UTD Dietary Trace Mineral Deficiency

3/20/2019 Overview of dietary trace minerals - UpToDate
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Overview of dietary trace minerals
Authors: Sassan Pazirandeh, MD, David L Burns, MD, Ian J Griffin, MB ChB
Section Editor: David Seres, MD
Deputy Editor: Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2019. | This topic last updated: Jan 02, 2019.
INTRODUCTION
Minerals form only 5 percent of the typical human diet but are essential for normal health and function. Macrominerals are defined
as minerals that are required by adults in amounts greater than 100 mg/day or make up less than 1 percent of total body weight.
Trace elements (or trace minerals) are usually defined as minerals that are required in amounts between 1 to 100 mg/day by
adults or make up less than 0.01 percent of total body weight. Ultratrace minerals generally are defined as minerals that are
required in amounts less than 1 microgram/day [1]. Although the classification of mineral may be controversial and somewhat
arbitrary, one outline is given in the table (table 1).
This topic review will discuss the physiological and biochemical functions, dietary requirements, and signs and symptoms of
excess and deficiency for the essential trace minerals, including iron, zinc, copper, manganese, fluoride, and selenium. Iodine (an
ultratrace mineral) will also be discussed because of its global importance in iodine deficiency. Several of these minerals are
considered in more depth elsewhere. (See "Iodine deficiency disorders" and "Zinc deficiency and supplementation in children and
adolescents".)
DEFINITIONS
Several systems have been used to describe nutritional requirements of a population. Dietary Reference Intakes (DRIs) were
developed by the Food and Nutrition Board of the Institute of Medicine to guide nutrient intake in a variety of settings; the DRIs for
minerals are summarized in this table. Under this system, requirements can be expressed as a Recommended Dietary Allowance
(RDA), which is defined as the dietary intake that is sufficient to meet the daily nutrient requirements of 97 percent of the
individuals in a specific life stage group. If there is insufficient data to determine an RDA for a given nutrient, requirements can be
expressed as an Adequate Intake (AI), which is an estimation of the nutrient intake necessary to maintain a healthy state. The
upper limit (UL) is the maximum daily intake of a nutrient that is likely to pose no risk of adverse effects. Intake of nutrients far in
excess of the RDA is considered to be "pharmacologic" dosing. Dietary guidelines, which incorporate the RDAs, are periodically
updated as new information arises.
The United States Department of Agriculture uses different nomenclature and age groupings, setting "Daily Values" to describe
recommended intake for adults and children older than four years of age. What appears on food labels is the estimation of the
amount of a nutrient provided based upon a 2000 calorie diet. Updated information can be found at the website of the Food and
Nutrition Information Center of the United States Department of Agriculture [2].
These terms are described in greater detail in a separate topic review. (See "Dietary history and recommended dietary intake in
children".)
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CHROMIUM
In 1957, a compound extracted from pork kidney was termed "glucose tolerance factor" because it corrected hyperglycemia in
rats [3]. Glucose tolerance factor was ultimately found to be chromium (Cr).
Chromium is a transition element and exists in multiple ionic states. Dietary chromium is in the trivalent state. The more oxidized
form Cr4+ is a toxic and hazardous substance. Chromium occurs as a component of a metalloenzymes and functions as a
coenzyme in various metabolic reactions [4].
Dietary sources — Chromium is found in various food products, including grains, cereals, fruits, vegetables, and processed
meats, which have a higher Cr content than unprocessed meats [5].
Metabolism — Chromium is absorbed predominantly in the small intestine and is transported in the circulation bound to albumin
and transferrin [6]. The total body Cr concentration is the main homeostatic control of its gut absorption. Dietary bioavailability of
chromium is very low and almost all of the ingested chromium is excreted via feces [7]. Urinary and biliary excretion are
alternative yet limited routes for its metabolism.
Other minerals influence absorption and cellular uptake of chromium. There is enhanced absorption of chromium in the setting of
zinc and iron deficiency, suggesting that these minerals compete for intestinal absorption, although these effects are inconsistent
[810]. Other factors that interfere with chromium absorption include certain drugs such as antacids, which contain magnesium,
calcium, or aluminum salts. Nonsteroidal antiinflammatory drugs that inhibit the production of prostaglandins also reduce
chromium absorption [11]. Chromium can be reduced by gastric acid to form insoluble salts that can precipitate and block its
absorption [12]. Administration of vitamin C enhances the uptake of chromium [13].
Deficiency — Chromium deficiency is generally limited to hospitalized patients with increased catabolism and metabolic
demands in the setting of malnutrition. Some of the first case reports of chromium deficiency were from patients receiving
parenteral nutrition [13,14]. In diabetic patients receiving chronic total parenteral nutrition, human chromium deficiency has been
associated with increased insulin requirements [13]. Chromium supplementation in these patients improved glucose tolerance
and respiratory quotient, which indicates a preference for fat metabolism and reduced utilization of carbohydrates as an energy
source.
Other patients at risk for chromium deficiency include patients with short bowel syndrome, burns, traumatic injuries, or those on
parenteral nutrition without appropriate trace mineral supplementation [15].
An association has been suggested between low chromium levels and impaired glucose tolerance and unfavorable lipid profiles.
Several studies suggest that chromium levels tend to be lower in patients with type 2 diabetes, but a causal association has not
been established [1618]. Randomized trials on chromium supplementation in patients with type 2 diabetes are of fair quality and
metaanalyses reach conflicting conclusions about whether supplementation improves glycemic control [1922]. (See "Nutritional
considerations in type 2 diabetes mellitus", section on 'Other supplements'.)
There is little evidence to support chromium supplementation in individuals without chromium deficiency. A popular interest has
developed in chromium supplementation as a method for improving lean body mass and muscle building. However, multiple
studies and systematic reviews have shown no clinically important changes in lean body mass, total body fat, or weight loss as a
result of chromium supplementation [8,23,24].
Toxicity — There are no reports of adverse effects of dietary chromium (trivalent chromium). Animal studies suggest that high
doses of chromium are nontoxic, because of poor oral bioavailability [25,26]. However, airborne hexavalent chromium (VI) toxicity
has been established as a workrelated etiology of lung cancer in stainless steel workers [27,28]. Pentavalent (chromium V) and
hexavalent chromium (chromium VI), which are not usually found in the diet, are toxic and carcinogenic by the inhalation route of
exposure [29]. Industrial exposure to chromium (V and VI) can result in toxicity manifested as contact dermatitis, skin ulcers, and
bronchogenic cancers. Tannery workers handling wet hides may develop elevated serum and urinary chromium levels [30].
Dietary reference intake — The adequate intake of chromium for adults is 20 to 35 mcg per day (table 2) [31].
COPPER
Two heritable diseases are caused by inborn errors of copper metabolism: Wilson's disease is a disorder of copper excretion and
is characterized by signs and symptoms of copper toxicity, whereas Menkes disease is a genetic disorder of copper uptake from
the intestine and is characterized by signs and symptoms of copper deficiency. (See 'Menkes disease' below.)
Dietary sources — In the Western diet, approximately 60 percent of dietary copper comes from vegetable products, with
vegetables, grains, and pulses (leguminous seeds such as beans, peas, and lentils) each providing approximately 20 percent. A
further 20 percent comes from meat, fish, and poultry [32]. The highest content of copper is found in liver (20 to 180 mg/kg versus
1 to 2.6 mg/kg in white bread and 0.02 to 0.08 mg/kg in cow's milk). According to the Third National Health and Nutrition Survey,
the average daily dietary copper intake for adults in the United States is 1 to 1.6 mg [31]. Absorption of copper may be impaired
by dietary iron, zinc, or ascorbic acid [3335].
Copper is found in high concentrations in liver, brain, bone and, to a lesser degree, in kidney, heart, and pancreas [35]. The total
copper content in the adult human body is estimated to be 50 to 120 mg. The newborn term infant contains approximately 12 mg
copper. Breast milk contains relatively little copper [36,37]. Early in lactation, breast milk contains up to 0.7 mg/L copper but this
rapidly falls to 0.2 mg/L and may provide less than the recommended copper intake by the World Health Organization (WHO)
[31]. During this period, any shortfall in copper intake can be met by mobilizing liver copper stores.
Metabolism — Copper is absorbed in the proximal small intestine and stomach [38,39]. The acidic environment in the stomach
facilitates solubilization of copper by dissociating it from copper containing dietary macromolecules. Absorption occurs by a
saturable active transport process at lower levels of dietary copper and by passive diffusion at high levels of dietary copper. The
Menkes Ptype ATPase (ATP7A) is responsible for copper trafficking to the secretory pathway for efflux from enterocytes and
other cells. Absorbed copper is loosely bound to plasma albumin and amino acids in the portal blood and taken to the liver where
most of it is taken up on the first pass.
