Vitamins, Trace Minerals, and Other Micronutrients

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS JOEL B. MASON

e47

The biochemical functions of trace elements appear to be as components of prosthetic groups or as cofactors for enzymes. Determination of essential trace element status is problematic with the exception of iron. The low concentrations of these elements in bodily fluids and tissues, the finding that blood levels frequently do not correlate well with levels in the target tissues, and the fact that functional tests cannot be devised until their biochemical functions are better understood preclude an accurate laboratory method of assessing the adequacy of most trace elements.

Additional Compounds with Nutritional Relevance MICRONUTRIENTS IN NUTRITIONAL SCIENCE Dietary Requirements

Micronutrients are a diverse array of dietary components necessary to sustain health. The physiologic roles of micronutrients are as varied as their composition; some micronutrients are used in enzymes as either coenzymes or prosthetic groups, others as biochemical substrates or hormones; in some instances, the functions are not well defined. Under normal circumstances, the average daily dietary intake for each micronutrient that is required to sustain normal physiologic functions is measured in milligrams or smaller quantities. In this manner, micronutrients are distinguished from macronutrients, which encompass carbohydrates, fats, and proteins, as well as the macrominerals calcium, magnesium, and phosphorus.

Optimal Intake

For orderly homeostasis to proceed, most dietary nutrients must be ingested in quantities that are neither too small nor too great. Disorders may arise, therefore, when intake regularly falls outside of this physiologic window. The size of this physiologic window varies for each micronutrient and should be kept in mind, particularly in this era when the administration of large quantities of certain micronutrients is increasingly explored for possible therapeutic implications. The dietary requirement for a particular micronutrient is determined by many factors, only one of which is the amount needed to sustain those physiologic functions for which it is used (Table 225-1). The U.S. Institute of Medicine Food and Nutrition Board regularly updates dietary guidelines that define the quantity of each micronutrient that is “adequate to meet the known nutrient needs of practically all healthy persons.” These recommended dietary allowances (RDAs) were most recently revised between 1998 and 2001, and the values for adults appear in Tables 225-2 and 225-3. Also established for the first time for each micronutrient were tolerable upper limits (TULs), which are the “maximal daily levels of oral intake likely to pose no adverse health risks” (see Tables 225-2 and 237-3). Adequate intake, the amount necessary to prevent a deficiency state, is not necessarily synonymous with optimal intake.

TYPES AND FUNCTION OF MICRONUTRIENTS Vitamins

Vitamins are categorized as either fat soluble (A, D, E, K) or water soluble (all the others), as shown in Table 225-2. This categorization remains physiologically meaningful. None of the fat-soluble vitamins appear to serve as coenzymes. Intestinal absorption of the fat-soluble vitamins is primarily through a micellar phase, and pathophysiologic conditions associated with fat malabsorption frequently are associated with selective deficiencies of the fat-soluble vitamins. Most of the functions of the water-soluble vitamins are as coenzymes, and they are not absorbed through the lipophilic phase in the intestine.

Trace Elements

Fifteen trace elements have been identified as essential for health: iron, zinc, copper, chromium, selenium, iodine, fluorine, manganese, molybdenum, cobalt, nickel, tin, silicon, vanadium, and arsenic (see Table 225-3), but only for the first 10 of these has compelling evidence indicated that they are essential nutrients in humans. Cobalt appears to be essential solely as a component of vitamin B12, but an isolated deficiency state has never been described. Deficiency syndromes for several of the essential trace elements were not recognized until recently because of their exceedingly small requirements and because of the ubiquitous nature of these elements in foodstuffs. Only under exceptional circumstances, such as long-term reliance on total parenteral nutrition lacking these elements, have some of the deficiency syndromes been observed.

Evidence indicates that humans also have an absolute requirement for the dietary component choline, which is a necessary precursor for acetylcholine and phospholipids and is needed to sustain normal levels of biologic methylation. To date, the most significant adverse effect of dietary inadequacy has been hepatic inflammation. Deficiency is nevertheless thought to be extremely rare, although pregnancy, and particularly lactation, increases the apparent requirement. Individuals whose long-term nutritional requirements are solely derived from total parenteral nutrition appear to be susceptible to choline deficiency. Both an RDA (425 mg, women; 550 mg, men) and a TUL (3.5 g) have now been established. l-Carnitine is a dietary component that participates in fatty acid metabolism in mitochondria. Although no evidence exists for a dietary requirement in children or adults, premature infants have very low stores of skeletal muscle carnitine. Therefore, preterm infants receiving parenteral nutrition without carnitine supplements appear to be the group at high risk for deficiency. Parenteral supplementation of carnitine in such infants may increase serum carnitine concentration and improve lipid tolerance, weight gain, and nitrogen retention.

CONDITIONS THAT INCREASE REQUIRED DIETARY INTAKE

Many physiologic, pathophysiologic, and pharmacologic factors increase the dietary requirements for micronutrients (see Table 225-1), thereby enhancing the risk of developing a deficiency state.

Physiologic Factors

Stages of the life cycle frequently have a significant impact on the requirements of nutrients. Phases of rapid growth and development, such as in utero development, infancy, adolescence, and pregnancy, are associated with increases in the utilization of certain micronutrients on a per-kilogram basis.

Pregnancy

Requirements for most micronutrients are increased in pregnancy, but, proportionately, the observed increases in the maternal requirements for iron and folate are particularly great and are related to the rapid proliferation of the placental and fetal tissues. Periods of lactation are similarly associated with remarkable increases in requirements; a lactating woman experiences disproportionately large increases in her requirements for zinc and vitamins A, E, and C to meet the metabolic demands incurred by milk production in addition to the aforementioned needs observed in pregnancy. Aside from its general role in supporting the rapid proliferation of placental and fetal tissues, folate plays a specific role in the prevention of particular birth defects. A 20 to 85% reduction in births complicated by neural tube defects (NTDs, i.e., spina bifida and anencephaly) has been realized by providing women with a daily supplement of folic acid in the form of supplements or fortified foods. The optimal dose is not well defined, but 200 to 400 µg/day clearly affords a substantial degree of protection. Populations with a high background rate of NTD births attain the largest reductions in NTDs from supplemental folate. However, because the nascent neural tube closes about day 20 after conception, the additional folate must be provided before this time in order to be effective.

Infancy

Infancy carries particular vulnerabilities to specific micronutrient inadequacies. Healthy infants in the United States are typically supplemented with vitamin K at birth and with iron and vitamin D during the course of the first year because of their particular susceptibility to deficiencies of these nutrients.

Women of Childbearing Age

The ability to maintain adequate iron status from menarche through menopause is compromised in women by the additional losses incurred by

e48

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

menstruation, pregnancy, and lactation. Therefore, it is not surprising that the population subset that almost invariably displays the highest rate of iron deficiency is women of childbearing age.

