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Vitamins, Trace Minerals, and Other Micronutrients
Micronutrients in Nutritional Science
Dietary Requirements
Micronutrients are a diverse array of dietary components that are 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, some are biochemical substrates or hormones; in some instances, functions are not well defined. Under normal circumstances, the average daily dietary intake required to sustain normal physiologic functions for each micronutrient is measured in milligrams or smaller quantities. In this manner, micronutrients are distinguished from macronutrients, which encompass carbohydrates, fats, and proteins, as well as macrominerals such as calcium, magnesium, phosphorus, sodium, potassium, and chloride ( Chapter 13 ).
Optimal Intake
For orderly homeostasis to proceed, most dietary nutrients must be ingested in quantities that are neither too small nor too great, because disorders may arise when intake regularly falls either below this physiologic window because of poor diet ( Chapter 198 ) or above this physiologic window, often because of the iatrogenic or self-selected administration of large quantities. The dietary requirement for a particular micronutrient is determined by many factors ( Table 199-1 ). The U.S. National Academy of Medicine periodically issues recommended dietary allowances (RDAs) that state the quantity of each micronutrient that is “adequate to meet the known nutrient needs of practically all healthy persons” ( Tables 199-2 and 199-3 ), as well as tolerable upper limits (TULs), which are the “maximal daily levels of oral intake likely to pose no adverse health risks.” Adequate intake , the amount necessary to prevent a deficiency state, is not necessarily synonymous with optimal intake . Since habitual dietary habits as well as the intake of specific nutrients play important roles in determining the risk of common degenerative diseases, ongoing efforts are trying to determine levels of nutrient intake that can ameliorate the risk of chronic disease.
TABLE 199-1
FACTORS THAT DETERMINE DIETARY REQUIREMENT OF A MICRONUTRIENT
| PHYSIOLOGIC FACTORS |
| Bioavailability: the proportion of an ingested micronutrient that 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 utilization) Lifestyle habits: smoking, ethanol consumption Drugs: may alter bioavailability or utilization |
TABLE 199-2
VITAMINS AND THEIR FUNCTIONS
| BIOCHEMISTRY AND PHYSIOLOGY | DEFICIENCY [RDA ∗ ] | TOXICITY [TUL † ] | ASSESSMENT OF STATUS | |
|---|---|---|---|---|
| FAT-SOLUBLE VITAMINS | ||||
| Vitamin A | A family of retinoid compounds, each member having biologic activity qualitatively similar to retinol. Carotenoids are structurally related to retinoids. Some carotenoids, most notably β-carotene, are metabolized into compounds with vitamin A activity and are therefore considered to be provitamin A compounds. Vitamin A is an integral component of rhodopsin and iodopsins, light-sensitive proteins in rod and cone cells in the retina. Additional functions: induction and maintenance of cellular differentiation in certain tissues; signal for appropriate morphogenesis in the developing embryo; maintenance of cell-mediated immunity. 1 µg of retinol = 3.33 IU of vitamin A. | Follicular hyperkeratosis and night blindness are early indicators. Conjunctival xerosis, degeneration of the cornea (keratomalacia), and dedifferentiation of rapidly proliferating epithelia are later indications of deficiency. Bitot spots (focal areas of the conjunctiva or cornea with foamy appearance) are an indication of xerosis. Blindness, due to corneal destruction and retinal dysfunction, ensues if left uncorrected. Increased susceptibility to infection is also a consequence. [F: 700 µg; M: 900 µg] | In adults, >150,000 µg may cause acute toxicity: fatal intracranial hypertension, skin exfoliation, and hepatocellular necrosis. Chronic toxicity may occur with habitual daily intake of >10,000 µg: alopecia, ataxia, bone and muscle pain, dermatitis, cheilitis, conjunctivitis, pseudotumor cerebri, hepatocellular necrosis, hyperlipidemia and hyperostosis are common. Single, large doses of vitamin A (30,000 µg) or habitual intake of >4500 µg/day in early pregnancy can be teratogenic. Excessive intake of carotenoids causes a benign condition characterized by yellowish discoloration of the skin. [3000 µg] | Retinol concentration in the plasma and vitamin A concentrations in the milk and tears are reasonably accurate measures of adequate status. Toxicity is best assessed by elevated levels of retinyl esters in plasma. A quantitative measure of dark adaptation for night vision and electroretinography are useful functional tests. |
