Minerals

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Minerals are elements that originate in the Earth and cannot be made by living organisms. Plants obtain minerals from the soil, and most of the minerals in our diets come directly from plants or indirectly from animal sources. Minerals may also be present in the water we drink, but this varies with geographic locale. Minerals from plant sources may also vary from place to place, because soil mineral content varies geographically.

The information from the Linus Pauling Institute's Micronutrient Information Center on vitamins and minerals is now available in a book titled, An Evidence-based Approach to Vitamins and Minerals: Health Benefits and Intake Recommendations. The book can be purchased from the Linus Pauling Institute or Thieme Medical Publishers.

Select a mineral from the list for more information.

Calcium

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Summary

  • Calcium is a major constituent of bones and teeth and also plays an essential role as second messenger in cell-signaling pathways. Circulating calcium concentrations are tightly controlled by the parathyroid hormone (PTH) and vitamin D at the expense of the skeleton when dietary calcium intakes are inadequate. (More information)
  • The recommended dietary allowance (RDA) for calcium is 1,000 mg/day-1,200 mg/day for adults. (More information)
  • The skeleton is a reserve of calcium drawn upon to maintain normal serum calcium in case of inadequate dietary calcium. Thus, calcium sufficiency is required to maximize the attainment of peak bone mass during growth and to limit the progressive demineralization of bones later in life, which leads to osteoporosis, bone fragility, and an increased risk of fractures(More information)
  • High concentrations of calcium and oxalate in the urine are major risk factors for the formation of calcium oxalate stones in the kidneys. Because dietary calcium intake has been inversely associated with stone occurrence, it is thought that adequate calcium consumption may reduce the absorption of dietary oxalate, thus reducing urinary oxalate and kidney stone formation. (More information)
  • Data from observational studies and randomized controlled trials support calcium supplementation in reducing the risk of high blood pressure and preeclampsia in pregnant women. The World Health Organization advises that all pregnant women in areas of low calcium intake (i.e., low-income countries with intakes around 300 to 600 mg/day) be given supplemental calcium starting in the 20th week of pregnancy. (More information)
  • Prospective cohort studies have reported an association between higher calcium intakes and lower risk of developing colorectal cancer; however, large clinical trials of calcium supplementation are needed. (More information)
  • Current available data suggest that adequate calcium intakes may play a role in body weight regulation and have therapeutic benefits in the management of moderate-to-severe premenstrual symptoms. (More information)
  • Adequate calcium intake is critical for maintaining a healthy skeleton. Calcium is found in a variety of foods, including dairy products, beans, and vegetables of the kale family. Yet, content and bioavailability vary among foods, and certain drugs are known to adversely affect calcium absorption. (More information)
  • Hypercalcemia, a condition of abnormally high concentrations of calcium in blood, is usually due to malignancy or primary hyperparathyroidism. However, the use of large doses of supplemental calcium, together with absorbable alkali, increases the risk of hypercalcemia, especially in postmenopausal women. Often associated with gastrointestinal disturbances, hypercalcemia can be fatal if left untreated. (More information)
  • High calcium intakes — either from dairy foods or from supplements — have been associated with increased risks of prostate cancer and cardiovascular events in some, but not all, observational and intervention studies. However, there is currently no evidence of such detrimental effects when people consume a total of 1,000 to 1,200 mg/day of calcium (diet and supplements combined), as recommended by the Food and Nutrition Board of the Institute of Medicine. (More information)


Calcium is the most abundant mineral in the human body. About 99% of the calcium in the body is found in bones and teeth, while the other 1% is found in the blood and soft tissue. Calcium concentrations in the blood and fluid surrounding the cells (extracellular fluid) must be maintained within a narrow concentration range for normal physiological functioning. The physiological functions of calcium are so vital to survival that the body will stimulate bone resorption (demineralization) to maintain normal blood calcium concentrations when calcium intake is inadequate. Thus, adequate intake of calcium is a critical factor in maintaining a healthy skeleton (1).

Function

Structure

Calcium is a major structural element in bones and teeth. The mineral component of bone consists mainly of hydroxyapatite [Ca10(PO4)6(OH)2] crystals, which contain large amounts of calcium, phosphorus, and oxygen. Bone is a dynamic tissue that is remodeled throughout life. Bone cells called osteoclasts begin the process of remodeling by dissolving or resorbing bone. Bone-forming cells called osteoblasts then synthesize new bone to replace the bone that was resorbed. During normal growth, bone formation exceeds bone resorption. Osteoporosis may result when bone resorption chronically exceeds formation (1).

Calcium homeostasis

Calcium concentrations in the blood and fluid that surround cells are tightly controlled in order to preserve normal physiological function. A slight drop in blood calcium concentration (e.g., in the case of inadequate calcium intake) is sensed by the parathyroid glands, resulting in their increased secretion of parathyroid hormone (PTH). In the kidneys, PTH stimulates the conversion of vitamin D into its active form (1,25-dihydroxyvitamin D; calcitriol), which rapidly decreases urinary excretion of calcium but increases urinary excretion of phosphorus. Elevations in PTH also stimulates bone resorption, resulting in the release of bone mineral (calcium and phosphate) — actions that also contribute to restoring serum calcium concentrations. Increased circulating 1,25-dihydroxyvitamin D also triggers intestinal absorption of both calcium and phosphorus. Like PTH, 1,25-dihydroxyvitamin D stimulates the release of calcium from bone by activating osteoclasts (bone-resorbing cells). When blood calcium rises to normal levels, the parathyroid glands stop secreting PTH. A slight increase in blood calcium concentration stimulates the production and secretion of the peptide hormone, calcitonin, by the thyroid gland. Calcitonin inhibits PTH secretion, decreases both bone resorption and intestinal calcium absorption, and increases urinary calcium excretion (Figure 1). Finally, acute changes in blood calcium concentrations do not seem to elicit the secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF-23), which is produced by bone-forming cells (osteoblasts/osteocytes) in response to increases in phosphorus intake (see the article on Phosphorus) (2). While this complex system allows for rapid and tight control of blood calcium concentrations, it does so at the expense of the skeleton (1).

Figure 1. Calcium Homeostasis. Calcium concentrations in the blood and fluid that surround cells are tightly controlled in order to preserve normal physiological function. A slight drop in blood calcium concentration (e.g., in the case of inadequate calcium intake) is sensed by the parathyroid glands, resulting in their increased secretion of parathyroid hormone (PTH). In the kidneys, PTH stimulates the conversion of vitamin D into its active form (1,25-dihydroxyvitamin D; calcitriol), which rapidly decreases urinary excretion of calcium but increases urinary excretion of phosphorus. Elevations in PTH also stimulates bone resorption, resulting in the release of bone mineral (calcium and phosphate) — actions that also contribute to restoring serum calcium concentrations. Increased circulating 1,25-dihydroxyvitamin D also triggers intestinal absorption of both calcium and phosphorus. Like PTH, 1,25-dihydroxyvitamin D stimulates the release of calcium from bone by activating osteoclasts (bone-resorbing cells). When blood calcium rises to normal levels, the parathyroid glands stop secreting PTH. A slight increase in blood calcium concentration stimulates the production and secretion of the peptide hormone, calcitonin, by the thyroid gland. Calcitonin inhibits PTH secretion, decreases both bone resorption and intestinal calcium absorption, and increases urinary calcium excretion.

[Figure 1 - Click to Enlarge]

Cell signaling

Calcium plays a role in mediating the constriction and relaxation of blood vessels (vasoconstriction and vasodilation), nerve impulse transmission, muscle contraction, and the secretion of hormones like insulin (1). Excitable cells, such as skeletal muscle and nerve cells, contain voltage-dependent calcium channels in their cell membranes that allow for rapid changes in calcium concentrations. For example, when a nerve impulse stimulates a muscle fiber to contract, calcium channels in the cell membrane open to allow calcium ions into the muscle cell. Within the cell, these calcium ions bind to activator proteins, which help release a flood of calcium ions from storage vesicles of the endoplasmic reticulum (ER) inside the cell. The binding of calcium to the protein troponin-c initiates a series of steps that lead to muscle contraction. The binding of calcium to the protein calmodulin activates enzymes that break down muscle glycogen to provide energy for muscle contraction. Upon completion of the action, calcium is pumped outside the cell or into the ER until the next activation (reviewed in 3).

Regulation of protein function

Calcium is necessary to stabilize a number of proteins, including enzymes, optimizing their activities. The binding of calcium ions is required for the activation of the seven "vitamin K-dependent" clotting factors in the coagulation cascade. The term, "coagulation cascade," refers to a series of events, each dependent on the other that stops bleeding through clot formation (see the article on Vitamin K).

Nutrient interactions

Vitamin D

Vitamin D is required for optimal calcium absorption (see Function or the article on Vitamin D). Several other nutrients (and non-nutrients) influence the retention of calcium by the body and may affect calcium nutritional status.

Sodium

Dietary sodium is a major determinant of urinary calcium loss (1). High-sodium intake results in increased loss of calcium in the urine, possibly due to competition between sodium and calcium for reabsorption in the kidneys or by an effect of sodium on parathyroid hormone (PTH) secretion. Every 1-gram (g) increment in sodium (2.5 g of sodium chloride; NaCl salt) excreted by the kidneys has been found to draw about 26.3 milligrams (mg) of calcium into the urine (1). A study conducted in adolescent girls reported that a high-salt diet had a greater effect on urinary sodium and calcium excretion in White compared to Black girls, suggesting differences among ethnic groups (4). In adult women, each extra gram of sodium consumed per day is projected to produce an additional rate of bone loss of 1% per year if all of the calcium loss comes from the skeleton.

A number of cross-sectional and intervention studies have suggested that high-sodium intakes are deleterious to bone health, especially in older women (5). A two-year longitudinal study in postmenopausal women found increased urinary sodium excretion (an indicator of increased sodium intake) to be associated with decreased bone mineral density (BMD) at the hip (6). Another study in 40 postmenopausal women found that adherence to a low-sodium diet (2 g/day) for six months was associated with significant reductions in sodium excretion, calcium excretion, and amino-terminal propeptide of type I collagen, a biomarker of bone resorption. Yet, these associations were only observed in women with elevated baseline urinary sodium excretions (7). Finally, in a randomized, placebo-controlled study in 60 postmenopausal women, potassium citrate supplementation has been found to prevent an increase in calcium excretion induced by the consumption of a high-sodium diet (≥5,000 mg/day of elemental sodium) for four weeks (8)

Protein

Increasing dietary protein intake enhances intestinal calcium absorption, as well as urinary calcium excretion (9). The RDA for protein is 46 grams (g)/day for adult women and 56 g/day for adult men; however, the average intake of protein in the US tends to be higher (about 70 g/day in adult women and over 100 g per day in adult men) (10). It was initially thought that high-protein diets may result in a negative calcium balance (when the sum of urinary and fecal calcium excretion becomes greater than calcium intake) and thus increase bone loss (11). However, most observational studies have reported either no association or positive associations between protein intake and bone mineral density in children, adults, and elderly subjects (reviewed in 12). The overall calcium balance appears to be unchanged by high dietary protein intake in healthy individuals (13), and current evidence suggests that increased protein intakes in those with adequate supplies of protein, calcium, and vitamin D do not adversely affect BMD or fracture risk (14).

Phosphorus

Phosphorus, which is typically found in protein-rich food, tends to increase the excretion of calcium in the urine. Diets with low calcium-to-phosphorus ratios (Ca:P ≤0.5) have been found to increase parathyroid hormone (PTH) secretion and urinary calcium excretion (15, 16). Also, the intestinal absorption and fecal excretion of calcium and phosphorus are influenced by calcium-to-phosphorus ratios of ingested food. Indeed, in the intestinal lumen, calcium salts can bind to phosphorus to form complexes that are excreted in the feces. This forms the basis for using calcium salts as phosphorus binders to lower phosphorus absorption in individuals with kidney insufficiency (17). Increasing phosphorus intakes from cola soft drinks (high in phosphoric acid) and food additives (high in phosphates) may have adverse effects on bone health (18). At present, there is no convincing evidence that the dietary phosphorus levels experienced in the US adversely affect bone health. Yet, the substitution of large quantities of phosphorus-containing soft drinks for milk or other sources of dietary calcium may represent a serious risk to bone health in adolescents and adults (see the article on Phosphorus).

Caffeine

Exposure to caffeine concentrations ≤400 mg/day have led to increased urinary calcium content in two randomized controlled trials (19, 20). However, caffeine intakes of 400 mg/day did not significantly change urinary calcium excretion over 24 hours in premenopausal women when compared to a placebo (21). A systematic review of 14 studies recently concluded that daily intake of ≤400 mg of caffeine was unlikely to interfere with calcium homeostasis, impact negatively bone mineral density, or increase the risks of osteoporosis and fracture in individuals with adequate calcium intakes (22).

Deficiency

A low blood calcium level (hypocalcemia) usually implies abnormal parathyroid function since the skeleton provides a large reserve of calcium for maintaining normal blood levels, especially in the case of low dietary calcium intake. Other causes of abnormally low blood calcium concentrations include chronic kidney failure, vitamin D deficiency, and low blood magnesium levels often observed in cases of severe alcoholism. Magnesium deficiency can impair parathyroid hormone (PTH) secretion by the parathyroid glands and lower the responsiveness of osteoclasts to PTH. Thus, magnesium supplementation is required to correct hypocalcemia in people with low serum magnesium concentrations (see the article on Magnesium). Chronically low calcium intakes in growing individuals may prevent the attainment of optimal peak bone mass. Once peak bone mass is achieved, inadequate calcium intake may contribute to accelerated bone loss and ultimately to the development of osteoporosis (see Disease Prevention) (1).

The Recommended Dietary Allowance (RDA)

Updated recommendations for calcium intake based on the optimization of bone health were released by the Food and Nutrition Board (FNB) of the Institute of Medicine in 2011 (9). The Recommended Dietary Allowance (RDA) for calcium is listed in Table 1 by life stage and gender.

Table 1. Recommended Dietary Allowance (RDA) for Calcium
Life Stage Age Males
(mg/day)
Females
(mg/day)
Infants  0-6 months 200 (AI 200 (AI) 
Infants  6-12 months  260 (AI)  260 (AI) 
Children  1-3 years  700  700 
Children 4-8 years  1,000  1,000 
Children  9-13 years  1,300  1,300 
Adolescents  14-18 years  1,300  1,300 
Adults  19-50 years  1,000  1,000 
Adults  51-70 years  1,000  1,200 
Adults  >70 years 1,200  1,200 
Pregnancy  14-18 years 1,300 
Pregnancy  19-50 years 1,000 
Breast-feeding  14-18 years 1,300 
Breast-feeding  19-50 years 1,000

Disease Prevention

Osteoporosis

Osteoporosis is a skeletal disorder in which bone mass and strength are compromised, resulting in an increased risk of fracture. Sustaining a hip fracture is one of the most serious consequences of osteoporosis. Nearly one-third of those who sustain osteoporotic hip fractures enter nursing homes within a year following the fracture, and one person in four dies within one year of experiencing an osteoporotic hip fracture (23). Despite being a common diagnosis in postmenopausal women, osteoporosis also affects 4%-6% of men over the age of 50 years (24).

Osteoporosis is a multifactorial disorder, and nutrition is only one factor contributing to its development and progression (25). Other factors that increase the risk of developing osteoporosis include, but are not limited to, increased age, female gender, estrogen deficiency, smoking, high alcohol intake (three or more drinks/day), metabolic disease (e.g., hyperthyroidism), and the use of certain medications (e.g., corticosteroids and anticonvulsants) (26). A predisposition to osteoporotic fracture is related to one's peak bone mass and to the rate of bone loss after peak bone mass has been attained. After adult height has been reached, the skeleton continues to accumulate bone until the third decade of life. Genetic factors exert a strong influence on peak bone mass, but lifestyle factors can also play a significant role. Strategies for reducing the risk of osteoporotic fracture include the attainment of maximal peak bone mass and the reduction of bone loss later in life. A number of lifestyle factors, including diet (especially calcium and protein intake) and physical activity, are amenable to interventions aimed at maximizing peak bone mass and limiting osteoporotic fracture risk (27).

Physical exercise is a lifestyle factor that has been associated with numerous health benefits and is likely to contribute to the prevention of osteoporosis and osteoporotic fracture. There is evidence to suggest that physical activity early in life contributes to the attainment of higher peak bone mass (27). Moreover, lifelong participation in physical activities in the presence of adequate calcium and vitamin D supply (from dietary sources and/or sunlight exposure) may have a modest effect on slowing the rate of bone loss later in life (28). Current National Osteoporosis Foundation guidelines include recommendations of regular muscle-strengthening and weight-bearing exercise to all postmenopausal women and men ages 50 and older (29). Although benefits in reducing bone loss might be limited, muscle-strengthening exercise, including weight training and other resistive exercises (e.g., yoga and Pilates) and weight-bearing exercise (e.g., walking, jogging, and stair climbing), may improve strength, posture, balance, and coordination, thus contributing to reduced risk of falls (29). One compilation of published calcium trials indicated that the beneficial skeletal effect of increased physical activity was achievable only at calcium intakes above 1,000 mg/day in women in late menopause (reviewed in 28).