TABLE 225-1 FACTORS THAT DETERMINE DIETARY REQUIREMENT OF A MICRONUTRIENT PHYSIOLOGIC FACTORS Bioavailability: the proportion of a micronutrient that is ingested and is capable of being assimilated and used for physiologic purposes Quantity required to fulfill physiologic roles Extent to which the body can reuse the micronutrient Distribution of nutrient in the body: storage compartments Gender Stage of life cycle: intrauterine development, childhood, adulthood, elder adulthood, pregnancy, lactation PATHOPHYSIOLOGIC AND PHARMACOLOGIC FACTORS Inborn errors of metabolism: variously affect assimilation, utilization, or excretion of micronutrients Acquired disease states that alter the amounts required to sustain homeostasis (e.g., malabsorption, maldigestion, states that increase use) Lifestyle habits: smoking, ethanol consumption Drugs: may alter bioavailability and/or utilization

Elderly Persons

Specific dietary recommendations for elderly people have been formally incorporated into the RDAs because aging has an impact on the need for certain micronutrients. Vitamin B12 status declines significantly with aging, in large part because of the high prevalence of atrophic gastritis and its associated impairment in protein-bound vitamin B12 absorption. Estimates suggest that 10 to 20% of the elderly population is at risk for clinically significant vitamin B12 deficiency. Consequently, elderly persons should consume some of their vitamin B12 requirement in the crystalline form rather than solely from the naturally occurring protein-bound forms found in food because absorption of the former is not impaired by atrophic gastritis. Elderly people also require greater quantities of vitamins B6 and D to maintain health compared with younger adults, as reflected in the new RDAs (see Table 225-3). For instance, the RDA of vitamin D in persons over the age of 70 is now set at 20 µg/day (800 international units), as opposed to adults who are 70 or

TABLE 225-2 VITAMINS AND THEIR FUNCTIONS BIOCHEMISTRY AND PHYSIOLOGY

DEFICIENCY [RDA*]

TOXICITY [TUL†]

ASSESSMENT OF STATUS

FAT-SOLUBLE VITAMINS Vitamin A

Retinol concentration in the A family of the retinoid compounds, each Follicular hyperkeratosis and night In adults, >150,000 µg may plasma and vitamin A member having biologic activity blindness are early indicators. cause acute toxicity: fatal concentrations in the milk qualitatively similar to retinol. Conjunctival xerosis, degeneration of intracranial hypertension, and tears are reasonably Carotenoids are structurally related to the cornea (keratomalacia), and skin exfoliation, and accurate measures of retinoids. Some carotenoids, most de-differentiation of rapidly hepatocellular necrosis. adequate status. Toxicity is notably β-carotene, are metabolized proliferating epithelia are later Chronic toxicity may occur best assessed by elevated into compounds with vitamin A indications of deficiency. Bitot spots with habitual daily intake of levels of retinyl esters in activity and are therefore considered to (focal areas of the conjunctiva or >10,000 µg: alopecia, ataxia, plasma. A quantitative be provitamin A compounds. Vitamin cornea with foamy appearance) are an bone and muscle pain, measure of dark adaptation A is an integral component of indication of xerosis. Blindness, due to dermatitis, cheilitis, for night vision or an rhodopsin and iodopsins, lightcorneal destruction and retinal conjunctivitis, pseudotumor electroretinogram are useful sensitive proteins in rod and cone cells dysfunction, ensues if left uncorrected. cerebri, hepatocellular functional tests. in the retina. Additional functions: Increased susceptibility to infection is necrosis, hyperlipidemia, and also a consequence. [F: 700 µg; M: induction and maintenance of cellular hyperostosis are common. 900 µg] differentiation in certain tissues; signal Single, large doses of vitamin for appropriate morphogenesis in the A (30,000 µg), or habitual developing embryo; maintenance of intake of >4500 µg/day in cell-mediated immunity. One early pregnancy can be microgram of retinol = 3.33 IU of teratogenic. Excessive intake vitamin A. of carotenoids causes a benign condition characterized by yellowish discoloration of the skin. Habitually large doses of canthaxanthin, a carotenoid, have the additional capability of inducing a retinopathy. [3000 µg]

Vitamin D

Deficiency results in disordered bone Excess amounts result in A group of sterol compounds whose modeling called rickets in childhood abnormally high parent structure is cholecalciferol and osteomalacia in adults. Expansion concentrations of calcium (vitamin D3). Cholecalciferol is formed in the skin from of the epiphyseal growth plates and and phosphate in the serum: 7-dehydrocholesterol (provitamin D3) replacement of normal bone with metastatic calcifications, by exposure to UVB radiation. A plant unmineralized bone matrix are the renal damage, and altered sterol, ergocalciferol (provitamin D2) cardinal features of rickets; the latter mentation may occur. [50 µg] can be similarly converted into vitamin feature also characterizes osteomalacia. D2 and has similar vitamin D activity. Deformity of bone and pathologic The vitamin undergoes sequential fractures occur. Decreased serum hydroxylations in the liver and kidney concentrations of calcium and phosphate may occur. [15 µg, ages at the 25 and 1 positions, respectively, 19-70 yr; 20 µg, age >70 yr] producing the most bioactive form of the vitamin, 1,25-dihydroxy vitamin D. Maintains intracellular and extracellular concentrations of calcium and phosphate by enhancing intestinal absorption of the two ions and, in conjunction with PTH, promoting their mobilization from bone mineral. Retards proliferation and promotes differentiation in certain epithelia. One microgram is = 40 IU.

The serum concentration of the major circulating metabolite, 25-hydroxyvitamin D, is an excellent indicator of systemic status except in chronic renal failure, in which the impairment of renal L-hydroxylation results in disassociation of the mono- and dihydroxyvitamin concentrations. Measuring the serum concentration of 1,25-dihydroxyvitamin D is then necessary.

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

e49

TABLE 225-2 VITAMINS AND THEIR FUNCTIONS—cont’d Vitamin E

Vitamin K

BIOCHEMISTRY AND PHYSIOLOGY DEFICIENCY [RDA*] A group of at least 8 naturally occurring Deficiency due to dietary inadequacy compounds, some of which are rare. Usually seen in (1) premature tocopherols and some of which are infants, (2) individuals with fat tocotrienols. At present, the only malabsorption, and (3) individuals dietary form that is thought to be with abetalipoproteinemia. Red blood biologically active in humans is cell fragility occurs and can produce a α-tocopherol. Acts as an antioxidant hemolytic anemia. Neuronal and free radical scavenger in lipophilic degeneration produces peripheral environments, most notably in cell neuropathies, ophthalmoplegia, and membranes. Acts in conjunction with destruction of posterior columns of other antioxidants such as selenium. spinal cord. Neurologic disease is frequently irreversible if deficiency is not corrected early enough. May contribute to the hemolytic anemia and retrolental fibroplasia seen in premature infants. Reported to suppress cell-mediated immunity. [15 mg]

TOXICITY [TUL†] ASSESSMENT OF STATUS Depressed levels of vitamin Plasma or serum concentration K-dependent procoagulants of α-tocopherol is most and potentiation of oral commonly used. Additional anticoagulants has been accuracy is obtained by reported, as has impaired expressing this value per mg WBC function. Doses of of total plasma lipid. RBC 800 mg/day have been peroxide hemolysis test is reported to increase slightly not entirely specific but is a the incidence of hemorrhagic useful functional measure of stroke. [1000 mg] the antioxidant potential of cell membranes.