| Vitamin D | A group of sterol compounds whose parent structure is cholecalciferol (vitamin D 3 ). Cholecalciferol is formed in the skin from 7-dehydrocholesterol (provitamin D 3 ) by exposure to UVB radiation. A plant sterol, ergocalciferol (provitamin D 2 ), can be similarly converted into vitamin D 2 and has similar vitamin D activity. The vitamin undergoes sequential hydroxylations in the liver and kidney at the 25 and 1 positions, respectively, producing the most bioactive form of the vitamin, 1,25-dihydroxy vitamin D. 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. It retards proliferation and promotes differentiation in certain epithelia. Purported actions of vitamin D as an antidiabetes, anti-inflammatory, and cancer preventive agent remain controversial and are under investigation. 1 µg = 40 IU. | Deficiency results in decreased mineralization of newly formed bone called rickets in childhood and osteomalacia in adults. Deficiency also contributes to osteoporosis and increased fracture risk in later life. Commonly appears following gastric bypass procedures. Expansion of the epiphyseal growth plates and replacement of normal bone with unmineralized bone matrix are the cardinal features of rickets; the latter feature also characterizes osteomalacia. Deformity of bone and pathologic fractures occur. Decreased serum concentrations of calcium and phosphate may occur. [15 µg, ages 19-70 yr; 20 µg, age >70 yr] | Excess amounts result in abnormally high concentrations of calcium and phosphate in the serum; metastatic calcifications, renal damage, and altered mentation may occur. [100 µg for ages ≥9 yr] | The serum concentration of the major circulating metabolite, 25-hydroxyvitamin D, is the best indicator of systemic status except in advanced kidney disease (stages 4 and 5), in which the impairment of renal 1-hydroxylation results in disassociation of the mono- and dihydroxyvitamin concentrations. Measurement of the serum concentration of 1,25-dihydroxyvitamin D is then necessary. Also, measuring free 25-hydroxyvitamin D rather than including protein-bound forms may minimize artifacts created by liver disease, sex hormones, kidney function, and genetic background. |
| Vitamin E | A group of at least eight naturally occurring compounds, some of which are tocopherols and some of which are tocotrienols. At present, the only dietary form that is thought to be biologically active in humans is α-tocopherol. Vitamin E acts as an antioxidant and free radical scavenger in lipophilic environments, most notably in cell membranes. It acts in conjunction with other antioxidants, such as selenium. | Deficiency due to dietary inadequacy is rare. It is usually seen in premature infants, individuals with fat malabsorption, and individuals with abetalipoproteinemia. Red blood cell fragility occurs and can produce a hemolytic anemia. Neuronal degeneration produces peripheral neuropathies, ophthalmoplegia, and destruction of posterior columns of the 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] | Depressed levels of vitamin K–dependent procoagulants and potentiation of oral anticoagulants have been reported, as has impaired WBC function. Doses of 800 mg/day have been reported to increase slightly the incidence of hemorrhagic stroke. [1000 mg] | Plasma or serum concentration of α-tocopherol is most commonly used. Additional accuracy is obtained by expressing this value per milligram of total plasma lipid. RBC peroxide hemolysis test is not entirely specific but is a useful functional measure of the antioxidant potential of cell membranes. |
| Vitamin K | A family of naphthoquinone compounds with similar biologic activity. Phylloquinone (vitamin K 1 ) is derived from plants; a variety of menaquinones (vitamin K 2 ) are derived from bacterial and animal sources. Vitamin K serves as an essential cofactor in the post-translational γ-carboxylation of glutamic acid residues in many proteins. These proteins include several circulating procoagulants and anticoagulants as well as proteins in a variety of tissues. | Deficiency syndrome is uncommon except in breast-fed newborns, in whom it may cause “hemorrhagic disease of the newborn,” especially among newborns whose parents refuse prophylactic administration of vitamin K at birth. Also occurs in adults with fat malabsorption or who are taking drugs that interfere with vitamin K metabolism (e.g., coumarin, phenytoin, broad-spectrum antibiotics) and in individuals taking large doses of vitamin E and anticoagulant drugs. Excessive hemorrhage is the usual manifestation. [F: 90 µg; M: 120 µg] | Rapid intravenous infusion of K 1 has been rarely associated with dyspnea, flushing, and cardiovascular collapse; this is likely related to the dispersing agents in the solution. Supplementation may interfere with coumarin-based anticoagulation. Pregnant women taking large amounts of the provitamin menadione may deliver infants with hemolytic anemia, hyperbilirubinemia, and kernicterus. [No TUL established.] | Prothrombin time is typically used as a measure of functional K status; it is neither sensitive nor specific for vitamin K deficiency. Determination of fasting plasma vitamin K is an accurate indicator of status. Undercarboxylated plasma prothrombin is also an accurate metric, but only for detecting the deficient state, and is less widely available than plasma vitamin K. |
