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MD Consult: Books: Goldman: Cecil Medicine: Chapter 237 – VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 237 – VITAMINS, TRACE MINERALS, AND OTHER MICRONUTRIENTS

Joel B. Mason

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 as prosthetic groups, others as biochemical substrates or hormones, and, 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 operations 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 this physiologic window is either not met or exceeded. 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 237-1 ). 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 revised between 1998 and 2001, and the values for adults appear in Tables 237-2 and 237-3 [2] [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 237-2 and 237-3 [2] [3]). Adequate intake, the amount necessary to prevent a deficiency state, is not necessarily synonymous with optimal intake.


TABLE 237-1   — 
FACTORS THAT DETERMINE DIETARY REQUIREMENT OF A MICRONUTRIENT

PHYSIOLOGIC FACTORS

   Bioavailability: 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 that 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 such as smoking, ethanol consumption
   Drugs that may alter bioavailability or utilization

TABLE 237-2   — 
VITAMINS AND THEIR FUNCTIONS

  Biochemistry and Physiology Deficiency [RDA[*]] Toxicity [TUL[]] Assessment of Status
FAT-SOLUBLE VITAMINS
Vitamin A A subset of the retinoid compounds, each member having biologic activity qualitatively similar to retinol, a member of the family. Follicular hyperkeratosis and night blindness are early indicators. 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. 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 an electroretinogram are useful functional tests.
  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. It is needed for the induction and maintenance of cellular differentiation in certain tissues. It serves as a signal for appropriate morphogenesis in the developing embryo and is needed for maintenance of cell-mediated immunity. One microgram of retinol is equivalent to 3.33IU of vitamin A. Conjunctival xerosis, degeneration of the cornea (keratomalacia), and de-differentiation of rapidly proliferating epithelia are later indications of deficiency. Bitot’s spots (focal areas of the conjunctiva or cornea with foamy appearance) are an indication of xerosis. Blindness from corneal destruction and retinal dysfunction ensues if the deficiency is left uncorrected. Increased susceptibility to infection is also a consequence. [F: 700 μg; M: 900 μg] Single, large doses of vitamin A (30,000 μg) or habitual intake of >4500 μg/day in early pregnancy can be teratogenic.  
      Chronic excessive intake of β-carotene can cause yellowish skin dis-coloration and is implicated in enhancing lung carcinogenesis in smokers. Habitually large doses of canthaxanthin may induce a retinopathy. [3000 μg]  
Vitamin D A group of sterol compounds whose parent structure is cholecalciferol (vitamin D3). Cholecalciferol is formed in the skin from 7-dehydrocholesterol (provitamin D3) by exposure to ultraviolet B radiation. A plant sterol, ergocalciferol (provitamin D2) can be similarly converted into vitamin D2 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. It maintains intracellular and extracellular concentrations of calcium and phosphate by enhancing intestinal absorption of the two ions and, in conjunction with parathyroid hormone, promoting their mobilization from bone mineral. Vitamin D retards proliferation and promotes differentiation in certain epithelia. One microgram is equivalent to 40IU. Deficiency results in disordered bone modeling called rickets in childhood and osteomalacia in adults. 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. Excess amounts result in abnormally high concentrations of calcium and phosphate in the serum: metastatic calcifications, renal damage, and altered mentation may occur. [50 μg] The serum concentration of the major circulating metabolite, 25-hydroxy vitamin D, is an excellent indicator of systemic status except in chronic renal failure, in which the impairment of renal 1-hydroxylation results in disassociation of in the mono- and dihydroxyvitamin concentrations.
