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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes as well as being components of hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
  • Influences carbohydrate and lipid metabolism Lipid Metabolism Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Lipid Metabolism

Intake and metabolism

  • RDA: 20–35 μg/day for adults
  • Source: processed meats, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, brewer’s yeast, whole grains, cereals, fruits, vegetables
  • Absorption: small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. 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 Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries 
    • Short bowel syndrome Short bowel syndrome Short bowel syndrome is a malabsorptive condition most commonly associated with extensive intestinal resection for etiologies such as Crohn's disease, bowel obstruction, trauma, radiation therapy, and vascular insufficiency. The short length of bowel results in insufficient surface area for fluid and electrolyte absorption. Short Bowel Syndrome 
    • Chronic total parenteral nutrition (especially in patients with diabetes and increased insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin requirements)
  • Excess:
    • Dietary chromium has poor oral bioavailability (so generally nontoxic). 
    • Hexavalent chromium (Cr (VI)) toxicity (airborne): ↑ risk of lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer in stainless steel workers
    • Pentavalent, or Cr (V), and Cr (VI) (by inhalation): bronchogenic cancer, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin ulcers, dermatitis

Copper

General description

  • Symbol: Cu
  • High concentrations in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, brain, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 
  • In acute-phase response, plasma levels are increased.
  • Heritable diseases associated with inborn errors of copper metabolism:
    • Wilson disease: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones formation) 
    • Dopamine β-hydrolase ( skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin pigmentation) 
    • Tyrosinase (melanin production)

Intake and metabolism

  • RDA:  
    • Children: 340 µg daily
    • Adults: 900 µg daily
  • Source: 
    • Highest content in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Vegetable products: vegetables, grains, and pulses (leguminous seeds such as beans, peas, and lentils) 
    • Meat, fish, and poultry
  • Absorption: stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine
  • Copper is taken up by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and is incorporated into ceruloplasmin.
  • Ceruloplasmin transports copper from the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (such as in celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease)
      • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of 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 Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide attempt
      • Water source contamination
      • Topical creams with copper salts
      • Wilson disease
    • Manifestations:
    • GI symptoms
    • Liver cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. 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 Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine
    • About 30% taken up in calcified tissues
    • Most fluoride is in the bones and teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin absorption.
    • GI symptoms (nausea, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea) are noted, but renal and cardiac failure occurs in severe cases.

Iodine

General description

  • Symbol: I
  • Essential component of the thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones triiodothyronine (T3) and thyroxine (T4)
  • Deficiency remains a public health issue in resource-limited countries.

Functions

Physiologic actions of thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones involve: 

  • Growth and development  
  • Control of metabolic processes in the body 
  • Energy production
  • Lipolysis 
  • Regulation of gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis and glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: 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 Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. 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 Goiter A goiter is a chronic enlargement of the thyroid gland due to nonneoplastic growth occurring in the setting of hypothyroidism, hyperthyroidism, or euthyroidism. Morphologically, thyroid enlargement can be diffuse (smooth consistency) or nodular (uninodular or multinodular). Goiter 
      • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism 
      • Increased risk of miscarriage, preterm birth Preterm birth Preterm labor refers to regular uterine contractions leading to cervical change prior to 37 weeks of gestation; preterm birth refers to birth prior to 37 weeks of gestation. Preterm birth may be spontaneous due to preterm labor, preterm prelabor rupture of membranes (PPROM), or cervical insufficiency. Preterm Labor and 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 Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
      • Iodine administration in Hashimoto’s thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel's thyroiditis). 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes necessary in:
    • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: 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 Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine
    • ↑ By vitamin C 
    • ↓ By calcium, phytic acid,  tannates
  • Transported in the blood bound to transferrin, then taken up in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
  • Losses: through desquamated skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, bleeding
  • Regulation:
    • Certain conditions require a decrease or increase in iron absorption.
    • Hepcidin: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver-derived peptide regulating the plasma iron concentration
      • ↑ Iron: ↑ hepcidin to reduce iron absorption
      • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation: ↑ hepcidin to limit iron availability to microorganisms
      • ↑ Erythropoietin: ↓ hepcidin to increase iron for hematopoiesis

Deficiency and toxicity

  • Deficiency: 
    • Seen as microcytic hypochromic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview:
      • 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, and grains
  • Absorption: small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. 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 Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies (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 Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion syndromes
      • Gastric bypass surgeries
      • Alcoholic cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis  
      • TPN
      • Acrodermatitis enteropathica: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisease with impaired zinc absorption
    • Manifestations:
      • Growth retardation
      • Sexual impairment (delayed maturation, impotence, hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism, oligospermia)
      • Immune dysfunction
      • Impaired wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Pneumoconiosis Pneumoconiosis is an occupational disease that results from the inhalation and deposition of mineral dusts and other inorganic particles in the lung. It can be categorized according to the type of causative particle involved or by the type of response provoked. Pneumoconiosis
  • Boron:
    • Deficiency: unclear, as biologic function is undetermined 
    • Toxicity: GI symptoms, developmental defects, male sterility, testicular atrophy

Clinical Relevance

  • Iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia: most common type of anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview worldwide. Iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. 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 Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder associated with mutations in the ATP7B gene, which regulates copper transport. This mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations causes copper to accumulate in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: condition characterized by the deficiency of thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones. Iodine deficiency and Hashimoto’s thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel's thyroiditis). 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 Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones T3 and T4. Graves’ disease is the most common cause of hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism. Manifestations are mostly due to the increased metabolic rate and overactivity of the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the 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 Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. 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 Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. 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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