| WATER-SOLUBLE VITAMINS | ||||
| Thiamin (vitamin B 1 ) | A water-soluble compound containing substituted pyrimidine and thiazole rings and a hydroxyethyl side chain. The coenzyme form is thiamin pyrophosphate (TPP). Thiamin serves as a coenzyme in many α-ketoacid decarboxylation and transketolation reactions. Inadequate thiamin availability leads to impairments of these reactions, resulting in inadequate adenosine triphosphate synthesis and abnormal carbohydrate metabolism, respectively. It may have an additional role in neuronal conduction independent of the aforementioned actions. | Classic deficiency syndrome (beriberi) remains endemic in Asian populations consuming a polished rice diet. Globally, alcoholism, chronic renal dialysis, and persistent nausea and vomiting after bariatric surgery are also common precipitants. High carbohydrate intake increases need for B 1 . Mild deficiency: irritability, fatigue, and headaches. More severe deficiency: combinations of peripheral neuropathy, cardiovascular dysfunction, and cerebral dysfunction. Cardiovascular involvement (wet beriberi): congestive heart failure and low peripheral vascular resistance. Cerebral disease: nystagmus, ophthalmoplegia, and ataxia (Wernicke encephalopathy); hallucinations, impaired short-term memory, and confabulation (Korsakoff 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] | Excess intake is largely excreted in the urine, although parenteral doses of >400 mg/day are reported to cause lethargy, ataxia, and reduced tone of the gastrointestinal tract. [TUL not established.] | The most effective measure of B 1 status is the erythrocyte transketolase activity coefficient, which measures enzyme activity before and after addition of exogenous TPP; RBCs from a deficient individual express a substantial increase in enzyme activity with addition of TPP. Thiamin concentrations in blood or urine are also used. |
| Riboflavin (vitamin B 2 ) | Consists of a substituted isoalloxazine ring with a ribitol side chain. Riboflavin serves as a coenzyme for a diverse array of biochemical reactions. The primary coenzymatic forms are flavin mononucleotide and flavin adenine dinucleotide. Riboflavin holoenzymes participate in oxidation-reduction reactions in myriad metabolic pathways. | Deficiency is usually seen in conjunction with deficiencies of other B vitamins. Isolated deficiency of riboflavin produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and a normochromic, normocytic anemia. [F: 1.1; M: 1.3] | Toxicity is not reported in humans. [TUL not established.] | The most common method of assessment is to determine the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose-6-phosphate dehydrogenase deficiency). Measurements of blood and urine concentrations are less desirable methods. |
| Niacin (vitamin B 3 ) | Refers to nicotinic acid and the corresponding amide, nicotinamide. The active coenzymatic forms are composed of nicotinamide affixed to adenine dinucleotide, forming NAD or NADP. More than 200 apoenzymes use these compounds as electron acceptors or hydrogen donors, either as a coenzyme or as a co-substrate. The essential amino acid tryptophan is a precursor of niacin; 60 mg of dietary tryptophan yields approximately 1 mg of niacin. Dietary requirements thus depend partly on tryptophan intake. Requirement is often determined on basis of calorie 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. | Pellagra is the classic deficiency syndrome and is often seen in populations in which corn is the major source of energy; it is still endemic in parts of China, Africa, and India. Diarrhea, dementia (or associated symptoms of anxiety or insomnia), and a pigmented dermatitis that develops in sun-exposed areas are typical features. Glossitis, stomatitis, vaginitis, vertigo, and burning dysesthesias are early signs. It is reported occasionally to occur in carcinoid syndrome because tryptophan is diverted to other synthetic pathways. [F: 14 mg; M: 16 mg] | Human toxicity is known largely through studies examining hypolipidemic effects. Includes vasomotor phenomenon (flushing), hyperglycemia, parenchymal liver damage, and hyperuricemia. [35 mg] | Assessment of status is problematic; blood levels of the vitamin are 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 B 6 | Refers to several derivatives of pyridine, including pyridoxine, pyridoxal, and pyridoxamine, which are interconvertible in the body. The coenzymatic forms are pyridoxal-5-phosphate (PLP) and pyridoxamine-5-phosphate. As a coenzyme, B 6 is involved in many transamination reactions (and thereby in gluconeogenesis), in the synthesis of niacin from tryptophan, in the synthesis of several neurotransmitters, and in the synthesis of