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Overview of dietary trace elements

Overview of dietary trace elements
Authors:
Sassan Pazirandeh, MD
David L Burns, MD
Ian J Griffin, MB ChB
Section Editor:
David Seres, MD
Deputy Editor:
Lisa Kunins, MD
Literature review current through: Apr 2022. | This topic last updated: Jan 24, 2022.

INTRODUCTION — Minerals form only 5 percent of the typical human diet but are essential for normal health and function. They are often categorized into macrominerals, trace elements, and ultratrace elements, depending on their nutritional requirements (see 'Definitions' below). Although this classification may be controversial and somewhat arbitrary, one outline is given in the table (table 1).

This topic review will discuss the physiologic and biochemical functions, dietary requirements, and signs and symptoms of excess and deficiency for the essential trace elements, including chromium, copper, fluoride, iodine, iron, manganese, selenium, and zinc. Several of these minerals are considered in more depth elsewhere. (See "Iodine deficiency disorders" and "Zinc deficiency and supplementation in children" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Iron requirements and iron deficiency in adolescents" and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

DEFINITIONS — The following terms are used throughout this topic:

Dietary minerals – Dietary minerals are elements that are required in small amounts for normal health and function. They can be classified according to the amount required, although the classification is somewhat arbitrary and controversial (table 1):

Macrominerals – Macrominerals are defined as minerals that are required by adults in amounts >100 mg/day. Examples include sodium, potassium, chloride, calcium, magnesium, and phosphorus. These minerals are not the focus of this topic review. Details on the metabolism of these minerals are provided separately.

Trace elements – Trace elements (or trace minerals) are usually defined as minerals that are required in amounts between 1 to 100 mg/day by adults. These include copper, fluoride, iodine (which is sometimes classified as an ultratrace element), manganese, and zinc, which are discussed in the following sections.

Ultratrace elements – Ultratrace elements usually are defined as minerals that are required in amounts <1 mg/day by adults. Examples include chromium and selenium, which are discussed below, as well as arsenic, boron, and molybdenum, which are not the focus of this topic review.

Terms used to describe nutritional requirements include the following:

Dietary reference intakes (DRIs) – 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 trace elements are summarized in the table (table 2), and DRIs for other minerals can be found here.

Recommended dietary allowance (RDA) – Using the DRI system, requirements can be expressed as an 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. Dietary guidelines, which incorporate the RDAs, are periodically updated as new information arises.

Adequate intake (AI) – If there are insufficient data to determine an RDA for a given nutrient, requirements can be expressed as an AI, which is an estimation of the nutrient intake necessary to maintain a healthy state.

Tolerable upper intake level (UL) - The 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.

Daily values – 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 [1].

These terms are described in greater detail in a separate topic review. (See "Dietary history and recommended dietary intake in children".)

CHROMIUM — 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 [2].

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 [3].

Dietary reference intake — The adequate intake of chromium for adults is 20 to 35 mcg/day (table 2) [4].

Metabolism — Chromium is absorbed predominantly in the small intestine and is transported in the circulation bound to albumin and transferrin [5]. 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 [6]. 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 [7-9]. 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 [10]. Chromium can be reduced by gastric acid to form insoluble salts that can precipitate and block its absorption [11]. Administration of vitamin C enhances the uptake of chromium [12].

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 [12,13]. In diabetic patients receiving chronic total parenteral nutrition (TPN), human chromium deficiency has been associated with increased insulin requirements [12]. 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, with traumatic injuries, or on parenteral nutrition without appropriate trace element supplementation [14].

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 [15-17]. Randomized trials on chromium supplementation in patients with type 2 diabetes are of fair quality and meta-analyses reach conflicting conclusions about whether supplementation improves glycemic control [18-21]. (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 [7,22,23].

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 [24,25]. However, airborne hexavalent chromium (VI) toxicity has been established as a work-related etiology of lung cancer in stainless steel workers [26,27]. 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 [28]. 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 [29].

COPPER — Two heritable diseases are caused by inborn errors of copper metabolism: Wilson 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 'Wilson disease' below and '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 [30]. 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 [4]. Absorption of copper may be impaired by dietary iron, zinc, or ascorbic acid [31-33].