In the liver, the copper is incorporated into the coppercontaining protein ceruloplasmin, which serves to transport copper from the
liver to peripheral tissues. Ceruloplasmin binds to its receptors on the cell surface; copper is then released from its binding protein
and enters the cell. Ceruloplasmin has an independent role in iron metabolism, in which it serves as a plasma ferroxidase,
converting iron to a valence that can be bound by plasma transferrin [4042]. Metallothionein, synthesized in the liver, may act as
a copper storage protein.
Approximately 50 percent of copper is excreted in the bile while the remaining half is excreted through other gastrointestinal
secretions [38,39]. This excretion of copper into the gastrointestinal tract is the major pathway that regulates copper homeostasis
and prevents deficiency or toxicity. The Wilson Ptype ATPase (ATP7B) is responsible for copper trafficking to the secretory
pathway for ceruloplasmin biosynthesis and for endosome formation prior to biliary secretion.
Biological role — A number of important coppercontaining enzymes have been described, including the following [43,44]:
Zinccopper superoxide dismutase (antioxidant defense)
Dopamine monooxygenase (neurotransmitter synthesis)
Lysyl oxidase (collagen crosslinking, bone formation)
Ceruloplasmin (copper transporter and ferroxidase)
Cytochrome c oxidase (electron transport)
Factor V (thrombosis)
Tyrosinase (melanin production)
These cuproenzymes help to explain some of the clinical features of severe copper deficiency, including lack of skin
pigmentation (decreased dopamine betahydrolase), weakness (decreased cytochrome c), and bleeding disorders (decreased
factor V).
Deficiency
Clinical features — Copper deficiency is characterized clinically by fragile, abnormallyformed hair, depigmentation of the
skin, muscle weakness (myeloneuropathy), neurological abnormalities, edema, and hepatosplenomegaly, and osteoporosis. The
neurologic manifestations include ataxia, neuropathy, and cognitive deficits that can mimic vitamin B12 deficiency [45,46]. (See
"Copper deficiency myeloneuropathy" and "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)
Hematologic features of copper deficiency include anemia (usually microcytic) and neutropenia [33,4750]. Because the anemia
is microcytic and hypochromic, it can be mistaken for the anemia of iron deficiency. If iron supplements are given, these can
worsen copper deficiency because excess iron competes with copper and decreases net copper absorption [34].
Thrombocytopenia also may occur but is relatively rare. (See "Sideroblastic anemias: Diagnosis and management", section on
'Copper deficiency'.)
Other laboratory findings include low plasma copper, ceruloplasmin, erythrocyte copperzinc superoxide levels, and diminished
24hour urinary copper excretion [32].
Treatment for copper deficiency consists of supplementation, and correction of the underlying cause of the deficiency, if possible
(see "Copper deficiency myeloneuropathy", section on 'Treatment' and "Sideroblastic anemias: Diagnosis and management",
section on 'Copper deficiency'). Patients on longterm total parenteral nutrition (TPN) require intravenous copper
supplementation, which is usually provided as part of a mixture of trace metals.
Risk factors — Though rare, acquired copper deficiency has been well documented in humans [31,44,51,52]. Acquired
copper deficiency in humans is associated with each of the following risk factors, which may be additive:
Foregut surgery, including gastrectomy or gastric bypass [5356]. Copper deficiency should be considered in patients with a
history of malabsorptive gastrointestinal surgery and myelopathy or new neurologic symptoms, which may mimic vitamin B12
deficiency [56]. This is the most common cause of acquired copper deficiency and likely to become even more prominent as
the rates of bariatric surgery increase. Typically, neurologic manifestations are delayed by years following gastric surgery.
(See "Bariatric surgery: Postoperative nutritional management", section on 'Copper'.)
Premature infants receiving milk formulas without adequate copper supplementation [57,58].
Chronic diarrhea or other malabsorptive conditions including celiac disease [44,51,59,60].
Chronic peritoneal dialysis or hemodialysis [61].
Excessive zinc ingestion. Because copper and zinc are competitively absorbed from the jejunum via metallothionein, high
doses of zinc can result in low copper levels, and occasionally symptomatic copper deficiency, in normal individuals,
particularly if combined with other risk factors such as gastric surgery. Excessive zinc has been ingested due to prolonged
use of zinc supplements (eg, for common colds, acrodermatitis enteropathica, or other conditions) [33,62], ingestion of
denture cream [63,64], or from swallowing zinccontaining coins [65]. Parenteral zinc overloading during chronic
hemodialysis has also been associated with copper deficiency myelopathy [61].
Treatment of Wilson's disease with chelation and zinc administration has occasionally caused iatrogenic copper deficiency
[66,67].
Treatment with the copper chelator Clioquinol (which was commonly used as an overthecounter antiparasitic agent in
Japan in the past) resulted in over 10,000 cases of myeloopticoneuropathy in Japan in the 1960s, which may have been
due to copper deficiency [6870]. Similarly, a case report describes copper deficiency due to selftreatment with
tetrathiomolybdate [71].
Prior to 1979, formulas for TPN did not include trace elements. As a result, those on chronic TPN often developed deficiencies in
copper and other elements [72]. Free amino acids in parenteral nutrition also increase the urinary losses of copper [73]. Although
trace elements are now included in standard TPN, copper and manganese are sometimes withheld in the setting of cholestasis,
which results in a decrease in excretion of these minerals. Copper deficiency has been reported in this setting [74].
Menkes disease — Menkes disease, also known as Menkes kinky hair syndrome, is a congenital xlinked genetic disorder
with an incidence of about 1:100,000 live births. It is caused by a mutation of the transport protein mediating copper uptake from
the intestine, encoded by the ATP7A gene. Inactivating mutations in this gene result in severe copper deficiency with progressive
neurologic deterioration and death during early childhood [75]. This gene is closely related to the gene responsible for copper
overload in Wilson's disease, as discussed separately. (See "Wilson disease: Epidemiology and pathogenesis", section on
'Genetic defect in wilson disease'.)
The clinical manifestations of Menkes disease are those of copper deficiency, but are severe and occur during early infancy.
Affected individuals present with developmental delay and epilepsy, which usually becomes apparent during early infancy, and
develop progressive neurologic symptoms [76]. Physical features include peculiar "kinky" hair, growth retardation,
hypopigmentation of the skin, and bony abnormalities, including osteoporosis and spur formation. The severity of the symptoms
and lifespan are variable [77]. Treatment consists of parenteral administration of a copperhistidine complex, which is not
consistently effective.
Toxicity
Clinical features — Acute copper poisoning in humans causes gastrointestinal symptoms, including abdominal pain, diarrhea,
and vomiting [31]. In more severe forms, it leads to cardiac and renal failure, intravascular hemolysis, hepatic necrosis,
encephalopathy, and ultimately death [78]. It can result from accidental consumption by children, contaminated water sources,
suicide attempts, and topical creams for burn treatment that contains copper salts.
Ceruloplasmin (like ferritin) is an acute phase reactant, so serum copper and ceruloplasmin levels are increased in inflammatory
processes, pregnancy, coronary artery disease, diabetes, malignancies, and renal failure. (See "Wilson disease: Diagnostic
tests", section on 'Limitations of serum ceruloplasmin'.)
Wilson's disease — Wilson's disease is an autosomal recessive disorder characterized by excessive copper accumulation
and is caused by a mutation in a copperATPase enzyme closely related to the Menkes disease gene product [79]. Excessive
copper is deposited in many tissues and leads to cardiac dysfunction, liver cirrhosis, pancreatic dysfunction (diabetes mellitus),
and neurologic abnormalities. (See "Wilson disease: Epidemiology and pathogenesis".)
Treatment for Wilson's disease consists of avoidance of high copper foods and copper chelation. In early stages, pharmacological
doses of zinc may be effective in delaying the onset of symptomatic disease, because zinc competes with copper for absorption
in the gastrointestinal tract. (See "Wilson disease: Treatment and prognosis".)
Dietary reference intake — The RDA for copper is 340 mcg daily for young children and rises to 900 mcg daily for adults [31].
The UL is 1000 mcg daily in young children and 10,000 mcg daily for adults (table 2).
FLUORIDE
Fluoride is relatively common in the earth's crust, but its concentration in water (a major dietary source) is very variable [80]. It
has an important role in preventing dental caries, and is considered beneficial rather than essential [81].
Dietary sources — Ground water contains fluoride in amounts between 0 and 40 mg/L [82]. The variability in water content
explains much of the variability in total fluoride intake. There is a well described inverse relationship between fluoride intake and
dental caries [82,83]. Many domestic water supplies are fluoridated in order to reduce the incidence of caries, although the
practice has raised controversy [84].
Other important sources of fluoride are tea, seafood that contains edible bones or shells (eg, canned sardines), medicinal
supplements, and fluoridated toothpastes [81].
Metabolism — Dietary fluoride is absorbed rapidly in the stomach and small intestine. Onequarter to onethird of the absorbed
fluoride is taken up into calcified tissues, whereas the rest is lost in the urine [82,85]. In bone and teeth, fluoride can displace
hydroxyl ions from hydroxyapatite to produce fluorapatite or fluorohydroxyapatite. About 99 percent of total body fluoride is
contained in bones and teeth [82], and the amount steadily increases during life.