Prothrombin time is typically A family of naphthoquinone compounds Deficiency syndrome, uncommon except Rapid intravenous infusion of K1 has been associated with in (1) breast-fed newborns, in whom it used as a measure of with similar biologic activity. dyspnea, flushing, and may cause “hemorrhagic disease of the functional K status; it is Phylloquinone (vitamin K1) is derived from plants; a variety of menaquinones cardiovascular collapse; this newborn,” (2) adults with fat neither sensitive nor specific (vitamin K2) is derived from bacterial is likely related to the malabsorption or who are taking drugs for vitamin K deficiency. sources. Serves as an essential cofactor dispersing agents in the that interfere with vitamin K Determination of in the post-translational solution. Supplementation metabolism (e.g., coumarin, phenytoin, undercarboxylated γ-carboxylation of glutamic acid may interfere with broad-spectrum antibiotics), and (3) prothrombin in the plasma is residues in many proteins. These coumarin-based individuals taking large doses of more accurate but less widely proteins include several circulating anticoagulation. Pregnant vitamin E and anticoagulant drugs. available. procoagulants and anticoagulants as women taking large amounts Excessive hemorrhage is the usual manifestation. [F: 90 µg; M: 120 µg] well as proteins in a variety of tissues. of the provitamin menadione may deliver infants with hemolytic anemia, hyperbilirubinemia, and kernicterus. [no TUL established]

WATER-SOLUBLE VITAMINS Thiamin (vitamin B1)

A water-soluble compound containing Classic deficiency syndrome (“beriberi”) Excess intake is largely excreted The most effective measure of substituted pyrimidine and thiazole in the urine, although B1 status is the erythrocyte described in Asian populations rings and a hydroxyethyl side chain. transketolase activity parenteral doses of >400 mg/ consuming polished rice diet. day are reported to cause The coenzyme form is thiamin coefficient, which measures Alcoholism and chronic renal dialysis lethargy, ataxia, and reduced pyrophosphate (TPP). Serves as a enzyme activity before and are also common precipitants. High tone of the gastrointestinal coenzyme in many α-ketoacid after addition of exogenous carbohydrate intake increases need for tract. [TUL not established] decarboxylation and transketolation TPP: RBCs from a deficient B1. Mild deficiency: irritability, fatigue, and headaches. More severe deficiency: reactions. Inadequate thiamin individual express a combinations of peripheral availability leads to impairments of substantial increase in neuropathy, cardiovascular above reactions, resulting in enzyme activity with dysfunction, and cerebral dysfunction. inadequate adenosine triphosphate addition of TPP. Thiamin Cardiovascular involvement (“wet synthesis and abnormal carbohydrate concentrations in blood or beriberi”): congestive heart failure and metabolism, respectively. May have an urine are also used. low peripheral vascular resistance. additional role in neuronal conduction Cerebral disease: nystagmus, independent of aforementioned ophthalmoplegia, and ataxia actions. (Wernicke’s encephalopathy); hallucinations, impaired short-term memory, and confabulation (“Korsakoff ’s psychosis”). Deficiency syndrome responds within 24 hr to parenteral thiamin but is partially or wholly irreversible after a certain stage. [F: 1.1 mg; M: 1.2 mg]

Riboflavin (vitamin B2)

Consists of a substituted isoalloxazine ring with a ribitol side chain. Serves as a coenzyme for a diverse array of biochemical reactions. The primary coenzymatic forms are flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Riboflavin holoenzymes participate in oxidation-reduction reactions in a myriad of metabolic pathways.

Deficiency is usually seen in conjunction Toxicity not reported in with deficiencies of other B vitamins. humans. [TUL not Isolated deficiency of riboflavin established] produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and a normochromic, normocytic anemia. [F: 1.1; M: 1.3]

The most common method of assessment is determining the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose-6phosphate dehydrogenase [G6PD] deficiency). Measurements of blood and urine concentrations are less desirable methods.

e50

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

TABLE 225-2 VITAMINS AND THEIR FUNCTIONS—cont’d BIOCHEMISTRY AND PHYSIOLOGY DEFICIENCY [RDA*] TOXICITY [TUL†] Refers to nicotinic acid and the Pellagra is the classic deficiency syndrome Human toxicity known largely corresponding amide, nicotinamide. through studies examining and is often seen in populations in The active coenzymatic forms are hypolipidemic effects. which corn is the major source of composed of nicotinamide affixed Includes vasomotor energy. Still endemic in parts of China, to adenine dinucleotide, forming NAD phenomenon (flushing), Africa, and India. Diarrhea, dementia or NADP. More than 200 apoenzymes hyperglycemia, parenchymal (or associated symptoms of anxiety or use these compounds as electron liver damage, and insomnia), and a pigmented dermatitis hyperuricemia. [35 mg] acceptors or hydrogen donors, either that develops in sun-exposed areas are as a coenzyme or as a co-substrate. The typical features. Glossitis, stomatitis, essential amino acid tryptophan is a vaginitis, vertigo, and burning precursor of niacin; 60 mg of dietary dysesthesias are early signs. Reported tryptophan yields approximately 1 mg to occasionally occur in carcinoid of niacin. Dietary requirements thus syndrome because tryptophan is depend partly on tryptophan intake. diverted to other synthetic pathways. [F: 14 mg; M: 16 mg] Requirement is often determined on basis of caloric intake (i.e., niacin equivalents/1000 kcal). Large doses of nicotinic acid (1.5-3 g/day) effectively lower low-density lipoprotein cholesterol and elevate high-density lipoprotein cholesterol.

ASSESSMENT OF STATUS Assessment of status is problematic: blood levels of vitamin not reliable. Measurement of urinary excretion of the niacin metabolites, N-methylnicotinamide and 2-pyridone, is thought to be the most effective means of assessment at present.

Vitamin B6

Refers to several derivatives of pyridine, Long-term use with doses Deficiency usually seen in conjunction exceeding 200 mg/day (in including pyridoxine (PN), pyridoxal with other water-soluble vitamin adults) may cause peripheral (PL), and pyridoxamine (PM), which deficiencies. Stomatitis, angular neuropathies and are interconvertible in the body. The cheilosis, glossitis, irritability, photosensitivity. [100 mg] coenzymatic forms are pyridoxal-5depression, and confusion occur in phosphate (PLP) and pyridoxamine-5moderate to severe depletion; phosphate (PMP). As a coenzyme, B6 normochromic, normocytic anemia is involved in many transamination has been reported in severe deficiency. reactions (and thereby in Abnormal electroencephalograms and, gluconeogenesis), in the synthesis of in infants, convulsions have also been niacin from tryptophan, in the observed. Some sideroblastic anemias synthesis of several neurotransmitters, respond to B6 administration. Isoniazid, cycloserine, penicillamine, and in the synthesis of ethanol, and theophylline can inhibit δ-aminolevulinic acid (and therefore in B6 metabolism. [Ages 19-50 yr: heme synthesis). It also has functions 1.3 mg; >50 yr: 1.5 mg for women, unrelated to coenzymatic activity: PL 1.7 mg for men] and PLP bind to hemoglobin and alter O2 affinity; PLP also binds to steroid receptors, inhibiting receptor affinity to DNA and thereby modulating steroid activity.

Many useful laboratory methods of assessment exist. The plasma or erythrocyte PLP levels are most common. Urinary excretion of xanthurenic acid after an oral tryptophan load or activity indices of RBC alanine or aspartic acid transaminases (ALT and AST, respectively) are all functional measures of B6-dependent enzyme activity.