The progressive loss of bone mineral density (BMD) leading to osteopenia (pre-osteoporosis) and osteoporosis is usually assessed by dual-energy x-ray absorptiometry (DEXA) at the hip and lumbar spine (30). Several randomized, placebo-controlled clinical trials have evaluated the effect of supplemental calcium in the preservation of BMD and the prevention of fracture risk in men and women aged 50 years and older. A meta-analysis of 15 randomized controlled trials, including 1,533 men and women >50 years of age, found that increasing calcium intake from dietary sources (i.e., milk, milk powder, dairy products, or hydroxyapatite preparations) increased BMD by 0.6%-1% at the hip (+0.6%) and total body (+1.0%) after one year and by 0.7%-1.8% at the lumbar spine (+0.7%), femoral neck (+1.8%), total hip (+1.5%), and total body (+0.9%) sites after two years (31). A meta-analysis of 51 randomized controlled trials in 12,257 adults (>50 years) found that BMD at all bone sites (lumbar spine, femoral neck, total hip, forearm) increased by 0.7%-1.4% after one year and 0.8%-1.5% after two years of supplemental calcium, alone or in combination with vitamin D (31). Such modest increases may help limit the average rate of BMD loss after menopause but are unlikely to translate into meaningful fracture risk reductions. A meta-analysis of 20 randomized controlled trials that reported on total fracture risk found an 11% risk reduction associated with supplemental calcium with or without vitamin D (32). However, there was no effect when the analysis was restricted to the largest trials with the lowest risk of bias. Additionally, no reductions were found in risks of hip, vertebral and forearm fractures with calcium supplementation (32). Because estrogen withdrawal significantly impairs intestinal absorption and renal reabsorption of calcium, the level of calcium requirement might depend on whether postmenopausal women receive hormone replacement therapy (28).

The US Preventive Services Task Force conducted a meta-analysis of 11 randomized placebo-controlled trials that included 52,915 older people (of whom 69% were postmenopausal women) and reported that the supplementation of vitamin D (300-1,000 IU/day) and calcium (500-1,200 mg/day) for up to seven years resulted in a 12% reduction in the risk of any new fracture (33). There was no significant effect of vitamin D without calcium (33). A recently updated meta-analysis of randomized, placebo-controlled trials commissioned by the National Osteoporosis Foundation found a 15% reduction in risk of total fracture (8 studies) and a 30% reduction in risk of hip fractures (six studies) with calcium and vitamin D supplementation in older people (34). The National Osteoporosis Foundation advises that adequate intake of calcium (1,000-1,200 mg/day) and vitamin D (800-1,000 IU/day) be included in the diet of all middle-aged men and women (35).

The role and efficacy of vitamin D supplementation in strengthening bone and preventing fracture in older people remain controversial topics. The active form of vitamin D, 1,25-dihydroxyvitamin D, stimulates calcium absorption by promoting the synthesis of calcium-binding proteins in the intestine. While no amount of vitamin D can compensate inadequate total calcium intake, vitamin D insufficiency (defined as circulating concentrations of 25-hydroxyvitamin D below 20 ng/mL [50 nmol/L]) can lead to secondary hyperparathyroidism and an increased risk of osteoporosis (9, 36). Conversely, in postmenopausal women (ages 57-90 years) with adequate total calcium intakes (1,400 IU/day), serum 25-hydroxyvitamin D concentrations ranging from 20 ng/mL to 66 ng/mL had little effect on calcium absorption (only 6% increase over the range) (37). In a randomized, placebo-controlled trial, the supplementation of 1,000 IU/day of vitamin D to postmenopausal women (mean age, 77.2 years) for one year was found to significantly increase circulating 25-hydroxyvitamin D concentrations by 34% from baseline but failed to enhance calcium absorption in the presence of high total calcium intakes (dietary plus supplemental calcium corresponding to an average 2,100 mg/day) (38). This study also reported no significant difference in measures of BMD at the hip and total body between placebo- and vitamin D-treated women. In addition, the pooled analysis of seven randomized controlled trials, including 65,517 older individuals living in the community or in an institution, found that vitamin D (400-800 IU/day) could reduce the risk of any fracture only when combined with calcium (1,000 mg/day) (39). Interestingly, the results of a series of trials included in three recent meta-analyses (33, 40, 41) have suggested that supplemental vitamin D and calcium may have greater benefits in the prevention of fracture in institutionalized, older people who are also at increased risk of vitamin D deficiency and fractures compared to community dwellers (42, 43).

For more information about bone health and osteoporosis, see the article, Micronutrients and Bone Health, and visit the National Osteoporosis Foundation website.

Kidney stones

Approximately 6% of women and 15% of men in industrialized countries will have a kidney stone during their lifetime. Most kidney stones are composed of calcium oxalate or calcium phosphate. Subjects with an abnormally high level of calcium in the urine (hypercalciuria) are at higher risk of developing kidney stones (a process called nephrolithiasis) (44). High urinary oxalate level is another risk factor for calcium oxalate stone formation. Most subjects with a history of kidney stones and/or idiopathic hypercalciuria have increased intestinal calcium absorption (45). Although it was initially recommended to limit dietary calcium intake in these patients, a number of prospective cohort studies have reported associations between lower total dietary calcium intake and increased risk of incident kidney stones (46-48). The prospective analyses of three large cohorts, including a total of 30,762 men and 195,865 women followed for a combined 56 years, have indicated that the risk of kidney stones was significantly lower in individuals in the highest versus lowest quintile of dietary calcium intake from dairy or nondairy sources (49). Additionally, a five-year randomized intervention study that enrolled 120 men with idiopathic hypercalciuria (mean age, 45 years) reported that those assigned to a low-calcium diet (approximately 400 mg/day) had a 51% higher risk of kidney stone recurrence compared to those on a normal-to-high calcium (1,200 mg/day), low animal-protein, low-salt diet (50).

Mechanisms by which increased dietary calcium might reduce the risk of incident kidney stones are not fully understood. An inverse relationship was reported between total calcium intake and intestinal calcium absorption in the recent cross-sectional analysis of a cohort of 5,452 postmenopausal women (45). Moreover, women with higher supplemental calcium intake and lower calcium absorption were less likely to report a history of kidney stones (45). Adequate intake of calcium with food may reduce the absorption of dietary oxalate and lower urinary oxalate through formation of the insoluble calcium oxalate salt (51, 52). A recent small intervention study in 10 non-stone-forming young adults observed that the ingestion of large amounts of oxalate did not increase the risk of calcium oxalate stone occurrence in the presence of recommended level of dietary calcium (53).

However, a randomized, double-blind, placebo-controlled trial in 36,282 postmenopausal women reported that a combination of supplemental calcium (1,000 mg/day) and vitamin D (400 IU/day) was associated with a significantly increased incidence of self-reported kidney stones during a seven-year treatment period. More controlled trials may be necessary to determine whether supplemental calcium affects kidney stone risk (54). However, a systematic review of observational studies and randomized controlled trials that primarily reported on bone-related outcomes failed to find an effect of calcium supplementation on stone incidence (55). A potential kidney stone risk associated with calcium supplementation may likely depend on whether supplemental calcium is co-ingested with oxalate-containing foods or consumed separately. Further research is needed to verify whether osteoporosis treatment drugs (e.g., biphosphonates) rather than calcium supplements might influence the risk of stone occurrence (56).

Current data suggest that diets providing adequate dietary calcium and low levels of animal protein, oxalate, and sodium may benefit the prevention of stone recurrence in subjects with idiopathic hypercalciuria (57-59).

Hypertensive disorders of pregnancy

Pregnancy-induced hypertensive disorders, including gestational hypertension, preeclampsia, and eclampsia, complicate approximately 10% of pregnancies and are a major health risk for pregnant women and their offspring (60). Gestational hypertension is defined as an abnormally high blood pressure that usually develops after the 20th week of pregnancy. Preeclampsia is characterized by poor placental perfusion and a systemic inflammation that may involve several organ systems, including the cardiovascular system, kidneys, liver, and hematological system (61). In addition to gestational hypertension, preeclampsia is associated with the development of severe swelling (edema) and the presence of protein in the urine (proteinuria). Eclampsia is the occurrence of seizures in association with the syndrome of preeclampsia and is a significant cause of maternal and perinatal mortality.

Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of women with eclampsia do not initially exhibit preeclamptic symptoms. Risk factors for preeclampsia include genetic predisposition, advanced maternal age, first pregnancies, multiple pregnancies (e.g., twins or triplets), obesity, diabetes, and some autoimmune diseases (61). While the pathogenesis of preeclampsia is not entirely understood, nutrition and especially calcium metabolism appear to play a role. Data from epidemiological studies have suggested an inverse relationship between calcium intake during pregnancy and the incidence of preeclampsia (reviewed in 62). Impairment of calcium metabolism when circulating vitamin D concentration is low and/or when dietary calcium intake is inadequate may contribute to the risk of hypertension during pregnancy.

Secondary hyperparathyroidism (high PTH level) due to vitamin D deficiency in young pregnant women has been associated with high maternal blood pressure and increased risk of preeclampsia (63). The risk for elevated PTH concentration was also found to be increased in vitamin D-sufficient women with low-calcium intakes (<480 mg/day) during pregnancy when compared with adequate-to-high calcium intakes (≥1,000 mg/day) (64). In addition, vitamin D deficiency may trigger hypertension through the inappropriate activation of the renin-angiotensin system (see the article on Vitamin D).

Potential beneficial effects of calcium in the prevention of preeclampsia have been investigated in several randomized, placebo-controlled studies. The most recent meta-analysis of 13 trials in 15,730 pregnant women found that calcium supplementation with at least 1,000 mg/day (mostly 1,500-2,000 mg/day) from about 20 weeks of pregnancy (34 weeks of pregnancy at the latest) was associated with significant reductions in the risk of high blood pressure, preeclampsia, and preterm birth (62). Greater risk reductions were reported among pregnant women at high risk of preeclampsia (5 trials; 587 women) or with low dietary calcium intake (8 trials; 10,678 women). Another meta-analysis of nine randomized controlled trials in high-risk women indicated that lower doses of calcium supplementation (≤800 mg/day), alone or with a co-treatment (i.e., vitamin D, linoleic acid, or antioxidants), could also lower the risk of preeclampsia by 62% (65). Yet, based on the systematic review of high-quality randomized controlled trials, which used mostly high-dose calcium supplements, the World Health Organization (WHO) recently recommended that all pregnant women in areas of low-calcium intake (i.e., low-income countries with intakes around 300-600 mg/day) be given 1.5 to 2 g (1,500 to 2,000 mg)/day of elemental calcium from the 20th week of pregnancy (66).

Because excessive calcium supplementation may be harmful (see Safety), further research is required to verify whether calcium supplementation above the current IOM recommendation (1,000 mg/day for pregnant women, ages 19-50 years) would provide greater benefits to women at high risk of preeclampsia. Finally, the lack of effect of supplemental calcium on proteinuria (reported in two trials only) suggested that calcium supplementation from mid-pregnancy might be too late to oppose the genesis of preeclampsia (67, 68). A randomized, double-blind, placebo-controlled study — the WHO Calcium and Pre-eclampsia (CAP) trial — is ongoing to evaluate the effect of calcium supplementation with 500 mg/day, starting before pregnancy and until the 20th week of pregnancy, on the risk of preeclampsia in high-risk women (69, 70).

Colorectal cancer

Colorectal cancer (CRC) is the most common gastrointestinal cancer and the second leading cause of cancer death in the US (71). CRC is caused by a combination of genetic and environmental factors, but the degree to which these two types of factors influence CRC risk in individuals varies widely. In individuals with familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC), the cause of CRC is almost entirely genetic, while modifiable lifestyle factors, including dietary habits, tobacco use, and physical activities, greatly influence the risk of sporadic (non-hereditary) CRC.

Prospective cohort studies have consistently reported an inverse association between dairy food consumption and CRC risk. Experimental studies in cell culture and animal models have suggested plausible mechanisms underlying a role for calcium, a major nutrient in dairy products, in preventing CRC (72). In the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study of 477,122 individuals, followed for an average of 11 years, 4,513 CRC cases were documented (73). Intakes of milk, cheese, and yogurt, were inversely associated with CRC risk. The highest versus lowest quintile of total dairy intake (≥490 g/day vs. <134 g/day) was associated with a 23% lower risk of CRC. Similarly, CRC risk was 25% lower in those in the top versus bottom quintile of calcium intake from dairy food (≥839 mg/day vs. <308 mg/day). The 16-year follow-up of 41,403 women (ages 26-46 years at inclusion) from the prospective Nurses’ Health Study II (NHS II) documented 2,273 diagnoses of colorectal adenomas (precancerous polyps). The analysis of the prospective cohort found that women with total calcium intake of 1,001-1,250 mg/day had a 76% lower risk of developing advanced adenomas (i.e., adenomas more likely to become malignant) compared to those with intakes equal to and below 500 mg/day (74). In addition, a dose-response analysis using data from eight prospective studies (11,005 CRC cases) estimated that an increase of 300 mg/day in total calcium intake was associated with a 5% reduction in CRC risk (75). Total daily intake of calcium ranged from 333 to 2,229 mg in the examined studies. In addition, the dose-response analysis of six prospective studies (8,839 CRC cases among 920,837 participants) showed 11% lower odds of high-risk adenomas for each 300 mg/day increment in total calcium (75).

However, the meta-analysis of seven randomized, double-blind, placebo-controlled studies found no evidence of an effect of calcium supplementation (≥500 mg/day) for a median period of 45 months on total cancer risk and CRC risk (76). In addition, the re-analysis of the Women’s Health Initiative placebo-controlled trial failed to show a reduction in CRC risk in postmenopausal women supplemented with both vitamin D (400 IU/day) and calcium (1,000 mg/day) for seven years (77). Finally, the results of the meta-analysis of four randomized, placebo-controlled trials have suggested that calcium supplementation (1,200-2,000 mg/day) may reduce the risk of adenoma recurrence by 13% over three to five years in subjects with a history of adenomas (78). At present, it is not clear whether calcium supplementation is beneficial in CRC prevention. Larger trials designed to assess primarily the effect of long-term calcium supplementation on the incidence of adenomas and/or CRC are needed before conclusions can be drawn.

Lead toxicity

Children who are chronically exposed to lead, even in small amounts, are more likely to develop learning disabilities, behavioral problems, and to have low IQs. Deficits in growth and neurological development may occur in the infants of women exposed to lead during pregnancy and lactation. In adults, lead toxicity may result in kidney damage and high blood pressure. Although the use of lead in paint products, gasoline, and food cans has been discontinued in the US, lead toxicity continues to be a significant health problem, especially in children living in urban areas (79).

In 2012, the US Centers for Disease Control and Prevention set the reference value for blood lead concentration at 5 micrograms per deciliter (mg/dL) to identify children at risk (80). Yet, there is no known blood lead concentration below which children are 100% safe. An early study of over 300 children in an urban neighborhood found that 49% of children ages 1 to 8 years had blood lead levels above the threshold of 10 mg/dL, indicating excessive lead exposure. In this study, only 59% of children ages 1 to 3 years and 41% of children ages 4 to 8 years met the recommended levels for calcium intakes (81).

Adequate calcium intake could be protective against lead toxicity in at least two ways. Increased dietary intake of calcium is known to decrease the gastrointestinal absorption of lead. Once lead enters the body it tends to accumulate in the skeleton, where it may remain for more than 20 years. Adequate calcium intake also prevents lead mobilization from the skeleton during bone demineralization. A study of circulating concentrations of lead during pregnancy found that women with inadequate calcium intake during the second half of pregnancy were more likely to have elevated blood lead levels, probably because of increased bone demineralization, leading to the release of accumulated lead into the blood (82). Lead in the blood of a pregnant woman is readily transported across the placenta resulting in fetal lead exposure at a time when the developing nervous system is highly vulnerable. In a randomized, double-blind, placebo-controlled study in 670 pregnant women (≤14 weeks’ gestation) with average dietary calcium intakes of 900 mg/day, daily supplementation of 1,200 mg of calcium throughout the pregnancy period resulted in 8%-14% reductions in maternal blood lead concentrations (83). Similar reductions in maternal lead concentrations in the blood and breast milk of lactating mothers supplemented with calcium were reported in earlier trials (84, 85). In postmenopausal women, factors known to decrease bone demineralization, including estrogen replacement therapy and physical activity, have been inversely associated with blood lead levels (86).

Disease Treatment

Overweight and obesity

High dietary calcium intake, usually associated with dairy product consumption, has been inversely related to body weight and central obesity in a number of cross-sectional studies (reviewed in 87). Cross-sectional baseline data analyses of a number of prospective cohort studies that were not designed and powered to examine the effect of calcium intake or dairy consumption on obesity or body fat have given inconsistent results (87). Yet, a meta-analysis of 18 cross-sectional and prospective studies predicted a reduction in body mass index (a relative measure of body weight; BMI) of 1.1 kg/m2 with an increase in calcium intake from 400 mg/day to 1,200 mg/day (87). In a placebo-controlled intervention study, 32 obese subjects were randomized to energy restriction regimens (500 kCal/day deficit) for 24 weeks with (1) a standard diet providing 400 to 500 mg/day of dietary calcium and a placebo ("low calcium" diet), (2) a standard diet and 800 mg/day of supplemental calcium ("high calcium" diet), or (3) a high-dairy diet providing 1,200 mg/day of dietary calcium and a placebo (88). Energy-restricted diets resulted in significant body weight and fat loss in all three groups. Yet, body weight and fat loss were significantly more reduced with the high-calcium diet compared to the standard diet, and further reductions were measured with the high-dairy diet compared to both high-calcium and low-calcium diets. These results suggested that while calcium intake may play a role in body weight regulation, additional benefits might be attributable to other bioactive components of dairy products, such as proteins, fatty acids, and branched chain amino acids.