Biological role — It remains unclear whether fluoride is truly essential, although fluoride may have some beneficial effects [81].
Animal models, such as rodents fed fluoridedeficient diets, have failed to show consistent findings of deficiency. However, once
taken up into bone, fluoride appears to increase osteoblast activity and bone density, especially in the lumbar spine [86]. Fluoride
has been suggested as a therapy for osteoporosis since the 1960s, but despite producing denser bone, fracture risk is not
reduced. Indeed, there is some evidence that nonvertebral fractures may be increased [87]. (See "Overview of the management
of osteoporosis in postmenopausal women", section on 'Therapies not recommended'.)
Deficiency — The only known association with low fluoride intake is the risk of dental caries, acting through both preeruptive
(systemic) and posteruptive (topical) mechanisms [84]. The American Dental Association strongly supports fluoridation of
community drinking water supplies [83]; however, strong contradictory opinions also are held [88].
Toxicity — Fluoride toxicity usually results from ingestion of high amounts of fluoride, either in water, fluoride supplements, or as
fluorinecontaining insecticides [84,89,90]. In industrial settings, toxicity also can occur by inhalation or by absorption through the
skin (eg, freon vapor or hydrofluoric acid spills) [80]. More than 80 percent of fluoride toxicity is seen in children younger than age
six, due to ingestion of fluoridecontaining toothpaste or mouthwashes [91]; it is rare in adults in the developed world.
Acute toxicity is characterized by nonspecific gastrointestinal disturbances such as pain, nausea, vomiting, and diarrhea [89,92].
In severe cases, this may progress to renal and cardiac dysfunction, coma, and ultimately death [93]. In children, as little as 8.4
mg/kg may produce symptoms [89].
Chronic fluoride toxicity is usually caused by high fluoride concentrations in drinking water or the use of fluoride supplements.
Chronic ingestion of high doses leads to dental fluorosis, a cosmetic disorder where the teeth become mottled [80]. In more
severe cases, it leads to skeletal fluorosis, in which bone is radiologically dense, but fragile. Fractures can occur, and there may
be calcification of ligaments and tendons, leading to reduced joint mobility [80]. The syndrome also may include extensive
calcification of ligaments and cartilage, as well as the bony outgrowths of osteophytes and exostoses [94].
To reduce dental fluorosis and systemic toxicity, the American Dental Association (ADA) recommends brushing with water rather
than fluoride toothpaste for children younger than two years. Children two to six years should use a small amount of fluoride
toothpaste (approximately peasized) [95]. (See "Preventive dental care and counseling for infants and young children", section
on 'Fluoride'.)
Dietary reference intake — The recommended intake for fluoride is expressed as an adequate intake (AI) rather than RDA,
because of the limited data available to determine the population needs. The AI for fluoride is 0.7 mg daily for toddlers, rising to 3
mg daily for adult women and 4 mg daily for adult men (table 2).
IODINE
The dietary importance of iodine lies in the metabolism and homeostasis of the thyroid gland. Iodine is predominantly found in the
thyroid gland where it is bound to tyrosine as monoiodothyronine (MIT), diiodothyronine (DIT), triiodothyronine (T3), and thyroxine
(T4).
Goiter, described as the enlargement of thyroid gland, was first associated with iodine deficiency in the early 1920s [96,97]. At
that time, goiter was endemic in certain parts of the world and the Midwestern United States. In one study, administration of
iodine treated and prevented goiter in children in goiterendemic areas of Ohio [97]. Iodized salt was then introduced and led to
reduction of hypothyroidismrelated growth retardation and successful prevention of goiter.
In the United States and other industrialized nations, iodine deficiency is rarely seen due to iodized water, salt, and bread.
Although there has been substantial progress in reducing the frequency of iodine deficiency worldwide, it still remains a major
public health issue in parts of the world where its incorporation into diet has been unsuccessful. The epidemiology of iodine
deficiency is described in greater detail in a separate topic review. (See "Iodine deficiency disorders".)
Dietary sources — Iodine is heterogeneously distributed in the environment, with soil and water varying greatly in their iodine
content. Iodine is found naturally in fish and seafood, as well as in drinking water and vegetables. Dairy products contain iodine
because of iodine absorption from iodinecontaining disinfectants. Some breads contain iodine from the dough oxidizers used in
their manufacture [81].
In many countries, food staples such as table salt are fortified with iodine. Approximately 86 percent of the world's population has
access to iodized table salt [98]. (See "Iodine deficiency disorders", section on 'Geographic distribution'.)
Metabolism — Ingested iodine is absorbed readily in the proximal small bowel. Iodine in the circulation is taken up by the thyroid
gland and any excess amount is filtered by the kidneys and excreted.
Significant amounts of iodine are stored in the thyroid as the intermediate products of the thyroxine synthetic pathway and as the
final hormones themselves [31]. Triiodotyrosine and thyroxine are secreted by the gland and have plasma halflives of
approximately two and eight days, respectively [99]. The principle excretory route for iodine is the urine; any losses into the
gastrointestinal tract are rapidly reabsorbed.
Biological role — The sole physiological role of iodine is to form a part of the two thyroid hormones: thyroxine (3,5,3',5'
tetraiodothyronine, T4) and triiodotyrosine (3,5,3'triiodothyronine T3). The thyroid hormones have many physiological roles,
including regulation of basal metabolic rate and gene regulation through specific thyroid response elements. In the setting of low
iodine intake, adequate levels of iodotyrosines cannot be maintained. (See "Iodineinduced thyroid dysfunction".)
Deficiency — Iodine deficiency is associated with goiter, hypothyroidism, mental retardation, and increased neonatal and infant
mortality. Levels of T4 and T3 are low and thyroid stimulating hormone (TSH) is high, due to loss of feedback inhibition on TSH
synthesis. The increased TSH levels lead to hyperplasia and hypertrophy of the thyroid gland, with visible and palpable thyroid
gland enlargement, known as goiter. Urinary excretion of iodine, whether over 24 hours or normalized to urinary creatinine, can
be used as a measure of iodine status or iodine intake [31]. (See "Iodineinduced thyroid dysfunction" and "Thyroid hormone
synthesis and physiology", section on 'Iodine economy'.)
The fetus is vulnerable to iodine deficiency (or any other cause of hypothyroidism) in the mother. Severe, irreversible mental
retardation can result unless iodine deficiency is treated with supplements in the second trimester [31]. Left untreated, cretinism
develops. The hallmark of this condition is severe mental retardation, with or without spasticity, umbilical hernia, and
characteristic facial features. (See "Neurologic manifestations of hypothyroidism".)
Toxicity — Sources of excess iodide include overthecounter and prescription medications that may be ingested or applied to
the skin or vaginal mucosa, radiographic contrast agents, and dietary supplements (kelp, seaweed).
The normal thyroid gland is able to adapt to a wide range of iodine intake. The effects of excessive iodide in patients with
abnormal thyroid glands differs from that in normal subjects, and depends upon the underlying disease process. As an example,
in patients with endemic goiter and iodide deficiency, iodide administration may abruptly increase thyroid hormone production,
causing hyperthyroidism. Conversely, in patients with Hashimoto's thyroiditis, iodide administration may induce or exacerbate
hypothyroidism. (See "Iodineinduced thyroid dysfunction".)
Dietary reference intake — The RDA for iodine is 90 mcg daily for children 1 to 8 years old, 120 mcg for children 9 to 13 years,
and rises to 150 mcg daily for older adolescents and adults. During pregnancy and lactation, the RDA is 220 and 290 mcg daily,
respectively (table 2).
IRON
Iron deficiency affects between 1 and 1.5 billion people worldwide, of whom 400 million also have iron deficiency anemia. Eighty
percent of these people live in resourcelimited countries, where iron deficiency may account for 20 to 30 percent of infant and
maternal mortality.
Dietary sources — Dietary iron is present in two main forms. Heme iron is found in meat, poultry, and fish, where it typically
comprises 40 percent of the total tissue iron. Its absorption is good and is relatively unaffected by underlying iron status. Typically,
nonheme iron is found in vegetables and fruit, as well as ironfortified food products. Absorption of nonheme iron increases as
iron status declines [31]. Ironfortified foods have become increasingly common in the Western diet, such that American children
now consume more iron from cereal or breads than from beef or chicken [100]. Common dietary sources of iron are shown in the
table (table 3).
In resourcelimited countries, heme iron intake is very low and most dietary iron intake is from nonheme food sources. These
foods, however, often have poor bioavailability of the nonheme iron because of the presence of phytate, which chelates iron and
prevents its absorption.
Metabolism — Heme and nonheme iron are absorbed through different mechanisms. Although the mechanism of heme iron
absorption remains poorly characterized, there is increasing knowledge about the molecular mechanisms of nonheme iron
absorption, and of the central role of liver hepcidin in the regulation of iron absorption [101]. Heme iron is absorbed about twice as
well as nonheme iron, and its absorption is unaffected by iron status [31]. Nonheme iron is absorbed throughout the small
intestine, especially in the duodenum. Absorption is increased by vitamin C and certain amino acids, and is inhibited by calcium,