Folate

A group of related pterin compounds. Women of childbearing age are most Doses >1000 µg/day may More than 35 forms of the vitamin are likely to be deficient. Classic deficiency partially correct the anemia found naturally. The fully oxidized syndrome: megaloblastic anemia, of B12 deficiency and may form, folic acid, is not found in nature diarrhea. The hematopoietic cells in therefore mask (and perhaps but is the pharmacologic form of the bone marrow become enlarged and exacerbate) the associated vitamin. All folate functions relate to have immature nuclei, reflecting neuropathy. Large doses also its ability to transfer one-carbon ineffective DNA synthesis. The reported to lower seizure groups. It is essential in the de novo peripheral blood smear demonstrates threshold in individuals synthesis of nucleotides and in the macro-ovalocytes and prone to seizures. Parenteral metabolism of several amino acids, and polymorphonuclear leukocytes with administration is rarely is an integral component for the an average of more than 3.5 nuclear reported to cause allergic regeneration of the “universal” methyl lobes. Megaloblastic changes also phenomena, which is donor, S-adenosylmethionine. occur in other epithelia that proliferate probably due to dispersion Inhibition of bacterial and cancer cell rapidly (e.g., oral mucosa, agents. [1000 µg] folate metabolism is the basis for the gastrointestinal tract), producing sulfonamide antibiotics and glossitis and diarrhea, respectively. chemotherapeutic agents such as Sulfasalazine and diphenytoin inhibit methotrexate and 5-fluorouracil, absorption and predispose to deficiency. [400 µg of dietary folate respectively. equivalents (DFE); 1 DFE = 1 µg food folate = 0.6 µg folic acid]

Serum folate measures short-term folate balance, whereas RBC folate is a better reflection of tissue status. Serum homocysteine rises early in deficiency but is nonspecific because B12 or B6 deficiency, renal insufficiency, and older age may also cause elevations.

Niacin (vitamin B3)

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

e51

TABLE 225-2 VITAMINS AND THEIR FUNCTIONS—cont’d BIOCHEMISTRY AND PHYSIOLOGY DEFICIENCY [RDA*] TOXICITY [TUL†] ASSESSMENT OF STATUS Vitamin C Ascorbic acid readily oxidizes to Plasma ascorbic acid Overt deficiency is uncommon in ≥500 mg/day (in adults) may (ascorbic and dehydroascorbic acid in aqueous concentration reflects recent developed countries. The classic cause nausea and diarrhea. dehydroascorbic solution. The latter can be reduced in dietary intake, whereas WBC deficiency syndrome is scurvy: fatigue, >1 g/day modestly increases acid) vivo, so it possesses vitamin C activity. levels more closely reflect depression, and widespread risk for oxalate kidney stones. Total vitamin C is therefore the sum of tissue stores. Women’s abnormalities in connective tissues, Supplementation may ascorbic and dehydroascorbic acid plasma levels are such as inflamed gingivae, petechiae, interfere with laboratory tests content. It serves primarily as a approximately 20% higher perifollicular hemorrhages, impaired based on redox potential biologic antioxidant in aqueous than men’s for any given wound healing, coiled hairs, (e.g., fecal occult blood environments. Biosyntheses of dietary intake. hyperkeratosis, bleeding into body testing, serum cholesterol, collagen, carnitine, bile acids, and cavities. In infants, defects in and glucose). Withdrawal norepinephrine, as well as proper ossification and bone growth may from chronic ingestion of functioning of the hepatic mixedoccur. Tobacco smoking lowers plasma high doses of vitamin C function oxygenase system, depend on and leukocyte vitamin C levels. supplements should be done [F: 75 mg; M: 90 mg; increase this property. Vitamin C in foodstuffs gradually because requirement for cigarette smokers by increases the intestinal absorption of accommodation appears to 35 mg/day] nonheme iron. occur, raising a concern of “rebound scurvy.” [2 g] Serum, or plasma, concentrations are generally accurate. Subtle deficiency with neurologic complications, as described in the “Deficiency” column, can best be established by concurrently measuring the concentration of plasma B12 and serum methylmalonic acid because the latter is a sensitive indicator of cellular deficiency.

Vitamin B12

A group of closely related cobalamin A few allergic reactions have Dietary inadequacy is a rare cause of compounds composed of a corrin ring been reported to crystalline deficiency except in strict vegetarians. (with a cobalt atom in its center) B12 preparations and are Most deficiencies arise from loss of probably due to impurities, connected to a ribonucleotide intestinal absorption, which may occur not the vitamin. [TUL not through an aminopropanol bridge. with pernicious anemia, pancreatic established] Microorganisms are the ultimate insufficiency, atrophic gastritis, small source of all naturally occurring B12. bowel bacterial overgrowth, or ileal The two active coenzyme forms are disease. Megaloblastic anemia and deoxyadenosylcobalamin and megaloblastic changes in other methylcobalamin. These coenzymes epithelia (see “Folate”) are the result of are needed for the synthesis of succinyl sustained depletion. Demyelination of coenzyme A (CoA), which is essential peripheral nerves, posterior and lateral in lipid and carbohydrate metabolism, columns of spinal cord, and nerves and for the synthesis of methionine. within the brain may occur. Altered The latter reaction is essential for mentation, depression, and psychoses amino acid metabolism, for purine occur. Hematologic and neurologic and pyrimidine synthesis, for many complications may occur methylation reactions, and for the independently. Folate supplementation, in doses of 1000 µg/ intracellular retention of folates. day, may partly correct the anemia, thereby masking (or perhaps exacerbating) the neuropathic complication. [2.4 µg]

Biotin

Isolated deficiency is rare. Deficiency in Toxicity has not been reported Plasma and urine A bi-cyclic compound consisting of a concentrations of biotin humans has been produced by in humans with doses as high ureido ring fused to a substituted are diminished in the prolonged total parenteral nutrition as 60 mg/day in children. tetrahydrothiophene ring. Endogenous [TUL not established] deficient state. Elevated lacking the vitamin and by ingestion of synthesis by intestinal flora may urine concentrations large quantities of raw egg white, contribute significantly to biotin of methyl citrate, which contains avidin, a protein that nutriture. Most dietary biotin is linked 3-methylcrotonylglycine, and binds biotin with such high affinity to lysine, a compound called biotinyl 3-hydroxyisovalerate are also that it renders it biounavailable. lysine, or biocytin. The lysine must be observed in deficiency. Alterations in mental status, myalgias, hydrolyzed by an intestinal enzyme hyperesthesias, and anorexia occur. called biotinidase before intestinal Later, a seborrheic dermatitis and absorption occurs. Acts primarily as a alopecia develop. Deficiency is usually coenzyme for several carboxylases; accompanied by lactic acidosis and each holoenzyme catalyzes an organic aciduria. [30 µg] ATP-dependent CO2 transfer. The carboxylases are critical enzymes in carbohydrate and lipid metabolism.

Pantothenic acid

Deficiency rare: only reported as a result Consists of pantoic acid linked to of feeding semisynthetic diets or an β-alanine through an amide bond. An antagonist to the vitamin. essential component of CoA and Experimental, isolated deficiency in phosphopantetheine, which are humans produces fatigue, abdominal essential for synthesis and β-oxidation pain, vomiting, insomnia, and of fatty acids, as well as synthesis of paresthesias of the extremities. [5 mg] cholesterol, steroid hormones, vitamins A and D, and other isoprenoid derivatives. CoA is also involved in the synthesis of several amino acids and δ-aminolevulinic acid, a precursor for the corrin ring of vitamin B12, the porphyrin ring of heme, and of cytochromes. CoA is also necessary for the acetylation and fatty acid acylation of a variety of proteins.

In doses of 10 g/day, diarrhea is Whole blood and urine reported to occur. [TUL not concentrations of established] pantothenate are indicators of status; serum levels are not thought to be accurate.