    Deformity of bone and pathologic fractures occur. Decreased serum concentrations of calcium and phosphate may occur. [5 μg, ages 19–50 yr; 10 μg, ages 51–70 yr; 15 μg, age >70 yr]   Measuring the serum concentration of 1,25-dihydroxy vitamin D is then necessary.
Vitamin E A group of at least 8 naturally occurring compounds, some of which are tocopherols and some of which are tocotrienols. At present, the only dietary form thought to be biologically active in humans is α-tocopherol. Deficiency from dietary inadequacy is rare in developed countries. It is usually seen in (1) premature infants, (2) individuals with fat malabsorption, and (3) individuals with abetalipoproteinemia. RBC fragility occurs and can produce hemolytic anemia. Depressed levels of vitamin K–dependent procoagulants and potentiation of oral anticoagulants has been reported, as has impaired WBC function. Doses of 800 mg/day have been reported to increase the incidence of hemorrhagic stroke slightly. [1000 mg] Plasma or serum concentration of α-tocopherol is most commonly used. Additional accuracy is obtained by expressing this value per milligrams of total plasma lipid. The RBC cell peroxide hemolysis test is not entirely specific but is a useful functional measure of the antioxidant potential of cell membranes.
  It 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. 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. It may contribute to hemolytic anemia and retrolental fibroplasia in premature infants. It has been reported to suppress cell-mediated immunity. [15 mg]    
Vitamin K A family of naphthoquinone compounds with similar biologic activity. Deficiency syndrome is uncommon, except in (1) breast-fed newborns, in whom it may cause “hemorrhagic disease of the newborn,” (2) adults with fat malabsorption or who are taking drugs that interfere with vitamin K metabolism (e.g., coumarin, phenytoin, broad-spectrum antibiotics), and (3) 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 vitamin K1 has been associated with dyspnea, flushing, and cardiovascular collapse, likely related to the dispersing agents in the solution. Prothrombin time is typically used as a measure of functional K status; it is neither sensitive nor specific for vitamin K deficiency.
  Phylloquinone (vitamin K1) is derived from plants; a variety of menaquinones (vitamin K2) is derived from bacterial sources. It 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 the bone matrix.   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] Determination of undercarboxylated prothrombin in the plasma is more accurate for detecting deficiency but less widely available.
WATER-SOLUBLE VITAMINS
Thiamine (vitamin B1) A water-soluble compound containing substituted pyrimidine and thiazole rings and a hydroxyethyl side chain. The classic deficiency syndrome (“beriberi”) is described in Asian populations consuming a polished rice diet. Alcoholism and chronic renal dialysis are common precipitants; can also occur after bariatric surgery complicated by persistent vomiting. 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 vitamin B1 status is the RBC transketolase activity coefficient, which measures enzyme activity before and after addition of exogenous thiamine pyrophosphate: RBCs from a deficient individual express a substantial increase in enzyme activity with addition of thiamine pyrophosphate.
  The coenzyme form is thiamine pyrophosphate. Mild deficiency commonly produces irritability, fatigue, and headaches. More pronounced deficiency produces various combinations of peripheral neuropathy, cardiovascular dysfunction, and cerebral dysfunction.   Thiamine concentrations in blood or urine are also used.
  It serves as a coenzyme in many α-ketoacid decarboxylation and transketolation reactions. Inadequate thiamine availability leads to impairments of the foregoing reactions, resulting in inadequate adenosine triphosphate synthesis and abnormal carbohydrate metabolism, respectively. It may have an additional role in neuronal conduction independent of aforementioned actions. Cardiovascular involvement (“wet beriberi”) includes congestive heart failure and low peripheral vascular resistance. Cerebral disease includes nystagmus, ophthalmoplegia, and ataxia (Wernicke’s encephalopathy) as well as hallucinations, impaired short-term memory, and confabulation (“Korsakoff’s psychosis”). The deficiency syndrome responds within 24 hr to parenteral thiamine but is partially or wholly irreversible after a certain stage. [F: 1.1 mg; M: 1.2 mg]    
