Trace Elements

Trace elements are minerals required in small amounts (1–100 mg/day in adults) to carry out biologic functions. These elements act as cofactors for essential enzymes as well as being components of hormones and antioxidant molecules. Trace elements have essential roles in oxygen transport, energy metabolism, and immune responses. Iron, chromium, copper, and iodine are among these elements. Overt deficiencies in resource-rich countries are rare because of varied food supply, food fortification, and supplement use. However, deficiencies can develop in certain medical conditions. Toxicity can also occur when there is exposure to concentrations larger than those physiologically required.

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Definition

Trace elements (also called trace minerals) are minerals required in small amounts (1–100 mg/day for adults):

  • Have several functions, including in enzyme systems, energy metabolism, and oxygen transport
  • Intake of large amounts over a long period can produce toxic effects.
  • Required intake is expressed as Recommended Dietary Allowance (RDA): dietary intake sufficient to meet the daily nutrient requirements of 97% of the individuals in a specific life stage group
  • If data regarding RDA are limited, Adequate Intake (AI) is used to indicate the amount estimated to be sufficient to maintain a healthy state.

Chromium

General description

  • Symbol: Cr
  • Multiple ionic states:
    • Dietary chromium: trivalent state
    • Cr4+: toxic form

Functions

  • Potentiates insulin
  • Influences carbohydrate and lipid metabolism

Intake and metabolism

  • RDA: 20–35 μg/day for adults
  • Source: processed meats, liver, brewer’s yeast, whole grains, cereals, fruits, vegetables
  • Absorption: small intestine
  • Transport (circulation): bound to albumin and transferrin
  • Regulation:
    • ↑ Absorption with vitamin C as well as in zinc and iron deficiency
    • ↓ Absorption with antacids and NSAIDs
    • Excretion: in feces

Deficiency and toxicity

  • Chromium deficiency is generally seen in:  
    • Conditions characterized by increased catabolism and metabolic demands (critical illness)
    • Malnutrition 
    • Short bowel syndrome 
    • Chronic total parenteral nutrition (especially in patients with diabetes and increased insulin requirements)
  • Excess:
    • Dietary chromium has poor oral bioavailability (so generally nontoxic). 
    • Hexavalent chromium (Cr (VI)) toxicity (airborne): ↑ risk of lung cancer in stainless steel workers
    • Pentavalent, or Cr (V), and Cr (VI) (by inhalation): bronchogenic cancer, skin ulcers, dermatitis

Copper

General description

  • Symbol: Cu
  • High concentrations in liver, brain, bone 
  • In acute-phase response, plasma levels are increased.
  • Heritable diseases associated with inborn errors of copper metabolism:
    • Wilson disease: autosomal recessive disorder characterized by features of copper toxicity
    • Menkes disease: X-linked genetic disorder characterized by defective transport protein mediating copper uptake from the intestine, leading to copper deficiency

Functions

  • Involved in oxidation–reduction reactions
  • Integral component of important enzymes:
    • Ceruloplasmin (copper transporter and ferroxidase) 
    • Cytochrome c oxidase (electron transport) 
    • Zinc–copper superoxide dismutase (antioxidant defense)
    • Dopamine monooxygenase (neurotransmitter synthesis) 
    • Lysyl oxidase (collagen cross-linking, bone formation) 
    • Dopamine β-hydrolase (skin pigmentation) 
    • Tyrosinase (melanin production)

Intake and metabolism

  • RDA:  
    • Children: 340 µg daily
    • Adults: 900 µg daily
  • Source: 
    • Highest content in liver
    • Vegetable products: vegetables, grains, and pulses (leguminous seeds such as beans, peas, and lentils) 
    • Meat, fish, and poultry
  • Absorption: stomach and small intestine
  • Copper is taken up by the liver and is incorporated into ceruloplasmin.
  • Ceruloplasmin transports copper from the liver to peripheral tissues.
  • Regulation:
    • Excretion via GI secretions and bile (50% each)
    • Copper homeostasis is maintained through the excretion process, especially through the GI tract (preventing deficiency and toxicity).