*Recommended daily allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001. In some instances, insufficient data exist to establish an RDA, in which case the adequate intake (AI) established by the board is listed. † Tolerated upper intake (TUL) established for adults by the U.S. Food and Nutrition Board, 1999-2001. PTH = parathyroid hormone; UVB = ultraviolet B.

e52

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

TABLE 225-3 NUTRITIONAL TRACE ELEMENTS AND THEIR CLINICAL IMPLICATIONS Chromium

BIOCHEMISTRY AND PHYSIOLOGY Dietary chromium consists of both inorganic and organic forms. Its primary function in humans is to potentiate insulin action. It accomplishes this function as a circulating complex called glucose tolerance factor, thereby affecting carbohydrate, fat, and protein metabolism.

DEFICIENCY [RDA*] TOXICITY [TUL†] ASSESSMENT OF STATUS Toxicity after oral ingestion is Plasma or serum concentration of Deficiency in humans only described in uncommon and seems confined to chromium is a crude indicator long-term total parenteral nutrition gastric irritation. Airborne exposure of chromium status; it appears (TPN) patients receiving insufficient may cause contact dermatitis, to be meaningful when the chromium. Hyperglycemia or impaired eczema, skin ulcers, and value is markedly above or glucose tolerance occurs. Elevated bronchogenic carcinoma. [no TUL below the normal range. plasma free fatty acid concentrations, established] neuropathy, encephalopathy, and abnormalities in nitrogen metabolism are also reported. Whether supplemental chromium may improve glucose tolerance in glucose-intolerant individuals remains controversial. [F: 25 µg; M: 35 µg]

Copper

Practical methods for detecting Acute copper toxicity has been Copper is absorbed by a specific Dietary deficiency is rare; it has been marginal deficiency are not described after excessive oral intake intestinal transport mechanism. It observed in premature and lowavailable. Marked deficiency is and with absorption of copper salts is carried to the liver where it is birthweight infants fed exclusively a reliably detected by diminished applied to burned skin. Milder bound to ceruloplasmin, which cow’s milk diet and in individuals on serum copper and manifestations include nausea, circulates systemically and delivers long-term TPN without copper. ceruloplasmin concentrations as vomiting, epigastric pain, and copper to target tissues in the body. Clinical manifestations include well as low red blood cell diarrhea; coma and hepatic Excretion of copper is largely depigmentation of skin and hair, (RBC) superoxide dismutase necrosis may ensue in severe cases. through bile, and then into the neurologic disturbances, leukopenia, activity. Toxicity may be seen with doses as feces. Absorptive and excretory hypochromic microcytic anemia, and low as 70 µg/kg/day. Chronic processes vary with the levels of skeletal abnormalities. Anemia arises toxicity is also described. Wilson’s dietary copper, providing a means from impaired utilization of iron and is disease is a rare, inherited disease of copper homeostasis. Copper therefore a conditioned form of iron associated with abnormally low serves as a component of many deficiency anemia. The deficiency ceruloplasmin levels and enzymes, including amine oxidases, syndrome, except the anemia and accumulation of copper in the liver ferroxidases, cytochrome c oxidase, leukopenia, is also observed in and brain, eventually leading to dopamine β-hydroxylase, Menkes’ disease, a rare inherited damage to these two organs. superoxide dismutase, and condition associated with impaired copper utilization. [900 µg] [10 mg] tyrosinase.

Fluorine

Known more commonly by its ionic form, fluoride. It is incorporated into the crystalline structure of bone, thereby altering its physical characteristics.

Iodine

Iodine status of a population can Readily absorbed from the diet, In the absence of supplementation, Large doses (>2 mg/day in adults) be estimated by the prevalence concentrated in the thyroid, and populations relying primarily on food may induce hypothyroidism by of goiter. Urinary excretion of integrated into the thyroid from soils with low iodine content blocking thyroid hormone iodine is an effective laboratory hormones, thyroxine (T4) and have endemic iodine deficiency. synthesis. Supplementation with triiodothyronine (T3). These means of assessment. Maternal iodine deficiency leads to >100 mg/day to an individual who hormones circulate largely bound Thyroid-stimulating hormone fetal deficiency, which produces was formerly deficient occasionally to thyroxine-binding globulin. They (TSH) blood level is an spontaneous abortions, stillbirths, induces hyperthyroidism. [1.1 mg] modulate resting energy indirect, and therefore not hypothyroidism, cretinism, and expenditure and, in the developing entirely specific, means of dwarfism. Permanent cognitive deficits human, growth and development. assessment. may result from iodine deficiency during first 2 years of life. In the adult, compensatory hypertrophy of the thyroid goiter occurs along with varying degrees of hypothyroidism. [150 µg]

Iron

Iron overload typically occurs when Negative iron balance initially leads Conveys the capacity to participate in The most common micronutrient habitual dietary intake is extremely to depletion of iron stores in the redox reactions to a number of deficiency in the world. Women of high, intestinal absorption is bone marrow: a bone marrow metalloproteins such as childbearing age are the highest-risk excessive, repeated parenteral biopsy and the concentration of hemoglobin, myoglobin, group because of menstrual blood administration occurs, or a serum ferritin are accurate cytochrome enzymes, and many losses, pregnancy, and lactation. The combination of these factors exists. indicators of early depletion. As oxidases and oxygenases. Primary classic deficiency syndrome is Excessive iron stores usually the severity of deficiency storage form is ferritin and, to a hypochromic, microcytic anemia. accumulate in the proceeds, serum iron (SI) lesser degree, hemosiderin. Glossitis and koilonychia (“spoon” reticuloendothelial tissues and decreases and total iron-binding Intestinal absorption is 15-20% for nails) are also observed. Easy cause little damage capacity (TIBC) increases: an “heme” iron and 1-8% for iron fatigability often is an early symptom, (“hemosiderosis”). If overload iron saturation (SI/TIBC) of contained in vegetables. before anemia appears. In children, continues, iron eventually begins to <16% suggests iron deficiency. Absorption of the latter form is mild deficiency of insufficient severity accumulate in tissues such as the Microcytosis, hypochromia, and enhanced by the ascorbic acid in to cause anemia is associated with hepatic parenchyma, pancreas, anemia ensue. Elevated levels of foodstuffs; by poultry, fish, or beef; behavioral disturbances and poor heart, and synovium, causing serum ferritin or an iron and by an iron-deficient state. It is school performance. [postmenopausal F and M: 8 mg; premenopausal F: hemochromatosis (Chapter 219). saturation of >60% suggest iron decreased by phytate and tannins. 18 mg] Hereditary hemochromatosis overload, although systemic results from homozygosity of a inflammation elevates serum common recessive trait. Excessive ferritin regardless of iron status. intestinal absorption of iron is seen in homozygotes. [45 mg]

Intake of <0.1 mg/day in infants and <0.5 mg/day in children is associated with an increased incidence of dental caries. Optimal intake in adults is between 1.5 and 4 mg/day. [F: 3 mg; M: 4 mg]

Acute ingestion of >30 mg/kg body weight is likely to cause death. Excessive chronic intake (0.1 mg/ kg/day) leads to mottling of teeth (dental fluorosis), calcification of tendons and ligaments, and exostoses and may increase the brittleness of bones. [10 mg]

Estimates of intake or clinical assessment are used because no good laboratory test exists.

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

e53

TABLE 225-3 NUTRITIONAL TRACE ELEMENTS AND THEIR CLINICAL IMPLICATIONS—cont’d Manganese

BIOCHEMISTRY AND PHYSIOLOGY A component of several metalloenzymes. Most manganese is in mitochondria, where it is a component of manganese superoxide dismutase.