Yet, several mechanisms have been proposed to explain the potential impact of calcium on body weight (reviewed in 87). The most-cited mechanism is based on studies in the agouti mouse model showing that low-calcium intakes, through increasing circulating parathyroid hormone (PTH) and vitamin D, could stimulate the accumulation of fat (lipogenesis) in adipocytes (fat cells) (89). Conversely, higher intakes of calcium may reduce fat storage, stimulate the breakdown of lipids (lipolysis), and drive fat oxidation. A recent meta-analysis of randomized controlled trials estimated that high (1,300 mg/day) versus low (488 mg/day) calcium intake for a minimum of seven days increased fat oxidation by 11% (90). However, a double-blind, placebo-controlled, randomized, cross-over trial in 10 low-calcium consuming overweight or obese individuals reported that the supplementation with 800 mg/day of calcium for 5 weeks failed to modify the expression of key factors involved in fat metabolism (91). Moreover, while the model suggests a role for vitamin D in lipogenesis (fat storage), human studies have shown that vitamin D deficiency — rather than sufficiency — is often associated with obesity, and supplemental vitamin D might be effective in lowering body weight when caloric restriction is imposed (92, 93). Another mechanism suggests that high-calcium diets may limit dietary fat absorption in the intestine and increase fecal fat excretion. Indeed, in the gastrointestinal tract, calcium may trap dietary fat into insoluble calcium soaps of fatty acids that are then excreted (94). In addition, despite very limited evidence, it has also been proposed that calcium might be involved in regulating appetite and energy intake (95).

To date, there is no consensus regarding the effect of calcium on body weight changes. A meta-analysis of 29 randomized controlled trials in 2,441 participants (median age, 41.4 years) found that calcium supplementation was only associated with body weight and fat loss in short-term studies (<1 year) that used energy-restricted diets (96). Another meta-analysis of 41 randomized controlled trials (4,802 participants) found little-to-no effect of increased calcium intake from supplements or dairy foods for >12 weeks on body weight and body composition (97). Finally, a meta-analysis of 33 randomized controlled trials (4,733 participants) found no overall effect of calcium supplementation (from food or supplements) for >12 weeks on body weight changes. Yet, further subgroup analyses showed weight reductions in children and adolescents (mean, -0.26 kg), in adults (mean, -0.91 kg), and in those with normal BMI (mean, -0.53 kg). Supplemental calcium did not lead to weight loss in postmenopausal women or in overweight/obese individuals (98). At present, additional research is warranted to examine the effect of calcium intake on fat metabolism, as well as its potential benefits in the management of body weight with or without caloric restriction (99).

Premenstrual Syndrome (PMS)

PMS refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begins sometime after ovulation (mid-cycle) and subsides with the onset of menstruation (the monthly period) (100). A severe form of PMS called premenstrual dysphoric disorder (PMDD) has been described in 3%-8% of women of childbearing age. PMDD interferes with normal functioning, affecting daily activities and relationships (101).

Low dietary calcium intakes have been linked to PMS in early reports, and supplemental calcium has been shown to decrease symptom severity (102). A nested case-control study within the Nurses' Health Study II (NHS II) found that women in the highest quintile of dietary (but not supplemental) calcium intake (median of 1,283 mg/day) had a 30% lower risk of developing PMS compared to those in the lowest quintile (median of 529 mg/day). Similarly, women in the highest versus lowest quintile of skim or low-fat milk intake (≥4 servings/day vs. ≤1 serving/week) had a 46% lower risk of PMS (103). In a randomized, double-blind, placebo-controlled clinical trial of 466 women with moderate-to-severe premenstrual symptoms, supplemental calcium (1,200 mg/day) for three menstrual cycles was associated with a 48% reduction in total symptom scores, compared to a 30% reduction observed in the placebo group (104). Similar positive effects were reported in earlier double-blind, placebo-controlled, cross-over trials that administered 1,000 mg of calcium daily (105, 106). Recent small randomized controlled trials also reported that supplemental calcium (400-500 mg/day) for three weeks to three months reduced severity and/or frequency of symptoms in women with mild-to-moderate PMS (107-110). Currently available data indicate that daily calcium intakes from food and/or supplements may have therapeutic benefits in women diagnosed with PMS or PMDD (111, 112).

Hypertension

The relationship between calcium intake and blood pressure has been investigated extensively over the past decades. A meta-analysis of 23 large observational studies conducted in different populations worldwide found a reduction in systolic blood pressure of 0.34 millimeters of mercury (mm Hg) per 100 mg of calcium consumed daily and a reduction in diastolic blood pressure of 0.15 mm Hg per 100 mg calcium (113). In the DASH (Dietary Approaches to Stop Hypertension) study, 549 people were randomized to one of three diets for eight weeks: (1) a control diet that was low in fruit, vegetables, and dairy products; (2) a diet rich in fruit (~5 servings/day) and vegetables (~3 servings/day); and (3) a combination diet rich in fruit and vegetables, as well as low-fat dairy products (~3 servings/day) (114). The combination diet represented an increase of about 800 mg of calcium/day over the control and fruit/vegetable-rich diets for a total of about 1,200 mg of calcium/day. Overall, the reduction in systolic blood pressure was greater with the combination diet than with the fruit/vegetable diet or the control diet. Among participants diagnosed with hypertension, the combination diet reduced systolic blood pressure by 11.4 mm Hg and diastolic pressure by 5.5 mm Hg more than the control diet, while the reduction for the fruit/vegetable diet was 7.2 mm Hg for systolic and 2.8 mm Hg for diastolic blood pressure compared to the control diet (115). This research suggested that calcium intake at the recommended level (1,000-1,200 mg/day) may be helpful in preventing and treating moderate hypertension (116).

Yet, two large systematic reviews and meta-analyses of randomized controlled trials have examined the effect of calcium supplementation on blood pressure compared to placebo in either normotensive or hypertensive individuals (117, 118). Neither of the analyses reported any significant effect of supplemental calcium on blood pressure in normotensive subjects. A small but significant reduction in systolic blood pressure, but not in diastolic blood pressure, was reported in participants with hypertension. Of note, calcium supplementation in these randomized controlled trials ranged from 400 to 2,200 mg/day, with 1,000 to 1,500 mg/day being the more common dosages. A more recent meta-analysis of 13 randomized controlled studies in 485 individuals with elevated blood pressure found a significant reduction of 2.5 mm Hg in systolic blood pressure but no change in diastolic blood pressure with calcium supplementation (119). The modest effect of calcium on blood pressure needs to be confirmed in larger, high-quality, well-controlled trials before any recommendation is made regarding the management of hypertension. Finally, a review of the literature on the effect of high-calcium intake (dietary and supplemental) in postmenopausal women found either no reduction or mild and transient reductions in blood pressure (120).

More information about the DASH diet is available from the National Institutes of Health (NIH).

Sources

Food sources

Data analysis of the US National Health and Nutrition Examination Surveys (NHANES) 2009-2010 and 2011-2012 found inadequate calcium intakes (defined as intakes below the Estimated Average Requirement [EAR]) in 37.7% of non-supplemented adults (ages, ≥19 years) and 19.6% of adults taking multivitamin/mineral supplements (121). Dairy foods provide 75% of the calcium in the American diet. However, it is typically during the most critical period for peak bone mass development that adolescents tend to replace milk with soft drinks (122). Dairy products represent rich and absorbable sources of calcium, but certain vegetables and grains also provide calcium.

However, the bioavailability of the calcium must be taken into consideration. The calcium content in calcium-rich plants in the kale family (broccoli, bok choy, cabbage, mustard, and turnip greens) is as bioavailable as that in milk; however, other plant-based foods contain components that inhibit the absorption of calcium. Oxalic acid, also known as oxalate, is the most potent inhibitor of calcium absorption and is found at high concentrations in spinach and rhubarb and somewhat lower concentrations in sweet potatoes and dried beans. Phytic acid (phytate) is a less potent inhibitor of calcium absorption than oxalate. Yeast possess an enzyme (phytase) that breaks down phytate in grains during fermentation, lowering the phytate content of breads and other fermented foods. Only concentrated sources of phytate, such as wheat bran or dried beans, substantially reduce calcium absorption (123).

Additional dietary constituents may affect calcium absorption (see Nutrient interactions). Table 2 lists a number of calcium-rich foods, along with their calcium content. For more information on the nutrient content of foods, search the USDA food composition database

Table 2. Some Food Sources of Calcium
Food Serving Calcium (mg)
Tofu prepared with calcium sulfate (raw) ½ cup 434
Yogurt, plain, low-fat 8 ounces 415
Sardines, canned 8 ounces 325
Cheddar cheese 1.5 ounces  303
Milk 8 ounces 300
White beans (cooked) ½ cup 81
Chinese cabbage (Bok choy/Pak choi, cooked) ½ cup 79
Figs (dried) ¼ cup 61
Orange 1 medium 60
Kale (cooked) ½ cup 47
Pinto beans (cooked) ½ cup 39
Broccoli (cooked) ½ cup 31
Red beans (cooked) ½ cup 25 

Supplements

Most experts recommend obtaining as much calcium as possible from food because calcium in food is accompanied by other important nutrients that assist the body in utilizing calcium. However, calcium supplements may be necessary for those who have difficulty consuming enough calcium from food (124). No multivitamin/mineral tablet contains 100% of the recommended daily value (DV) for calcium because it is too bulky, and the resulting pill would be too large to swallow. The "Supplement Facts" label, required on all supplements marketed in the US, lists the calcium content of the supplement as elemental calcium. Calcium preparations used as supplements include calcium carbonate, calcium citrate, calcium citrate malate, calcium lactate, and calcium gluconate. To determine which calcium preparation is in your supplement, you may have to look at the ingredient list. Calcium carbonate is generally the most economical calcium supplement. To maximize absorption, take no more than 500 mg of elemental calcium at one time. Most calcium supplements should be taken with meals, although calcium citrate and calcium citrate malate can be taken anytime. Calcium citrate is the preferred calcium formulation for individuals who lack stomach acids (achlorhydria) or those treated with drugs that limit stomach acid production (H2 blockers and proton-pump inhibitors) (reviewed in 125).

Lead in calcium supplements

Several decades ago, concern was raised regarding lead concentrations in calcium supplements obtained from natural sources (oyster shell, bone meal, dolomite) (126). In 1993, investigators found measurable quantities of lead in most of the 70 different preparations they tested (127). Since then, manufacturers have reduced the amount of lead in calcium supplements to less than 0.5 micrograms (mg)/1,000 mg of elemental calcium (128). The US Food and Drug Administration (FDA) has developed provisional total tolerable intake levels (PTTI) for lead for specific age and sex groups (129). Because lead is so widespread and long lasting, no one can guarantee entirely lead-free food or supplements. A study found measurable lead in 8 out of 21 supplements, in amounts averaging 1 to 2 mg/1,000 mg of elemental calcium, which is below the tolerable limit of 7.5 mg/1,000 mg of elemental calcium (130). A more recent survey of 324 multivitamin/mineral supplements labeled for use in children or women found that most supplements would result in lead exposure ranging from 1%-4% of the PTTI (131).

Calcium inhibits intestinal absorption of lead, and adequate calcium intake is protective against lead toxicity, so trace amounts of lead in calcium supplementation may pose less of a risk of excessive lead exposure than inadequate calcium consumption. While most calcium sources today are relatively safe, look for supplements approved or certified by independent testing (e.g., US Pharmacopeia, ConsumerLab.com) (125), follow label instructions, and avoid large doses of supplemental calcium (≥1,500 mg/day).

Safety

Toxicity

Malignancy and primary hyperparathyroidism are the most common causes of elevated calcium concentrations in the blood (hypercalcemia) (132). Hypercalcemia has not been associated with the over consumption of calcium occurring naturally in food. Hypercalcemia has been initially reported with the consumption of large quantities of calcium supplements in combination with antacids, particularly in the days when peptic ulcers were treated with large quantities of milk, calcium carbonate (antacid), and sodium bicarbonate (absorbable alkali). This condition is termed calcium-alkali syndrome (formerly known as milk-alkali syndrome) and has been associated with calcium supplement levels from 1.5 to 16.5 g/day for 2 days to 30 years. Since the treatment for peptic ulcers has evolved and because of the widespread use of over-the-counter calcium supplements, the demographic of this syndrome has changed in that those at greater risk are now postmenopausal women, pregnant women, transplant recipients, patients with bulimia, and patients on dialysis, rather than men with peptic ulcers (reviewed in 133). Supplementation with calcium (0.6 g/day-2 g/day for two to five years) has been associated with a higher risk of adverse gastrointestinal events like constipation, cramping, bloating, pain, diarrhea (134). Mild hypercalcemia may be without symptoms or may result in loss of appetite, nausea, vomiting, constipation, abdominal pain, fatigue, frequent urination (polyuria), and hypertension (132). More severe hypercalcemia may result in confusion, delirium, coma, and if not treated, death (1).

In 2011, the Food and Nutrition Board of the Institute of Medicine updated the tolerable upper intake level (UL) for calcium (9). The UL is listed in Table 3 by age group.

Table 3. Tolerable Upper Intake Level (UL) for Calcium
Age Group UL (mg/day)
Infants 0-6 months 1,000
Infants 6-12 months 1,500
Children 1-8 years 2,500
Children 9-13 years 3,000
Adolescents 14-18 years 3,000
Adults 19-50 years 2,500
Adults 51 years and older 2,000

Although the risk of forming kidney stones is increased in individuals with abnormally elevated urinary calcium (hypercalciuria), this condition is not usually related to calcium intake, but rather to increased absorption of calcium in the intestine or increased excretion by the kidneys (9). Overall, increased dietary calcium intake has been associated with a decreased risk of kidney stones (see Kidney stones). Concerns have also been raised regarding the risks of prostate cancer and vascular disease with high intakes of calcium.

Do high calcium intakes increase the risk for prostate cancer?

Prostate cancer is the second most common cancer in men worldwide (135). Several observational studies have raised concern that high-dairy intakes are associated with increased risk of prostate cancer (136-138).

The analysis of a prospective cohort study (2,268 men followed for nearly 25 years) conducted in Iceland, a country with a high incidence of prostate cancer, found a positive association between the consumption of milk (at least once daily) during adolescence and developing prostate cancer later in life (139). Another large prospective cohort study in the US followed 21,660 male physicians for 28 years and found that men with daily skim or low-fat milk intake of at least 237 mL (8 oz) had a higher risk of developing prostate cancer compared to occasional consumers (140). The risk of low-grade, early-stage prostate cancer was associated with higher intake of skim milk, and the risk of developing fatal prostate cancer was linked to the regular consumption of whole milk (140). In a cohort of 3,918 male health professionals diagnosed with prostate cancer, 229 men died of prostate cancer and 69 developed metastasized prostate cancer during a median follow-up of 7.6 years (141). The risk of prostate cancer death was found to be increased in men with high (>4 servings/week) versus low (≤3 servings/month) intakes of whole milk. Yet, no increase in risk of prostate cancer-related mortality was associated with consumption of skim and low-fat milk, total milk, low-fat dairy products, full-fat dairy products, or total dairy products (141). A recent meta-analysis of 32 prospective cohort studies found high versus low intakes of total dairy product (15 studies), total milk (15 studies), whole milk (6 studies), low-fat milk (5 studies), cheese (11 studies), and dairy calcium (7 studies) to be associated with modest, yet significant, increases in the risk of developing prostate cancer (142). However, there was no increase in prostate cancer risk with nondairy calcium (4 studies) and calcium from supplements (8 studies). Moreover, high dairy intakes were not linked to fatal prostate cancer (142).

There is some evidence to suggest that milk consumption may result in higher circulating concentrations of insulin-like growth factor-I (IGF-I), a protein known to regulate cell proliferation (143). Circulating IGF-I concentrations have been positively correlated to the risk of developing prostate cancer in a recent meta-analysis of observational studies (144). Milk-borne IGF-I, as well as dairy proteins and calcium, may contribute to increasing circulating IGF-I in milk consumers (143). In the large EPIC study, which examined the consumption of dairy products in relation to cancer in 142,520 men, the risk of prostate cancer was found to be significantly higher in those in the top versusbottom quintile of both protein and calcium intakes from dairy foods (145). Another mechanism underlying the potential relationship between calcium intake and prostate cancer proposed that high levels of dietary calcium may lower circulating concentrations of 1,25-dihydroxyvitamin D, the active form of vitamin D, thereby suppressing vitamin D-mediated cell differentiation (146). However, studies to date have provided little evidence to suggest that vitamin D status can modify the association between dairy calcium and risk of prostate cancer development and progression (147-149)

In a multicenter, double-blind, placebo-controlled trial, 672 healthy men (mean age of 61.8 years) were randomized to daily calcium supplementation (1,200 mg) for four years. While no increase in the risk for prostate cancer has been reported during a 10.3-year follow-up, calcium supplementation resulted in a significant risk reduction in the period spanning from two years after treatment started to two years after treatment ended (150). In a review of the literature published in 2009, the US Agency for Healthcare Research and Quality indicated that not all epidemiological studies found an association between calcium intake and prostate cancer (151). The review reported that 6 out of 11 observational studies failed to find statistically significant positive associations between prostate cancer and calcium intake. Yet, in five studies, daily intakes of 921 to 2,000 mg of calcium were found to be associated with an increased risk of developing prostate cancer when compared to intakes ranging from 455 to 1,000 mg/day (151). Inconsistencies among studies suggest complex interactions between the risk factors for prostate cancer, as well as reflect the difficulties of assessing the effect of calcium intake in free-living individuals. For example, the fact that individuals with higher dairy and/or calcium intakes were found to be more likely to be engaged in healthy lifestyles or more likely to seek medical attention can mitigate the statistical significance of an association with prostate cancer risk (152). Until the relationship between calcium and prostate cancer is clarified, it is reasonable for men to consume a total of 1,000 to 1,200 mg/day of calcium (diet and supplements combined), which is recommended by the Food and Nutrition Board of the Institute of Medicine (see RDA) (9).