Riboflavin (vitamin B2) A compound consisting of a substituted isoalloxazine ring with a ribitol side chain. The vitamin 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 a myriad of metabolic pathways. Deficiency is usually seen in conjunction with deficiencies of other B vitamins. Toxicity is not reported in humans. [TUL not established] The most common method of assessment is determining the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose-6-phosphate dehydrogenase deficiency).
    Isolated deficiency of riboflavin produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and normochromic, normocytic anemia. [F: 1.1; M: 1.3]   Measurements of blood and urine concentrations are less desirable methods.
Niacin (vitamin B3) 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. Pellagra is the classic deficiency syndrome and is often seen in populations where 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 pigmented dermatitis that develops in sun-exposed areas are typical features. Human toxicity is known largely through studies examining hypolipidemic effects. It 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.
  More than 200 apoenzymes use these compounds as electron acceptors or hydrogen donors, either as a coenzyme or a cosubstrate. The essential amino acid tryptophan is used as a precursor of niacin; 60 mg dietary tryptophan yields approximately 1 mg niacin. Dietary requirements thus depend partly on the tryptophan content of the diet. The requirement is often determined on the basis of caloric intake (i.e., niacin equivalents/1000kcal). Glossitis, stomatitis, vaginitis, vertigo, and burning dysesthesias are early signs. It is reported to occur occasionally in carcinoid syndrome, because tryptophan is diverted to other synthetic pathways. [F: 14 mg; M: 16 mg]   Measurement of urinary excretion of the niacin metabolites, N-methylnicotinamide and 2-pyridone, are thought to be the most effective means of assessment at present.
  Large doses of nicotinic acid (1.5–3 g/day) effectively lower low-density lipoprotein cholesterol and elevate high-density lipoprotein cholesterol.      
Vitamin B6 Refers to several derivatives of pyridine, including pyridoxine, pyridoxal, and pyridoxamine, which are interconvertible in the body. The coenzymatic forms are PLP and pyridoxamine-5-phosphate. As a coenzyme, vitamin B6 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 modulates steroid activity. Deficiency is usually seen in conjunction with other water-soluble vitamin deficiencies. 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 RBC PLP levels are most common. Urinary excretion of xanthurenic acid after an oral tryptophan load and activity indices of RBC alanine or aspartic acid transaminases are functional measures of vitamin B6–dependent enzyme activity.
    Stomatitis, angular cheilosis, glossitis, irritability, depression, and confusion occur in moderate to severe depletion; normochromic, normocytic anemia has been reported in severe deficiency.    
    Abnormal electroencephalograms and, in infants, convulsions have been observed. Some sideroblastic anemias respond to vitamin B6 administration.    
    Isoniazid, cycloserine, penicillamine, ethanol, and theophylline can inhibit vitamin B6 metabolism. [Ages 19–50 yr: 1.3 mg; >50: 1.5 mg for women, 1.7 mg for men]    
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. All folate functions relate to its ability to transfer one-carbon groups. It is essential in the de novo synthesis of nucleotides, in the metabolism of several amino acids, and is an integral component for the regeneration of the “universal” methyl donor, S-adenosylmethionine. Women of childbearing age are most likely to be deficient. The classic deficiency syndrome is megaloblastic anemia. 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.