Copper is found in high concentrations in liver, brain, and bone and, to a lesser degree, in kidney, heart, and pancreas [33]. The total copper content in the human body is estimated to be approximately 12 mg for a newborn infant and 50 to 120 mg for an adult. Breast milk contains relatively little copper [34,35]. Early in lactation, breast milk contains up to 0.7 mg/L of 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) [4]. During this period, any shortfall in copper intake can be met by mobilizing liver copper stores.

Dietary reference intake — The recommended dietary allowance (RDA) for copper is 340 mcg/day for young children and rises to 900 mcg/day for adults [4]. The tolerable upper intake level (UL) is 1000 mcg/day in young children and 10,000 mcg/day for adults (table 2).

Metabolism — Copper is absorbed in the proximal small intestine and stomach [36,37]. 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 P-type 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 copper-containing 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 [38-40]. 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 one-half is excreted through other gastrointestinal secretions [36,37]. This excretion of copper into the gastrointestinal tract is the major pathway that regulates copper homeostasis and prevents deficiency or toxicity. The Wilson P-type ATPase (ATP7B) is responsible for copper trafficking to the secretory pathway for ceruloplasmin biosynthesis and for endosome formation prior to biliary secretion.

Biologic role — A number of important copper-containing enzymes have been described, including the following [41,42]:

Zinc-copper superoxide dismutase (antioxidant defense)

Dopamine mono-oxygenase (neurotransmitter synthesis)

Lysyl oxidase (collagen cross-linking, bone formation)

Ceruloplasmin (copper transporter and ferroxidase)

Cytochrome c oxidase (electron transport)

Factor V (thrombosis)

Tyrosinase (melanin production)

These cupro-enzymes help to explain some of the clinical features of severe copper deficiency, including lack of skin pigmentation (decreased dopamine beta-hydrolase), weakness (decreased cytochrome c), and bleeding disorders (decreased factor V).

Deficiency

Clinical features — Copper deficiency is characterized clinically by fragile, abnormally formed hair, depigmentation of the skin, muscle weakness (myeloneuropathy), neurologic abnormalities, edema, hepatosplenomegaly, and osteoporosis. The neurologic manifestations include ataxia, neuropathy, and cognitive deficits that can mimic vitamin B12 deficiency [43,44]. (See "Copper deficiency myeloneuropathy".)

Hematologic features of copper deficiency include anemia (usually normocytic; sometimes macrocytic and occasionally with microcytic cells) and neutropenia [31,45-48]. In some cases, the hematologic findings, including dysplastic changes in the bone marrow, may be mistaken for myelodysplastic syndrome (MDS) [49]. If copper deficiency manifests as microcytic anemia and is mistaken for iron deficiency, iron supplementation can worsen the copper deficiency by decreasing net copper absorption [32].

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 copper-zinc superoxide levels, and diminished 24-hour urinary copper excretion [30].

Risk factors — Though rare, acquired copper deficiency has been well documented in humans [4,42,50,51]. 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 [52-55]. 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 [55]. 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'.)

Preterm infants on prolonged parenteral nutrition or who are fed with a formula that contains insufficient copper [56,57]. Preterm formulas available in North America generally contain adequate amounts of copper to meet estimated requirements [58].

Chronic diarrhea or other malabsorptive conditions including celiac disease [42,50,59,60].

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) [31,62], ingestion of denture cream [63,64], or swallowing zinc-containing coins [65]. Parenteral zinc overloading during chronic hemodialysis has also been associated with copper deficiency myelopathy [61].

Treatment of Wilson 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 over-the-counter antiparasitic agent in Japan in the past) resulted in over 10,000 cases of myelo-optico-neuropathy in Japan in the 1960s, which may have been due to copper deficiency [68-70]. Similarly, a case report describes copper deficiency due to self-treatment with tetrathiomolybdate [71].

Total parenteral nutrition (TPN) with insufficient copper. 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]. Trace elements are now included in standard TPN; however, 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]. Moreover, shortages of multitrace elements and/or individual trace element solutions for injection may result in deficiency.