Deficiency and toxicity

  • Acquired deficiency:
    • Seen in:
      • Malabsorptive GI surgery (e.g., gastric bypass), manifesting with myelopathy or neurologic symptoms similar to those of vitamin B12 deficiency
      • Prolonged parenteral nutrition (especially in preterm infants)
      • Chronic diarrhea (such as in celiac disease)
      • Dialysis
      • Excessive zinc intake
      • Iatrogenic (treatment of Wilson disease with chelation and zinc → ↓ copper level)
      • Menkes disease
    • Manifestations:
      • Depigmentation
      • Muscle weakness
      • Neurologic abnormalities
      • Hepatosplenomegaly
  • Excess:
    • Seen in:
      • Accidental ingestion
      • Suicide attempt
      • Water source contamination
      • Topical creams with copper salts
      • Wilson disease
    • Manifestations:
    • GI symptoms
    • Liver cirrhosis
    • Renal and cardiac failure

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Fluoride

General description

  • Fluoride (F–): monovalent anion derived from fluorine
  • Common in the earth’s crust as calcium fluoride

Functions

Provides benefits (but not necessary):

  • Together with calcium, stimulates osteoblastic activity (although reduction in fractures are not seen)
  • Used in preventing dental caries

Intake and metabolism

  • No RDA due to limited data, but AI is defined as:
    • Adult females: 3 mg daily
    • Adult males: 4 mg daily
  • Source: found in tea, seafood that contains edible bones or shells (e.g., canned sardines), and fluoridated toothpaste
  • Absorption: stomach and small intestine
    • About 30% taken up in calcified tissues
    • Most fluoride is in the bones and teeth.
  • Excretion: in urine

Deficiency and toxicity

  • Low levels of fluorine in drinking water lead to dental decay. 
  • Excess:
    • High levels cause dental fluorosis and mottling of tooth enamel.
    • In settings of exposure to Freon vapor or hydrofluoric acid spills, toxicity can follow inhalation or skin absorption.
    • GI symptoms (nausea, vomiting, diarrhea) are noted, but renal and cardiac failure occurs in severe cases.

Iodine

General description

  • Symbol: I
  • Essential component of the thyroid hormones triiodothyronine (T3) and thyroxine (T4)
  • Deficiency remains a public health issue in resource-limited countries.

Functions

Physiologic actions of thyroid hormones involve: 

  • Growth and development  
  • Control of metabolic processes in the body 
  • Energy production
  • Lipolysis 
  • Regulation of gluconeogenesis and glycolysis

Intake and metabolism

  • RDA:
    • Children 1–8 years of age:  90 µg daily
    • Children 9–13 years of age: 120 µg daily
    • Adolescents and adults: 150 µg daily
    • Pregnancy: 220 µg daily
    • Lactation: 290 µg daily
  • Source: 
    • Seafood
    • Foods grown in iodine-rich soil
    • Iodized salt
    • Bread and dairy products
  • Absorption: proximal small intestine
    • Goes into circulation and stored in the thyroid
    • T3 and T4 are secreted by the thyroid.
  • Excretion:  
    • In urine
    • GI losses are reabsorbed.

Deficiency and toxicity

  • Iodine deficiency: 
    • From inadequate intake
    • Effects:
      • Goiter 
      • Hypothyroidism 
      • Increased risk of miscarriage, preterm birth, congenital fetal abnormalities 
      • High incidence of neonatal death
  • Excess: 
    • From dietary supplements, prescription medications, radiographic contrast agents
    • Effects:
      • Abrupt increase in iodine in endemic goiter or iodide deficiency → hyperthyroidism
      • Iodine administration in Hashimoto’s thyroiditis → may induce hypothyroidism

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Iron

General description

  • Symbol: Fe
  • Most abundant essential trace element in the human body
  • Forms of iron (total content of iron in the body of 3–4 g in males):
    • 75% in heme proteins:
      • In the form of hemoglobin (for oxygen transport)
      • Myoglobin (for oxygen storage in tissues)
      • Cytochrome c (electron transport)
      • Cytochrome P450
      • Peroxidases
    • 20%–30% in storage form:
      • Ferritin (major intracellular iron-storage protein)
      • Hemosiderin (ferritin breakdown product)

Functions

  • Oxygen transport
  • Essential component of a number of enzymes necessary in:
    • DNA and RNA synthesis
    • Collagen synthesis
    • Antibody synthesis
  • Metalloenzymes (needed in tyrosine, dopamine, serotonin, and noradrenaline synthesis) 
  • Other biologic effect(s): able to cycle between ferrous (Fe2+) and ferric (Fe3+) forms, catalyzing reactions that produce reactive oxygen species, causing oxidative damage

