Trace elements

Essential trace elements are dietary elements including iron, copper, zinc, iodine, selenium, and sulfur that the body requires in minute amounts for proper physiological function and development. While most essential trace elements primarily function as cofactors for a variety of reactions, some also function as constituents of essential molecules (e.g., iron in hemoglobin and myoglobin), transcription factors (e.g., zinc finger), and amino acids (e.g., sulfur in methionine and cysteine). Excess and deficiency of essential trace elements can cause symptoms and diseases, the most important of which are discussed below.

• Definition: In biochemistry, trace elements are dietary elements that the body requires in minute amounts for proper function and development.

General

• RDA: 10 mg/d (only 10% of iron is absorbed from the intestines)
• Iron stores in the body
  • Total body iron content is ∼ 3 g in ♀ and ∼ 6 g in ♂.
  • Total iron exists in two forms:
    • Functional iron (80%): hemoglobin (majority), myoglobin, cytochrome enzymes
    • Storage iron (20%): mainly liver (as ferritin/hemosiderin)
• Dietary iron
  • Heme iron: from meat
  • Non-heme iron: from plants
• Free iron can lead to reactive oxygen species via the Fenton reaction.
  • H₂O₂ + Fe²⁺ → OH- + Fe³⁺ + ^•OH (hydroxyl radical)
  • Hydroxyl radicals → oxidative stress → DNA damage

Iron absorption and transport^[1]

• Iron absorption
  • Occurs in the duodenum and upper jejunum
  • The enzyme hepcidin regulates intestinal absorption of iron.
    • Hepcidin is synthesized in the liver
    • Its production is regulated by the human hemochromatosis protein (HFE protein)
    • Increased body stores of iron → ↑ HFE protein → ↑ hepcidin → prevention of iron absorption
    • Iron deficiency → ↓ hepcidin → ↑ iron absorption
  • Ferric iron (non-heme iron, Fe³⁺) is mainly reduced to ferrous iron (Fe²⁺) and then absorbed.
    • Vitamin C increases absorption (converts Fe³⁺→ Fe²⁺).
    • Calcium decreases absorption (due to chelation of iron).
    • A minority of iron is absorbed as ferric iron (Fe³⁺).
  • Heme iron can be directly absorbed into intestinal cells.
• Iron transport
  • The enzyme ferroxidase (also known as ceruloplasmin) oxidizes ferrous iron back to ferric iron (converts Fe²⁺ → Fe³⁺).
  • Transferrin binds and transports the ferric iron to the erythroid precursor cells (in bone marrow) for hemoglobin synthesis.

Iron storage, recycling, and loss ^[2][3]

• Iron storage: stored mainly in the liver as ferritin and hemosiderin
• Iron recycling
  • Reticuloendothelial macrophages (in the spleen and liver) phagocytose senescent RBCs and release iron from hemoglobin.
  • Transferrin binds the released iron and transports it to the bone marrow for erythropoiesis.
• Iron loss
  • Shedding of skin and mucosal epithelial cell → daily loss of 1–2 mg of iron
  • Any source of bleeding (e.g., menstruation, occult GI bleed) increases iron loss.

Function

• Cofactor for
  • Cytochrome C, cytochrome P450
  • Peroxidases
  • Metalloproteases (e.g., NADH dehydrogenase)
  • Phosphoenolpyruvate carboxykinase (gluconeogenesis), aconitase (Krebs cycle)
  • Ribonucleotide reductase (DNA and RNA synthesis).
• Integral component of hemoglobin and myoglobin

Deficiency

For more details regarding the clinical features, diagnosis, and etiology of iron deficiency, see the article on iron deficiency anemia.