Treatment — 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 long-term TPN require intravenous copper supplementation, which is usually provided as part of a mixture of trace metals. (See "Parenteral nutrition in infants and children" and "Nutrition support in critically ill patients: Parenteral nutrition".)

Menkes disease — Menkes disease (MIM #309400), also known as Menkes kinky hair syndrome, is a congenital X-linked genetic disorder with an incidence of approximately 1:100,000 live births. It is caused by a defect in the transport protein mediating copper uptake from the intestine, encoded by the ATP7A gene. Inactivating variants 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 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 they 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 failure, 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 copper-histidine complex, which is not consistently effective.

Toxicity

Clinical features — Acute copper poisoning in humans causes gastrointestinal symptoms, including abdominal pain, diarrhea, and vomiting [4]. 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 and food products [79], 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 disease — Wilson disease is an autosomal recessive disorder characterized by excessive copper accumulation and is caused by a variant in the gene encoding a copper-ATPase enzyme, which is closely related to the Menkes disease gene product [80]. 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 disease consists of avoidance of high copper foods and copper chelation. In early stages, pharmacologic 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".)

FLUORIDE — Fluoride is relatively common in the earth's crust, but its concentration in water (a major dietary source) is very variable [81]. It has an important role in preventing dental caries and is considered beneficial rather than essential [82].

Dietary sources — Ground water contains fluoride in amounts between 0 and 40 mg/L [83]. 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 [83,84]. Many domestic water supplies are fluoridated in order to reduce the incidence of caries, although the practice has raised controversy [85].

Other important sources of fluoride are tea, seafood that contains edible bones or shells (eg, canned sardines), medicinal supplements, and fluoridated toothpastes [82].

Dietary reference intake — The recommended intake for fluoride is expressed as an adequate intake (AI) rather than recommended dietary allowance (RDA) because of the limited data available to determine the population needs. The AI for fluoride is 0.7 mg/day for toddlers, rising to 3 mg/day for adult females and 4 mg/day for adult males (table 2).

Metabolism — Dietary fluoride is absorbed rapidly in the stomach and small intestine. One-quarter to one-third of the absorbed fluoride is taken up into calcified tissues, whereas the rest is lost in the urine [83,86]. In bone and teeth, fluoride can displace hydroxyl ions from hydroxyapatite to produce fluorapatite or fluorohydroxyapatite. Approximately 99 percent of total body fluoride is contained in bones and teeth [83], and the amount steadily increases during life.

Biologic role — It remains unclear whether fluoride is truly essential, although fluoride may have some beneficial effects [82]. Animal models, such as rodents fed fluoride-deficient 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 [87]. 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 [88]. (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 pre-eruptive (systemic) and post-eruptive (topical) mechanisms [85]. The American Dental Association (ADA) strongly supports fluoridation of community drinking water supplies [84]; however, strong contradictory opinions also are held [89].

Toxicity — Fluoride toxicity usually results from ingestion of high amounts of fluoride, either in water, in fluoride supplements, or as fluorine-containing insecticides [85,90,91]. In industrial settings, toxicity also can occur by inhalation or by absorption through the skin (eg, Freon vapor or hydrofluoric acid spills) [81]. More than 80 percent of fluoride toxicity is seen in children younger than age six, due to ingestion of fluoride-containing toothpaste or mouthwashes [92]; it is rare in adults in the developed world.

Acute toxicity is characterized by nonspecific gastrointestinal disturbances such as pain, nausea, vomiting, and diarrhea [90,93]. In severe cases, this may progress to renal and cardiac dysfunction, coma, and ultimately death [94]. In children, as little as 8.4 mg/kg may produce symptoms [90].

Chronic fluoride toxicity (fluorosis) is usually caused by high fluoride concentrations in drinking water or the use of fluoride supplements. High levels of fluoride in groundwater are found in some regions near the Mediterranean sea, India, Northern Thailand, and China, as described in an overview of fluorosis from the World Health Organization (WHO). Chronic ingestion of high doses leads to dental fluorosis, a cosmetic disorder where the teeth become mottled [81]. 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 [81]. The syndrome also may include extensive calcification of ligaments and cartilage, as well as the bony outgrowths of osteophytes and exostoses [95].