δ-aminolevulinic acid (and therefore in heme synthesis). It also has functions unrelated to coenzymatic activity: pyridoxal and PLP bind to hemoglobin and alter oxygen affinity; PLP also binds to steroid receptors, inhibiting receptor affinity to DNA and thereby modulating steroid activity. | Deficiency is usually seen in conjunction with other water-soluble vitamin deficiencies. Stomatitis, angular cheilosis, glossitis, irritability, depression, and confusion occur in moderate to severe depletion; normochromic, normocytic anemia has been reported in severe deficiency. Abnormalities on electroencephalography and, in infants, convulsions have also been observed. Some sideroblastic anemias respond to B 6 administration. Isoniazid, cycloserine, penicillamine, ethanol, and theophylline can inhibit B 6 metabolism. [Ages 19-50 yr: 1.3 mg; >50 yr: 1.5 mg for women, 1.7 mg for men] | Long-term use with doses exceeding 200 mg/day (in adults) may cause peripheral neuropathies and photosensitivity. [100 mg] | 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 and activity indices of RBC alanine or aspartate transaminase are functional measures of B 6 -dependent enzyme activity. |
| Folate | A group of related pterin compounds. More than 35 forms of the vitamin are found naturally. The fully oxidized form, folic acid, is not found in nature but is the pharmacologic form of the vitamin used in supplements and fortification programs. All folate functions relate to its ability to transfer one-carbon groups. It is essential in the de novo synthesis of nucleotides and in the metabolism of several amino acids; it is an integral component for the regeneration of the “universal” methyl donor, S -adenosylmethionine. Inhibition of bacterial and cancer cell folate metabolism is the basis for the sulfonamide antibiotics and chemotherapeutic agents, such as methotrexate and 5-fluorouracil, respectively. | Women of childbearing age are most likely to be deficient. Classic deficiency syndrome: megaloblastic anemia, diarrhea. The hematopoietic cells in bone marrow become enlarged and have immature nuclei, reflecting ineffective DNA synthesis. The peripheral blood smear demonstrates macro-ovalocytes and polymorphonuclear leukocytes with an average of more than 3.5 nuclear lobes. Megaloblastic changes also occur in other epithelia that proliferate rapidly (e.g., oral mucosa and gastrointestinal tract, producing glossitis and diarrhea, respectively). Sulfasalazine and diphenytoin inhibit absorption and predispose to deficiency. [400 µg of dietary folate equivalents (DFE); 1 DFE = 1 µg food folate = 0.6 µg folic acid] | Doses >1000 µg/day may partially correct the anemia of B 12 deficiency and may therefore mask (and perhaps exacerbate) the associated neuropathy. Large doses are also reported to lower seizure threshold in individuals prone to seizures. Parenteral administration is rarely reported to cause allergic phenomena, which is probably due to dispersion agents. [1000 µg] | 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 B 12 or B 6 deficiency, renal insufficiency, and older age may also cause elevations. |
| Vitamin C (ascorbic and dehydroascorbic acid) | Ascorbic acid readily oxidizes to dehydroascorbic acid in aqueous solution. Dehydroascorbic acid can be reduced in vivo, so it possesses vitamin C activity. Total vitamin C is therefore the sum of ascorbic and dehydroascorbic acid content. Vitamin C serves primarily as a biologic antioxidant in aqueous environments. Biosyntheses of collagen, carnitine, bile acids, and norepinephrine, as well as proper functioning of the hepatic mixed-function oxygenase system, depend on this property. Vitamin C in foodstuffs increases the intestinal absorption of nonheme iron. | Overt deficiency is uncommon in developed countries. The classic deficiency syndrome is scurvy: fatigue, depression, and widespread abnormalities in connective tissues, such as inflamed gingivae, petechiae, perifollicular hemorrhages, impaired wound healing, coiled hairs, hyperkeratosis, and bleeding into body cavities. In infants, defects in ossification and bone growth may occur. Tobacco smoking lowers plasma and leukocyte vitamin C levels. [F: 75 mg; M: 90 mg; increase requirement for cigarette smokers by 35 mg/day] | ≥500 mg/day (in adults) may cause nausea and diarrhea. >1 g/day modestly increases risk for oxalate kidney stones. Supplementation may interfere with laboratory tests based on redox potential (e.g., fecal occult blood testing, serum cholesterol, and glucose). Withdrawal from chronic ingestion of high doses of vitamin C supplements should be done gradually because accommodation appears to occur, raising a concern of “rebound scurvy.” [2 g] | Plasma ascorbic acid concentration reflects recent dietary intake, whereas WBC levels more closely reflect tissue stores. Women’s plasma levels are approximately 20% higher than men’s for any given dietary intake. |