Molybdenum A cofactor in several enzymes, most prominently xanthine oxidase and sulfite oxidase.

DEFICIENCY [RDA*] TOXICITY [TUL†] Manganese deficiency in the human has Toxicity by oral ingestion is unknown not been conclusively demonstrated. It in humans. Toxic inhalation causes is said to cause hypocholesterolemia, hallucinations, other alterations in weight loss, hair and nail changes, mentation, and extrapyramidal movement disorders. [11 mg] dermatitis, and impaired synthesis of vitamin K–dependent proteins. [F: 1.8 mg; M: 2.3 mg]

ASSESSMENT OF STATUS Until the deficiency syndrome is better defined, an appropriate measure of status will be difficult to develop.

Toxicity not well described in humans, Laboratory means of assessment A probable case of human deficiency is although it may interfere with not meaningful until deficiency described as being secondary to copper metabolism at high doses. syndrome is better described. parenteral administration of sulfite and [2 mg] resulted in hyperoxypurinemia, hypouricemia, and low sulfate excretion. [45 µg]

Selenium

Toxicity is associated with nausea, Most dietary selenium is in the form Deficiency is rare in North America but diarrhea, alterations in mental of an amino acid complex. Nearly has been observed in individuals on status, peripheral neuropathy, loss complete absorption of such forms long-term TPN lacking selenium. Such of hair and nails: such symptoms occurs. Homeostasis is largely individuals have myalgias and/or were observed in adults who performed by the kidney, which cardiomyopathies. Populations in inadvertently consumed regulates urinary excretion as a some regions of the world, most 27-2400 mg. [400 µg] function of selenium status. notably some parts of China, have Selenium is a component of several marginal intake of selenium. In these enzymes, most notably glutathione regions Keshan’s disease, a condition peroxidase and superoxide characterized by cardiomyopathy, is dismutase. These enzymes protect endemic; it can be prevented (but not against oxidative and free radical treated) by selenium supplementation. [55 µg] damage of various cell structures. The antioxidant protection conveyed by selenium apparently operates in conjunction with vitamin E because deficiency of one seems to potentiate damage induced by a deficiency of the other. Selenium also participates in the enzymatic conversion of thyroxine to its more active metabolite, triiodothyronine.

Zinc

Acute zinc toxicity can usually be No accurate indicators of zinc Intestinal absorption occurs by a Zinc deficiency has its most profound induced by ingestion of >200 mg of status exist for routine clinical specific process that is enhanced by effect on rapidly proliferating tissues. zinc in a single day (in adults). It is use. Plasma, RBC, and hair zinc pregnancy and corticosteroids and Mild deficiency: growth retardation in manifested by epigastric pain, concentrations are often diminished by coingestion of children. More severe deficiency: growth nausea, vomiting, and diarrhea. misleading. Acute illness, in phytates, phosphates, iron, copper, arrest, teratogenicity, hypogonadism Hyperpnea, diaphoresis, and particular, is known to diminish lead, or calcium. Diminished intake and infertility, dysgeusia, poor wound weakness may follow inhalation of plasma zinc levels, in part by of zinc leads to an increased healing, diarrhea, dermatitis on the zinc fumes. Copper and zinc inducing a shift of zinc out of efficiency of absorption and extremities and around orifices, compete for intestinal absorption: the plasma compartment and decreased fecal excretion, providing glossitis, alopecia, corneal clouding, long-term ingestion of >25 mg/day into the liver. Functional tests a means of zinc homeostasis. Zinc loss of dark adaptation, and behavioral of zinc may lead to copper that determine dark adaptation, is a component of more than 100 changes. Impaired cellular immunity is deficiency. Long-term ingestion of taste acuity, and rate of wound enzymes, among which are DNA observed. Excessive loss of >150 mg/day has been reported to healing lack specificity. polymerase, RNA polymerase, and gastrointestinal secretions through cause gastric erosions, low transfer RNA synthetase. chronic diarrhea and fistulas may high-density lipoprotein cholesterol precipitate deficiency. Acrodermatitis levels, and impaired cellular enteropathica is a rare, recessively immunity. [40 mg] inherited disease in which intestinal absorption of zinc is impaired. [F: 8 mg; M: 11 mg]

Erythrocyte glutathione peroxidase activity and plasma, or whole blood, selenium concentrations are the most commonly used methods of assessment. They are moderately accurate indicators of status.

*Recommended daily allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001. In some instances, insufficient data exist to establish an RDA, in which case the adequate intake (AI) established by the board is listed. † Tolerated upper limit (TUL) established for adults by the U.S. Food and Nutrition Board, 1999-2001.

younger, whose RDA is 15 µg/day. This increase appears to result from diminished cutaneous synthesis of vitamin D by senile skin and from decreased sun exposure, which is particularly important in elderly patients in institutional facilities. The need for crystalline vitamin B12 and for a quantity of vitamin D that is difficult to achieve without resorting to a supplement suggests that universal use of a daily supplement pill containing these nutrients would benefit elderly people. Widespread use among elders of a multivitamin that contains a wide spectrum of micronutrients is more controversial, in part because of concerns regarding subtle toxicity. For example, elders with chronic renal failure appear to have a vulnerability to vitamin A toxicity, suggesting that use of supplements containing this vitamin is contraindicated.

PATHOPHYSIOLOGIC AND PHARMACOLOGIC FACTORS Diseases of the Gastrointestinal Tract

Intestinal malabsorptive and maldigestive states predispose to multiple micronutrient deficiencies. Both fat-soluble and water-soluble micronutrients (except vitamin B12) are absorbed predominantly in the proximal small intestine. Therefore, diffuse mucosal diseases affecting the proximal portion of the gastrointestinal tract are likely to result in deficiencies. Even in the absence of mucosal disease of the proximal small intestine, extensive ileal disease, small bowel bacterial overgrowth, and chronic cholestasis can each interfere with the maintenance of adequate intraluminal conjugated bile acid

e54

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

concentrations and can thereby impair absorption of fat-soluble vitamins. Maldigestion is usually the result of chronic pancreatitis. Untreated, it frequently causes malabsorption and deficiencies of fat-soluble vitamins. Vitamin B12 malabsorption can often be demonstrated in this setting, a result of inadequate R-protein digestion, but clinical vitamin B12 deficiency is rarely reported.

Inborn Errors of Metabolism

Myriad rare inborn errors of metabolism have been described for vitamins and minerals that impair an individual’s ability to assimilate, utilize, or retain a particular micronutrient (Chapter 212). Such defects are usually partial and can often be overcome, to a certain extent, by administering doses of the nutrient that are several degrees of magnitude greater than usually required. Suspicion for such defects should be entertained if (1) a known defect exists in the family, (2) a deficiency syndrome arises at birth or during infancy, or (3) the deficiency syndrome is present despite adequate dietary intake and the absence of any disease that would impair the ability to assimilate the nutrient.

Medications

Long-term administration of many drugs may adversely affect micronutrient status. The manner in which drug-nutrient interactions occur varies; some of the more common mechanisms are outlined in Table 225-4. Some drugs exert their therapeutic effects by specifically inhibiting the actions of a micronutrient. Examples include coumarin, which inhibits γ-carboxylation reactions mediated by vitamin K, and methotrexate, which binds tightly to dihydrofolate reductase, thereby inhibiting folate metabolism.