To reduce dental fluorosis and systemic toxicity, the 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 pea-sized) [96]. (See "Preventive dental care and counseling for infants and young children", section on 'Fluoride'.)

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 [97,98]. 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 goiter endemic areas of Ohio [98]. Iodized salt was then introduced and led to reduction of hypothyroidism-related growth failure 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 iodine-containing disinfectants. Some breads contain iodine from the dough oxidizers used in their manufacture [82].

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 [99]. (See "Iodine deficiency disorders", section on 'Geographic distribution'.)

Dietary reference intake — The recommended dietary allowance (RDA) for iodine is 90 mcg/day for children 1 to 8 years old, 120 mcg/day for children 9 to 13 years, and rises to 150 mcg/day for older adolescents and adults. During pregnancy and lactation, the RDA is 220 and 290 mcg/day, respectively (table 2).

Metabolism — Ingested iodine is absorbed readily in the proximal small bowel. Circulating iodine 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 [4]. Tri-iodotyrosine and thyroxine are secreted by the gland and have plasma half-lives of approximately two and eight days, respectively [100]. The principle excretory route for iodine is the urine; any losses into the gastrointestinal tract are rapidly reabsorbed.

Biologic role — The sole physiologic role of iodine is to form a part of the two thyroid hormones: thyroxine (3,5,3',5'-tetraiodothyronine, T4) and tri-iodotyrosine (3,5,3'-tri-iodothyronine T3). The thyroid hormones have many physiologic 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 "Iodine-induced thyroid dysfunction".)

Deficiency — Iodine deficiency is associated with goiter, hypothyroidism, intellectual disability, 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 [4]. (See "Iodine-induced 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 intellectual disability can result unless iodine deficiency is treated with supplements in the second trimester [4]. Left untreated, cretinism develops. The hallmark of this condition is severe intellectual disability, with or without spasticity, umbilical hernia, and characteristic facial features. (See "Neurologic manifestations of hypothyroidism" and "Iodine deficiency disorders", section on 'Severe iodine deficiency during pregnancy'.)

Toxicity — Sources of excess iodide include over-the-counter 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 "Iodine-induced thyroid dysfunction".)

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 resource-limited 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 iron-fortified food products. Absorption of nonheme iron increases as iron status declines [4]. Iron-fortified 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 [101]. Common dietary sources of iron are shown in the table (table 3).

In resource-limited 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.

Dietary reference intake — The recommended intake for iron in different life stages varies. The requirements are higher in reproductive-aged females (18 mg/day) compared with adult males (8 mg/day) and increase to 27 mg/day during pregnancy (table 4) [102].

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 [103]. Heme iron is absorbed approximately twice as well as nonheme iron, and its absorption is unaffected by iron status [4]. 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 non-transferrin bound iron are found in the plasma [104], 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 [105]. In addition, free iron can cycle between the Fe(2+) and Fe(3+) forms and produce potentially toxic free radicals by Fenton chemistry [106]. (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 [107]. Menstruating individuals 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'.)

Biologic role — Iron's biologic 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 [105].

A typical adult male has a total body iron content of approximately 3 to 4 g (table 5), 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 [108]. Other metalloenzymes include aldehyde oxidase, NADH dehydrogenase, tryptophan hydroxylase, succinic dehydrogenase, and xanthine oxidase [109,110]. 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 [111]. 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 [111]. (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 [112]. Details are discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Nutrition in pregnancy: Dietary requirements and supplements", 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 White individuals. 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 "HFE and other hemochromatosis genes".)

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 "Overview of cancer prevention", section on 'Iron'.)

Epidemiologic 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", section on 'Cardiac iron overload'.)

If confirmed, these findings suggest that maintaining low but adequate iron stores is an important health goal in resource-rich countries. In resource-limited countries, high iron status is rare and public health efforts generally focus on the prevention of iron deficiency.

MANGANESE — Manganese (Mn) was first shown to be essential for normal growth and development of rodents [113,114]. Deficiency in humans is unusual.

Dietary sources — Grains, dried fruit, vegetables, and nuts are good sources of manganese, but absorption is very variable [4,115]. Tea also contains large amounts of manganese, but its bioavailability may be low [116,117].