phytic acid, and tannates. (See "Regulation of iron balance", section on 'Intestinal iron absorption'.)
Once absorbed, iron is bound to a specific transport protein, transferrin, from which it is readily taken up by the bone marrow.
Only trace amounts of nontransferrin bound iron are found in the plasma [102], usually chelated to amino acids or citrate. Non
transferrin bound iron is readily taken up by the liver, by evolutionarily primate mechanisms. The body has elaborate mechanisms
to prevent "free" iron from being available to invading microorganisms or malignant cells [103]. In addition, free iron can cycle
between the Fe(2+) and Fe(3+) forms and produce potentially toxic free radicals by Fenton chemistry [104]. (See "Regulation of
iron balance" and "Approach to the patient with suspected iron overload", section on 'Consequences of excess iron stores'.)
Iron losses from the body generally are very low (approximately 1 mg/day), and occur in desquamated skin cells and occult blood
loss in urine and feces [105]. Menstruating women have additional iron losses of approximately 1 to 2 mg/day. The principle
source of iron homeostasis is through changes in iron absorption. (See "Regulation of iron balance", section on 'Iron loss'.)
Biological role — Iron's biological role arises from its reactivity, specifically the ability to cycle between the Fe(2+) and Fe(3+)
forms. This cycling is also responsible for its potentially deleterious effect as a generator of free radicals [103].
A typical adult male has a total body iron content of about 3 to 4 g, of which 75 percent is in the form of heme proteins. Most
common is hemoglobin (the oxygen transport protein), but others include myoglobin (an oxygen storage protein in tissues),
cytochrome c (electron transport), cytochrome P450, and peroxidases. Of total body iron, 20 to 30 percent is in the form of
storage proteins such as ferritin and hemosiderin (a complex ferritin breakdown product). (See "Causes and diagnosis of iron
deficiency and iron deficiency anemia in adults", section on 'Normal body iron content'.)
Less than 1 percent of iron is present as iron metalloenzymes, but these are critical in tyrosine, dopamine, serotonin, and
noradrenaline synthesis [106]. Other metalloenzymes include aldehyde oxidase, NADH dehydrogenase, tryptophan hydroxylase,
succinic dehydrogenase, and xanthine oxidase [107,108]. Iron is required as a cofactor by several enzymes, including
phosphoenolpyruvate carboxykinase (the rate limiting step in gluconeogenesis), ribonucleotide reductase (DNA and RNA
synthesis), and aconitase (a component of the tricarboxylic acid cycle).
Deficiency — The most familiar feature of iron deficiency is a microcytic, hypochromic anemia [109]. However, this is the
extreme end of a spectrum of deficiency. Other features include lethargy and decreased work performance, which are not fully
corrected by treatment of any associated anemia [109]. (See "Iron requirements and iron deficiency in adolescents" and "Causes
and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Clinical manifestations'.)
There is increasing evidence that iron deficiency anemia in toddlers can lead to developmental delays, which appear to be
irreversible, even if iron therapy sufficient to correct the anemia is given. Observational studies suggest that maternal iron
deficiency can triple the risk of delivering a low birth weight infant and double the risk of delivering a preterm infant [110]. Details
are discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations,
and diagnosis" and "Nutrition in pregnancy", section on 'Iron'.)
Toxicity — The archetypal disease of iron overload is hereditary hemochromatosis. It is inherited in an autosomal recessive
manner and affects 3:1000 Caucasians. It is characterized by iron overload, cardiomyopathy, cirrhosis of the liver, diabetes, and
arthritis. The molecular basis of hereditary hemochromatosis has been identified. (See "Approach to the patient with suspected
iron overload" and "Genetics of hereditary hemochromatosis".)
Iron overload states are associated with an increased risk of several malignancies (especially hepatocellular carcinoma). In
addition, observational studies and one intervention trial suggest an association between iron stores and cancer risk even in the
healthy population. (See "Cancer prevention", section on 'Iron'.)
Epidemiological studies suggest a possible link between increased iron stores and cardiovascular disease, even in individuals
without hereditary iron overload syndromes, but data are conflicting. (See "Clinical manifestations and diagnosis of hereditary
hemochromatosis".)
If confirmed, these findings suggest that maintaining low but adequate iron stores is an important health goal in resourcerich
countries. In resourcelimited countries, high iron status is rare and public health efforts generally focus on the prevention of iron
deficiency.
Dietary reference intake — The recommended intake for iron in different life stages is shown in this table. The requirements are
higher in reproductiveaged females (18 mg/day) compared with adult males (8 mg/day), and increase to 27 mg/day during
pregnancy [111].
MANGANESE
Manganese (Mn) was first shown to be essential for normal growth and development of rodents [112,113]. Deficiency in humans
is unusual.
Dietary sources — Grains, dried fruit, vegetables, and nuts are good sources of manganese, but absorption is very variable
[31,114]. Tea also contains large amounts of manganese, but its bioavailability may be low [115,116].
Metabolism — Manganese is absorbed throughout the small intestine, but the coefficient of absorption generally is very low,
possibly as low as 5 percent [117]. Manganese is converted from the Mn(2+) to the Mn(3+) form before being taken up by an
active mechanism and passive diffusion that are rapidly saturable [118,119]. Absorption is decreased following high dietary
intakes or if total body manganese status is good [120]. Absorption is inhibited by high dietary intakes of calcium, phosphate, and
fiber, and increased in the setting of iron deficiency [31,121].
Following absorption, manganese is transported in the portal blood bound to albumin and alpha2macroglobulin [122,123]. Once
taken up by the liver, a proportion is rapidly excreted into the bile, while some enters mitochondrial, nuclear, or lysosomal pools
[115]. It is not known how manganese is transported from the liver to peripheral tissues, but it may be bound to transferrin [115].
Approximately onequarter of total body manganese is found in the bones [115]. Significant amounts also are found in tissues rich
in mitochondria (liver, kidney, pancreas) and rich in melanin (retina, pigmented skin) [115].
Excretion of manganese is primarily through bile into the gastrointestinal tract, and is lower during infancy.
Biological role — Manganese is found in manganese superoxide dismutase (MnSOD), arginase, glutamate synthetase, and
pyruvate carboxylase [115]. It also is found in other enzymes, where it may replace magnesium [124].
Deficiency — Most studies of manganese deficiency are in experimental animals, where it leads to poor growth, decreased
fertility, ataxia, skeletal deformities, and abnormal fat and carbohydrate metabolism [31,125]. In some animal models, the
offspring of manganesedeficient mothers develop irreversible ataxia [115].
Manganese deficiency in humans is very unusual, but has been reported in individuals on a highly restricted diet. In experimental
studies in humans, manganese deprivation was associated with a scaly dermatitis and dyslipidemia [126]. One study suggested a
possible link between low blood manganese levels and Perthes disease, but a second study in the same population failed to
confirm the finding [127,128].
Toxicity — Manganese toxicity (manganism) is a wellrecognized hazard in workers exposed to manganese aerosols or dust, as
may occur in welding or steel industries; it has also been reported in individuals drinking well water with high concentrations of
manganese [129,130]. High levels of manganese can be neurotoxic, affecting primarily the extrapyramidal parts of the brain.
Symptoms are similar to those of Parkinson's disease, and include dyscoordination, loss of balance, and confusion [115,131,132].
Headache, vomiting, and hepatic dysfunction have also been reported.
While only a small percentage of manganese is absorbed from food sources, almost all intravenously administered manganese is
retained. This has raised concern for potential manganese toxicity from parenteral nutrition solutions containing manganese,
which is a standard component of the trace element mixture commonly added to the solution [133]. Cases of probable
manganese toxicity in children and adults on chronic parenteral nutrition have been reported [131,134]. Intravenously fed
neonates may be at risk, particularly if they have cholestasis, which decreases manganese excretion. More current
recommendations are that intravenous manganese be limited to less than 1 mcg/kg/day for neonates and children weighing up to
40 kg [135,136]. However, formulations of multiple trace elements available in the United States, exceed these limits. These
multiple component additives are used commonly, for convenience, in the compounding of parenteral nutrition. Formulations of
individual trace elements are also available and may be used to adjust the dose in parenteral nutrition provided to atrisk patients,
including those with cholestasis and those on chronic parenteral nutrition [137].
Biomarkers for manganese toxicity have not been established [134,136]. Elevations in serum and whole blood manganese
concentrations are often found in individuals on chronic parenteral nutrition, and correlate with manganeseassociated changes in
signal intensity on brain MRI, but the association between these measurements and clinical symptoms has not been fully
established.
Manganese absorption is increased in the setting of iron deficiency [121]. Manganese concentrations are increased by formula
feeding (particularly soy formulas), biliary obstruction, or longterm parenteral nutrition. Whether the mild increases in serum
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manganese that occur in healthy infants as a result of formula feeding have any detectable effects on development has not been