Do calcium supplements increase the risk for cardiovascular disease?

Several observational studies and randomized controlled trials have raised concerns regarding the potential adverse effects of calcium supplements on cardiovascular risk. The analysis of data from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) prospective study found that users of calcium supplements amongst 10,555 Finnish women (ages 52-62 years) had a 14% greater risk of developing coronary artery disease compared to non-supplement users during a mean follow-up of 6.75 years (153). The prospective study of 23,980 participants (35-64 years old) of the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition cohort (EPIC-Heidelberg) observed that supplemental calcium intake was positively associated with the risk of myocardial infarction (heart attack) but not with the risk of stroke or cardiovascular disease (CVD)-related mortality after a mean follow-up of 11 years (154). Yet, the use of calcium supplements (≥400 mg/day vs. 0 mg/day) was associated with an increased risk of CVD-related mortality in 219,059 men, but not in 169,170 women, included in the National Institute of Health (NIH)-AARP Diet and Health study and followed for a mean period of 12 years. CVD mortality in men was also found to be significantly higher with total (dietary plus supplemental) calcium intakes of 1,500 mg/day and above (155).

In addition, the secondary analyses of two randomized placebo-controlled trials initially designed to assess the effect of calcium on bone health outcomes also suggested an increased risk of CVD in participants daily supplemented with 1,000 mg of calcium for five to seven years (156, 157). In the Auckland Calcium Study of 1,471 healthy postmenopausal women (ages ≥55 years), calcium supplementation resulted in increased risks of myocardial infarction and of a composite cardiovascular endpoint, including myocardial infarction, stroke, or sudden death (156). The analysis of data from 36,282 healthy postmenopausal women randomized to receive a combination of calcium (1,000 mg/day) and vitamin D (400 IU/day) or a placebo in the Women’s Health Initiative/Calcium-Vitamin D supplementation study (WHI/CaD study) initially reported no adverse effect on any cardiovascular endpoints with calcium (and vitamin D) compared to placebo (158). A re-analysis was performed with data from 16,718 women who did not take personal calcium supplements (outside protocol) during the five-year study (157). Although criticized on the approach taken (134, 159), the investigators estimated that women supplemented with calcium and vitamin D had a 16% increased risk of clinical myocardial infarction or stroke and a 21% increased risk of myocardial infarction compared to those who received a placebo (157). However, in another randomized, double-blind, placebo-controlled trial — the Calcium Intake Fracture Outcome (CAIFOS) study — in elderly women (median age, 75.1 years), the supplementation of 1,200 mg/day of calcium for five years was not found to increase the risk of vascular disease or related mortality (160). The WHI/CaD data re-analysis also failed to show an increased risk of mortality due to myocardial infarction or coronary artery disease with calcium therapy (156). Also, after an additional follow-up of 4.5 years at the end of the treatment period in the CAIFOS trial, the investigators reported fewer cases of heart failure-related deaths with supplemental calcium compared to placebo (160). In another randomized, placebo-controlled trial of calcium and/or vitamin D3 (RECORD trial), the evaluation of the effect of 1,000 mg/day of calcium (alone or with 800 IU/day of vitamin D) reported no significant increase in the rate of mortality due to vascular disease in 5,292 participants ages 70 years and older (161). A recent cross-sectional analysis of the Third National Health and Nutrition Examination Survey (NHANES III) evaluated the association between calcium intakes and cardiovascular mortality in 18,714 adults with no history of heart disease. No evidence of an association was observed between dietary calcium intake, supplemental calcium intake, or total calcium intake and cardiovascular mortality in either men or women (162).

A few prospective studies have reported positive correlations between high calcium concentrations in the blood and increased rates of cardiovascular events (163, 164). Because supplemental calcium may have a greater effect than dietary calcium on circulating calcium concentrations (see Toxicity), it has been speculated that the use of calcium supplements might promote vascular calcification — a surrogate marker of the burden of atherosclerosis and a major risk factor for cardiovascular events — by raising calcium serum concentrations. In 1,471 older women from the Auckland Calcium Study and 323 healthy older men from another randomized, placebo-controlled trial of daily calcium supplementation (600 mg or 1,200 mg) for two years, serum calcium concentrations were found to be positively correlated with abdominal aortic calcification or coronary artery calcification (165). However, there was no effect of calcium supplementation on measures of vascular calcification scores in men or women. Data from 1,201 participants of the Framingham Offspring study were also used to assess the relationship between calcium intake and vascular calcification. Again, no association was found between coronary calcium scores and total, dietary, or supplemental calcium intake in men or women (166). Nonetheless, in the Multi-Ethnic Study of Atherosclerosis (MESA), a US multicenter prospective study in 6,814 participants followed for a mean 10 years, the greatest risk of developing coronary artery calcification was found in supplement users with the lowest total calcium intake (~306 mg/day of dietary calcium and ~91 mg/day of supplemental calcium), when compared to supplement users with higher total calcium intakes and nonusers (167). Finally, an assessment of atherosclerotic lesions in the carotid artery wall of 1,103 participants in the CAIFOS trial was also conducted after three years of supplementation (168). When compared with placebo, calcium supplementation showed no effect on carotid artery intimal medial thickness (CIMT) and carotid atherosclerosis. Yet, carotid atherosclerosis (but not CIMT) was significantly reduced in women in the highest versus lowest tertile of total (diet and supplements) calcium intakes (≥1,795 mg/day vs. <1,010 mg/day) (168).

The most recent meta-analysis of 18 randomized clinical trials, including a total of 63,563 postmenopausal women, found no evidence of an increased risk for coronary artery disease and all-cause mortality with calcium (≥500 mg/day) supplementation for at least one year (169). Because these clinical trial data are limited to analyses of secondary endpoints, meta-analyses should be interpreted with caution. There is a need for studies designed to examine the effect of calcium supplements on CVD risk as a primary outcome before definite conclusions can be drawn. Based on an updated review of the literature that included four randomized controlled trials, one nested case-control study, and 26 prospective cohort studies (170), the National Osteoporosis Foundation (NOF) and the American Society for Preventive Cardiology (ASPC) concluded that the use of supplemental calcium for generally healthy individuals was safe from a cardiovascular health standpoint when total calcium intakes did not exceed the UL (171). NOF and ASPC support the use of calcium supplements to correct shortfalls in dietary calcium intake and meet current recommendations (171).

Drug interactions

Taking calcium supplements in combination with thiazide diuretics (e.g., hydrochlorthiazide) increases the risk of developing hypercalcemia due to increased reabsorption of calcium in the kidneys. High doses of supplemental calcium could increase the likelihood of abnormal heart rhythms in people taking digoxin (Lanoxin) for heart failure (172). Calcium, when provided intravenously, may decrease the efficacy of calcium channel blockers (173). However, dietary and oral supplemental calcium do not appear to affect the action of calcium channel blockers (174). Calcium may decrease the absorption of tetracycline, quinolone class antibiotics, bisphosphonates, sotalol (a β-blocker), and levothyroxine; therefore, it is advisable to separate doses of these medications and calcium-rich food or supplements by two hours before calcium or four-to-six hours after calcium (175). Supplemental calcium can decrease the concentration of dolutegravir (Tivicay), elvitegravir (Vitekta), and raltegravir (Isentress), three antiretroviral medications, in blood such that patients are advised to take them two hours before or after calcium supplements (175). Intravenous calcium should not be administrated within 48 hours following intravenous ceftriaxone (rocephine), a cephalosporin antibiotic, since a ceftriaxone-calcium salt precipitate can form in the lungs and kidneys and be a cause of death (175). Use of H2 blockers (e.g., cimetidine) and proton-pump inhibitors (e.g., omeprazole) may decrease the absorption of calcium carbonate and calcium phosphate (reviewed in 176, 177), whereas lithium may increase the risk of hypercalcemia in patients (175). The topical use of calcipotriene, a vitamin D analog, in the treatment of psoriasis places patients at risk of hypercalcemia if they take calcium supplements.

Calcium-nutrient interactions

The presence of calcium decreases iron absorption from nonheme sources (i.e., most supplements and food sources other than meat). However, calcium supplementation up to 12 weeks has not been found to change iron nutritional status, probably due to a compensatory increase in iron absorption (1). Individuals taking iron supplements should take them two hours apart from calcium-rich food or supplements to maximize iron absorption. Although high calcium intakes have not been associated with reduced zinc absorption or zinc nutritional status, an early study in 10 men and women found that 600 mg of calcium consumed with a meal halved the absorption of zinc from that meal (see the article on Zinc) (178). Supplemental calcium (500 mg calcium carbonate) has been found to prevent the absorption of lycopene (a nonprovitamin A carotenoid) from tomato paste in 10 healthy adults randomized into a cross-over study (179).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the recommended dietary allowance (RDA) set by the Food and Nutrition Board of the Institute of Medicine. Following these recommendations should provide adequate calcium to promote skeletal health and may also decrease the risks of some chronic diseases.

Children and adolescents (9-18 years)

To promote the attainment of maximal peak bone mass, children and adolescents should consume a total (diet plus supplements) of 1,300 mg/day of calcium.

Adults (women: 19-50 years; men: 19-70 years)

After adult height has been reached, the skeleton continues to accumulate bone until the third decade of life when peak bone mass is attained. To promote the attainment of maximal peak bone mass and to minimize bone loss later in life, adult women (50 years of age and younger) and adult men (70 years of age and younger) should consume a total (diet plus supplements) of 1,000 mg/day of calcium. 

Older women (>50 years)

To minimize bone loss, postmenopausal women should consume a total (diet plus supplements) of 1,200 mg/day of calcium. Taking a multivitamin/mineral supplement containing at least 10 mg (400 IU)/day of vitamin D will help to ensure adequate calcium absorption (see the article on Vitamin D).

Older men (>70 years)

To minimize bone loss, older men should consume a total (diet plus supplements) of 1,200 mg/day of calcium. Taking a multivitamin/mineral supplement containing at least 10 μg (400 IU)/day of vitamin D will help to ensure adequate calcium absorption (see the article on Vitamin D). 

Pregnant and breast-feeding women

Pregnant and breast-feeding adolescents (<19 years) should consume a total of 1,300 mg/day of calcium, while pregnant and breast-feeding adults (≥19 years) should consume a total of 1,000 mg/day of calcium.


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in September 2017 by:
Connie M. Weaver, Ph.D.
Distinguished Professor and Head of Foods and Nutrition
Purdue University

The 2017 update of this article was sponsored by a grant from Pfizer Inc.

Copyright 2001-2017  Linus Pauling Institute


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Chromium

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Summary

  • Chromium (Cr0) is an ubiquitous trace metal. The predominant chromium form in the body is trivalent chromium (Cr3+), which may play a role in normal insulin function. (More information)
  • Trivalent chromium has been proposed to be the cofactor for an oligopeptide called chromodulin. Chromodulin may be able to potentiate the action of insulin, hence improving tissue sensitivity to insulin and facilitating glucose transport into cells. (More information)
  • Potential chromium deficiency cases have been associated with symptoms resembling diabetes mellitus: impaired glucose tolerance and increased insulin requirements. (More information)
  • The lack of an accurate measure of chromium nutritional status prevents the identification of individuals who may be susceptible to chromium deficiency. In 2001, the US Institute of Medicine set the adequate intake (AI) of chromium at 20-35 μg/day for adults. (More information)
  • Randomized controlled trials have failed to provide any evidence of benefits of chromium supplementation in the prevention or treatment of impaired glucose tolerance and type 2 diabetes mellitus. (More information)
  • A well-balanced diet that includes fruit, vegetables, meat, fish, and grains should easily cover dietary needs of chromium. (More information)
  • Few adverse events have been reported with chromium supplementation. (More information)

Chromium was first discovered in 1797. The most stable oxidation state of chromium in biological systems is trivalent chromium (Cr3+), which forms relatively inert complexes with proteins and nucleic acids (1). The essentiality of trivalent chromium is questioned, and its presumed function in the body remains poorly understood. Another common and stable form of chromium in the environment is hexavalent chromium (Cr6+). Hexavalent chromium is derived from trivalent chromium by heating at alkaline pH and is used as a source of chromium for industrial purposes. Hexavalent chromium is highly toxic and is classified as a human carcinogen when inhaled (2). In the acidic environment of the stomach, hexavalent chromium can be readily reduced to trivalent chromium by reducing substances present in food, which limits the ingestion of hexavalent chromium (3-5).

Function

Trivalent chromium has been proposed to be the cofactor for a biologically active molecule that could enhance the effects of insulin on target tissues. Insulin is secreted by specialized cells in the pancreas in response to increased blood glucose levels, such as after a meal. Insulin binds to insulin receptors on the surface of cells, activating the receptors and stimulating glucose uptake by cells. Through its interaction with insulin receptors, insulin provides cells with glucose for energy and helps maintain blood glucose within a narrow range of concentrations. In addition to its effects on carbohydrate (glucose) metabolism, insulin also influences the metabolism of fat and protein (6). Together, a decreased response to insulin or decreased insulin sensitivity in peripheral tissues (adipose tissue, muscle, and liver) and a progressive defect in insulin secretion may result in impaired glucose tolerance, frequently leading to overt type 2 diabetes mellitus. The body initially increases the secretion of insulin by specialized pancreatic cells to overcome the decrease in insulin sensitivity. However, the pancreas eventually fails to produce enough insulin to maintain normal blood glucose concentrations. Individuals with type 2 diabetes are at increased risk for cardiovascular disease (7).

Possible mechanism of action

The precise structure of the biologically active form of chromium is not known. The current model postulates that trivalent chromium might be the cofactor of a low-molecular-weight chromium-binding substance known as LMWCr or chromodulin (8). Chromodulin is thought to enhance the cascade of signaling events induced by the binding of insulin to extracellular α-subunit of the insulin receptor (IR). Upon insulin binding, the tyrosine kinase domain of the intracellular β-subunit of the IR becomes activated and causes the phosphorylation of tyrosine residues in the β-subunit itself. Subsequently, IR activation triggers a series of rapid phosphorylation reactions that activate many downstream effectors, eventually resulting in an increase in glucose uptake and storage (8).

Regarding the effect of trivalent chromium on insulin signaling, an early model (Figure 1) suggested that the binding of insulin to the IR could stimulate the movement of chromium into the cell and result in the binding of chromium to apochromodulin, a form of chromodulin that lacks chromium (9, 10). Chromodulin could then bind to the IR and upregulate insulin signaling molecules, ultimately increasing the translocation of glucose transporters (GLUT-4) from cytosolic vesicles to the cell membrane (11-13). Some, but not all, studies conducted in cell-based and animal models of insulin resistance and diabetes have found that chromium inhibits the activity of protein tyrosine phosphatase-1B (PTP-1B) and other negative regulators of insulin signaling, suggesting that chromium might improve insulin sensitivity under insulin-resistant conditions (reviewed in 8). A recent study in diabetic mice also suggested that chromium may reduce insulin clearance and enhance insulin signaling by inhibiting the proteolysis (degradation) of insulin and some downstream effectors (14). Additional mechanisms that may underlie the effect of chromium on insulin sensitivity, such as the reduction of markers of oxidative stress and inflammation known to contribute to insulin resistance, are under investigation (reviewed in 8, 10).

Figure 1. A Proposed Model for the Potential Effects of Chromium on Insulin Action. 1. Insulin binds to and activates the insulin receptor. 2. Insulin receptor activation stimulates the movement of chromium into the cell. 3. Chromium binds to a peptide known as Apo-LMWCr* (Apo-LC). 4. Functional LMWCr (LC) binds to the insulin receptor and enhances its activity.  *LMWCr = low-molecular weight chromium-binding substance. Figure adapted from Vincent, J.B. Quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr Rev. 2000; 58: 67-72.

Nutrient interactions

Iron

Chromium competes for one of the binding sites on the iron transport protein, transferrin. However, supplementation of older men with 925 μg/day of chromium for 12 weeks did not significantly affect measures of iron nutritional status (15). A study of younger men found an insignificant decrease in transferrin saturation with iron after supplementation of 200 μg/day of chromium for eight weeks, but no long-term studies have addressed this issue (16). In a 12-week, randomized controlled trial, supplementation with chromium picolinate (200 μg/day) did not affect iron nutritional status in premenopausal women when compared to picolinic acid or placebo (17). Iron overload in hereditary hemochromatosis may interfere with chromium transport by competing for transferrin binding. It has been hypothesized that decreased chromium transport might contribute to the pathogenesis of diabetes mellitus in patients with hereditary hemochromatosis (3).

Vitamin C

Chromium uptake is enhanced in animals when given at the same time as vitamin C (5). In a study of three women, administration of 100 mg of vitamin C together with 1 mg of chromium resulted in higher plasma levels of chromium than 1 mg of chromium without vitamin C (3).

Carbohydrates

Compared to diets rich in complex carbohydrates (e.g., whole grains), diets high in simple sugars (e.g., sucrose) result in increased urinary chromium excretion in adults. This effect may be related to increased insulin secretion in response to the consumption of simple sugars compared to complex carbohydrates (3).

Deficiency

Potential cases of chromium deficiency have been described in a few patients on long-term intravenous feeding (parenteral nutrition) who did not receive supplemental chromium in their intravenous solutions. The subjects developed abnormal glucose utilization and increased insulin requirements that responded to chromium supplementation (18). However, because intravenous solutions provide chromium at doses well above dietary levels, it has been suggested that chromium might produce biological effects only at pharmacological doses (10). Because chromium appeared to enhance the action of insulin and chromium deficiency has been proposed to result in impaired glucose tolerance, chromium insufficiency has been hypothesized to be a contributing factor to the development of type 2 diabetes (3, 19). However, evidence for this is ambiguous at best.