Intake and metabolism

  • RDA: 
    • Women of childbearing age: 18 mg/day (due to losses in menstruation)
    • Pregnancy: 27 mg/day
    • Adult males: 8 mg/day 
  • Sources:
    • Heme iron: meat, poultry, fish
    • Nonheme iron: vegetables, fruits, fortified food products
  • Absorption:  
    • In the small intestine
    • ↑ By vitamin C 
    • ↓ By calcium, phytic acid,  tannates
  • Transported in the blood bound to transferrin, then taken up in the bone marrow
  • Losses: through desquamated skin, bleeding
  • Regulation:
    • Certain conditions require a decrease or increase in iron absorption.
    • Hepcidin: liver-derived peptide regulating the plasma iron concentration
      • ↑ Iron: ↑ hepcidin to reduce iron absorption
      • ↑ Inflammation: ↑ hepcidin to limit iron availability to microorganisms
      • ↑ Erythropoietin: ↓ hepcidin to increase iron for hematopoiesis

Deficiency and toxicity

  • Deficiency: 
    • Seen as microcytic hypochromic anemia:
      • Blood loss
      •  ↓ Intake or inability to keep up with demand (such as in pregnancy and lactation)
    • Manifestations include pallor, fatigue, and shortness of breath.
  • Excess: seen in hemochromatosis, iron poisoning

Selenium

General description

  • Symbol: Se
  • Discovered during experiments in rats: Selenium was shown to protect rats against dietary liver necrosis.

Functions

  • Part of active site of glutathione peroxidase, an antioxidant enzyme
  • Regulates immune, thyroid, and reproductive function

Intake and metabolism

  • RDA: 
    • Children: 20 μg/day
    • Adults: 55 μg/day
  • Source: seafood, kidney and liver, and grains
  • Absorption: small intestine (methionine absorptive pathway)
  • Exerts effects through 2 forms:
    • Selenomethionine: storage pool
    • Selenocysteine: active form of selenium found in proteins
  • Excretion: in urine

Deficiency and toxicity

  • Deficiency:
    • Seen in:
      • Aging
      • Smoking
      • Reduced intake (seen in endemic areas)
      • Total parenteral nutrition (TPN; not supplemented with selenium)
    • Effects:
      • Cardiomyopathy (Keshan disease in China, from low-Se diets)
      • Skeletal muscle dysfunction
      • Thyroiditis can increase with selenium deficiency
      • Impairment of both innate and adaptive immunity
  • Excess:
    • Seen in increased supplementation
    • Effects:
      • GI: nausea, vomiting, diarrhea
      • Neurologic: altered mental status, visual loss, peripheral neuropathy
      • Dermatologic: hair loss, nail changes

Zinc

General description

  • Symbol: Zn
  • Essential element related to a common deficiency worldwide
  • In resource-limited countries, supplementation helps reduce serious infections and improve immunity.

Functions

  • Important in immune response
  • Deficiency leads to phagocytic impairment and decreased IL-2 and immunoglobulin production.
  • Stabilizer of the molecular structure of cellular constituents and membranes 
  • Participates in the metabolic activity of carbohydrates, proteins, and lipids
  • Plays an important role in growth (cell proliferation, differentiation, and metabolic activity)
  • Involved in wound repair and healing

Intake and metabolism

  • RDA varies by age and sex:
    • Children: 3 mg daily
    • Adult females: 8 mg daily (higher in pregnancy and lactation)
    • Adult males: 11 mg daily
  • Source:
    • Shellfish (especially oysters), beef, and other red meats
    • Nuts, whole grains, legumes
  • Absorption: mainly jejunum and duodenum
    • Zinc is released and forms complexes with amino acids, phosphates, and histidines.
    • These complexes are absorbed through the intestines → portal circulation → liver
  • Regulation:
    • Metallothionein (in the enterocyte) regulates absorption by binding heavy metals (has more affinity for copper) to reduce oxidative damage.
    • Excretion: mainly via GI tract (10% in urine)