established.
Dietary reference intakes — The recommended intake for manganese is expressed as an Adequate Intake (AI), because of the
limited data available to determine the population needs [31]. The tolerable upper limit for manganese is 2 mg daily in toddlers,
and up to 11 mg daily for adults (table 2).
SELENIUM
Selenium (Se) is a trace mineral with a role in multiple biologic functions. Se deficiency was first identified in experiments in rats,
which were made nutritionally deficient in vitamin E [138]. The resulting liver injury could be prevented by Se supplementation.
The optimal range for dietary intake of selenium is narrow; potentially toxic intakes are closer to recommended dietary intakes
than for other dietary trace minerals. Thus, supplementation may be beneficial for individuals with low selenium intake, but could
be detrimental to those with normal or high selenium intake [139].
Dietary sources — In freeliving animals and humans, selenium is mostly in the form of two seleniumcontaining amino acids:
selenocysteine and selenomethionine [140]. Inorganic forms of selenium are used in supplements [141].
Seafood, kidney and liver, and meat are good sources of selenium [81]. Drinking water usually contains very little selenium [142].
The selenium content of grains and seeds is variable and depends on the selenium content of the soil and the form in which
selenium is present [81].
Metabolism — Dietary selenium has a high bioavailability (>50 percent). Selenomethionine is actively absorbed in the small
intestine by the methionine absorptive pathway [140,141]. The absorptive route of selenocysteine is unknown. Inorganic
selenium (in supplements) is passively absorbed in the duodenum [141]. Selenium absorption appears to be independent of the
individual's selenium status and may be unregulated [141].
In vivo, selenium is a component of selenoproteins. Selenomethionine is incorporated into proteins in place of methionine and
seems to serve as a storage pool [141]. Selenocysteine is the active form of selenium found in proteins [141]. It is absorbed
directly from the diet, synthesized from selenomethionine [141], or synthesized by direct replacement of an oxygen residue on
serine while it is bound to a specific tRNA [140]. Selenocysteine and selenomethionine are catabolized to release selenium. The
principal excretory route of selenium is the urine [141].
Biological role — More than 30 selenoproteins have been identified, of which the best known are the four forms of glutathione
peroxidase [143,144], which are important in antioxidant defense, and iodothyronine deiodinase 2 (three forms), which serves as
a catalyst for production of thyroid hormone [81,145]. Other selenoproteins include selenoprotein P and selenoprotein
synthetase [143]. Some have well defined roles, while others are still under investigation.
Deficiency — Severe selenium deficiency is associated with skeletal muscle dysfunction and cardiomyopathy [145147] and may
also cause mood disorders and impaired immune function [148150], macrocytosis, and whitened nailbeds [151].
Keshan disease, an endemic cardiomyopathy that affects children and women of childbearing age in areas of China, has been
linked to selenium deficiency [152]. The geographical distribution of Keshan disease is associated with local diets, which are
nearly devoid of selenium. The disorder responds to selenium supplements.
Total parenteral nutrition — Trace elements (trace metals) added to total parenteral nutrition (TPN) were historically not
supplemented with selenium. Several cases of selenium deficiency in chronic TPN users have been reported with
cardiomyopathy and skeletal muscle dysfunction [153]. A case report describes selenium deficiency in a child with increased
selenium loss in chylous fluid due to lymphangiomatosis, despite adequate selenium supplementation in TPN [154].
Other potential roles — Other clinical effects of selenium deficiency have been suggested, but are not well established [146]:
Immune function — Selenium is found in relatively high amounts in several tissues with hematopoietic and immune function
potential, including liver, spleen, and lymph nodes, and indirect evidence suggests that it may have a role in immune function
[155]. A number of studies have shown a linear relationship between selenium deficiency and a reduction in CD4 cell counts
in HIVinfected patients [156]. Impaired cellmediated immunity has been demonstrated when tissue stores of selenium are
depleted [150]. Natural killer cell activity is enhanced when selenium is supplemented in the diet of selenium depleted
individuals [157].
Thyroiditis — Selenium supplementation may decrease inflammatory activity in patients with autoimmune thyroiditis [158],
and may reduce the risk of postpartum thyroiditis in women who are positive for thyroid peroxidase (TPO) antibodies. (See
"Postpartum thyroiditis".)
Cancer — Epidemiologic studies support a possible relationship between Se and cancer mortality [159,160]. As a result, a
number of studies have investigated the role of selenium supplementation for prevention of cancer. (See "Cancer
prevention", section on 'Selenium' and "Risk factors for prostate cancer".)
Cardiovascular disease — As mentioned previously, glutathione peroxidase (GPx), a selenoprotein dependent enzyme,
reduces hydrogen peroxide and other molecules with oxidative potential. In theory, the antioxidative effect protects lipid
membranes, inhibits oxidative modification of low density lipoprotein, and suppresses platelet aggregation [146,161]. These
effects would predict that Se supplementation should be protective of atherosclerotic disease. However, prospective and
epidemiologic studies have shown mixed results, as discussed separately. (See "Nutritional antioxidants in atherosclerotic
cardiovascular disease", section on 'Multivitamin supplements'.)
Glucose metabolism — Animal models suggest that low doses of selenium may improve glucose metabolism [162], but
clinical studies in humans suggest that selenium supplementation does not confer benefit and may increase the risk of type 2
diabetes. (See "Risk factors for type 2 diabetes mellitus".)
Toxicity — Clinical manifestations of selenium toxicity include nausea, emesis, diarrhea, hair loss, nail changes, mental status
changes, visual loss, and peripheral neuropathy. There may be associated abnormalities on brain magnetic resonance imaging
(MRI) that resemble reversible posterior encephalopathy syndrome [163]. (See "Reversible posterior leukoencephalopathy
syndrome".)
Selenium toxicity occurs with excess dietary intake, either through diets naturally high in selenium or "megadose"
supplementation. In Enshi County, China, chronic consumption of nearly 5 mg/day of selenium from a plantbased diet resulted in
hair and nail loss, tooth decay, dermatologic lesions, and neurologic effects [164]. Selenium toxicity occurred in 201 individuals in
the United States who took a liquid dietary supplement containing 200 times the labeled content of selenium [165]. The median
estimated dose of selenium consumed was over 41,000 micrograms/day, which is almost 800 times the recommended dietary
allowance of 55 micrograms/day, and more than 100 times the tolerable upper intake limit of 400 micrograms/day. A previous
outbreak of selenium poisoning occurred in 13 individuals who took a mislabeled supplement in 1983 [166].
Dietary reference intake — Dietary selenium is available from seafoods, organ meats, and plant foods. Plant Se content
depends upon soil Se concentrations. The RDA for selenium is 20 mcg daily for young children, rising to 55 mcg daily for adults
(table 2) [31].
ZINC
Zinc has been recognized as a distinct element since 1509, but was not identified as an essential mineral until the 1900s. In
1961, a link was established between zinc deficiency, endemic hypogonadism, and dwarfism in rural Iran [167169].
In more recent years much interest has been generated by the possibility that subclinical zinc deficiency may significantly
increase the incidence of and morbidity and mortality from diarrhea and upper respiratory tract infections. Along with iron, iodine,
and vitamin A, zinc deficiency is one of the most important micronutrient deficiencies globally. Several studies have now
demonstrated that supplementation of high risk populations can have substantial health benefits. (See "Zinc deficiency and
supplementation in children and adolescents".)
Dietary sources — Meat and chicken are excellent sources of zinc [170], as are nuts and lentils. In the Western diet, food
products such as breakfast cereal are fortified with zinc and these products provide an increasingly important source of zinc.
Approximately 45 percent of adults may have inadequate zinc intakes [171].
Metabolism — Total body zinc averages 1.5 to 2.5 g in adults [170], similar to that of iron. A large proportion (60 percent) of total
body zinc is in bone and muscle pools with slow turnover. Zinc is actively absorbed throughout the small intestine [172]. Typically,
zinc absorption is 20 to 40 percent efficient, and may be related to zinc status.
Zinc is absorbed mainly in the duodenum and jejunum, and to a lesser extent in the ileum and large intestine [172,173]. During
digestion, dietary zinc is released and forms complexes with different ligands, namely amino acids, phosphates, organic acids,
and histidines [174]. Zincligand complexes are then absorbed through the intestinal mucosa by both an active and passive
process. Once absorbed, the portal circulation carries zinc to the liver [175].
There is an intricate homeostatic control of zinc absorption, regulated by metallothionein, a metalloprotein that binds copper and
other divalent cations. Metallothionein in the gut enterocyte is more avid for copper than zinc. This is advantageous for the
treatment of Wilson's disease since regular intake of zinc will competitively block gut copper uptake. (See "Wilson disease:
Treatment and prognosis".)
Zinc absorption may be impaired in pancreatic disease or insufficiency. Pancreatic enzymes are necessary for release of dietary
zinc, and pancreatic juices may contain zinccomplexing ligands. Phytic acid is known to reduce zinc absorption. Zinc shares
