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 (425mg, women; 550mg, men) and a
TUL (3.5g) 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
400g/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 20g/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, >150,000g 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 -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
>10,000g: 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: 700g; M:
induction and maintenance of cellular
hyperostosis are common.
900g]
differentiation in certain tissues; signal
Single, large doses of vitamin
for appropriate morphogenesis in the
A (30,000g), or habitual
developing embryo; maintenance of
intake of >4500g/day in
cell-mediated immunity. One
early pregnancy can be
microgram of retinol = 3.33IU 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.
[3000g]

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.
[50g]
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. [15g, ages
at the 25 and 1 positions, respectively,
19-70yr; 20g, age >70yr]
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 = 40IU.

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 FUNCTIONScontd

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
-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.
[15mg]

TOXICITY [TUL]
ASSESSMENT OF STATUS
Depressed levels of vitamin
Plasma or serum concentration
K-dependent procoagulants
of -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
800mg/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. [1000mg]
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
-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: 90g; M: 120g]
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 >400mg/
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 -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.
(Wernickes encephalopathy);
hallucinations, impaired short-term
memory, and confabulation
(Korsakoff s psychosis). Deficiency
syndrome responds within 24hr to
parenteral thiamin but is partially or
wholly irreversible after a certain stage.
[F: 1.1mg; M: 1.2mg]

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 FUNCTIONScontd

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. [35mg]
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; 60mg of dietary
dysesthesias are early signs. Reported
tryptophan yields approximately 1mg
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: 14mg; M: 16mg]
Requirement is often determined on
basis of caloric intake (i.e., niacin
equivalents/1000kcal). Large doses of
nicotinic acid (1.5-3g/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 200mg/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. [100mg]
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
-aminolevulinic acid (and therefore in
B6 metabolism. [Ages 19-50yr:
heme synthesis). It also has functions
1.3mg; >50yr: 1.5mg for women,
unrelated to coenzymatic activity: PL
1.7mg 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 >1000g/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. [1000g]
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. [400g of dietary folate
respectively.
equivalents (DFE); 1DFE = 1g food
folate = 0.6g 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 FUNCTIONScontd

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
500mg/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,
>1g/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. Womens
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 mens 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: 75mg; M: 90mg; increase
this property. Vitamin C in foodstuffs
gradually because
requirement for cigarette smokers by
increases the intestinal absorption of
accommodation appears to
35mg/day]
nonheme iron.
occur, raising a concern of
rebound scurvy. [2g]
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 1000g/
intracellular retention of folates.
day, may partly correct the anemia,
thereby masking (or perhaps
exacerbating) the neuropathic
complication. [2.4g]

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 60mg/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. [30g]
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
-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 -oxidation
pain, vomiting, insomnia, and
of fatty acids, as well as synthesis of
paresthesias of the extremities. [5mg]
cholesterol, steroid hormones,
vitamins A and D, and other
isoprenoid derivatives. CoA is also
involved in the synthesis of several
amino acids and -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 10g/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:
25g; M: 35g]

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
cows 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 70g/kg/day. Chronic
processes vary with the levels of
skeletal abnormalities. Anemia arises
toxicity is also described. Wilsons
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 -hydroxylase,
Menkes disease, a rare inherited
damage to these two organs.
superoxide dismutase, and
condition associated with impaired
copper utilization. [900g]
[10mg]
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 (>2mg/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
>100mg/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. [1.1mg]
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.
[150g]

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: 8mg; premenopausal F:
hemochromatosis (Chapter 219).
saturation of >60% suggest iron
decreased by phytate and tannins.
18mg]
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. [45mg]

Intake of <0.1mg/day in infants and

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

Acute ingestion of >30mg/kg body

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

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 IMPLICATIONScontd

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. [11mg]
dermatitis, and impaired synthesis of
vitamin Kdependent proteins. [F:
1.8mg; M: 2.3mg]

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
[2mg]
resulted in hyperoxypurinemia,
hypouricemia, and low sulfate
excretion. [45g]

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
27-2400mg. [400g]
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 Keshans 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.
[55g]
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 >200mg 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 >25mg/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
>150mg/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. [40mg]
inherited disease in which intestinal
absorption of zinc is impaired. [F:
8mg; M: 11mg]

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 15g/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 individuals 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 -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 400g/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 400g/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
400g/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 1000g/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 -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 (~30mg/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 -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 800IU 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 -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 -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 -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 -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
-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
-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 -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 900pg/mL. Values greater than 150pg/
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 400pg/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 400pg/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.