Dietary reference intake — The recommended intake for manganese is expressed as an adequate intake (AI) because of the limited data available to determine the population needs [4]. The tolerable upper intake level (UL) for manganese is 2 mg/day in toddlers and up to 11 mg/day for adults (table 2).

Metabolism — Manganese is absorbed throughout the small intestine, but the coefficient of absorption generally is very low, possibly as low as 5 percent [118]. Manganese is converted from the Mn2+ to the Mn3+ form before being taken up by an active mechanism and passive diffusion that are rapidly saturable [119,120]. Absorption is decreased following high dietary intakes or if total body manganese status is good [121]. Absorption is inhibited by high dietary intakes of calcium, phosphate, and fiber, and increased in the setting of iron deficiency [4,122].

Following absorption, manganese is transported in the portal blood bound to albumin and alpha-2-macroglobulin [123,124]. Once taken up by the liver, a proportion is rapidly excreted into the bile, while some enters mitochondrial, nuclear, or lysosomal pools [116]. It is not known how manganese is transported from the liver to peripheral tissues, but it may be bound to transferrin [116]. Approximately one-quarter of total body manganese is found in the bones [116]. Significant amounts also are found in tissues rich in mitochondria (liver, kidney, pancreas) and rich in melanin (retina, pigmented skin) [116].

Excretion of manganese is primarily through bile into the gastrointestinal tract and is lower during infancy.

Biologic role — Manganese is found in manganese superoxide dismutase (Mn-SOD), arginase, glutamate synthetase, and pyruvate carboxylase [116]. It also is found in other enzymes, where it may replace magnesium [125].

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 [4,126]. In some animal models, the offspring of manganese-deficient mothers develop irreversible ataxia [116].

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 [127]. 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 [128,129].

Toxicity — Manganese toxicity (manganism) is a well-recognized 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 [130,131]. High levels of manganese can be neurotoxic, affecting primarily the extrapyramidal parts of the brain. Symptoms are similar to those of Parkinson disease and include dyscoordination, loss of balance, and confusion [116,132,133]. 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 [134]. Cases of probable manganese toxicity in children and adults on chronic parenteral nutrition have been reported [132,135]. Intravenously fed neonates may be at risk, particularly if they have cholestasis, which decreases manganese excretion. Although recommendations are that intravenous manganese be limited to less than 1 mcg/kg/day for neonates and children weighing up to 40 kg [136,137], 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 at-risk patients, including those with cholestasis and those on chronic parenteral nutrition [138].

Biomarkers for manganese toxicity have not been established [135,137]. Elevations in serum and whole blood manganese concentrations are often found in individuals on chronic parenteral nutrition, and correlate with manganese-associated changes in signal intensity on brain magnetic resonance imaging (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 [122]. Manganese concentrations are increased by formula feeding (particularly soy formulas), biliary obstruction, or long-term parenteral nutrition. Whether the mild increases in serum manganese that occur in healthy infants as a result of formula feeding have any detectable effects on development has not been established.

SELENIUM — Selenium (Se) is an ultratrace element with a role in multiple biologic functions. Se deficiency was first identified in experiments in rats, which were made nutritionally deficient in vitamin E [139]. 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 [140].

Dietary sources — In free-living animals and humans, selenium is mostly in the form of two selenium-containing amino acids: seleno-cysteine and seleno-methionine [141]. Inorganic forms of selenium are used in supplements [142].

Seafood, kidney and liver, and meat are good sources of selenium [82]. Drinking water usually contains very little selenium [143]. 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 [82].

Dietary reference intake — The recommended dietary allowance (RDA) for selenium is 20 mcg/day for young children, rising to 55 mcg/day for adults (table 2) [4].

Metabolism — Dietary selenium has a high bioavailability (>50 percent). Seleno-methionine is actively absorbed in the small intestine by the methionine absorptive pathway [141,142]. The absorptive route of seleno-cysteine is unknown. Inorganic selenium (in supplements) is passively absorbed in the duodenum [142]. Selenium absorption appears to be independent of the individual's selenium status and may be unregulated [142].