• Causes
  • Decreased intake
  • Decreased absorption
  • Increased demand (e.g., lactation, growth spurt, pregnancy)
  • Iron loss (e.g., menorrhagia, gastrointestinal bleeding)
• Symptoms
  • Fatigue, lethargy, pallor

Excess

• Causes
  • Hemochromatosis
  • Iron toxicity (poisoning)

General

• Source: meat, fish, poultry, vegetables, grains, legumes (e.g., lentils, beans)
• Metabolism
  • Absorbed in the stomach and small intestine
    • Absorbed by active transport and passive diffusion
    • Exported from enterocytes via Menkes P-type ATPase
    • Binds albumin and is transported as part of the enterohepatic circulation
    • Transported by ceruloplasmin from the liver to peripheral tissue
  • Stored primarily in the liver and brain. Small amounts are stored in the heart, kidney, and pancreas.

Function

• Cofactor for
  • Cytochrome c oxidase (electron transport chain)
  • Tyrosinase (melanin synthesis)
  • Lysyl oxidase (important for cross-linking during collagen synthesis)
  • Factor V (coagulation cascade)

Deficiency

• Causes: primarily due to genetic mutations
  • Menkes disease
    • Causes inability to transport copper from enterocytes to the liver and other cells of the body → ↓ copper levels
    • Due to a mutation in the Menkes P-type ATPase, a protein encoded by the ATP7A gene
• Clinical features
  • Depigmentation of the skin
  • Abnormal hair growth
  • Muscle weakness
  • Hepatosplenomegaly
  • Edema
  • Osteoporosis
  • Neurologic manifestations: ataxia, neuropathy
  • Delayed wound healing
  • Sideroblastic anemia

Excess

• Causes: Wilson disease, rarely from toxic water or cooking with copper pots

General

• Source: poultry, oysters, fish, meat, zinc-fortified food products (e.g., cereals), nuts
• Metabolism
  • Absorbed primarily in the duodenum and jejunum
  • Absorption is regulated by metallothionein
  • Excreted primarily via the gastrointestinal tract

Function

• Protein structure
  • Forms bonds between cysteine and histidine
  • Forms zinc finger transcription factors
• Aids in maintenance and stability of the nuclear membrane
• Essential part of many enzymes (> 100), including alkaline phosphatase, carbonic anhydrase, metallothionein, superoxide dismutase, ACE, and collagenases

Deficiency

• Causes
  • Inadequate dietary intake
  • Crohn disease, liver, and renal disease
  • Acrodermatitis enteropathica: congenital deficiency of the zinc/iron-regulated transporter-like protein (ZIP)
  • Total parenteral nutrition
  • Chronic liver disease (esp. liver cirrhosis)
• Clinical features
  • Impaired wound healing
  • Dysgeusia
  • Anosmia
  • Immune dysfunction
  • Male hypogonadism
  • Dermatitis
  • Alopecia
  • In patients with liver cirrhosis: associated with accelerated progression of cirrhosis and aggravated clinical symptoms (e.g., hepatic encephalopathy).
  • Impaired growth and development
  • Diarrhea

Excess

• Causes
  • Rare, but can develop due to excess zinc intake
• Clinical features
  • Abdominal pain
  • Nausea, vomiting, diarrhea

References:^[4]

General

• Source: seafood, seaweed, plants grown in iodine-rich soil, water, vegetables, iodized table salt
• Metabolism
  • Absorbed in the small intestine
  • Most iodide is taken up and stored by the thyroid gland; excess is excreted by the kidneys.
• Elemental iodine can be used as a disinfectant.

Function

• Integral part of 3-iodotyrosine (T3) and thyroxine (T4)
• See also thyroid hormones.