Toxins

Tobacco smoking alters the metabolism of several vitamins, including folate and vitamins C and E. In large surveys, diminished plasma levels of folate and ascorbic acid have been observed in chronic smokers. Smoking is also associated with diminished levels of folate in cells of the oral mucosa, diminished ascorbic acid levels in leukocytes, and decreased concentrations of vitamin E in the alveolar fluid, findings providing evidence that many tissues can be affected by smoking and that the effect does not simply represent a shift of these micronutrients out of the plasma compartment.

ADVANCES IN NUTRITIONAL SCIENCE New Frontiers in Marginal Deficiency States of Micronutrients

Does Optimal Intake of Micronutrients Optimize Health?

Updating the definition of a micronutrient deficiency and establishing recommended daily intakes that are consistent with the most recent evidence has proved difficult for several reasons. In some instances, a novel biochemical or physiologic role for a nutrient has been identified, but an appropriate question that arises is whether optimization of such functions translates into optimization of health. For example, providing supplemental vitamin E to elderly individuals who are vitamin E replete enhances T-lymphocyte responsiveness; nevertheless, it is unclear whether this translates into diminished infection rates. Another difficult problem pertains to the use of micronutrients in supraphysiologic quantities that exceed all conventional concepts of

TABLE 225-4 DRUG-MEDIATED EFFECTS ON MICRONUTRIENT STATUS: EXAMPLES DRUG NUTRIENT MECHANISM OF INTERACTION Dextroamphetamine, Potentially all Induces anorexia fenfluramine, levodopa micronutrients Cholestyramine

Vitamin D, folate Adsorbs nutrient, decreases absorption

Omeprazole

Vitamin B12

Modest bacterial overgrowth, decreases gastric acid, impairs absorption

Sulfasalazine

Folate

Impairs absorption and inhibits folate-dependent enzymes

Isoniazid

Pyridoxine

Impairs utilization of B6

Nonsteroidal antiinflammatory drugs

Iron

Gastrointestinal blood loss

Penicillamine

Zinc

Increases renal excretion

what is necessary for health. Some micronutrients, when taken in such large quantities, have effects on physiologic functions that impart apparent health benefits. The ingestion of gram quantities of niacin to reduce low-density lipoprotein (LDL) cholesterol is an example. Such physiologic effects are not observed at more conventional levels of intake and are therefore usually considered pharmacologic effects of the nutrient. Thus, the determination of optimal nutrient intake is highly dependent on which physiologic effect is sought. Furthermore, if only a segment of the population will benefit from supraphysiologic quantities of a nutrient, should dietary guidelines for the remainder of the population be established according to this effect? Determining an adequate level of intake implies the existence of a means of measuring nutrient status. In seeking an appropriate measure of nutrient status, the diversity of function often makes it difficult to decide which measurement is the most germane. Tobacco smoking, for example, diminishes vitamin E levels in alveolar fluid but not in the serum. Thus, the concepts of localized nutrient deficiencies and tissue-specific requirements add an additional level of complexity to the determination of nutrient status.

Redefinition of Nutritional Requirements Folate

An example of the complexities that have arisen in redefining the criteria for vitamin deficiencies and vitamin requirements is the water-soluble vitamin, folate. In the past, guidelines regarding its necessary intake were straightforward because they were based solely on the prevention of megaloblastic anemia. Measuring serum and erythrocyte folate concentrations were the most common means of assessing status, and maintaining these levels within accepted normative ranges provided assurance that folate status was adequate to prevent anemia. However, degrees of deficiency that are insufficient to cause anemia may still disturb normal biochemical and physiologic homeostasis and, in some instances, cause clinical disease. Clinical trials have demonstrated that women taking folic acid supplements at the time of conception have a markedly lower chance of delivering a baby with an NTD compared with women who are not folate supplemented but whose folate status falls within a conventionally accepted range. This observation compelled the U.S. government to mandate the fortification of flour, beginning in 1998. Present recommendations are that women of childbearing age consume 400 µg/day of folic acid in the form of supplements or fortified foods, although the doseresponse curve of this effect is ill defined. Less than optimal intake of folate is also evidenced by an increase in serum homocysteine, an amino acid that is normally metabolized by a folatedependent pathway. Before the federally mandated fortification of flour, the median intake of folate among adults was one half of the present RDA, and a substantial minority of Americans had significantly elevated serum homocysteine levels. Elevated homocysteine has been associated with the development of occlusive vascular disease and accelerated cognitive decline. In randomized clinical trials, however, supplementation with folate, vitamin B12, and vitamin B6 has shown no benefit against cardiovascular disease despite its ability to lower homocysteine levels. 1  Such supplementation also has no clear benefit for cognitive function, except perhaps in patients with low baseline folate levels. 2  A compelling body of observations in both humans and animals has demonstrated that habitually low consumption of folate is also associated with a substantial increase in the risk for colorectal cancer, and perhaps cancers of other organs such as those of the breast and pancreas. This inverse relationship is observed even when folate status (or dietary intake) falls within the range of conventionally accepted normative values. This relationship has further complicated the determination of what constitutes an optimal intake of folate. The issue is further confounded by newer observations suggesting that an exceptionally high intake of folate among those who unknowingly harbor precancerous or cancerous lesions may paradoxically enhance the progression of these neoplasms, thereby underscoring the potential for harm produced by taking a nutrient outside of its physiologic window. The most recent update of the U.S. RDA for folate, which occurred in 1998, raised the value from 200 to 400 µg/day, citing both the prevention of anemia and optimization of serum homocysteine as criteria, and recommended that women capable of becoming pregnant consume an additional 400 µg/day in the form of supplements or fortified food. The issues surrounding the prevention of cardiovascular disease, cancer, and cognitive decline were not incorporated into the 1998 determination because the existing data at the time were thought to be inconclusive. However, it may prove appropriate to integrate some of the knowledge surrounding these issues in future revisions of the RDAs. The potential for toxicity, the criterion

e55

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

for which was primarily linked to its ability to mask vitamin B12 deficiency, was dealt with by setting the TUL at 1000 µg/day of folic acid obtained from supplements and fortified foods in addition to that obtained from natural food sources (see Table 225-2). The electronic version of this chapter describes two other instances that exemplify how our expanding understanding of the biologic effects of micronutrients has complicated the process of determining guidelines for optimal intake. 3-5 