In vivo, selenium is a component of seleno-proteins. Seleno-methionine is incorporated into proteins in place of methionine and seems to serve as a storage pool [142]. Seleno-cysteine is the active form of selenium found in proteins [142]. It is absorbed directly from the diet, synthesized from seleno-methionine [142], or synthesized by direct replacement of an oxygen residue on serine while it is bound to a specific tRNA [141]. Seleno-cysteine and seleno-methionine are catabolized to release selenium. The principal excretory route of selenium is the urine [142].

Biologic role — More than 30 selenoproteins have been identified, of which the best known are the four forms of glutathione peroxidase [144,145], which are important in antioxidant defense, and iodo-thyronine deiodinase 2 (three forms), which serves as a catalyst for production of thyroid hormone [82,146]. Other seleno-proteins include seleno-protein P and seleno-protein synthetase [144]. Some have well-defined roles, while others are still under investigation.

Deficiency — Severe selenium deficiency is associated with skeletal muscle dysfunction and cardiomyopathy [146-148] and may also cause mood disorders, impaired immune function, macrocytosis, and whitened nailbeds [149-152].

Keshan disease, an endemic cardiomyopathy that affects children and females of childbearing age in areas of China, has been linked to selenium deficiency [153]. 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 [154]. 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 [155].

Other potential roles — Other clinical effects of selenium deficiency have been suggested but are not well established [147]:

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 [156]. A number of studies have shown a linear relationship between selenium deficiency and a reduction in CD4 cell counts in HIV-infected patients [157]. Impaired cell-mediated immunity has been demonstrated when tissue stores of selenium are depleted [151]. Natural killer cell activity is enhanced when selenium is supplemented in the diet of selenium depleted individuals [158].

Thyroiditis – Selenium supplementation may decrease inflammatory activity in patients with autoimmune thyroiditis [159] and may reduce the risk of postpartum thyroiditis in patients who are positive for thyroid peroxidase (TPO) antibodies. (See "Postpartum thyroiditis".)

Cancer – Epidemiologic studies support a possible relationship between Se and cancer mortality [160,161]. As a result, a number of studies have investigated the role of selenium supplementation for prevention of cancer. (See "Risk factors for prostate cancer".)

Cardiovascular disease – As mentioned previously, glutathione peroxidase (GPx), a seleno-protein 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 [147,162]. These effects would predict that Se supplementation should be protective of atherosclerotic disease, although there is limited evidence demonstrating such a benefit [163].

Glucose metabolism – Animal models suggest that low doses of selenium may improve glucose metabolism [164], but clinical studies in humans suggest that selenium supplementation does not confer benefit and may increase the risk of type 2 diabetes. (See "Type 2 diabetes mellitus: Prevalence and risk factors".)

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 [165]. (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 plant-based diet resulted in hair and nail loss, tooth decay, dermatologic lesions, and neurologic effects [166]. Selenium toxicity occurred in 201 individuals in the United States who took a liquid dietary supplement containing 200 times the labeled content of selenium [167]. The median estimated dose of selenium consumed was over 41,000 mcg/day, which is almost 800 times the recommended dietary allowance of 55 mcg/day, and more than 100 times the tolerable upper intake limit of 400 mcg/day. A previous outbreak of selenium poisoning occurred in 13 individuals who took a mislabeled supplement in 1983 [168].

ZINC — Historically, severe zinc deficiency was recognized as a cause of endemic hypogonadism and dwarfism in rural Iran [169-171]. 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".)

Dietary sources — Meat and chicken are excellent sources of zinc [172], 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 [173].

Dietary reference intake — The recommended dietary reference intake (DRI) for zinc varies by age and sex, rising from 3 mg/day in early childhood to 8 mg/day for adult females and 11 mg/day for adult males [4,174]. Requirements are slightly higher during pregnancy and lactation (table 2).

Metabolism — Total body zinc averages 1.5 to 2.5 g in adults [172], 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 [175]. 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 [175,176]. During digestion, dietary zinc is released and forms complexes with different ligands, namely amino acids, phosphates, organic acids, and histidines [177]. Zinc-ligand 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 [178].