Urinary chromium loss was reportedly increased by endurance exercise in male runners, suggesting that chromium needs may be greater in individuals who exercise regularly (20). In one study, weightlifting (resistive exercise) was found to increase urinary excretion of chromium in older men. However, chromium absorption also increased, leading to little or no net loss of chromium as a result of resistive exercise (21).

At present, research on the effects of potentially inadequate chromium intake and risk factors for chromium insufficiency is limited by the lack of analytical tools to determine chromium nutritional status (3, 5). Moreover, the absence of animal models for chromium deficiency makes it difficult to study possible biochemical, physiological, and functional abnormalities associated with inadequate intakes of chromium (22).

The Adequate Intake (AI)

Because there was not enough information to set an estimated average requirement (EAR), the Food and Nutrition Board (FNB) of the US Institute of Medicine (IOM) established an adequate intake (AI) based on the chromium content in healthy diets (3; Table 1).

Table 1. Adequate Intake (AI) for Chromium
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months  0.2 0.2
Infants  7-12 months  5.5 5.5
Children  1-3 years  11 11
Children  4-8 years  15 15
Children  9-13 years  25 21
Adolescents  14-18 years  35 24
Adults  19-50 years  35 25
Adults  51 years and older  30 20
Pregnancy  18 years and younger  - 29
Pregnancy  19 years and older - 30
Breast-feeding  18 years and younger  - 44
Breast-feeding  19 years and older - 45

The case of trivalent chromium essentiality has been questioned in both animals and humans in the last decades, and the European Food Safety Authority — which provides dietary guidelines for the EU community — recently concluded that requirements for chromium could not be established (22). The IOM is not currently reconsidering the AIs for chromium.

Disease Prevention

Impaired glucose tolerance and type 2 diabetes mellitus

Early controlled studies in subjects with impaired glucose tolerance have reported that chromium supplementation improved some measure of glucose utilization or had beneficial effects on blood lipid profiles (23). Impaired glucose tolerance refers to a prediabetic state and is currently defined by the presence of impaired fasting glucose (fasting plasma glucose concentration of 110-125 mg/dL) and impaired glucose tolerance status (plasma glucose concentration of 140-199 mg/dL during a two-hour challenge test with a 75-g oral glucose load) (24). Impaired glucose tolerance is associated with modest increases in risk of cardiovascular disease, as well as other traditional microvascular complications of diabetes (25). Current estimates suggest that up to 70% of individuals with impaired glucose tolerance may eventually develop type 2 diabetes (26).

In a recent randomized, double-blind, placebo-controlled study in 56 subjects at risk of type 2 diabetes, six months of daily chromium picolinate supplementation (500 μg or 1,000 μg) had no effect on glucose and insulin concentrations, insulin sensitivity, and blood lipid profiles (27). Another randomized, placebo-controlled trial in 31 non-diabetic individuals reported a great variability in serum and urinary chromium concentrations in response to a daily supplementation with 1,000 μg of chromium picolinate for 16 weeks. Also, in the chromium-supplemented group, participants with higher vs. lower serum chromium concentrations (>3.1 μg/L vs. ≤3.1 μg/L) exhibited a decline in insulin sensitivity that could not be explained by expression changes in the genes involved in insulin signaling (28). Additionally, a meta-analysis of nine randomized clinical trials published between 1992 and 2010 reported that chromium at doses of 200-1,000 μg/day for 8-16 weeks had no effect on fasting glucose concentrations in 309 non-diabetic individuals (29). Although evidence is lacking to support chromium supplementation, there is a need for an accurate measure of chromium nutritional status to identify the individuals who might be deficient and thus most likely to benefit from chromium supplementation (29).

Cardiovascular disease

Impaired glucose tolerance and type 2 diabetes are associated with adverse changes in lipid profiles and increased risk of cardiovascular disease. Studies examining the effects of chromium supplementation on lipid profiles have given inconsistent results. While some studies have observed reductions in serum total cholesterol, LDL-cholesterol, and triglyceride levels or increases in HDL-cholesterol levels, others have observed no effect. Such mixed responses of lipid and lipoprotein levels to chromium supplementation may reflect differences in chromium nutritional status. It is possible that only individuals with insufficient dietary intake of chromium will experience beneficial effects on lipid profiles after chromium supplementation (4, 5, 30).

Health claims

Increases muscle mass

Claims that chromium supplementation increases lean body mass and decreases body fat are based on the relationship between chromium and insulin action (see Function). In addition to regulating glucose metabolism, insulin is known to affect fat and protein metabolism (6). At least 12 placebo-controlled studies have compared the effect of chromium supplementation (172-1,000 μg/day of chromium as chromium picolinate) with or without an exercise program on lean body mass and measures of body fat (reviewed in 31). In general, the studies that used the most sensitive and accurate methods of measuring body fat and lean mass (dual energy x-ray absorbtiometry or DEXA and hydrodensitometry or underwater weighing) did not find a beneficial effect of chromium supplementation on body composition (4, 30).

Promotes weight loss

Controlled studies of chromium supplementation have demonstrated little if any beneficial effect on weight or fat loss, and claims of weight loss in humans appear to be exaggerated. In 1996, the US Federal Trade Commission (FTC) ruled that there was no scientific basis for claims that chromium picolinate could promote weight loss and fat loss in humans (32). Recently, a meta-analysis of 11 randomized, double-blind, placebo-controlled trials in 866 overweight or obese subjects found a significant 0.50-kilogram (1.10-pound) reduction in body weight with supplemental chromium (most exclusively in the form of chromium picolinate) at doses between 137 μg/day and 1,000 μg/day for 8-24 weeks (33). However, such a small change did not reach a clinically significant weight loss of ≥5% of the initial body weight (34). Recent reports have suggested that supplemental chromium may reduce food craving and intake in overweight or obese women (35, 36). Yet, current available data remain insufficient to support the use of chromium supplements in weight-loss strategies (37).

Disease Treatment

Type 2 diabetes mellitus

Type 2 diabetes mellitus is characterized by chronic hyperglycemia (elevated blood glucose concentration) and insulin resistance. Because resistance to insulin is usually associated with a compensatory rise in insulin secretion, circulating insulin concentrations in type 2 diabetic subjects may be higher than in healthy individuals. Yet, the resistance of peripheral tissues (especially liver and skeletal muscle) to insulin also implies that the physiological effects of insulin are reduced.

Since cell culture and rodent models of diabetes have implicated chromium in the regulation of insulin sensitivity and blood glucose levels, the relationship between chromium nutritional status and type 2 diabetes mellitus has generated considerable scientific interest. Early reports observed that individuals with overt type 2 diabetes for over two years had higher rates of urinary chromium loss than healthy individuals (38). Small, well-designed studies of chromium supplementation in individuals with type 2 diabetes showed no improvement in blood glucose control, although they provided some evidence of reduced insulin concentrations and improved blood lipid profiles (39). In 1997, the results of a placebo-controlled trial conducted in China indicated that chromium supplementation might be beneficial in the treatment of type 2 diabetes (40). One hundred and eighty participants were randomized to receive either a placebo or chromium supplements in the form of chromium picolinate at either 200 μg/day or 1,000 μg/day. After four months of treatment, fasting blood glucose concentrations were found to be 15% to 19% lower in those who took 1,000 μg/day of chromium compared to those who took the placebo. Yet, blood glucose concentrations in those taking 200 μg/day of chromium did not differ significantly from those who took placebo. Chromium picolinate at either 200 μg/day or 1,000 μg/day was also associated with reduced insulin concentrations compared to placebo. The level of glycated hemoglobin A1c (HbA1c), a measure of glycemic control, was also significantly reduced in both chromium-supplemented groups. However, a number of limitations made it difficult to extrapolate the results to the US population (41). Besides, the study was excluded from recent meta-analyses of randomized controlled trials due to insufficient data quality (29, 42).

A recent meta-analysis of seven randomized, placebo-controlled studies indicated that chromium intake of at least 250 μg/day for no less than three months significantly reduced fasting glucose concentrations in diabetic subjects but had no effect on the levels of HbA1c (42). Another meta-analysis of nine randomized controlled trials, including a total of 440 participants with diabetes, failed to find a significant reduction in fasting glucose concentrations with chromium monotherapy (200-1,000 μg/day) (29). However, large-scale randomized controlled trials of chromium supplementation are needed to demonstrate if chromium is effective in the treatment of type 2 diabetes mellitus. Additionally, recent suggestions have been made that greater doses of chromium may be required to observe beneficial effects of chromium supplementation (10).

Gestational diabetes

Few studies have examined the effects of chromium supplementation on gestational diabetes, a condition that is estimated to affect 4.6% to 9.2% of pregnant women in the US (43). The occurrence of gestational diabetes during pregnancy is associated with insufficient insulin secretion and glucose intolerance of variable severity (44). Peripheral insulin resistance usually increases in the second or third trimester of pregnancy. Because elevated maternal blood glucose concentrations can have adverse effects on the developing fetus, women with gestational diabetes are at increased risk of pregnancy complications (45). After delivery, impaired glucose tolerance generally reverts to normal glucose tolerance. However, nearly one-third of women who have had gestational diabetes develop postpartum glucose intolerance (prediabetes or type 2 diabetes) (46, 47).

An observational study in pregnant women did not find serum chromium levels to be associated with measures of glucose tolerance or insulin resistance in late pregnancy (48). However, it is not known whether measures of serum chromium levels truly reflect tissue chromium levels and chromium status during pregnancy. A more recent prospective study following 425 pregnant women also failed to find a correlation between serum chromium concentrations and incidence of gestational diabetes (49). A cross-sectional study of 90 pregnant women in southern India found that those with gestational diabetes had significantly lower serum chromium concentrations compared to gestational diabetes-free women. Given the above mixed results, it should be noted that different methods were used to measure circulating chromium concentrations in each study. Also, it is possible that nutritional chromium status may vary among ethnically distinct populations so that studies including pregnant women from different ethnic backgrounds and/or geographical areas would give different results.

In addition, there is currently insufficient evidence to evaluate the effect of supplemental chromium on gestational diabetes. Women with gestational diabetes whose diets were supplemented with 4 μg of chromium per kilogram of body weight daily as chromium picolinate for eight weeks had decreased fasting blood glucose and insulin concentrations compared to those who took a placebo. Yet, insulin therapy rather than chromium picolinate was required to normalize severely elevated blood glucose levels (4, 50).

Sources

Food sources

The amount of chromium in food is variable and has been measured accurately in relatively few foods. Presently, there is no large database for the chromium content of food. Processed meats, whole-grain products, high-bran cereals, green beans, broccoli, nuts, and egg yolk are good sources of chromium. Foods high in simple sugars, such as sucrose and fructose, are usually low in chromium and may actually promote chromium excretion (4). Estimated average chromium intakes in the US range from 23-29 μg/day for adult women and 39-54 μg/day for adult men (3). The chromium content of some foods is listed in the table below and expressed in micrograms (μg) (51). Since chromium content varies significantly between different batches of the same food, the information provided in Table 2 should serve only as a guide to the chromium content of food.

Table 2. Some Food Sources of Chromium
Food Serving Chromium (μg)
Broccoli ½ cup 11.0
Green beans ½ cup 1.1
Potatoes (mashed) 1 cup 2.7
Grape juice 8 fl. ounces 7.5
Orange juice 8 fl. ounces 2.2
Beef 3 ounces 2.0
Turkey breast 3 ounces 1.7
Turkey ham (processed) 3 ounces 10.4
Waffle 1 (~2.5 ounces) 6.7
Bagel 1 2.5
English muffin 1 3.6
Apple w/ peel 1 medium 1.4
Banana 1 medium 1.0 

Supplements

A recent cross-sectional survey indicated that 19% of the US population uses chromium-containing dietary supplements (i.e., single-nutrient supplements and multiple ingredient supplements), with the highest proportion of users (29%) found in adults aged over 50 years (52). Trivalent chromium is available as a supplement in several forms, including chromium chloride, chromium nicotinate, chromium picolinate, and high-chromium yeast. These are available as stand-alone supplements or in combination products. Doses typically range from 50 to 200 μg of elemental chromium (53). Much of the research on impaired glucose tolerance and type 2 diabetes uses chromium picolinate as the source of chromium, although recent investigations suggest that its bioavailability may not be greater than that of dietary chromium (54). Some concerns have been raised over the long-term safety of chromium picolinate supplementation (see Safety).

Safety

Toxicity

Hexavalent chromium (chromium VI; Cr6+) is a recognized carcinogen. Exposure to hexavalent chromium in dust has been associated with an increased incidence of lung cancer and is known to cause inflammation of the skin (dermatitis).

In contrast, there is little evidence that trivalent chromium (chromium III; Cr3+) is toxic to humans. The toxicity from oral intakes is considered to be low because ingested chromium is poorly absorbed, and most absorbed chromium is rapidly excreted in the urine (55). Because no adverse effects have been convincingly associated with excess intake of trivalent chromium from food or supplements, the Food and Nutrition Board (FNB) of the Institute of Medicine did not set a tolerable upper intake level (UL) for chromium. Yet, despite limited evidence for adverse effects, the FNB acknowledged the possibility of a negative impact of high oral intakes of supplemental trivalent chromium on health and advised caution (3).

Chromium picolinate

Most of the concerns regarding the long-term safety of trivalent chromium supplementation arise from several studies in cell culture, suggesting trivalent chromium, especially in the form of chromium picolinate, may increase DNA damage (56-58). Presently, there is no evidence that trivalent chromium increases DNA damage in living organisms (3), and a study in 10 women taking 400 μg/day of chromium as chromium picolinate found no evidence of increased oxidative damage to DNA as measured by antibodies to an oxidized DNA base (59).

Many studies have demonstrated the safety of daily doses of up to 1,000 μg of chromium for several months (40, 60). However, there have been a few isolated reports of serious adverse reactions to chromium picolinate. Kidney failure was reported five months after a six-week course of 600 μg/day of chromium in the form of chromium picolinate (61), while kidney failure and impaired liver function were reported after the use of 1,200-2,400 μg/day of chromium in the form of chromium picolinate over a period of four to five months (62). Additionally, a 24-year old healthy male reportedly developed reversible, acute renal failure after taking chromium picolinate-containing supplements for two weeks (63). Individuals with pre-existing kidney or liver disease may be at increased risk of adverse effects and should limit supplemental chromium intake (3).

Drug interactions

Little is known about drug interactions with chromium in humans. Large doses of calcium carbonate or magnesium hydroxide-containing antacids decreased chromium absorption in rats. In contrast, non-steroidal anti-inflammatory drugs, aspirin and indomethacin, can increase chromium absorption in rats (5).

Linus Pauling Institute Recommendation

The lack of sensitive indicators of chromium nutritional status in humans makes it difficult to determine the level of chromium intake most likely to promote optimum health. Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (DV) of most nutrients will generally provide 60-120 μg/day of chromium, well above the adequate intake of 20-25 μg/day for adult women and 30-35 μg/day for adult men.

Older adults (>50 years)

Although the requirement for chromium is not known to be higher for older adults, one study found that chromium concentrations in hair, sweat, and urine decreased with age (64). Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (DV) of most nutrients should provide sufficient chromium for older adults.

Because impaired glucose tolerance and type 2 diabetes mellitus are associated with serious health problems, individuals with either condition should seek medical advice if considering the use of high-dose chromium supplementation.


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in October 2014 by:
John B. Vincent, Ph.D.
Professor, Department of Chemistry
The University of Alabama
Tuscaloosa, Alabama

Copyright 2001-2017  Linus Pauling Institute


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Copper

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Summary

  • Copper is an essential cofactor for oxidation-reduction reactions involving copper-containing oxidases. Copper enzymes regulate various physiologic pathways, such as energy production, iron metabolism, connective tissue maturation, and neurotransmission. (More information)
  • Copper deficiency can result from malnutrition, malabsorption, or excessive zinc intake and can be acquired or inherited. Symptoms include deficiencies in blood cells, bone and connective tissue abnormalities, and neurologic disorders. (More information)
  • Marginal copper imbalance has been linked to impaired immune function, bone demineralization, and increased risk of cardiovascular and neurodegenerative diseases. However, the use of more precise indicators of nutritional copper status needs to be considered for future research. (More information)
  • Organ meats, shellfish, nuts, seeds, wheat-bran cereals, and whole-grain products are good sources of copper. (More information)
  • Copper toxicity is rare and often associated with genetic defects of copper metabolism. (More information)


    Copper (Cu) is an essential trace element for humans and animals. In the body, copper shifts between the cuprous (Cu1+) and cupric (Cu2+) forms, though the majority of the body's copper is in the Cu2+ form. The ability of copper to easily accept and donate electrons explains its important role in oxidation-reduction (redox) reactions and in scavenging free radicals (1). Although Hippocrates is said to have prescribed copper compounds to treat diseases as early as 400 B.C. (2), scientists are still uncovering new information regarding the functions of copper in the human body (3).

Function

Copper is a critical functional component of several essential enzymes known as cuproenzymes (4). Some of the physiologic functions known to be copper-dependent are discussed below. 

Energy production

The copper-dependent enzyme, cytochrome c oxidase, plays a critical role in cellular energy production. By catalyzing the reduction of molecular oxygen (O2) to water (H2O), cytochrome c oxidase generates an electrical gradient used by the mitochondria to create the vital energy-storing molecule, ATP (5).

Connective tissue formation

Another cuproenzyme, lysyl oxidase, is required for the cross-linking of collagen and elastin, which are essential for the formation of strong and flexible connective tissue. The action of lysyl oxidase helps maintain the integrity of connective tissue in the heart and blood vessels and also plays a role in bone formation (2).