some common absorptive components with iron and copper, and the three minerals may compete for absorption. Zinc is
transported bound to albumin. It is taken up by peripheral tissues, especially bone and muscle, and by the liver where it may be
stored as metallothionein [31,176].
The major route of zinc excretion is via the gastrointestinal tract. Up to 10 percent of the circulating zinc is also excreted through
urine [167]. Zinc homeostasis is probably maintained by a combination of changes in fractional absorption and endogenous fecal
zinc excretion.
Biological role — Zinc owes its biological role to the ability to form tight bonds with certain amino acids, especially histidine and
cysteine. When zinc binds four amino acids (tetradentate configuration), it serves a structural role maintaining protein structure
(such as the betapleated sheet), and maintains nuclear stability and histone structure [177]. It is in this form that zinc contributes
to zinc finger proteins that interact with DNA. When zinc binds three amino acids, the fourth site is temporarily taken by a water
molecule; in this form, zinc can play a role in the metabolic activity of many proteins.
Approximately 250 proteins contain zinc. These include enzymes such as angiotensin converting enzyme, alkaline phosphatase,
carbonic anhydrase, DNA and RNA polymerases, copperzinc superoxide dismutase, and metallothionein, as well as a large
family of zinc proteins involved in gene transcription (such as the zinc finger proteins) [31,178,179]. Zinc has important roles both
in cell division as well as apoptosis (programmed cell death).
Deficiency — Mild dietary zinc deficiency impairs growth velocity while severe depletion of zinc leads to growth retardation.
Other clinical manifestations of zinc deficiency include delayed sexual maturation, impotence, hypogonadism, oligospermia,
alopecia, dysgeusia (impaired taste), immune dysfunction, night blindness, impaired wound healing, and various skin lesions. The
dermatologic changes occur primarily in the extremities or around body orifices and are often characterized by erythematous,
vesiculobullous, and pustular lesions (picture 1) [180]. Other signs and symptoms of zinc deficiency include loss of taste, change
in hair color, and easy pluckability of hair. Also seen but not specific are night blindness, impaired appetite, delayed wound
healing, decubitus ulcers, and decreased sperm counts. (See "Zinc deficiency and supplementation in children and adolescents".)
Findings such as these, suggesting zinc deficiency, have been described in chronic diseases such as malnutrition, malabsorption
syndromes (such as chronic inflammatory bowel disease), prolonged breastfeeding, and following necrotizing enterocolitis in
preterm infants. Reduced zinc absorption and stores, and occasional cases of symptomatic zinc deficiency have been
demonstrated in patients who have undergone gastric bypass for obesity [181,182]. Pregnancy also increases the risk for zinc
deficiency. Alcoholic cirrhotic patients often have low hepatic concentrations of zinc [183]. Cases of zinc deficiency have been
reported among elderly individuals with poor diet quality [184]. In these cases, the dietary zinc deficiency may have been
exacerbated by medications that increase urinary losses of zinc, including thiazides, loop diuretics, and angiotensin receptor
blockers.
Zinc deficiency can be seen in patients receiving chronic total parenteral nutrition (TPN) solutions lacking adequate zinc
supplementation, or chronic TPN use with an underlying condition causing zinc losses, such as diarrhea, inflammatory bowel
disease, or other conditions [185].
Diabetics also have some alterations of zinc metabolism. Both type 1 and type 2 diabetics can exhibit hyperzincuria, which may
have a role in the immune dysfunction associated with diabetes mellitus [186]. Zinc supplementation in diabetic patients may
improve immune function, but also increases the HbA1c levels and leads to worsening glucose intolerance [187].
Mild zinc deficiency appears to be common, especially in resourcelimited countries. Individuals in resourcelimited countries are
at risk of zinc deficiency because the diet is relatively low in zinc and contains significant amounts of phytates (which reduce zinc
absorption). There is some evidence supporting the role of zinc supplementation to increase growth velocity in children, and
several studies have suggested a benefit of zinc supplementation in children with acute diarrhea in resourcelimited countries.
(See "Zinc deficiency and supplementation in children and adolescents".)
Zinc supplementation during pregnancy for women with mild zinc deficiency appears to promote fetal growth and reduce the risk
of premature birth and infant diarrhea [188191]. Zinc has also been used to treat the common cold, but probably has little clinical
value. (See "The common cold in adults: Treatment and prevention".)
Acrodermatitis enteropathica — Acrodermatitis enteropathica (AE) is an autosomal recessive disease in which zinc
absorption is impaired. The disorder is caused by mutations in the SLC39A4 gene on chromosome 8q24.3, which encodes a
protein that appears to be involved in zinc transportation [192,193].
AE is characterized by signs and symptoms of severe zinc deficiency, including diarrhea, dermatitis (especially perioral and
perianal), alopecia, poor growth, and poor immune function [169]. The dermatitis consists of hyperpigmented skin lesions on the
acral surfaces of the upper and the lower extremities, as well as the face and buttocks (picture 2). Symptoms usually appear in
early infancy, once breastfeeding is completely discontinued. Systemic signs include intestinal disturbances, growth failure,
irritability, and lethargy. Thymic hypoplasia has also been described in association with AE [194].
Oral supplementation with zinc (30 to 45 mg per day) leads to a rapid and complete remission of the symptoms. Therapy needs
to be continued indefinitely [194].
Toxicity — Humans are very tolerant of high zinc intakes up to 100 mg/day [195]. Megadose supplementation or high zinc intake
from contaminated food or beverages has been associated with nonspecific gastrointestinal symptoms, including abdominal pain,
diarrhea, nausea, and vomiting [194,196]. Zinc may interfere with copper absorption, and high zinc intakes (>150 mg/day) can
lead to copper deficiency [197]. (See 'Copper' above.)
Treatment for zinc toxicity is primarily supportive, although chelation with calcium disodium ethylenediaminetetraacetate
(CaNa2EDTA) has been used in some cases of severe toxicity [142].
Evaluation of zinc status — Plasma levels of zinc do not correlate well with tissue levels and do not reliably identify individuals
with zinc deficiency. Although plasma levels are generally a good index of zinc status in healthy individuals, these levels are
depressed during inflammatory disease states. Erythrocyte concentrations of zinc may provide a more useful measure of zinc
status during acute or chronic inflammation [198]. Several functional indices also can be used to indirectly assess zinc status.
Alkaline phosphatase activity can serve as a supportive marker of zinc status [31].
Because most zinc is bound to albumin, zinc levels may be reduced in patients with hypoalbuminemia [199,200]. Given the low
risks of zinc replacement therapy, it may be indicated for patients with low zinc levels, regardless of albumin status, depending
upon the clinical context.
Dietary reference intake — The Food and Nutrition Board of the Institute of Medicine and the World Health Organization (WHO)
have published standard recommendations for daily zinc intake [31,201]. Requirements vary by age and gender, rising from 3 mg
daily in early childhood to 8 mg daily for adult women, and 11 mg daily for adult men. Requirements are slightly higher during
pregnancy and lactation (table 2).
SOCIETY GUIDELINE LINKS
Links to society and governmentsponsored guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Vitamin deficiencies".)
SUMMARY
Minerals that are required in small amounts for human health are known as trace minerals or trace elements. These include
chromium, copper, fluoride, iodine, iron, manganese, selenium, and zinc. (See 'Introduction' above.)
Recommended intakes for trace elements are expressed as Recommended Dietary Allowances (RDA) or Adequate Intake
(AI). The Upper Limit (UL) is the quantity of the nutrient considered to cause no adverse effects in healthy individuals. These
parameters have been estimated for each trace mineral (table 2). (See 'Definitions' above.)
Copper deficiency can be caused by an xlinked mutation of the transport protein mediating copper uptake from the intestine
(Menkes disease). It can also be caused by malabsorption after gastrointestinal surgery (including gastric bypass for weight
loss and gastric resection for malignancy or peptic ulcer disease), or by ingestion of high doses of zinc. Clinical
manifestations include anemia, ataxia, and myeloneuropathy. (See 'Copper' above and "Copper deficiency myeloneuropathy"
and "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)
Iodine deficiency is characterized by goiter and hypothyroidism, which in turn has effects on growth, development, and
cognitive function. (See 'Iodine' above.)
Selenium deficiency is unusual, but has been reported in parts of China where the local diet is devoid of selenium; the
deficiency also occurs in individuals maintained on total parenteral nutrition without trace minerals. Clinical features of
selenium deficiency are cardiomyopathy and skeletal muscle dysfunction. (See 'Selenium' above.)
Zinc deficiency causes growth retardation in children, hypogonadism, oligospermia, alopecia, dysgeusia (impaired taste),
immune dysfunction, night blindness, impaired wound healing, and skin lesions. Infants with an inherited defect in zinc
absorption develop a severe deficiency state known as acrodermatitis enteropathica. (See 'Zinc' above and "Zinc deficiency
and supplementation in children and adolescents".)
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Topic 2585 Version 33.0
GRAPHICS
Macro, trace, and ultratrace minerals in man
Macrominerals Trace minerals Ultratrace minerals