| Vitamin B 12 | A group of closely related cobalamin compounds composed of a corrin ring (with a cobalt atom in its center) connected to a ribonucleotide through an aminopropanol bridge. Microorganisms are the ultimate source of all naturally occurring B 12 . The two active coenzyme forms are deoxyadenosylcobalamin and methylcobalamin. These coenzymes are needed for the synthesis of succinyl CoA, which is essential in lipid and carbohydrate metabolism, and for the synthesis of methionine. The synthesis of methionine is essential for amino acid metabolism, for purine and pyrimidine synthesis, for many methylation reactions, and for the intracellular retention of folates. | Dietary inadequacy is a rare cause of deficiency except in strict vegetarians. Most deficiencies arise from loss of intestinal absorption, which may occur with pernicious anemia, pancreatic insufficiency, atrophic gastritis, small bowel bacterial overgrowth, or ileal disease. Megaloblastic anemia and megaloblastic changes in epithelia (see Folate) are the result of sustained depletion. Demyelination of peripheral nerves, posterior and lateral columns of the spinal cord, and nerves within the brain may occur. Altered mentation, depression, and psychoses occur. Hematologic and neurologic complications may occur independently. Folate supplementation, in doses of 1000 µg/day, may partly correct the anemia, thereby masking (or perhaps exacerbating) the neuropathic complication. [2.4 µg] | A few allergic reactions have been reported to crystalline B 12 preparations and are probably due to impurities, not the vitamin. [TUL not established.] | Serum or plasma B 12 concentrations are generally accurate, although subtle deficiency with neurologic and/or hematologic complications can occur with levels in the low-normal range (148-258 pmol/L or 200–350 pg/mL). In this setting deficiency can be established by concurrently measuring the concentration of plasma B 12 and serum methylmalonic acid, which is a sensitive indicator of cellular deficiency. This subtle deficiency state has been increasingly recognized among older populations. Serum holotranscobalamin is another metric, although it is not clearly superior to plasma B 12 . |
| Biotin | A bi-cyclic compound consisting of a ureido ring fused to a substituted tetrahydrothiophene ring. Endogenous synthesis by intestinal flora may contribute significantly to biotin nutriture. Most dietary biotin is linked to lysine, a compound called biotinyl lysine, or biocytin. The lysine must be hydrolyzed by an intestinal enzyme called biotinidase before intestinal absorption occurs. Biotin acts primarily as a coenzyme for several carboxylases; each holoenzyme catalyzes an adenosine triphosphate–dependent carbon dioxide transfer. The carboxylases are critical enzymes in carbohydrate and lipid metabolism. | Isolated deficiency is rare. Deficiency in humans has been produced by prolonged total parenteral nutrition lacking the vitamin and by ingestion of large quantities of raw egg white, which contains avidin, a protein that binds biotin with such high affinity that it renders it biounavailable. Alterations in mental status, myalgias, hyperesthesias, and anorexia occur. Later, a seborrheic dermatitis and alopecia develop. Deficiency is usually accompanied by lactic acidosis and organic aciduria. [30 µg] | Toxicity has not been reported in humans with doses as high as 60 mg/day in children. [TUL not established.] | Plasma and urine concentrations of biotin are diminished in the deficient state. Elevated urine concentrations of methyl citrate, 3-methylcrotonylglycine, and 3-hydroxyisovalerate are also observed in deficiency. |
| Pantothenic acid | Consists of pantoic acid linked to β-alanine through an amide bond. Pantothenic acid is an essential component of CoA and phosphopantetheine, which are essential for synthesis and β-oxidation of fatty acids as well as for synthesis of 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 B 12 , the porphyrin ring of heme, and of cytochromes. CoA is also necessary for the acetylation and fatty acid acylation of a variety of proteins. | Deficiency is rare; it has been reported only as a result of feeding of semisynthetic diets or consumption of an antagonist such as calcium homopantothenate (which has been used to treat Alzheimer disease). Experimental, isolated deficiency in humans produces fatigue, abdominal pain, vomiting, insomnia, and paresthesias of the extremities. [5 mg] | In doses of 10 g/day, diarrhea is reported to occur. [TUL not established.] | Whole blood and urine concentrations of pantothenate are indicators of status; serum levels are not thought to be accurate. |
CoA = coenzyme A; F = female; M = male; NAD = nicotinamide adenine dinucleotide; NADP = nicotinamide adenine dinucleotide phosphate; PLP = pyridoxal phosphate; PTH = parathyroid hormone; RBC = red blood cell; TUL = tolerable upper limit; UVB = ultraviolet B; WBC = white blood cell.