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 disease since regular intake of zinc will competitively block gut copper uptake. (See "Wilson disease: Treatment and prognosis".)

Zinc absorption may be impaired in exocrine pancreatic insufficiency [179]. Dietary phytic acid is known to reduce zinc absorption [180]. 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 [4,181].

The major route of zinc excretion is via the gastrointestinal tract. Up to 10 percent of the circulating zinc is also excreted through urine [169]. Zinc homeostasis is probably maintained by a combination of changes in fractional absorption and endogenous fecal zinc excretion [179].

Biologic role — Zinc has structural, regulatory, and catalytic functions. It has important roles both in cell division as well as apoptosis (programmed cell death) and thus plays a role in growth, tissue repair, and wound healing. It is also involved in lipid and glucose metabolism and in immunity and the response to infection [182]. Zinc deficiency is associated with impaired phagocytic function, lymphocyte depletion, decreased immunoglobulin production, reduction in the T4+/T8+ ratio, and decreased interleukin 2 (IL-2) production [183-185].

Zinc owes its biologic 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 beta-pleated sheet) and maintains nuclear stability and histone structure [186]. 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, copper-zinc superoxide dismutase, and metallothionein, as well as a large family of zinc proteins involved in gene transcription (such as the zinc finger proteins) [4,187,188].

Deficiency

Dietary deficiency — Mild dietary zinc deficiency impairs growth velocity while severe depletion of zinc leads to growth failure. 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) [189]. Other signs and symptoms of zinc deficiency include hair changes [190] (ie, change in hair color and hair loss), impaired appetite, and decubitus ulcers. (See "Zinc deficiency and supplementation in children".)

Findings such as these, suggesting zinc deficiency, have been described in chronic diseases such as malnutrition, malabsorption syndromes (eg, 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 [191,192]. Pregnancy also increases the risk for zinc deficiency. Patients with alcohol-related cirrhosis often have low hepatic concentrations of zinc [193]. Cases of zinc deficiency have been reported among older individuals with poor diet quality [194]. 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 [195].

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 [196]. Zinc supplementation in diabetic patients may improve immune function, but also increases the HbA1c levels and leads to worsening glucose intolerance [197].

Mild zinc deficiency appears to be common, especially in resource-limited countries. Individuals in resource-limited 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 resource-limited countries. (See "Zinc deficiency and supplementation in children".)

Zinc supplementation during pregnancy for individuals with mild zinc deficiency appears to promote fetal growth and reduce the risk of premature birth and infant diarrhea [198-201]. 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; MIM #201100) is an autosomal recessive disease in which zinc absorption is impaired. The disorder is caused by variants in the SLC39A4 gene, which encodes a protein that appears to be involved in zinc transport [202,203].

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 [171]. 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 [204].

Oral supplementation with zinc (30 to 45 mg/day) leads to a rapid and complete remission of the symptoms. Therapy needs to be continued indefinitely [204].

Toxicity — Humans are very tolerant of high zinc intakes up to 100 mg/day [205]. Mega-dose supplementation or high zinc intake from contaminated food or beverages has been associated with nonspecific gastrointestinal symptoms, including abdominal pain, diarrhea, nausea, and vomiting [204,206]. Zinc may interfere with copper absorption, and high zinc intakes (>150 mg/day) can lead to copper deficiency [207]. (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 [143].

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 [208]. Several functional indices also can be used to indirectly assess zinc status. Alkaline phosphatase activity can serve as a supportive marker of zinc status [4].

Because most zinc is bound to albumin, zinc levels may be reduced in patients with hypoalbuminemia [209,210]. 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.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin deficiencies".)

SUMMARY AND RECOMMENDATIONS

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 tolerable upper intake level (UL) is the quantity of the nutrient considered to cause no adverse effects in healthy individuals. These parameters have been estimated for each trace element (table 2). (See 'Definitions' above.)

Copper deficiency can be caused by an X-linked variant in the gene encoding 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 (TPN) without trace minerals. Clinical features of selenium deficiency are cardiomyopathy and skeletal muscle dysfunction. (See 'Selenium' above.)

Zinc deficiency causes growth failure 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".)

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