Calcium Copper Arsenic
Chloride Iron Boron
Magnesium Fluoride Chromium
Phosphate Manganese Iodine
Potassium Zinc Molybdenum
Sodium Nickel
Selenium
Silicon
Vanadium
Graphic 73583 Version 2.0
Dietary Reference Index (DRIs) of trace elements
Zinc Selenium Iodine Copper Chromium Manganese Fluoride Molybdenum

Life
(mg/d) (µg/d) (µg/d) (µg/d) (µg/d) (mg/d) (mg/d) (µg/d)
stage
group RDA*
UL Δ RDA/AI ¶ UL RDA/AI ¶ UL RDA/AI ¶ UL RDA/AI ¶ UL RDA/AI ¶ UL RDA/AI ¶ UL RDA/AI ¶ UL
AI ¶
Infants
06 2¶ 4 15 ¶ 45 110 ¶ ND 200 ¶ ND 0.2 ¶ ND 0.003 ¶ ND 0.01 ¶ 0.7 2¶ ND

mo
712 3 5 20 ¶ 60 130 ¶ ND 220 ¶ ND 5.5 ¶ ND 0.6 ¶ ND 0.5 ¶ 0.9 3¶ ND

mo
Children
13 y 3 7 20 90 90 200 340 1000 11 ¶ ND 1.2 ¶ 2 0.7 ¶ 1.3 17 300
48 y 5 12 30 150 90 300 440 3000 15 ¶ ND 1.5 ¶ 3 1¶ 2.2 22 600
Males
913 8 23 40 280 120 600 700 5000 25 ¶ ND 1.9 ¶ 6 2¶ 10 34 1100

y
14 11 34 55 400 150 900 890 8000 35 ¶ ND 2.2 ¶ 9 3¶ 10 43 1700

18 y
19 11 40 55 400 150 1100 900 10,000 35 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

30 y
31 11 40 55 400 150 1100 900 10,000 35 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

50 y
51 11 40 55 400 150 1100 900 10,000 30 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

70 y
>70 11 40 55 400 150 1100 900 10,000 30 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

y
Females
913 8 23 40 280 120 600 700 5000 21 ¶ ND 1.6 ¶ 6 2¶ 10 34 1100

y
14 9 34 55 400 150 900 890 8000 24 ¶ ND 1.6 ¶ 9 3¶ 10 43 1700

18 y
19 8 40 55 400 150 1100 900 10,000 25 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

30 y
31 8 40 55 400 150 1100 900 10,000 25 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

50 y
51 8 40 55 400 150 1100 900 10,000 20 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

70 y
>70 8 40 55 400 150 1100 900 10,000 20 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

y
Pregnancy
14 12 34 60 400 220 900 1000 8000 29 ¶ ND 2.0 ¶ 9 3¶ 10 50 1700

18 y
19 11 40 60 400 220 1100 1000 10,000 30 ¶ ND 2.0 ¶ 11 3¶ 10 50 2000

30 y
31 11 40 60 400 220 1100 1000 10,000 30 ¶ ND 2.0 ¶ 11 3¶ 10 50 2000

50 y
Lactation
14 13 34 70 400 290 900 1300 8000 44 ¶ ND 2.6 ¶ 9 3¶ 10 50 1700

18 y
19 12 40 70 400 290 1100 1300 10,000 45 ¶ ND 2.6 ¶ 11 3¶ 10 50 2000

30 y
31 12 40 70 400 290 1100 1300 10,000 45 ¶ ND 2.6 ¶ 11 3¶ 10 50 2000

50 y
RDA: recommended dietary allowance; AI: adequate intake; UL: upper tolerable level.
* Values in this column represent the RDA, unless otherwise indicated. The RDA is the level of dietary intake that is sufficient to meet the daily nutrient
requirements of 97 percent of the individuals in a specific life stage group.
¶ These values represent the AI. The AI is an approximation of the average nutrient intake that sustains a defined nutritional state, based on observed or
experimentally determined values in a defined population.
Δ The UL is the maximum level of daily nutrient intake that is likely to pose no risk of adverse health effects in almost all individuals in the specified lifestage or
gender group.
Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Otten JJ, Hellwig JP, Meyers LD (Eds), The National Academies Press, Washington, DC
2006. pp.530541. Reprinted with permission from the National Academies Press, Copyright © 2006, National Academy of Sciences.
Sources: Dietary reference intakes for Thiamin, Riboflavin, Niacin, Vitamin B 6 , Folate, Vitamin B 12 , Panthothenic acid, Biotin, and Choline (1998); Dietary
reference intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000). These reports may be accessed via www.nap.edu.
Dietary sources of iron
Food Approximate measure Iron (mg)
High iron sources
Cream of Wheat (quick or instant)* 1/2 cup 7.8
Kidney, beef ¶ 2 oz (60 g) 5.3
Liver, beef ¶ 2 oz (60 g) 5.8
Liver, calf ¶ 2 oz (60 g) 9
Liver, chicken ¶ 2 oz (60 g) 6
Liverwurst ¶ 2 oz (60 g) 3.6
Prune juice 1/2 cup 5.1
Spinach 1/2 cup 3.2
Moderate iron sources
AllBran cereal 1/2 cup 2.9
Almonds, dried unblanched 1/2 cup 3
Dried beans and peas
Baked beans, no pork 1/4 cup 1.5
Blackeye peas, cooked 1/4 cup 0.8
Chick peas, dry 1/4 cup 3.5
Great northern beans, cooked 1/4 cup 1.3
Green peas, cooked 1/4 cup 1.4
Lentils, dry 1/4 cup 3.4
Lima beans, cooked 1/4 cup 1.3
Navy beans, cooked 1/4 cup 1.3
Red beans, dry 1/4 cup 3.5
Soybeans, cooked 1/4 cup 1.4
White beans, dry 1/4 cup 3.9
Beef, cooked 2 oz (60 g) 23 Δ
Ham, cooked 2 oz (60 g) 1.3
Lamb, cooked 2 oz (60 g) 1.9
Peaches, dried 1/4 cup 2.4
Peanuts, roasted without skins 3 1/2 oz (100 g) 3.2
Pork, cooked 2 oz (60 g) 23 ◊
Prunes, dried 2 large 1.1
Scallops 2 oz (60 g) 1.6
Turkey, cooked 2 oz (60 g) 1.7
Approximate iron content of children's favorite foods
Hamburger, small 1 3
Large 1 5.2
Big Mac 1 4.3
Quarter Pounder 1 5.1
Spaghetti with meatballs 1 cup 3.3
Frankfurter and beans 1 cup 4.8
Pork and beans 1 cup 5.9
Raisins § 5/8 cup 3.5
Cereals, fortified 1 serving 4.517.8
Nuts § 1 cup 57
Seeds, sunflower § 3 1/2 oz (100 g) 7.1
Chile con carne 1 cup 3.6
Beef burrito or tostado 1 medium 3.44.6
Cheese pizza 2 slices 3
Cheese pizza with beef 2 slices 4.8
White bread 1 piece 0.7
* Or other fortified cereals which contain 10 mg of iron per ounce or 100 percent RDA per serving.
¶ As organ meats are generally high in cholesterol, these ironrich foods should be eaten in moderation.
Δ Depending on cut, the greatest amounts of iron are generally found in the chuck, flank, and bottom round cuts of beef.
◊ Depending on cut, the greatest amounts of iron are generally found in the loin, sirloin, tenderloin, and picnic shoulder cuts of pork.
§ Raisins, nuts, and seeds are not generally recommended for children under age three because of risk of choking.
Data from: Walker WA, Watkins JB (Eds), Nutrition in Pediatrics, 2nd ed, BC Decker, Inc, London 1997.
Dermatitis in zinc deficiency
Perianal dermatitis in a child with zinc deficiency, which developed because of total
parenteral nutrition with insufficient zinc supplementation. The second panel shows
dramatic improvement in the dermatitis after only seven days of systemic zinc
supplementation.
Courtesy of William J Klish, MD.
Acrodermatitis enteropathica
Acrodermatitis enteropathica in an infant. Moist erythematous plaques are present on the
cheeks and buttocks. The buttock lesions are typically symmetric.
(A) Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights
reserved.
(B) Courtesy of Robert Sidbury, MD.
Contributor Disclosures
Sassan Pazirandeh, MD Nothing to disclose David L Burns, MD Nothing to disclose Ian J Griffin, MB ChB Nothing to disclose David
Seres, MD Grant/Research/Clinical Trial Support: Nestle Devices [Dysphagea]. Consultant/Advisory Boards: Community Surgical Supply
[Home nutrition support (Home Infusion)]; Filament Biosystems [Medical Foods]; Medaware Systems [Biomedical informatics (provides
instantaneous meta analyses)]; Blue Mesa [Diabetes prevention (app using NIH Diabetes Prevention Program)]; Dietary DNA/Dineable [Dietary
adherence (food profile online app)]. Equity Ownership/Stock Options: Filament Biosystems [Medical Foods]; Medaware Systems [Biomedical
informatics (provides instantaneous meta analyses)]; Blue Mesa [Diabetes prevention (app using NIH Diabetes Prevention Program)]; Dietary
DNA/Dineable [Dietary adherence (food profile online app)]. Alison G Hoppin, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
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UTD Dietary Trace Mineral Deficiency