∗ Recommended daily allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999-2001 (updated in 2010 for vitamin D and calcium). In some instances, insufficient data exist to establish an RDA, in which case the adequate intake (AI) established by the board is listed.
† Tolerable upper limit (TUL) established for adults by the U.S. Food and Nutrition Board, 1999-2001.
TABLE 199-3
NUTRITIONAL TRACE ELEMENTS AND THEIR CLINICAL IMPLICATIONS
| BIOCHEMISTRY AND PHYSIOLOGY | DEFICIENCY [RDA ∗ ] | TOXICITY [TUL † ] | ASSESSMENT OF STATUS | |
|---|---|---|---|---|
| Chromium | 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 in humans has been described only in long-term total parenteral nutrition (TPN) patients receiving insufficient chromium. Hyperglycemia or impaired glucose tolerance occurs. Elevated plasma free fatty acid concentrations, 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] | Toxicity after oral ingestion is uncommon and seems confined to gastric irritation. Airborne exposure may cause contact dermatitis, eczema, skin ulcers, and bronchogenic carcinoma. [No TUL established.] | Plasma or serum concentration of chromium is a crude indicator of chromium status; it appears to be meaningful when the value is markedly above or below the normal range. |
| Copper | Copper is absorbed by a specific intestinal transport mechanism. It is carried to the liver, where it is bound to ceruloplasmin, which circulates systemically and delivers copper to target tissues in the body. Excretion of copper is largely through bile and then into the feces. Absorptive and excretory processes vary with the levels of dietary copper, providing a means of copper homeostasis. Copper serves as a component of many enzymes, including amine oxidases, ferroxidases, cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase, and tyrosinase. | Dietary deficiency is rare; it has been observed in premature and low-birthweight infants fed exclusively a cow’s milk diet and in individuals on long-term TPN lacking copper. It has also been described after gastric bypass surgery and with chronic zinc supplementation. Clinical manifestations include depigmentation of skin and hair, myelopathy and other neurologic lesions, leukopenia, anemia, and skeletal abnormalities. Anemia arises from impaired utilization of iron and therefore often is manifested as a sideroblastic anemia. The peripheral smear and bone marrow may mimic myelodysplasia. A deficiency syndrome is also observed in Menkes disease, a rare inherited condition associated with impaired copper utilization. [900 µg] | Acute copper toxicity has been described after excessive oral intake and with absorption of copper salts applied to burned skin. Milder manifestations include nausea, vomiting, epigastric pain, and diarrhea; coma and hepatic necrosis may ensue in severe cases. Toxicity may be seen with doses as low as 70 µg/kg/day. Chronic toxicity is also described. Wilson disease is a rare, inherited disease associated with abnormally low ceruloplasmin levels and accumulation of copper in the liver and brain, eventually leading to damage to these two organs. [10 mg] | Practical methods to detect marginal deficiency are not available. Marked deficiency is reliably detected by diminished serum copper and ceruloplasmin concentrations as well as by low red blood cell superoxide dismutase activity. |
| Fluorine | Known more commonly by its ionic form, fluoride. Fluorine is incorporated into the crystalline structure of bone, thereby altering its physical characteristics. Fluoridation of water has reduced incidence of caries in communities with fluoridation programs. | 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 and clinical assessment are used because no good laboratory test exists. |
| Iodine | Iodine is readily absorbed from the diet, concentrated in the thyroid, and integrated into the thyroid hormones thyroxine and triiodothyronine. These hormones circulate largely bound to thyroxine-binding globulin. They modulate resting energy expenditure and, in the developing human, growth and development. | In the absence of supplementation, populations relying primarily on food from soils with low iodine content have endemic iodine deficiency. Maternal iodine deficiency leads to fetal deficiency, which produces spontaneous abortions, stillbirths, hypothyroidism, cretinism, and dwarfism. Permanent cognitive deficits may result from iodine deficiency during the first 2 years of life. In the adult, compensatory hypertrophy of the thyroid (goiter) occurs along with varying degrees of hypothyroidism. [150 µg] | Large doses (>2 mg/day in adults) may induce hypothyroidism by blocking thyroid hormone synthesis. Supplementation with >100 mg/day to an individual who was formerly deficient occasionally induces hyperthyroidism. [1.1 mg] | Iodine status of a population can be estimated by the prevalence of goiter. Urinary excretion of iodine is an effective laboratory means of assessment. Thyroid-stimulating hormone blood level is an indirect and therefore not entirely specific means of assessment. |
