 4-6 7-10 40 45 45 0.7 0.9 1.0 0.8 1.1 1.2 9 12 13 1.0 1.1 1.4 50 75 100 0.7 1.0 1.4 Males 11-14 15-18 19-24 25-50 51 + 50 60 60 60 60 1.3 1.5 1.5 1.5 1.2 1.5 1.8 1.7 1.7 1.4 17 20 19 19 15 1.7 2.0 2.0 2.0 2.0 150 200 200 200 200 2.0 2.0 2.0 2.0 2.0 Females 11-14 15-18 19-24 25-50 51 + 50 60 60 60 60 1.1 1.1 1.1 1.1 1.0 1.3 1.3 1.3 1.3 1.2 15 15 15 15 13 1.4 1.5 1.6 1.6 1.6 150 180 180 180 180 2.0 2.0 2.0 2.0 2.0 70 1.5 1.6 17 2.2 400 2.2 95 90 1.6 1.6 1.8 1.7 20 20 2.1 2.1 280 260 2.6 2.6 Pregnant Lactating 1st 6mo 2nd 6mo 17 TABLE ONE (CONT'D.) Recommended Dietary Allowances, Revised 1989 for Minerals Group Calcium (mg) Phosph (mg) Magnesium (mg) Iron (mg) Zinc (mg) Iodine Selenium (mcg) (mcg) Infants 0-6m 6mo-1yr 400 600 300 500 40 60 6 10 5 5 40 50 10 15 Children 1-3 4-6 7-10 800 800 800 800 800 800 80 120 170 10 10 10 10 10 10 70 90 120 20 20 30 Males 11-14 15-18 19-24 25-50 51 + 1200 1200 1200 800 800 1200 1200 1200 800 800 270 400 350 350 350 12 12 10 10 10 15 15 15 15 15 150 150 150 150 150 40 50 70 70 70 Females 11-14 15-18 19-24 25-50 51 + 1200 1200 1200 800 800 1200 1200 1200 800 800 280 300 280 280 280 15 15 15 15 15 12 12 12 12 12 150 150 150 150 150 45 50 55 55 55 1200 1200 320 30 15 175 65 1200 1200 1200 1200 355 340 15 15 19 16 200 200 75 75 Pregnant Lactating 1st 6 mo 2nd 6mo 18 TABLE TWO LABORATORY ASSESSMENT OF VITAMIN-MINERAL NUTRITURE Nutrient Population at Risk Pregnant Women Elderly Smokers/Alcohol Abusers Vitamins folate thiamin vitamin B6 vitamin B12 vitamin A vitamin C vitamin E Carotenoids Panel x x x x x x x x x x x x x x x x x x x x x x x x x x Minerals iron calcium zinc Other transferrin albumin prealbumin 19 REFERENCES 1. 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