Iodine deficiency

• Causes: decreased intake (e.g., a diet low in iodine )
• Clinical features: Iodine deficiency presents with features of decreased thyroid hormone synthesis.
  • Increased infant mortality
  • Hypothyroidism
  • Congenital iodine deficiency syndrome
  • Myxedema coma
  • Goiter

Iodine excess

• Causes: Excess iodine is rare but can be caused by administration of iodine-containing contrast agents or excessive consumption of dietary supplements (seaweed, kelp).
• Clinical features
  • In patients with normal thyroid function, excess iodine is usually well tolerated.
  • Jod-Basedow phenomenon
    • Hyperthyroidism following iodine excess (e.g., after IV contrast administration, due to intake of amiodarone or other iodine-containing drugs, etc.)
    • Occurs due to activation of the entire thyroid or foci of autonomously functioning thyroid tissue (e.g., thyroid nodule)
    • Induced in patients with pre-existing hypothyroidism (e.g., endemic goiter, Hashimoto thyroiditis) and patients with latent or overt hyperthyroidism
    • Characterized by symptoms of hyperthyroidism or thyrotoxicosis
  • Wolff-Chaikoff effect ^[5][6]
    • Hypothyroidism following iodine excess (opposite effect to Jod-Basedow phenomenon)
    • Temporary autoregulatory compensation mechanism for the prevention of a hypermetabolic state in the event of iodine excess
    • Mechanism: excess iodine inhibits thyroid peroxidase → decreases T3/T4 production

General

• Source: meat, seafood, grains and seeds (e.g., brazil nut)
• Metabolism
  • Present in two forms (in animals): seleno-methionine and seleno-cysteine
  • Absorbed in the small intestine
  • Stored as seleno-methionine
  • Active form: seleno-cysteine
  • Excreted in the urine

Function

• Cofactor for enzymes such as glutathione peroxidase; , and iodothyronine deiodinase 2 (thyroid hormone production)

Selenium plays an important role in neutralizing oxidant stress as part of the glutathione peroxidase.

Deficiency

• Causes
  • Malnutrition
  • Total parenteral nutrition (TPN)
• Clinical features
  • Cardiomyopathy
  • Skeletal muscle dysfunction
  • Immune system dysfunction
  • Macrocytosis

Excess

• Causes: excess selenium intake (→ selenosis)
• Clinical features
  • Nausea, vomiting, diarrhea
  • Hair loss
  • Nail changes
  • Fatigue
  • Peripheral neuropathy

General

• Source: meat, eggs, nuts, salmon, leafy green vegetables (e.g., kale, spinach), legumes

Function

• Form disulfide bonds (between cysteine residues)
  • Integral part in the tertiary structure of proteins
• Present in methionine, cysteine, homocysteine, cystine, and taurine
• Present in thiamine and biotin
• Present in coenzyme-A
• Present in keratin (aids in maintenance of skin, hair, and nails)
• Essential for collagen synthesis

Deficiency

• Causes
  • Deficiency is very rare.
  • Diet based on products grown in sulfur-depleted soils
  • Low-protein diets
• Clinical features
  • Arthritis
  • Brittle nails and hair
  • Nausea, vomiting, diarrhea
  • Skin rash
  • Cognitive impairment (e.g., memory loss)
  • May contribute to obesity, heart disease, Alzheimer disease

Excess

• Causes: excess consumption of sulfur-rich foods
• Clinical features
  • Nausea, diarrhea, vomiting
  • Headache

1. Iron Absorption. https://courses.washington.edu/conj/bess/iron/iron.htm. Updated: February 28, 2017. Accessed: February 28, 2017.
2. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Elsevier Saunders ; 2014
3. Soe-Lin S, Apte SS, Andriopoulos B Jr. Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci U S A. 2009; 106 (14): p.5960-5965. doi: 10.1073/pnas.0900808106 . | Open in Read by QxMD
4. Dela Rosa KM. Acrodermatitis Enteropathica. In: James WD, Acrodermatitis Enteropathica. New York, NY: WebMD. https://emedicine.medscape.com/article/1102575. Updated: November 12, 2018. Accessed: December 29, 2018.
5. Leung AM, Braverman LE. Consequences of excess iodine. Nat Rev Endocrinol. 2013; 10 (3): p.136-142. doi: 10.1038/nrendo.2013.251 . | Open in Read by QxMD
6. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-Induced Hypothyroidism. Thyroid. 2001; 11 (5): p.501-510. doi: 10.1089/105072501300176462 . | Open in Read by QxMD