Iron metabolism

Four copper-containing enzymes, known as multi-copper oxidases (MCO) or ferroxidases, have the capacity to oxidize ferrous iron (Fe2+) to ferric iron (Fe3+), the form of iron that can be loaded onto the protein transferrin for transport to the site of red blood cell formation. The MCO family comprises the circulating ceruloplasmin (which represents ~90% of plasma copper), the membrane-bound ceruloplasmin (called GPI-ceruloplasmin), and two proteins called Hephaestin and Zyklopen found in the intestine and the placenta, respectively (6). Interestingly, mice that do not express ceruloplasmin (Cp-/-) have normal copper metabolism but abnormal iron accumulation in the liver (7, 8). Similarly, individuals lacking ceruloplasmin display iron overload in selected tissues, including liver, brain, and retina (9). This supports the idea that the ferroxidase activity of ceruloplasmin is essential to the flux of iron in the body. Moreover, the fact that iron mobilization from storage sites is impaired in copper deficiency supports the role of MCO in iron metabolism (10).

Central nervous system

A number of reactions essential to normal function of the brain and nervous system are catalyzed by cuproenzymes.

Neurotransmitter synthesis

Dopamine β-hydroxylase catalyzes the conversion of dopamine to the neurotransmitter, norepinephrine (11).

Formation and maintenance of myelin

The myelin sheath is made of phospholipids whose synthesis depends on cytochrome c oxidase activity (2).

Melanin formation

The cuproenzyme, tyrosinase, is required for the formation of the pigment melanin. Melanin is formed in cells called melanocytes and plays a role in the pigmentation of the hair, skin, and eyes (2).

Antioxidant functions

Superoxide dismutase

Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of superoxide radicals (free radicals or ROS) to hydrogen peroxide, which can subsequently be reduced to water by other antioxidant enzymes (12). Two forms of SOD contain copper: (1) copper/zinc SOD is found within most cells of the body, including red blood cells; and (2) extracellular SOD is a copper-containing enzyme found at high levels in the lungs and low levels in plasma (2).

Ceruloplasmin

Ceruloplasmin may function as an antioxidant in two different ways. Free copper and iron ions are powerful catalysts of free-radical damage. By binding copper, ceruloplasmin prevents free copper ions from catalyzing oxidative damage. The ferroxidase activity of ceruloplasmin (oxidation of ferrous iron) facilitates iron loading onto its transport protein, transferrin, and may prevent free ferrous ions (Fe2+) from participating in harmful free-radical-generating reactions (12).

Regulation of gene expression

Cellular copper levels may affect the synthesis of proteins by enhancing or inhibiting the transcription of specific genes. Copper may regulate the expression of genes by increasing the level of intracellular oxidative stress. A number of signal transduction pathways are activated in response to oxidative stress and can lead to an increase in the expression of genes involved in the detoxification of reactive oxygen species (13).

Nutrient interactions

Iron

Adequate copper nutritional status is necessary for normal iron metabolism and red blood cell formation. Anemia is a clinical sign of copper deficiency, and iron has been found to accumulate in the livers of copper-deficient animals, indicating that copper (via the copper-containing ceruloplasmin) is required for iron transport to the bone marrow for red blood cell formation (see Iron metabolism) (2). The connection between copper availability and iron metabolism has also been established in humans; copper deficiency can lead to secondary ceruloplasmin deficiency and hepatic iron overload and/or cirrhosis (10). Oral copper supplementation restored normal ceruloplasmin levels and plasma ferroxidase activity and corrected the iron-metabolism disorder in a copper-deficient subject (14). Moreover, infants fed a high iron formula absorbed less copper than infants fed a low iron formula, suggesting that high iron intakes may interfere with copper absorption in infants (15).

Zinc

High supplemental zinc intakes of 50 mg/day or more for extended periods of time may result in copper deficiency. High dietary zinc intakes increase the synthesis of an intestinal cell protein called metallothionein, which binds certain metals and prevents their absorption by trapping them in intestinal cells. Metallothionein has a stronger affinity for copper than zinc, so high levels of metallothionein induced by excess zinc cause a decrease in copper absorption. In contrast, high copper intakes have not been found to affect zinc nutritional status (2, 15). Zinc supplementation (10 mg/day for eight weeks) was able to restore normal plasma copper/zinc ratios in 65 subjects on long-term hemodialysis who initially exhibited low zinc levels and elevated copper levels. Whether improving zinc and copper status of hemodialysis patients can impact their clinical outcomes needs to be assessed (16).

Fructose

High fructose diets have exacerbated copper deficiency in rats but not in pigs whose gastrointestinal systems are more like those of humans. Very high levels of dietary fructose (20% of total calories) did not result in copper depletion in humans, suggesting that fructose intake does not result in copper depletion at levels relevant to normal diets (2, 15).

Vitamin C

Although vitamin C supplements have produced copper deficiency in guinea pigs (17), the effect of vitamin C supplements on copper nutritional status in humans is less clear. Two small studies in healthy, young adult men indicate that the oxidase activity of ceruloplasmin may be impaired by relatively high doses of supplemental vitamin C. In one study, vitamin C supplementation of 1,500 mg/day for two months resulted in a significant decline in ceruloplasmin oxidase activity (18). In the other study, supplements of 605 mg/day of vitamin C for three weeks resulted in decreased ceruloplasmin oxidase activity, although copper absorption did not decline (19). Neither of these studies found vitamin C supplementation to adversely affect copper nutritional status.

Deficiency

Clinically evident or frank dietary copper deficiency is relatively uncommon. Serum copper and ceruloplasmin levels may fall to 30% of normal in cases of severe copper deficiency. Hypocupremia (low copper content in blood) is also observed in genetic disorders of copper metabolism, such as aceruloplasminemia and, paradoxically, in Wilson's disease, which are not linked to dietary copper deficiency. One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but corrected by copper supplementation. Although the anemia is thought to result from defective iron mobilization due to decreased ceruloplasmin activity, the absence of ceruloplasmin in individuals with inherited aceruloplasminemia is not always associated with overt anemia (20). Copper deficiency may also lead to abnormally low numbers of white blood cells known as neutrophils (neutropenia), a condition that may be accompanied by increased susceptibility to infection. Copper depletion studies have suggested that reduced copper availability might affect erythroid and myeloid cell lineage, supporting a role for copper in the regulation of blood cell renewal (21, 22). More research is clearly needed to uncover the mechanisms underlying copper deficiency-induced anemia and neutropenia (4, 23). Osteoporosis and other abnormalities of bone development related to copper deficiency are most common in copper-deficient, low-birth-weight infants and young children. Less common features of copper deficiency may include loss of pigmentation, neurological symptoms, and impaired growth (2, 5).

Individuals at risk of deficiency

Cow's milk is relatively low in copper, and cases of copper deficiency have been reported in high-risk infants and children fed only cow's milk formula (24). High-risk individuals include premature infants (especially low-birth-weight infants); infants with prolonged diarrhea; infants and children recovering from malnutrition; and individuals with malabsorption syndromes, including celiac disease, sprue, and short bowel syndrome due to surgical removal of large portions of the intestine. Individuals receiving intravenous total parenteral nutrition lacking copper or other restricted diets may also require supplementation with copper and other trace elements (2, 5). Copper deficiency in infants with cholestasis (reduced biliary excretion of copper) has been linked to long-term parenteral nutrition lacking copper (25). Case reports indicate that cystic fibrosis patients may also be at increased risk of copper insufficiency (26). Finally, excessive zinc intake has led to secondary copper deficiency in individuals using zinc supplements or zinc-enriched dental creams (27, 28).

Acquired copper deficiency

A neurologic syndrome has been described in adults with acquired copper deficiency (29). The symptoms include central nervous system demyelination, polyneuropathy, myelopathy, and inflammation of the optic nerve. The etiology is unknown in absence of prominent risk factors (see Individuals at risk of deficiency); case reports describe increased intestinal copper content suggesting a malabsorption syndrome like Menkes disease, but mutations in ATP7A gene were not linked to the condition (30) (see Inherited copper deficiency). Oral copper replacement (2 mg/day of elemental copper) normalizes serum copper and ceruloplasmin concentrations, stabilizes the condition, and significantly improves the quality of life of affected subjects. However, the duration of copper supplementation has not yet been established, and dosing increments might be required in cases of relapse (29).

Inherited copper deficiency

Copper trafficking within most cells except hepatocytes (liver cells) is facilitated by a Cu1+-transporting ATPase called ATP7A. Mutations in the ATP7A gene impair the transport of intracellular copper, which accumulates in the cytosol of enterocytes and vascular endothelial cells (31). This results in systemic copper deficiency and decreased cuproenzyme activity. Copper transport into the brain is also affected, leading to copper accumulation in the blood-brain barrier and reduced cuproenzyme activity in neurons. Affected individuals are diagnosed with Menkes disease (MD) or with a milder form of the disease called occipital horn syndrome (OHS). The clinical features of MD include intractable seizures, connective tissue disorders, subdural hemorrhage, and hair abnormalities ("kinky hair"). OHS patients exhibit muscular hypotonia and connective tissue abnormalities, including exostosis on occipital bones. Subcutaneous injections of copper-histidine are used to bypass the defective intestinal absorption and improve copper metabolic function in patients. However, copper entry into the brain remains limited (reviewed in 32).

The Recommended Dietary Allowance (RDA)

A variety of indicators were used to establish the RDA for copper, including plasma copper concentration, serum ceruloplasmin activity, superoxide dismutase activity in red blood cells, and platelet copper concentration (15). The RDA for copper reflects the results of depletion-repletion studies and is based on the prevention of deficiency (Table 1).

Table 1. Recommended Dietary Allowance (RDA) for Copper
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months 200 (AI) 200 (AI)
Infants  7-12 months  220 (AI) 220 (AI)
Children  1-3 years  340 340
Children  4-8 years  440 440
Children  9-13 years  700 700
Adolescents  14-18 years  890 890
Adults  19 years and older 900 900
Pregnancy  all ages   - 1,000
Breast-feeding  all ages   -  1,300

Disease Prevention

Cardiovascular disease

While it is clear that severe copper deficiency results in heart abnormalities and damage (cardiomyopathy) in some animal species, the pathology differs from atherosclerotic cardiovascular disease that is prevalent in humans (15). Studies in humans have produced inconsistent results, and their interpretation is hindered by the lack of a reliable marker of copper nutritional status. Outside the body, free copper is known to be a pro-oxidant and is frequently used to produce oxidation of low-density lipoprotein (LDL) in the test tube. The copper-containing protein ceruloplasmin has been found to stimulate LDL oxidation in the test tube (33), leading some scientists to propose that increased copper levels could increase the risk of atherosclerosis by promoting the oxidation of LDL. However, there is little evidence that copper or ceruloplasmin promotes LDL oxidation in the human body. Additionally, the cuproenzymes, superoxide dismutase and ceruloplasmin, are known to have antioxidant properties, leading some experts to propose that copper deficiency rather than excess copper increases the risk of cardiovascular disease (34).

Epidemiological studies

Several epidemiological studies have found increased serum copper levels to be associated with increased risk of cardiovascular disease. A prospective cohort study in the US examined serum copper levels in more than 4,500 men and women 30 years of age and older (35). During the following 16 years, 151 participants died from coronary heart disease (CHD). After adjusting for other risk factors of heart disease, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from CHD. Three other case-control studies conducted in Europe had similar findings. One small study in 60 patients with chronic heart failure or ischemic heart disease reported that serum copper was a predictor of short-term outcome (36). Another prospective cohort study in 4,035 middle-aged men reported that high serum copper levels were significantly related to a 50% increase in all-cause mortality; however, serum copper was not significantly associated with cardiovascular mortality in this study (37). Additionally, serum copper has been found to be elevated in patients with rheumatic heart disease (38).

It is important to note that serum copper largely reflects serum ceruloplasmin and is not a sensitive indicator of copper nutritional status (39). Serum ceruloplasmin levels are known to increase by 50% or more under certain conditions of physical stress, such as trauma, inflammation, or disease. Because over 90% of serum copper is carried in ceruloplasmin, which is increased in many inflammatory conditions, elevated serum copper may simply be a marker of inflammation that accompanies atherosclerosis. In contrast to the epidemiological findings linking increased serum copper levels to heart disease, two autopsy studies found copper levels in heart muscle were actually lower in patients who died of CHD than those who died of other causes (40). Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients (41, 42). Further, patients with a history of myocardial infarction (MI) had lower concentrations of extracellular superoxide dismutase (SOD) than those without a history of MI (43). Thus, due to a lack of a reliable biomarker of copper nutritional status, it is not clear whether copper is related to cardiovascular disease.

Intervention studies

While studies in very small numbers of adults fed experimental diets low in copper have demonstrated adverse changes in blood cholesterol levels, including increased total and LDL-cholesterol levels and decreased HDL-cholesterol levels (44), other studies have not confirmed those results (45). Copper supplementation of 2-3 mg/day for four to eight weeks did not result in clinically significant changes in cholesterol levels (34, 46, 47). Further, research has failed to find evidence that increased copper intake increases oxidative stress. In a multi-center, placebo-controlled trial, copper supplementation of 3 or 6 mg/day for six weeks did not result in increased susceptibility of LDL to oxidation induced outside the body (ex vivo) by copper or peroxynitrite (a reactive nitrogen species) (48). Moreover, supplementation with 3 or 6 mg/day of copper decreased the in vitro oxidizability of red blood cells (49), indicating that relatively high intakes of copper do not increase the susceptibility of LDL or red blood cells to oxidation.

Summary

Although free copper and ceruloplasmin can promote LDL oxidation in the test tube, there is little evidence that increased dietary copper increases oxidative stress in the human body. Increased serum copper levels have been associated with increased cardiovascular disease risk, but the significance of these findings is unclear due to the association between serum ceruloplasmin levels and inflammatory conditions. Clarification of the relationships between copper nutritional status, ceruloplasmin levels, and cardiovascular disease risk requires further research.

Notably, it was suggested that elevated plasma copper concentrations could be linked to high homocysteine levels in individuals with vascular diseases (50, 51). Increased levels of homocysteine are associated with arterial wall lesions and increased risk of cardiovascular disease (52). The interaction between homocysteine and copper was linked to impaired vascular endothelial function in animal models (53, 54). However, although copper restriction in animals has shown some beneficial effects on homocysteine levels and atherogenic lesions (55, 56), it is not known whether copper imbalance contributes to the atherogenic effect of homocysteine in humans.

Immune system function

Copper is known to play an important role in the development and maintenance of immune system function, but the exact mechanism of its action is not yet known. Neutropenia (abnormally low numbers of white blood cells called neutrophils) is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune function appear most pronounced in infants. Infants with Menkes disease, a genetic disorder that results in severe copper deficiency, suffer from frequent and severe infections (57, 58). In a study of 11 malnourished infants with evidence of copper deficiency, the ability of certain white blood cells to engulf pathogens increased significantly after one month of copper supplementation (59). Moreover, 11 men on a low-copper diet (0.66 mg copper/day for 24 days and 0.38 mg/day for another 40 days) showed a decreased proliferation response when white blood cells, called monocytes, were isolated from their blood and presented with an immune challenge in cell culture (60). Recent mechanistic studies support a role for copper in innate immune response against bacterial infections (reviewed in 61). While severe copper deficiency has adverse effects on immune function, the effects of marginal copper insufficiency in humans are not yet clear.

Osteoporosis

The progressive loss of bone mineral density (BMD) leading to osteopenia (pre-osteoporosis) and osteoporosis is commonly observed in the elderly population. Women are more often affected by osteoporosis than men, (e.g., prevalence ratio is 5:1 in non-Hispanic whites) (62), primarily due to the postmenopausal reduction in estrogen production that is essential for maintaining strength of muscle, bone, and connective tissue (63). Osteoporosis is associated with an increased risk of falls, bone fracture, and mortality in individuals over 65 years of age (64). Osteoporosis has also been reported in infants with severe copper deficiency (65, 66), but it is not clear whether marginal copper deficiency during adulthood contributes to osteoporosis. While an increase in bone resorption (breakdown) was observed in 11 healthy adult males with a marginal copper intake of 0.7 mg/day for six weeks (67), the supplementation of 3 to 6 mg/day of copper for six weeks had no effect on biochemical markers of bone resorption or bone formation in two studies of healthy adult men and women (68, 69). However, it is possible that a reduction in copper intake and absorption in older people reduces the activity of the copper-dependent enzyme, lysyl oxidase, which is required for the maturation (cross-linking) of collagen—a key element in the organic matrix of bone.

Overall, research regarding the role of copper nutritional status in age-related osteoporosis is limited. An early study found that serum copper levels in 46 elderly patients with hip fractures were significantly lower than those of matched controls (70). However, another study found no differences in serum copper levels among postmenopausal women with normal BMD (N=40), osteopenia (N=40), or osteoporosis (N=40) (71). A small study in perimenopausal women, who consumed an average of 1 mg of dietary copper daily, reported decreased loss of BMD from the lumbar spine after copper supplementation of 3 mg/day for two years (72). Additionally, a two-year double-blind, placebo-controlled trial in 59 postmenopausal women found that a combination of supplemental calcium and trace minerals, including 2.5 mg of copper daily, resulted in maintenance of spinal bone density, whereas supplemental calcium or trace minerals, alone, were not effective in preventing loss of bone density (73). However, a more recent randomized, double-blind, placebo-controlled study, which initially enrolled 224 healthy, postmenopausal women aged 51 to 80 years, found daily supplementation with 600 mg of calcium, 2 mg of copper, and 12 mg of zinc for two years decreased whole-body BMD compared to supplemental calcium alone. Moreover, although BMD was clearly reduced in subjects with dietary copper intakes below the RDA (0.9 mg/day), supplemental copper did not prevent the progressive loss of BMD as well as the calcium regimen alone (74). Finally, several studies have suggested that tooth loss might be related to poor systemic BMD (75, 76). When compared with 20 healthy-matched controls, 50 patients (mean age 47.5 years) with low spinal BMD and advanced tooth wear were found with significantly lower copper content in tooth enamel. However, despite evidence suggesting bone demineralization, the serum copper levels in this population were similar to those of the healthy group (77). More research is required to draw conclusions regarding the effects of marginal copper deficiency and copper supplementation on bone metabolism and age-related osteoporosis.