   Doses >1000 g/day may partially correct the anemia of vitamin B12 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.
Serum folate measures short-term folate balance, whereas RBC folate is a better reflection of tissue status. Serum homocyst(e)ine rises early in deficiency but is nonspecific because vitamin B12 or B6 deficiency, renal insufficiency, and older age may also cause elevations.
  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. Megaloblastic changes also occur in other epithelia that proliferate rapidly (e.g., oral mucosa, gastrointestinal tract, producing glossitis and diarrhea, respectively). Parenteral administration is rarely reported to cause allergic phenomena, which is probably the result of dispersion agents. [1000 μg]  
    Sulfasalazine and diphenytoin inhibit absorption and predispose to deficiency. [400 μg of dietary folate equivalents (DFE); 1 μg folic acid = 1 μg DFE; 1 μg food folate = 0.6 μg DFE]    
Vitamin C (ascorbic and dehydroascorbic acid) Ascorbic acid readily oxidizes to dehydroascorbic acid in aqueous solution. Overt deficiency is uncommon in developed countries. Quantities 500 mg/day (in adults) sometimes cause nausea and diarrhea. 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.
  Because the latter can be reduced in vivo, it possesses vitamin C activity. Total vitamin C is therefore measured as the sum of ascorbic and dehydroascorbic acid concentrations. Because of its reductant properties, it serves primarily as a biologic antioxidant in aqueous environments. The classic deficiency syndrome is scurvy: characterized by 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] Acidification of the urine with supplementation and the potential for enhanced oxalate synthesis have raised concerns about nephrolithiasis, but this has yet to be demonstrated.  
  Biosyntheses of collagen, carnitine, bile acids, and norepinephrine, as well as proper functioning of the hepatic mixed-function oxygenase system, depend on this property.   Supplementation may interfere with laboratory tests based on redox potential (e.g., fecal occult blood testing, serum cholesterol, and glucose).  
  Vitamin C in foodstuffs increases the intestinal absorption of nonheme iron.   Withdrawal from long-term ingestion of high doses of vitamin C supplements should occur gradually over a month because accommodation seems to occur, raising a concern of “rebound scurvy.” [2 g]  
Vitamin B12 A group of closely related cobalamin compounds composed of a corrin ring (with a cobalt atom in its center) connected to a ribonucleotide via an aminopropanol bridge. Dietary inadequacy is a rare cause of deficiency except in strict vegetarians. A few allergic reactions have been reported to crystalline vitamin B12 preparations and are probably caused by impurities, not by the vitamin. [TUL not established] Serum, or plasma, concentrations are generally accurate.
  Microorganisms are the ultimate source of all naturally occurring vitamin B12. The two active coenzyme forms are desoxyadenosyl-cobalamin and methylcobalamin. Most deficiencies arise from loss of intestinal absorption: this may be a result of pernicious anemia, pancreatic insufficiency, atrophic gastritis, small bowel bacterial overgrowth, or ileal disease.   Subtle deficiency with neurologic complications, as described in the Deficiency column, can best be established by concurrently measuring the concentration of plasma vitamin B12 and serum methylmalonic acid, because the latter is a sensitive indicator of cellular deficiency.
  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 latter reaction is essential for amino acid metabolism, for purine and pyrimidine synthesis, for many methylation reactions, and for the intracellular retention of folates. Megaloblastic anemia and megaloblastic changes in other epithelia (see Folate) are the result of sustained depletion.    
    Demyelination of peripheral nerves, posterior and lateral columns of 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]    
Biotin A bicyclic compound consisting of a ureido ring fused to a substituted tetrahydrothiophene ring. Isolated deficiency is rare. Deficiency in humans has been produced experimentally (by dietary inadequacy), 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. 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.
  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. It 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. Alterations in mental status, myalgias, hyperesthesias, and anorexia occur. Later, seborrheic dermatitis and alopecia develop. Biotin deficiency is usually accompanied by lactic acidosis and organic aciduria. [30 μg]   Elevated urine concentrations of methyl citrate, 3-methylcrotonylglycine, and 3-hydroxyisovalerate are also observed in deficiency.
Pantothenic acid Pantoic acid linked to β-alanine through an amide bond. It serves as an essential component of CoA and phosphopantetheine, which are needed 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-minolevulinic 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. Deficiency is rare, reported only as a result of feeding semisynthetic diets or an antagonist to the vitamin. 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.
    Experimental, isolated deficiency in humans produces fatigue, abdominal pain, vomiting, insomnia, and paresthesias of the extremities. [5 mg]    