| Iron | Conveys the capacity to participate in redox reactions to a number of metalloproteins, such as hemoglobin, myoglobin, cytochrome enzymes, and many oxidases and oxygenases. The primary storage form of iron is ferritin and, to a lesser degree, hemosiderin. Intestinal absorption is 15-20% for “heme” iron and 1-8% for iron contained in vegetables. Absorption of the latter form is enhanced by the ascorbic acid in foodstuffs; by poultry, fish, or beef; and by an iron-deficient state. It is decreased by phytate and tannins. | Iron deficiency is the most common micronutrient deficiency in the world. Women of childbearing age are the group at highest risk because of menstrual blood losses, pregnancy, and lactation. The classic deficiency syndrome is hypochromic, microcytic anemia. Glossitis and koilonychia (“spoon” nails) are also observed. Easy fatigability often is an early symptom, before anemia appears. In children, mild deficiency of insufficient severity to cause anemia is associated with behavioral disturbances and poor school performance. [postmenopausal F and M: 8 mg; premenopausal F: 18 mg] | Iron overload typically occurs when habitual dietary intake is extremely high, intestinal absorption is excessive, repeated parenteral administration occurs, or a combination of these factors exists. Excessive iron stores usually accumulate in the reticuloendothelial tissues and cause little damage (hemosiderosis). If overload continues, iron eventually begins to accumulate in tissues such as the hepatic parenchyma, pancreas, heart, and synovium, causing hemochromatosis ( Chapter 196 ). Hereditary hemochromatosis results from homozygosity of a common recessive trait. Excessive intestinal absorption of iron is seen in homozygotes. [45 mg] | Negative iron balance initially leads to depletion of iron stores in the bone marrow; a bone marrow biopsy and the concentration of serum ferritin are accurate indicators of early depletion. As the severity of deficiency proceeds, serum iron (SI) decreases and total iron-binding capacity (TIBC) increases; an iron saturation (SI/TIBC) of <16% suggests iron deficiency. Microcytosis, hypochromia, and anemia ensue. Elevated levels of serum ferritin or an iron saturation of >60% suggests iron overload, although systemic inflammation elevates serum ferritin regardless of iron status. |
| Manganese | A component of several metalloenzymes. Most manganese is in mitochondria, where it is a component of manganese superoxide dismutase. | Manganese deficiency in the human has not been conclusively demonstrated. It is said to cause hypocholesterolemia, weight loss, hair and nail changes, dermatitis, and impaired synthesis of vitamin K–dependent proteins. [F: 1.8 mg; M: 2.3 mg] | Toxicity by oral ingestion is unknown in humans. Toxic inhalation causes hallucinations, other alterations in mentation, and extrapyramidal movement disorders. [11 mg] | Until the deficiency syndrome is better defined, an appropriate measure of status will be difficult to develop. |
| Molybdenum | A cofactor in several enzymes, most prominently xanthine oxidase and sulfite oxidase. | A probable case of human deficiency is described as being secondary to parenteral administration of sulfite and resulted in hyperoxypurinemia, hypouricemia, and low sulfate excretion. [45 µg] | Toxicity not well described in humans, although it may interfere with copper metabolism at high doses. [2 mg] | Laboratory means of assessment are not meaningful until the deficiency syndrome is better described. |
| Selenium | Most dietary selenium is in the form of an amino acid complex. Nearly complete absorption of such forms occurs. Homeostasis is largely performed by the kidney, which regulates urinary excretion as a function of selenium status. Selenium is a component of several enzymes, most notably glutathione peroxidase and superoxide dismutase. These enzymes protect against oxidative and free radical 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. | Deficiency is rare in North America but has been observed in individuals on long-term TPN lacking selenium. Such individuals have myalgias or cardiomyopathies. Populations in some regions of the world, most notably some parts of China, have marginal intake of selenium. In these regions Keshan disease , a condition characterized by cardiomyopathy, is endemic; it can be prevented (but not treated) by selenium supplementation. [55 µg] | Toxicity is associated with nausea, diarrhea, alterations in mental status, peripheral neuropathy, and loss of hair and nails; such symptoms were observed in adults who inadvertently consumed 27-2400 mg. [400 µg] | 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. |