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3/20/2019 Overview of dietary trace minerals - UpToDate

Macro­minerals Trace minerals Ultra­trace minerals

Chloride Iron Boron

Magnesium Fluoride Chromium

Phosphate Manganese Iodine

Potassium Zinc Molybdenum

Zinc Selenium Iodine Copper Chromium Manganese Fluoride Molybdenum

0­6 2¶ 4 15 ¶ 45 110 ¶ ND 200 ¶ ND 0.2 ¶ ND 0.003 ¶ ND 0.01 ¶ 0.7 2¶ ND

7­12 3 5 20 ¶ 60 130 ¶ ND 220 ¶ ND 5.5 ¶ ND 0.6 ¶ ND 0.5 ¶ 0.9 3¶ ND

1­3 y 3 7 20 90 90 200 340 1000 11 ¶ ND 1.2 ¶ 2 0.7 ¶ 1.3 17 300

4­8 y 5 12 30 150 90 300 440 3000 15 ¶ ND 1.5 ¶ 3 1¶ 2.2 22 600

9­13 8 23 40 280 120 600 700 5000 25 ¶ ND 1.9 ¶ 6 2¶ 10 34 1100

14­ 11 34 55 400 150 900 890 8000 35 ¶ ND 2.2 ¶ 9 3¶ 10 43 1700

19­ 11 40 55 400 150 1100 900 10,000 35 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

31­ 11 40 55 400 150 1100 900 10,000 35 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

51­ 11 40 55 400 150 1100 900 10,000 30 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

>70 11 40 55 400 150 1100 900 10,000 30 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

9­13 8 23 40 280 120 600 700 5000 21 ¶ ND 1.6 ¶ 6 2¶ 10 34 1100

14­ 9 34 55 400 150 900 890 8000 24 ¶ ND 1.6 ¶ 9 3¶ 10 43 1700

19­ 8 40 55 400 150 1100 900 10,000 25 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

31­ 8 40 55 400 150 1100 900 10,000 25 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

51­ 8 40 55 400 150 1100 900 10,000 20 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

>70 8 40 55 400 150 1100 900 10,000 20 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

14­ 12 34 60 400 220 900 1000 8000 29 ¶ ND 2.0 ¶ 9 3¶ 10 50 1700

19­ 11 40 60 400 220 1100 1000 10,000 30 ¶ ND 2.0 ¶ 11 3¶ 10 50 2000

31­ 11 40 60 400 220 1100 1000 10,000 30 ¶ ND 2.0 ¶ 11 3¶ 10 50 2000

14­ 13 34 70 400 290 900 1300 8000 44 ¶ ND 2.6 ¶ 9 3¶ 10 50 1700

19­ 12 40 70 400 290 1100 1300 10,000 45 ¶ ND 2.6 ¶ 11 3¶ 10 50 2000

31­ 12 40 70 400 290 1100 1300 10,000 45 ¶ ND 2.6 ¶ 11 3¶ 10 50 2000

Food Approximate measure Iron (mg)

Cream of Wheat (quick or instant)* 1/2 cup 7.8

Kidney, beef ¶ 2 oz (60 g) 5.3

Liver, beef ¶ 2 oz (60 g) 5.8

Liverwurst ¶ 2 oz (60 g) 3.6

Prune juice 1/2 cup 5.1

Spinach 1/2 cup 3.2

All­Bran cereal 1/2 cup 2.9

Beef, cooked 2 oz (60 g) 2­3 Δ

Ham, cooked 2 oz (60 g) 1.3

Lamb, cooked 2 oz (60 g) 1.9

Peaches, dried 1/4 cup 2.4

Peanuts, roasted without skins 3 1/2 oz (100 g) 3.2

Pork, cooked 2 oz (60 g) 2­3 ◊

Prunes, dried 2 large 1.1

Scallops 2 oz (60 g) 1.6

Turkey, cooked 2 oz (60 g) 1.7

Spaghetti with meatballs 1 cup 3.3

Frankfurter and beans 1 cup 4.8

Pork and beans 1 cup 5.9

Raisins § 5/8 cup 3.5

Cereals, fortified 1 serving 4.5­17.8

Nuts § 1 cup 5­7

Seeds, sunflower § 3 1/2 oz (100 g) 7.1

Chile con carne 1 cup 3.6

Beef burrito or tostado 1 medium 3.4­4.6

Cheese pizza with beef 2 slices 4.8

White bread 1 piece 0.7

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Macrominerals Trace minerals Ultratrace minerals

06 2¶ 4 15 ¶ 45 110 ¶ ND 200 ¶ ND 0.2 ¶ ND 0.003 ¶ ND 0.01 ¶ 0.7 2¶ ND

712 3 5 20 ¶ 60 130 ¶ ND 220 ¶ ND 5.5 ¶ ND 0.6 ¶ ND 0.5 ¶ 0.9 3¶ ND

13 y 3 7 20 90 90 200 340 1000 11 ¶ ND 1.2 ¶ 2 0.7 ¶ 1.3 17 300

48 y 5 12 30 150 90 300 440 3000 15 ¶ ND 1.5 ¶ 3 1¶ 2.2 22 600

913 8 23 40 280 120 600 700 5000 25 ¶ ND 1.9 ¶ 6 2¶ 10 34 1100

14 11 34 55 400 150 900 890 8000 35 ¶ ND 2.2 ¶ 9 3¶ 10 43 1700

19 11 40 55 400 150 1100 900 10,000 35 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

31 11 40 55 400 150 1100 900 10,000 35 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

51 11 40 55 400 150 1100 900 10,000 30 ¶ ND 2.3 ¶ 11 4¶ 10 45 2000

913 8 23 40 280 120 600 700 5000 21 ¶ ND 1.6 ¶ 6 2¶ 10 34 1100

14 9 34 55 400 150 900 890 8000 24 ¶ ND 1.6 ¶ 9 3¶ 10 43 1700

19 8 40 55 400 150 1100 900 10,000 25 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

31 8 40 55 400 150 1100 900 10,000 25 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

51 8 40 55 400 150 1100 900 10,000 20 ¶ ND 1.8 ¶ 11 3¶ 10 45 2000

14 12 34 60 400 220 900 1000 8000 29 ¶ ND 2.0 ¶ 9 3¶ 10 50 1700

19 11 40 60 400 220 1100 1000 10,000 30 ¶ ND 2.0 ¶ 11 3¶ 10 50 2000

31 11 40 60 400 220 1100 1000 10,000 30 ¶ ND 2.0 ¶ 11 3¶ 10 50 2000

14 13 34 70 400 290 900 1300 8000 44 ¶ ND 2.6 ¶ 9 3¶ 10 50 1700

19 12 40 70 400 290 1100 1300 10,000 45 ¶ ND 2.6 ¶ 11 3¶ 10 50 2000

31 12 40 70 400 290 1100 1300 10,000 45 ¶ ND 2.6 ¶ 11 3¶ 10 50 2000

AllBran cereal 1/2 cup 2.9

Beef, cooked 2 oz (60 g) 23 Δ

Pork, cooked 2 oz (60 g) 23 ◊

Cereals, fortified 1 serving 4.517.8

Nuts § 1 cup 57

Beef burrito or tostado 1 medium 3.44.6