* Recommended dietary allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999 to 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 intake (TUL) established for adults by the U.S. Food and Nutrition Board, 1999 to 2001. CoA, coenzyme A; PLP = pyridoxal-5-phosphate; RBC = red blood cell; WBC = white blood cell.


TABLE 237-3   — 
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 is described only in patients receiving long-term TPN with insufficient chromium. Toxicity after oral ingestion is uncommon and seems confined to gastric irritation. Plasma or serum concentration of chromium is a crude indicator of chromium status; it appears to be meaningful when the value is markedly higher or lower than the normal range.
    Hyperglycemia or impaired glucose tolerance is uniformly observed. Elevated plasma free fatty acid concentrations, neuropathy, encephalopathy, and abnormalities in nitrogen metabolism are also reported. Whether supplemental chromium may improve glucose tolerance in mildly glucose-intolerant but otherwise healthy individuals remains controversial. [F: 25 μg; M: 35 μg] Airborne exposure may cause contact dermatitis, eczema, skin ulcers, and bronchogenic carcinoma. [no TUL established]  
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 receiving long-term TPN without copper. Clinical manifestations include depigmentation of skin and hair, neurologic disturbances, leukopenia, hypochromic microcytic anemia, and skeletal abnormalities. Anemia arises from impaired utilization of iron and is therefore a conditioned form of iron deficiency anemia. 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. Practical methods for detecting marginal deficiency are not available. Marked deficiency is reliably detected by diminished serum copper and ceruloplasmin concentrations as well as low RBC superoxide dismutase activity.
    The deficiency syndrome, except the anemia and leukopenia, is also observed in Menkes’ disease, a rare inherited condition associated with impaired copper utilization. [900 μg] Toxicity may be seen with doses as low as 70 μg/kg/day. Chronic toxicity is also described. Wilson’s disease is a rare, inherited disease associated with abnormally low ceruloplasmin levels and accumulation of copper in the liver and brain that eventually leads to damage to these two organs. [10 mg]  
Fluorine Known more commonly by its ionic form, fluoride. It is incorporated into the crystalline structure of bone, thereby altering its physical characteristics. 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 long-term 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.
Iodine 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. Rapid brain development continues through the second year, and permanent cognitive deficits may be induced by iodine deficiency over that period. 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. 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.
      Supplementation with >100 mg/day to an individual who was formerly deficient occasionally induces hyperthyroidism. [1.1 mg]  
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. This is the most common micronutrient deficiency in the world. Women of childbearing age are the highest-risk group because of menstrual blood losses, pregnancy, and lactation. The classic deficiency syndrome is hypochromic, microcytic anemia. Glossitis and koilonychia (“spoon” nails) are also observed. 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, thus causing hemochromatosis ( Chapter 231 ). 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 and early indicators of such 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 as latter stages of the deficient state. Elevated levels of serum ferritin or an iron saturation >60% suggest iron overload, although systemic inflammation elevates serum ferritin regardless of iron status.
  Primary storage form 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. 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. [M and postmenopausal F: 8 mg; premenopausal F: 18 mg] Hereditary hemochromatosis results from homozygosity of a common recessive trait. Excessive intestinal absorption of iron is seen in homozygotes. [45 mg]  
Manganese A component of several metalloenzymes. 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.
  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. 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 is not well described in humans, although it may interfere with copper metabolism at high doses. [2 mg] Laboratory means of assessment will not be 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 appear to prevent oxidative and free radical damage of various cell structures. Evidence suggests that the antioxidant protection conveyed by selenium operates in conjunction with vitamin E because deficiency of one seems to enhance 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 receiving 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’s 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, loss of hair and nails: such symptoms were observed in adults who inadvertently consumed 27–2400 mg. [400 μg] RBC 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 is diminished by co-ingestion of phytates, phosphates, iron, copper, lead, or calcium. Diminished intake of zinc leads to an increased efficiency of absorption and decreased fecal excretion, thus 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 causes growth retardation in children. More severe deficiency is associated with 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. 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 zinc/day 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, RBC, 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.
    Acrodermatitis enteropathica is a rare, recessively inherited disease in which intestinal absorption of zinc is impaired. [F: 8 mg; M: 11 mg]    

* Recommended dietary allowance (RDA) established for female (F) and male (M) adults by the U.S. Food and Nutrition Board, 1999 to 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 to 2001. RBC = red blood cell; TPN = total parenteral nutrition.

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