| Zinc | Intestinal absorption occurs by a specific process that is enhanced by pregnancy and corticosteroids and diminished by coingestion of phytates, phosphates, iron, copper, lead, or calcium. Diminished intake of zinc leads to an increased efficiency of absorption and decreased fecal excretion, providing a means of zinc homeostasis. Zinc is a component of more than 100 enzymes, among which are DNA polymerase, RNA polymerase, and transfer RNA synthetase. | Zinc deficiency has its most profound effect on rapidly proliferating tissues. Mild deficiency: growth retardation in children. More severe deficiency: growth arrest, teratogenicity, hypogonadism and infertility, dysgeusia, poor wound healing, diarrhea, dermatitis on the extremities and around orifices, glossitis, alopecia, corneal clouding, loss of dark adaptation, and behavioral changes. Impaired cellular immunity is observed. Excessive loss of gastrointestinal secretions through chronic diarrhea and fistulas may precipitate deficiency. Acrodermatitis enteropathica is a rare, recessively inherited disease in which intestinal absorption of zinc is impaired. [F: 8 mg; M: 11 mg] | Acute zinc toxicity can usually be induced by ingestion of >200 mg of zinc in a single day (in adults). It is manifested by epigastric pain, nausea, vomiting, and diarrhea. Hyperpnea, diaphoresis, and weakness may follow inhalation of zinc fumes. Copper and zinc compete for intestinal absorption: long-term ingestion of >25 mg/day of zinc may lead to copper deficiency. Long-term ingestion of >150 mg/day has been reported to cause gastric erosions, low high-density lipoprotein cholesterol levels, and impaired cellular immunity. [40 mg] | No accurate indicators of zinc status exist for routine clinical use. Plasma, red blood cell, and hair zinc concentrations are often misleading. Acute illness, in particular, is known to diminish plasma zinc levels, in part by inducing a shift of zinc out of the plasma compartment and into the liver. Functional tests that determine dark adaptation, taste acuity, and rate of wound healing lack specificity. |
∗ 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.
† Tolerable upper limit (TUL) established for adults by the U.S. Food and Nutrition Board, 1999-2001.
Types and Function of Micronutrients
Vitamins
Vitamins are categorized as either fat soluble (A, D, E, K) or water soluble (all the others; see Table 199-2 ). Fat-soluble vitamins rarely serve as coenzymes, whereas most of the functions of the water-soluble vitamins are as coenzymes. Intestinal absorption of the fat-soluble vitamins is primarily through a micellar phase, and pathophysiologic conditions that are associated with fat malabsorption frequently are also associated with selective deficiencies of fat-soluble vitamins. In contrast, water-soluble vitamins are not absorbed through the lipophilic phase in the intestine and are not linked to the absorption of fats.
Trace Elements
Fifteen trace minerals (iron, zinc, copper, chromium, selenium, iodine, fluorine, manganese, molybdenum, cobalt, nickel, tin, silicon, vanadium, and arsenic; see Table 199-3 ) are essential for health, but only the first 10 of these have compelling evidence to indicate that they are essential nutrients in humans. Cobalt appears to be essential solely as a component of vitamin B 12 , but an isolated deficiency state has never been described. Only under exceptional circumstances, such as long-term reliance on total parenteral nutrition ( Chapter 198 ), have deficiencies of some of these trace minerals (e.g., selenium) been observed.
The biochemical functions of trace elements appear to be as components of prosthetic groups (i.e., tightly bound units required for the biologic function of some proteins) or as cofactors for enzymes (i.e., units bound to an apoenzyme by noncovalent binding). With the exception of iron, blood levels of these trace elements frequently do not correlate well with levels in the target tissues, and accurate functional tests are not available.
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