Deficiency and toxicity

  • Deficiency 
    • Seen in:
      • Exocrine pancreatic insufficiency
      • Reduced intake
      • Malabsorption syndromes
      • Gastric bypass surgeries
      • Alcoholic cirrhosis  
      • TPN
      • Acrodermatitis enteropathica: autosomal recessive disease with impaired zinc absorption
    • Manifestations:
      • Growth retardation
      • Sexual impairment (delayed maturation, impotence, hypogonadism, oligospermia)
      • Immune dysfunction
      • Impaired wound healing
      • Skin lesions (e.g., decubitus ulcers, vesiculobullous, and pustular lesions) 
      • Hair changes (e.g., hair loss)
  • Excess:
    • Can occur with contaminated food or beverages
    • Manifests with abdominal pain, diarrhea, nausea, and vomiting

Other Trace Elements

  • Molybdenum:
    • Deficiency: neurologic abnormalities
    • Toxicity: fetal and reproductive abnormalities
  • Manganese: 
    • Deficiency:
      • Impaired growth and skeletal development 
      • Reproductive abnormalities
      • Dysfunction in lipid and carbohydrate metabolism
      • Upper body rash
    • Toxicity:
      • Neurotoxicity
      • Parkinson-like symptoms
      • Psychosis
      • Pneumoconiosis
  • Boron:
    • Deficiency: unclear, as biologic function is undetermined 
    • Toxicity: GI symptoms, developmental defects, male sterility, testicular atrophy

Clinical Relevance

  • Iron deficiency anemia: most common type of anemia worldwide. Iron deficiency anemia is due to a decreased supply, an increased loss, or an increased demand for iron. The RBCs are microcytic and hypochromic. Iron studies are pivotal to diagnosis. The key to treatment is correction of the cause of the iron deficiency and iron supplementation.
  • Wilson disease (hepatolenticular degeneration): autosomal recessive disorder associated with mutations in the ATP7B gene, which regulates copper transport. This mutation causes copper to accumulate in the liver, brain, cornea, and other organs. Patients often present  with hepatic, neurologic (often resembling Parkinsonism), and psychiatric symptoms. Diagnosis is established by detection of corneal deposits of copper (Kayser-Fleischer rings), low plasma ceruloplasmin, and/or elevated levels of copper in the urine.
  • Menkes disease: inherited X-linked copper deficiency. Menkes disease 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. The ATP7A gene is closely related to the gene responsible for copper overload in Wilson’s disease. 
  • Hypothyroidism: condition characterized by the deficiency of thyroid hormones. Iodine deficiency and Hashimoto’s thyroiditis are the 2 leading etiologies. Clinical features reflect the effects of slowed organ function/decreased metabolic rate. Lab tests show elevated thyroid-stimulating hormone (TSH) and a low free T4. Treatment is with levothyroxine.
  • Hyperthyroidism: condition caused by sustained overproduction and release of the thyroid hormones T3 and T4. Graves’ disease is the most common cause of hyperthyroidism. Manifestations are mostly due to the increased metabolic rate and overactivity of the sympathetic nervous system. Lab tests show low TSH and elevated free T4. Treatment depends on the underlying condition.

References

  1. Anderson, G.J., Frazer, D.M. (2017). Current understanding of iron homeostasis. Am J Clin Nutr 106:1559S–1566S
  2. Bhattacharya, P.T., Misra, S.R., Hussain, M. (2016). Nutritional aspects of essential trace elements in oral health and disease: an extensive review. Scientifica 2016:5464373
  3. Calabria A.  (2020). Hypothyroidism in infants and children. Merck Manual Professional Edition. Retrieved June 2, 2021, from https://www.merckmanuals.com/professional/pediatrics/endocrine-disorders-in-children/hypothyroidism-in-infants-and-children
  4. Mehri, A. (2020). Trace elements in human nutrition (II)—an update. Int J Prev Med 11:2.
  5. Pazirandeh, S., Burns, D. (2021). Overview of dietary trace elements. UpToDate. Retrieved June 30, 2021, from https://www.uptodate.com/contents/overview-of-dietary-trace-elements
  6. Steinmaus, C. (2013). Water pollution. LaDou J, & Harrison R.J.(Eds.),  CURRENT Diagnosis & Treatment: Occupational & Environmental Medicine, 5e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1186&sectionid=66486752
  7. Suter P.M., Russell R.M. (2018). Vitamin and trace mineral deficiency and excess. Chapter 326 of Jameson, J., Fauci A.S., Kasper D.L., Hauser S.L., Longo D.L., Loscalzo J. (Eds.),  Harrison’s Principles of Internal Medicine, 20th ed. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192283003

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