Antioxidant and Free Radical Scavenging Vitamins and Provitamins

Vitamins A, C, and E, as well as many of the carotenoids, are effective antioxidants. In addition, vitamins C and E and some of the carotenoids can scavenge free radicals when these nutrients are taken in adequate quantities. Oxidation and free radical damage have been implicated as important contributors to common degenerative illnesses such as atherosclerosis, cancer, cataracts, and retinal degeneration. Clinical trials to test the efficacy of antioxidant supplements have shown no benefit and oftentimes harm, although growing evidence indicates that the adverse effects of the large doses used in many trials may have obscured the health benefits of these nutrients and that populations with marginal antioxidant status may benefit from such supplements. 3  Two large-scale clinical intervention trials with β-carotene supplements conducted in the 1990s reported increased rates of lung cancer among the recipients of the carotenoid. Subsequent mechanistic studies indicated that the large doses administered (~30 mg/day) result in asymmetrical cleavage of the carotenoid into unnatural products that antagonize normal signaling pathways in the lung epithelium, whereas lower supplemental doses undergo symmetrical cleavage into two molecules of vitamin A, thereby protecting against neoplastic transformation. LDL oxidized in vivo is atherogenic. Prevention of LDL oxidation, at least in animal models, retards the process of atherogenesis. Supplementation of human subjects with several times the RDA of α-tocopherol, and perhaps some of the other antioxidant micronutrients, is an effective means of preventing LDL oxidation. Human intervention trials with vitamin E or other antioxidant nutrients, however, have generally been unable to demonstrate clinical benefits in the reduction of cardiovascular events. There nevertheless has been a sizeable reduction in cardiovascular events observed with vitamin E supplementation among populations of patients who are under exceptional oxidative stress, such as those with chronic renal failure and certain classes of diabetes, suggesting that it is only among select groups of individuals that a clinical benefit may be realized. Nonalcoholic steatohepatitis (NASH) (Chapter 155), a disease that is closely associated with features of the metabolic syndrome (Chapter 237), can progress to cirrhosis in up to 15% of patients. Oxidative stress (as well as insulin resistance) has been implicated as a key factor contributing to hepatic injury in NASH. In a recent study of 247 nondiabetic patients with NASH, vitamin E at a dose of 800 IU daily for 96 weeks was associated with a significantly higher rate of improvement in NASH than placebo (43% vs. 19%, P = .001). 4  Epidemiologic studies indicate that occurrence of cancers of the oral cavity, lung, esophagus, and stomach (and perhaps the colorectum) is inversely related to dietary intake of fresh vegetables and fruits. Careful dissection of dietary data suggests that β-carotene and vitamin E content are strongly predictive components of these foodstuffs. High doses of vitamin A and some of its synthetic analogues (e.g., 13-cis-retinoic acid) can effectively reduce the recurrence of head and neck cancers, although hepatic toxicity is sometimes a limiting factor in such cancer preventive therapy. Similarly, these agents, as well as β-carotene or vitamin E, when taken in large doses have been shown significantly to promote the regression of oral leukoplakia, a premalignant lesion. Daily supplementation with one to three times the U.S. RDA of β-carotene, selenium, and vitamin E has been shown to reduce the incidence of adenocarcinoma of the stomach in a region of China where the disease, as well as marginal vitamin status, is particularly prevalent. However, as mentioned earlier, trials conducted in developed Western countries have observed no diminution of lung cancer among smokers with daily supplementation of β-carotene and vitamin E. Epidemiologic associations also suggest an inverse relationship between lens cataract or macular degeneration and the intake of vitamins C, E, and β-carotene. These common degenerative conditions of the eye are caused, at least in part, by photo-oxidation. Some evidence in animal models indicates that they can be retarded by supraphysiologic supplementation with vitamins C or E. When tested under the conditions of a rigorously conducted

TABLE 225-5 NEWLY IDENTIFIED ROLES FOR VITAMINS VITAMIN OR PROVITAMIN β-Carotene

CLASSIC ROLE Pro-vitamin A

NEW ROLE Antioxidant, free radical

Niacin

NAD/NADP coenzyme

Reduction of LDL, elevation of HDL and cholesterol

Folate

Hemopoietic factor

Diminishes homocysteinemia

Vitamin A

Transduction of visual input in retina

Induction and maintenance of epithelial differentiation, signal in embryogenesis

Vitamin D

Regulator of calcium

Retards epithelial proliferation; promotes differentiation

Vitamin B6

Coenzyme for transamination

Modulation of steroid activity

HDL = high-density lipoprotein; LDL = low-density lipoprotein; NAD = nicotinamide adenine dinucleotide; NADP = nicotinamide-adenine dinucleotide phosphate.

multicenter, controlled trial, daily supplementation with a combination of vitamins C, E, and β-carotene (with or without zinc) had no effects compared with placebo on the likelihood of developing cataracts. However, the combination that included zinc produced about a 30% decline in the progression of early macular degeneration to an advanced stage and the likelihood of moderate visual acuity loss. 4  Further investigation is necessary to define the circumstances more clearly under which antioxidant nutrients can be used to prevent or treat chronic degenerative diseases.

Vitamin B12 and Neuropsychiatric Disease

Plasma vitamin B12 concentrations are considered an accurate indication of vitamin B12 status. The normative range for a healthy population has typically been reported to be 150 (or 200) to 900 pg/mL. Values greater than 150 pg/ mL were thought, until recently, to exclude vitamin B12 deficiency as a cause of neurologic or psychiatric syndromes. Recent observations now indicate that 7 to 10% of individuals who have plasma vitamin B12 values between 150 and 400 pg/mL may develop neuropsychiatric complications of vitamin B12 deficiency in the absence of any indications of megaloblastic anemia. Such individuals can be identified by the demonstration of an elevated level of methylmalonic acid in the blood that decreases to normal levels with parenteral vitamin B12 administration. An elevation in serum methylmalonic acid is both a sensitive and a specific indication of cellular vitamin B12 deficiency. An alternative approach is to administer several parenteral injections of vitamin B12 to an individual who has an otherwise unexplained neuropsychiatric syndrome and whose plasma vitamin B12 level falls in the range of 150 to 400 pg/mL. Awareness of this phenomenon is particularly important because it is has become clear that atrophic gastritis, an asymptomatic condition that affects approximately 30% of the elderly population, frequently produces a modest decrease in vitamin B12 status. Table 225-5 lists several examples of biochemical functions of vitamins that have only recently been identified. As the clinical significance of each of these new roles is defined and as quantities of each vitamin needed to optimize such functions are determined, redefinition of the desirable range of vitamin status is likely to occur. Future efforts to refine appropriate dietary goals further for each micronutrient will, however, need to take into consideration an important theme that is underscored by the previous discussion: that the level of consumption of a particular micronutrient that conveys health benefits to one segment of the population is not necessarily beneficial, or even appropriate, for all segments of society.

1. SEARCH Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010;303:2486-2494. 2. Balk EM, Raman G, Tatsioni A, et al. Vitamin B6, B12, and folic acid supplementation and cognitive function: a systematic review of randomized trials. Arch Intern Med. 2007;167:21-30. 3. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297:842-857. 4. Sanyal AJ, Chalasani N, Kowdley KV, et al, for the NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675-1685.

e56

CHAPTER 225  VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS  

5. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene and zinc for age-related macular degeneration and vision loss: AREDS report no. 8 [erratum in Arch Ophthalmol. 2008;126:1251]. Arch Ophthalmol. 2001;119:1417-1436.

SUGGESTED READINGS Larsson SC, Orsini N, Wolk A. Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA. 2010;303:1077-1083. Systemic review with meta-analysis concluding that vitamin B6 intake and blood levels of the active form of vitamin B6 are inversely associated with the risk for colorectal cancer. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-58. Review concluding that the prevalence of vitamin D inadequacy in North America has been overestimated.

Swanson AM, Hughey LC. Acute inpatient presentation of scurvy. Cutis. 2010;86:205-207. An unusual case report.

ADDITIONAL SUGGESTED READINGS Huang HY, Caballero B, Chang S, et al. The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference. Ann Intern Med. 2006;145:372-385. A review of the efficacy and safety of multivitamin and mineral supplement use to prevent cancer and other chronic diseases in adults. Lykkesfeldt J, Poulsen HE. Is vitamin C supplementation beneficial? Lessons learned from randomised controlled trials. Br J Nutr. 2010;103:1251-1259. No evidence of benefit in the Western population due to saturation through their normal diet.