Neurodegenerative diseases

Alzheimer's disease

Cognitive deterioration in individuals with Alzheimer's disease (AD) is linked to the presence of β-amyloid plaques and abnormal Tau protein-forming aggregates. The possibility that copper imbalance is involved in the onset of AD is currently investigated. First, it appears that the fraction of 'free' copper (not bound to ceruloplasmin) is augmented in copper homeostasis disorders, as well as in AD individuals (78, 79). Moreover, AD patients appear to have higher levels of serum copper compared to healthy controls (80). Among the many hypotheses supporting a role for copper in AD onset or progression, it is suggested that copper could be involved in the formation of senile plaques through hypermetallation of the β-amyloid peptides, possibly leading to zinc depletion, enhanced oxidative stress, and even brain damage (81, 82). Recent research has also identified genetic variations (polymorphisms) in the ATP7B gene that may modify the risk of developing AD (83). The protein, ATP7B, is responsible for the excretion of hepatic copper into the biliary tract, and its impairment in Wilson's disease results in increased 'free' copper level in blood and copper accumulation in liver and brain.

More research is needed to investigate whether genetic variants could influence the susceptibility of environmental exposure to high levels of copper. The addition of copper to drinking water has been associated with enhanced pathologic features in animal models of AD (84, 85). One study in a rabbit model reported that combining a high-cholesterol diet and copper (0.12 mg/L in drinking water) could impair cognition (84). A prospective cohort study in 3,718 elderly participants of the Chicago Health and Aging Project, followed for 5.5 years, evaluated the impact of fat and copper intakes using food frequency questionnaires and various cognitive assessments. For individuals with high intakes of saturated and trans fat, cognitive decline was greater for those in the highest quintile of total copper intake compared to the lowest quintile (median intake of 2.75 vs. 0.88 mg/day) (86).

Although a dysfunctional copper metabolism is suggested as a risk factor for AD, it could also be symptomatic of the disease. Moreover, it is still unclear whether copper supplementation or restriction could delay the progression of AD. A small, double-blind, placebo-controlled trial in 68 individuals with mild AD found that supplementation of 8 mg/day of copper for one year delayed the decrease of the β-amyloid peptide Aβ42 in cerebrospinal fluid; a decrease in Aβ42 has been linked to cognitive deterioration (87). However, this delay was not associated with improved cognitive performance (88). Based on the utilization of copper-chelating agents in Wilson's disease, the recent use of slow-release zinc acetate (150 mg/day for six months) in a randomized, placebo-controlled study of 60 patients with mild to moderate AD resulted in a decrease in serum 'free' copper and stabilization of cognition deficits (81). Additional human studies are needed to clarify the role of copper in AD onset and progression, and to evaluate whether dietary copper might help prevent AD in high-risk individuals or manage the disease in AD patients.

Parkinson's disease

Both neurologically presenting Wilson's disease and inherited aceruloplasminemia are characterized by copper accumulation in the brain, resulting in neurologic symptoms (dystonia and cognitive impairment) that resemble Parkinson's disease (PD) (89). The level of copper is diminished in brain regions of neuronal loss in PD patients (90). However, the recent meta-analysis of studies measuring copper levels in serum, plasma, and cerebrospinal fluid did not find any difference between PD patients and healthy elderly subjects (91).

Sources

Food sources

Copper is found in a wide variety of foods and is most plentiful in organ meats, shellfish, nuts, and seeds. Wheat-bran cereals and whole-grain products are also good sources of copper. According to national surveys, the average dietary intake of copper in the US is approximately 1.0 to 1.1 mg (1,000 to 1,100 μg) per day for adult women and 1.2 to 1.6 mg (1,200 to 1,600 μg) per day for adult men (15). The copper content of some foods that are relatively rich in copper is listed in micrograms (μg) in Table 2. For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Copper
Food Serving Copper (μg)
Liver (beef), cooked, pan-fried 1 ounce 4,128
Mollusks, oysters, eastern, wild, cooked, moist heat 6 medium oysters 2,397
Crab meat, Alaskan king, cooked 3 ounces 1,005
Crab meat, blue, cooked, moist heat 3 ounces 692
Mollusks, clams, mixed species, cooked, moist heat 3 ounces 585
Cashews nuts, raw 1 ounce 622
Sunflower seed kernels, dry roasted 1 ounce 519
Hazelnuts, dry roasted 1 ounce 496
Almonds 1 ounce 292
Peanut butter, chunk style, without salt 2 tablespoons 185
Lentils, mature seeds, cooked, boiled, without salt 1 cup 497
Mushrooms, white, raw 1 cup (sliced) 223
Shredded wheat cereal 2 biscuits 167
Chocolate (semisweet) 1 ounce 198

Supplements

Copper supplements are available as cupric oxide, copper gluconate, copper sulfate, and copper amino acid chelates (92).

Safety

Toxicity

Copper toxicity is rare in the general population. Acute copper poisoning has occurred through the contamination of beverages by storage in copper-containing containers, as well as from contaminated water supplies (93). Guideline values for copper in drinking water have been set by the US Environmental Protection Agency (1.3 mg/liter) and by the World Health Organization (2 mg/liter) (94). Symptoms of acute copper toxicity include abdominal pain, nausea, vomiting, and diarrhea; such symptoms help prevent additional ingestion and absorption of copper. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death. Of more concern from a nutritional standpoint is the possibility of liver damage resulting from long-term exposure to lower doses of copper. In generally healthy individuals, doses of up to 10,000 μg (10 mg) daily have not resulted in liver damage. For this reason, the US Food and Nutrition Board set the tolerable upper intake level (UL) for copper at 10 mg/day from food and supplements (15; Table 3). It should be noted that individuals with genetic disorders affecting copper metabolism (e.g., Wilson's disease, Indian childhood cirrhosis, and idiopathic copper toxicosis) may be at risk for adverse effects of chronic copper toxicity at significantly lower intake levels. There is some concern that the UL of 10 mg/day might be too high. In particular, men in a research study consumed 7.8 mg/day of copper for 147 days. They accumulated copper during that time, and some indices of immune function and antioxidant status suggested that these functions were adversely affected by the high intakes of copper (95, 96). However, another study did not report any adverse effects in individuals supplemented with 8 mg/day of copper for six months (88).

Table 3. Tolerable Upper Intake Level (UL) for Copper
Age Group UL (μg/day)
Infants 0-12 months Not possible to establish* 
Children 1-3 years 1,000 
Children 4-8 years   3,000 
Children 9-13 years   5,000 
Adolescents 14-18 years 8,000 
Adults 19 years and older 10,000
*Source of intake should be from food and formula only.

Drug interactions

Relatively little is known about the interaction of copper with drugs. Penicillamine is used to bind copper and enhance its elimination in Wilson's disease, a genetic disorder resulting in hepatic copper overload. Because penicillamine dramatically increases the urinary excretion of copper, individuals taking the medication for reasons other than copper overload may have an increased copper requirement.

Linus Pauling Institute Recommendation

The RDA for copper (900 μg/day for adults) is sufficient to prevent deficiency, but the lack of clear indicators of copper nutritional status in humans makes it difficult to determine the level of copper intake most likely to promote optimum health or prevent chronic disease. A varied diet should provide enough copper for most people. For those who are concerned that their diet may not provide adequate copper, a multivitamin/mineral supplement will generally provide at least the RDA for copper.

Older adults (>50 years)

Because aging has not been associated with significant changes in the requirement for copper, our recommendation for older adults is the same as that for adults 50 and younger (97).


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2014 by:
Joseph R. Prohaska, Ph.D.
Professor of Biochemistry, Emeritus
University of Minnesota Medical School Duluth

Copyright 2001-2017  Linus Pauling Institute


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74.  Nielsen FH, Lukaski HC, Johnson LK, Roughead ZK. Reported zinc, but not copper, intakes influence whole-body bone density, mineral content and T score responses to zinc and copper supplementation in healthy postmenopausal women. Br J Nutr. 2011;106(12):1872-1879.  (PubMed)

75.  Sidiropoulou-Chatzigiannis S, Kourtidou M, Tsalikis L. The effect of osteoporosis on periodontal status, alveolar bone and orthodontic tooth movement. A literature review. J Int Acad Periodontol. 2007;9(3):77-84.  (PubMed)

76.  Darcey J, Horner K, Walsh T, Southern H, Marjanovic EJ, Devlin H. Tooth loss and osteoporosis: to assess the association between osteoporosis status and tooth number. Br Dent J. 2013;214(4):E10.  (PubMed)

77.  Sierpinska T, Konstantynowicz J, Orywal K, Golebiewska M, Szmitkowski M. Copper deficit as a potential pathogenic factor of reduced bone mineral density and severe tooth wear. Osteoporos Int. 2013 [Epub ahead of print].  (PubMed)

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Fluoride

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Summary

  • Fluoride is the ionic form of the naturally occurring fluorine element. The anion increases the structural stability of teeth and bones through interactions with calcium phosphates. (More information)
  • The daily intake recommendations for fluoride are based on the safest and most effective intakes to prevent dental caries. (More information)
  • The use of fluoridated dental products and adequate intakes of fluoride reduce the occurrence of caries throughout life by promoting tooth mineralization and re-mineralization. Large randomized, placebo-controlled studies are needed to evaluate whether the topical application of fluoridated agents could also prevent dental erosion. (More information)
  • Epidemiological and clinical evidence is currently limited to support a role for water fluoridation in the prevention of osteoporosis and bone fracture. (More information)
  • Therapeutic trials have found a dose-dependent effect of fluoride on fracture risk in osteoporotic patients. However, the occurrence of numerous side effects warrants additional studies to guarantee that safe and effective doses can be used alone or in combination with current therapies. (More information)
  • The major sources of systemic and topical fluoride are drinking water, foods and beverages made with fluoridated water, infant formulas, and fluoride-containing oral care products. Fluoridated salt and milk are currently available outside the US in Europe, Latin America, and Southeast Asia. (More information)
  • While increased exposure to fluoride has led to a decline in dental caries, the prevalence of white speckling or mottling of the permanent teeth, known as dental fluorosis, has increased. Bone tissue homeostasis may also be affected by excess fluoride intake. (More information)


Fluorine occurs naturally as the negatively charged ion, fluoride (F-). Fluoride is considered a trace element because only small amounts are present in the body (about 2.6 grams in adults), and because the daily requirement for maintaining dental health is only a few milligrams a day. About 95% of the total body fluoride is found in bones and teeth (1). Although its role in the prevention of dental caries (tooth decay) is well established, fluoride is not generally considered an essential mineral element because humans do not require it for growth or to sustain life (2). However, if one considers the prevention of chronic disease (dental caries) an important criterion in determining essentiality, then fluoride might well be considered an essential trace element (3)

Function

Fluoride is absorbed in the stomach and small intestine. Once in the bloodstream it rapidly enters mineralized tissue (bones and developing teeth). At usual intake levels, fluoride does not accumulate in soft tissue. The predominant mineral elements in bone are crystals of calcium and phosphate, known as hydroxyapatite crystals. Fluoride's high chemical reactivity and small radius allow it to either displace the larger hydroxyl (-OH) ion in the hydroxyapatite crystal, forming fluoroapatite, or to increase crystal density by entering spaces within the hydroxyapatite crystal. Fluoroapatite hardens tooth enamel and stabilizes bone mineral (4).

Nutrient interactions

Both calcium and magnesium form insoluble complexes with fluoride and are capable of significantly decreasing fluoride absorption when present in the same meal. However, the absorption of fluoride in the form of monofluorophosphate (unlike sodium fluoride) is unaffected by calcium. Also, a diet low in chloride (salt) has been found to increase fluoride retention by reducing urinary excretion of fluoride (1).

Deficiency

In humans, the only clear effect of inadequate fluoride intake is an increased risk of dental caries (tooth decay) for individuals of all ages. Epidemiological investigations of patterns of water consumption and the prevalence of dental caries across various US regions with different water fluoride concentrations led to the development of a recommended optimum range of fluoride concentration of 0.7-1.2 milligrams/liter (mg/L) or parts per million (ppm); the lower concentration was recommended for warmer climates where water consumption is higher, and the higher concentration was recommended for colder climates. Recently, the US Department of Health and Human Services recommended that all community water systems adjust the fluoride concentration to 0.7 mg/L, as more "recent data do not show a convincing relationship between fluid intake and ambient air temperature" (5). This recommendation was made in an effort to reduce the risk of dental fluorosis and in light of the widespread availability of fluoride from other sources, including fluoride-containing oral-care products (6). A number of studies conducted prior to the introduction of fluoride-containing toothpastes demonstrated that the prevalence of dental caries was 40% to 60% lower in communities with optimal water fluoride concentrations than in communities with low water fluoride concentrations (7).

The Adequate Intake (AI)

The Food and Nutrition Board (FNB) of the US Institute of Medicine updated its recommendations for fluoride intake in 1997. Because data were insufficient to establish a Recommended Dietary Allowance (RDA), Adequate Intake (AI) levels were set based on estimated intakes that have been shown to reduce the occurrence of dental caries most effectively without causing the unwanted side effect of tooth enamel mottling known as dental fluorosis (0.05 mg/kg of body weight) (7; Table 1). See the section below on Safety for a discussion of dental fluorosis.

Table 1. Adequate Intake (AI) for Fluoride
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months 0.01 0.01
Infants  7-12 months  0.5 0.5
Children  1-3 years  0.7 0.7
Children  4-8 years  1.0 1.0
Children  9-13 years  2.0 2.0
Adolescents  14-18 years  3.0 3.0
Adults  19 years and older 4.0 3.0
Pregnancy  all ages  - 3.0
Breast-feeding  all ages  - 3.0

Disease Prevention

Dental caries (cavities and tooth decay)

Specific cariogenic (cavity-causing) bacteria (mainly Streptococcus mutans and Streptococcus sobrinus) found in dental plaque are capable of metabolizing fermentable carbohydrates (sugars) and converting them to organic acids that can dissolve sensitive tooth enamel. If unchecked, the bacteria may penetrate deeper layers of the tooth and progress into the soft pulp tissue at the center. Untreated caries can lead to severe pain, local infection, tooth loss or extraction, nutritional problems, and serious systemic infections in susceptible individuals (7). Recent studies have suggested a link between systemic inflammation in individuals with periodontal (gum) infection and insulin resistance (9), type 2 diabetes (10), and hypertension (11). Moreover, poor oral health may constitute a risk factor for cardiovascular disease (12, 13).

Systemic effects of fluoride on teeth

Increased fluoride exposure, most commonly through community water fluoridation, has been found to decrease the incidence of dental caries in children and adults (14). Between 1976 and 1987, clinical studies in several countries demonstrated that the addition of fluoride to community water supplies (0.7-1.2 ppm) reduced caries by 30%-60% in primary (baby) teeth and 15%-35% in permanent teeth (15). Fluoride consumed in water appears to have a systemic effect in children before all teeth have erupted—typically through 12 years of age. Fluoride is incorporated into the developing enamel of teeth and increases the resistance to caries. Since the caries preventative effect of fluoride is also topical (surface) in children after teeth have erupted and in adults, the optimal protection achieved by fluoridated water likely occurs through both systemic exposure before and after tooth eruption and topical exposure after tooth eruption.

Topical effects of fluoride on teeth

Research has indicated that the primary action of fluoride occurs topically after the teeth erupt into the mouth. Ingested fluoride is secreted in the saliva and contributes to topical protection. When enamel is partially demineralized by organic acids, fluoride in the saliva can enhance the remineralization of enamel through its interactions with calcium and phosphate. Fluoride containing remineralized enamel is more resistant to acid attack and demineralization. In salivary concentrations associated with optimum fluoride intake, fluoride has been found to inhibit bacterial enzymes, resulting in reduced acid production by cariogenic bacteria (8, 14). Moreover, the use of topically applied fluoride-containing products, including toothpaste, gel, varnish, and mouth rinse, is thought to have contributed to the substantial decrease in the prevalence of caries over the last decades (16). A recent meta-analysis of fluoride interventions in children and adolescents (up to 16 years of age) found that the application of fluoride varnish for at least one year was associated with a 37% reduction in decayed, missing, filled tooth surfaces in decayed tooth surfaces of primary teeth; the anti-caries effect on the permanent teeth corresponded to a 43% decrease compared to no treatment or placebo (17). Another meta-analysis of 67 placebo-controlled trials conducted in children and adolescents demonstrated a 23% reduction in decayed, missing, and filled tooth surfaces on mixed and permanent dentitions with toothpastes containing at least 1,000 ppm of fluoride. The decrease reached 36% with toothpaste fluoride concentrations of 2,400-2,800 ppm, while there was no difference between fluoride levels below 600 ppm and placebo (18).

Dental erosion (tooth wear)

The attack of dental hard tissue by acids other than those produced by the bacterial plaque may lead to the loss of tooth enamel, also known as dental erosion. Factors involved in dental erosion include acidic foods and beverages (e.g., carbonated drinks) and acid reflux (19). The protective effect of fluoridated agents against dental erosion has mainly been observed in in vitro studies (reviewed in 19). Nevertheless, a recent meta-analysis of four small, randomized trials examining the effect of fluoride in toothpaste, varnish, and saliva on dental erosion did not find any overall benefit compared to placebo (20). Larger clinical studies are needed to evaluate whether topical fluoride applications can prevent dental erosion and/or reduce the progression of existing erosive lesions.

Osteoporosis

Although fluoride in pharmacologic doses has been shown to be a potent therapeutic agent for increasing spinal bone mass (see Disease Treatment), there is little evidence that water fluoridation at optimum levels for the prevention of dental caries is helpful in the prevention of osteoporosis. The majority of studies conducted to date have failed to find clinically significant differences in bone mineral density (BMD) or fracture incidence when comparing residents of areas with fluoridated water supplies to residents in areas without fluoridated water supplies (21). However, two studies found that drinking water fluoridation was associated with decreased incidence of hip fracture in the elderly. In addition, one study in Italy found a significantly greater risk of femoral (hip) fractures in men and women residing in an area with low water fluoridation (0.05 ppm) compared to the risk in a similar population whose water supply was naturally fluoridated (1.45 ppm) at higher than optimum levels for prevention of dental caries (22). Another study in Germany found no significant difference in BMD between residents of a community whose water supply had been optimally fluoridated for 30 years (1 ppm) compared with those who resided in a community without fluoridated water. However, this study reported that the incidence of hip fracture in men and women, aged 85 years or older, was significantly lower in the community with fluoridated water compared to the community with non-fluoridated water, despite higher calcium levels in the non-fluoridated water supply (23). Another community-based study in 1,300 women found that elevated serum fluoride concentrations were not related to BMD or to osteoporotic fracture incidence (24). Finally, a nationwide cohort study in Sweden found no association between chronic exposure to fluoridated water and incidence of hip fracture (25).

Disease Treatment

Osteoporosis

Osteoporosis is characterized by decreased bone mineral density (BMD) and increased bone fragility and susceptibility to fracture. In general, decreased BMD is associated with increased risk of fracture. However, the usual relationship between BMD and fracture risk does not always hold true when very high (pharmacologic) doses of fluoride are used to treat osteoporosis. Most available therapies for osteoporosis (e.g., estrogen, calcitonin, and bisphosphonates) decrease bone loss (resorption), resulting in very small increases in BMD. Pharmacologic doses of fluoride are capable of producing large increases in the BMD of the lumbar spine. Overall, therapeutic trials of fluoride in patients with osteoporosis have not consistently demonstrated significant decreases in the occurrence of vertebral fracture despite dramatic increases in lumbar spine BMD (26). A meta-analysis of 11 controlled studies, including 1,429 participants, found that fluoride treatment resulted in increased BMD at the lumbar spine but was not associated with a lower risk of vertebral fractures (27). This meta-analysis also found that higher concentrations of fluoride were associated with increased risk of non-vertebral fractures after four years of treatment. Early studies using high doses of fluoride (>20 mg/day) may have induced rapid bone mineralization in the absence of adequate calcium and vitamin D, resulting in denser bones that were not mechanically stronger (28, 29). Analysis of bone architecture has also shed some light on the inconsistent effect of fluoride therapy in reducing vertebral fractures. Research has indicated that osteoporosis may be associated with an irreversible change in the architecture of bone known as decreased trabecular connectivity. Normal bone consists of a series of plates interconnected by thick rods. Severely osteoporotic bone has fewer plates, and the rods may be fractured or disconnected (decreased trabecular connectivity) (30). Despite fluoride therapy increasing bone density, it probably cannot reduce bone resorption and restore connectivity in patients with severe bone loss. Thus, fluoride therapy may be less effective in osteoporotic individuals who have already lost substantial trabecular connectivity (26, 31).

On the other hand, randomized controlled trials using lower fluoride doses (≤20 mg/day), intermittent dosage schedules, or slow-release formulations (enteric coated sodium fluoride) have demonstrated a decreased incidence of vertebral and non-vertebral fractures along with increased bone density of the lumbar spine (32). Yet, bone biopsies from postmenopausal, osteoporotic women treated with 20 mg/day of fluoride showed evidence of abnormal bone mineralization despite calcium and vitamin D supplementation (33). Additionally, a recent randomized, double-blind, placebo-controlled study did not find any increase in lumbar spine BMD in 180 postmenopausal women with osteopenia (early osteoporosis) who were given daily supplements of up to 10 mg/day of fluoride for one year (34). Additional studies are required to assess whether a safe dose of fluoride can be found to maximize bone formation while preventing mineralization defects.

Safety of fluoride therapy for osteoporosis

Serious side effects have been associated with the high doses of fluoride used to treat osteoporosis (32). They include gastrointestinal irritation, joint pain in the lower extremities, and the development of calcium deficiency and stress fractures. The reasons for the occurrence of lower extremity joint pain and stress fractures in patients taking fluoride for osteoporosis remain unclear, but they may be related to rapid increases in bone formation without sufficient calcium to support such an increase (26). Presently, enteric coated sodium fluoride or monofluorophosphate preparations offer a lower side effect profile than the high-dose sodium fluoride used in earlier trials. Additionally, sufficient calcium and vitamin D must be provided to support fluoride-induced bone formation. Although fluoride therapy may be beneficial for the treatment of osteoporosis in appropriately selected and closely monitored individuals, uncertainty about its safety and benefit in reducing fractures has kept the US Food and Drug Administration (FDA) from approving fluoride therapy for osteoporosis (35). Combinations of lower doses of fluoride with antiresorptive agents, such as estrogen or bisphosphonates, may improve therapeutic results while minimizing side effects (36, 37). Yet, recent randomized studies have shown that the risk of fractures remained unchanged whether treatments include fluoride, antiresorptives, or both (32, 33). Additional studies are warranted to determine whether any treatment combinations could provide substantial therapeutic benefits over monotherapy.

Sources

Water fluoridation

The major source of dietary fluoride in the US diet is drinking water. Controlled addition of fluoride to water is used by communities as a public health measure to adjust fluoride concentration in drinking water to an optimal level of 0.7 to 1.2 milligrams (mg) per liter, which corresponds to 0.7-1.2 ppm. This concentration range has been found to decrease the incidence of dental caries while minimizing the risk of dental fluorosis and other adverse effects. The US Department of Health and Human Services has recently recommended that the optimal concentration in drinking water be set at 0.7 ppm (see Safety) (6). Approximately 74% of the US population receives water with sufficient fluoride for the prevention of dental caries (38). The average fluoride intake for adults living in fluoridated communities ranges from 1.4 to 3.4 mg/day compared to 0.3 to 1 mg/day in non-fluoridated areas (7). Since well water can vary greatly in its fluoride content, people who consume water from wells should have the fluoride content of their water tested by their local water district or health department. Water fluoride testing may also be warranted in households that use home water treatment systems. While water softeners are not thought to change water fluoride levels, reverse osmosis systems, distillation units, and some water filters have been found to remove significant amounts of fluoride from water. However, Brita-type filters do not remove fluoride (7, 35).

Bottled water sales have grown exponentially in the US in the last decades, and studies have found that most bottled waters contain sub-optimal levels of fluoride, although there is considerable variation (39). For example, a study of 105 different bottled water products in the Greater Houston metropolitan area found that over 80% had fluoride concentrations of less than 0.4 ppm; only 5% of the tested products had fluoride concentrations within the recommended range (40). Several other studies have reported similar findings, with most bottled waters relatively low in fluoride, but a few in the optimal range or higher (41-43). The FDA-approved claim that "drinking fluoridated water may reduce the risk of tooth decay" is only used by bottlers when the water contains between 0.6 ppm and 1.0 ppm of fluoride. However, bottlers are not required to provide the fluoride concentration in bottled water unless fluoride was added (44).

Infant formulas

While consumption of fluoride from water presents very little risk of adverse effects in adults except in extreme circumstances (see Safety), consumption of relatively large amounts of water mixed with formula concentrates appears to increase the risk for the development of dental fluorosis in infants (45-47). One study found that, on average, at least half of all fluoride ingested by infants six months and younger was from water mixed with formula concentrates (48). The study of 49 commercially available infant formulas in the Chicago area showed that milk-based ready-to-feed, liquid concentrate, and powdered formulas (reconstituted with deionized water) had mean fluoride concentrations of 0.15 ppm, 0.27 ppm, and 0.12 ppm, respectively (49). Fluoride content was significantly higher in soy-based compared to milk-based liquid concentrate formulas (0.50 ppm vs. 0.27 ppm). Using average body weights and total formula intakes during the first year of life, the authors estimated that the risk of exceeding the tolerable upper intake level for fluoride ingestion was minimal when liquid concentrate and powdered formulas were reconstituted with water containing less than 0.5 ppm of fluoride, but the risk was maximal with 1.0 ppm fluoridated water. Fluoride-free or low-fluoride water labeled as "deionized," "purified," "demineralized," "distilled," or "produced through reverse-osmosis" can be used in order to minimize the risk for mild fluorosis (44). However, infants between 6 and 12 months may not reach the adequate intake of fluoride if they are fed ready-to-feed formulas or formulas reconstituted with water containing less than 0.4 ppm (49).

Food and beverage sources

The fluoride content of most foods is low (less than 0.05 mg/100 grams or 0.5 ppm). Rich sources of fluoride include tea (see the article on Tea), which concentrates fluoride in its leaves, and marine fish that are consumed with their bones (e.g., sardines). Foods made with mechanically separated (boned) chicken, such as canned meats, hot dogs, and infant foods, also add fluoride to the diet (50). In addition, certain fruit juices, particularly grape juices, often have relatively high fluoride concentrations (51). Foods generally contribute only 0.3-0.6 mg of the daily intake of fluoride. An adult male residing in a community with fluoridated water has an intake range from 1-3 mg/day. Intake is less than 1 mg/day in non-fluoridated areas (2). Table 2 provides a range of fluoride content for a few fluoride-rich foods. For more information on the fluoride content of foods and beverages, search the USDA national fluoride database.

Table 2. Some Food Sources of Fluoride
Food Serving Fluoride (mg) Fluoride (ppm)*
Fruit juice 100 mL (3.5 fluid ounces) 0.02-0.21 0.2-2.1
Crab (canned) 100 g (3.5 ounces) 0.21 2.1
Rice (cooked) 100 g (3.5 ounces) 0.04 0.4
Fish (cooked) 100 g (3.5 ounces) 0.02 0.2
Chicken 100 g (3.5 ounces) 0.015 0.15
*1.0 part per million (ppm) = 1 milligram/liter (mg/L)

Fluoride supplements

Fluoride supplements — available only by prescription in the US — are intended for infants six months and older and children up to 16 years of age living in areas with suboptimal water fluoridation for the purpose of bringing their intake to approximately 1 mg/day (7). The American Dental Association Council on Scientific Affairs recommends the prescription of fluoride supplements only to children at high risk of developing dental caries (52). The supplemental fluoride dosage schedule in Table 3 was recommended by the American Dental Association, the American Academy of Pediatric Dentistry, and the American Academy of Pediatrics (52, 53). It requires knowledge of the fluoride concentration of local drinking water, as well as other possible sources of fluoride intake. For more detailed information regarding fluoride and the prevention of dental caries, visit the American Dental Association website.

Table 3. American Dental Association Fluoride Supplement Schedule
Age Fluoride Ion Level in Drinking Water (ppm)*
<0.3 ppm 0.3-0.6 ppm >0.6 ppm
Birth - 6 months None None None
6 months - 3 years 0.25 mg/day** None None
3 years - 6 years 0.50 mg/day 0.25 mg/day None
6 years - 16 years 1.0 mg/day 0.50 mg/day None
*1.0 part per million (ppm) = 1 milligram/liter (mg/L)
**2.2 mg sodium fluoride contains 1 mg fluoride ion.

Toothpaste

Fluoridated toothpastes are very effective in preventing dental caries but also add considerably to fluoride intake of children, especially young children who are more likely to swallow toothpaste. Researchers estimate that children under six years of age may ingest an average of 0.3 mg of fluoride from toothpaste with each brushing. Children under the age of six years who ingest more than two or three times the recommended fluoride intake are at increased risk of a white speckling or mottling of the permanent teeth, known as dental fluorosis. A major source of excess fluoride intake in this age group comes from swallowing fluoride-containing toothpaste. To prevent dental fluorosis while providing optimum protection from tooth decay, it is recommended that parents supervise children under six years of age while brushing with fluoridated toothpaste. In addition to discouraging the swallowing of toothpaste, children should be supervised during teeth brushing, and young children should be encouraged to use very small amounts of toothpaste—a "smear amount" (a thin layer of toothpaste that covers less than half of the bristle surface of a child-size toothbrush) for children younger than three years, and no more than a pea-size application of toothpaste for children three to six years of age (54, 55). Interestingly, it has been suggested that the management of the fluorosis risk in young children who ingest fluoridated toothpaste could include the use of toothpaste formulation that reduces gastrointestinal absorption and bioavailability of fluoride (56).

Salt fluoridation

Fluoridation of salt has been implemented in several countries worldwide as an alternative to water fluoridation to promote the ingestion of fluoride and improve oral care. Since the fluoridation of water is extensively practiced in the US, fluoride is not added to salt. Epidemiological studies have shown that the incidence of teeth with caries dramatically decreased in the regions where salt fluoridation programs were developed. While concerns around hypertension and the monitoring of population intakes should be addressed, no adverse health effects linked to the fluoridation of salt have been reported (reviewed in 57). According to the World Health Organization (WHO), salt fluoridation and, to a lesser extent, milk fluoridation are affordable alternatives to improve oral hygiene in areas where access to oral health services is limited and fluoridation of public water is not feasible (58).

Safety

Adverse effects

Fluoridation of public drinking water in the US was initiated nearly 70 years ago. Since then, a number of adverse effects have been attributed to water fluoridation. However, extensive scientific research has uncovered no evidence of increased risks of cancer, heart disease, kidney disease, liver disease, thyroid disease, Alzheimer's disease, birth defects, or Down's syndrome (659, 60). A number of epidemiological studies, mostly published in Chinese journals, have investigated the association between fluoride content in drinking water and children's neurodevelopment. A meta-analysis of 27 studies, mainly conducted in China, found lower intelligence quotients (IQs) in children exposed to fluoride concentrations ranging from 1.8 mg/L to 11.5 mg/L of drinking water (61). Serious limitations, including substantial heterogeneity among studies and co-occurrence of other neurotoxicants in drinking water, hinder the strength of the finding and its application to US settings. The Academy of Nutrition and Dietetics has recently estimated that only limited evidence supports an association between fluoride content in water and the IQs of children (44). Finally, a recent prospective study in a New Zealand population-based cohort followed for nearly four decades found no association between fluoride exposure in the context of community water fluoridation programs and IQs measured during childhood and at 38 years of age (62)

Acute toxicity

Fluoride is toxic when consumed in excessive amounts, so concentrated fluoride products should be used and stored with caution to prevent the possibility of acute fluoride poisoning, especially in children and other vulnerable individuals. The lowest dose that could trigger adverse symptoms is considered to be 5 mg/kg of body weight, with the lowest potentially fatal dose considered 15 mg/kg of body weight. Nausea, abdominal pain, and vomiting almost always accompany acute fluoride toxicity. Other symptoms like diarrhea, excessive salivation and tearing, sweating, and generalized weakness may also occur (60). In order to prevent acute fluoride poisoning, the American Dental Association has recommended that no more than 120 mg of fluoride (224 mg of sodium fluoride) be dispensed at one time (35). The use of high doses of fluoride to treat osteoporosis has been associated with some adverse effects, which are discussed in the Disease Treatment section above.

Dental fluorosis

The mildest form of dental fluorosis is detectable only to the trained observer and is characterized by small opaque white flecks or spots on the enamel of the teeth. Moderate dental fluorosis is characterized by mottling and mild staining of the teeth, and severe dental fluorosis results in marked staining and pitting of the teeth. In its moderate to severe forms, dental fluorosis becomes a cosmetic concern when it affects the incisors and canines (front teeth). Dental fluorosis is a result of excess fluoride intake prior to the eruption of the first permanent teeth (generally before eight years of age). It is also a dose dependent condition, with higher fluoride intakes being associated with more pronounced effects on the teeth. The incidence of mild and moderate dental fluorosis has increased over the past decades, mainly due to increasing fluoride intake from reconstituted infant formula and toothpaste, although inappropriate use of fluoride supplements may also contribute (47). According to a US national survey, the National Health and Nutrition Examination Survey, 1999-2004, 23% of people aged 6 to 49 years had some degree of dental fluorosis (63). In 1997, the US Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper intake level (UL) for fluoride based on the prevention of moderate enamel fluorosis (7; Table 4).

Table 4. Tolerable Upper Intake Level (UL) for Fluoride
Age Group UL (mg/day)
Infants 0-6 months 0.7
Infants 7-12 months 0.9
Children 1-3 years 1.3
Children 4-8 years   2.2
Children 9-13 years   10.0
Adolescents 14-18 years 10.0
Adults 19 years and older 10.0

Following recommendations from the National Research Council, the US EPA is currently re-evaluating the maximum allowable level of fluoride in drinking water (set at 4 mg/L) to ensure that it protects children from developing severe dental fluorosis (44, 59). The EPA has also set a non-enforceable standard fluoride level of 2 mg/L to prevent moderate dental fluorosis (64).

Skeletal fluorosis

Intake of fluoride at excessive levels for long periods of time may lead to changes in bone structure known as skeletal fluorosis. The early stages of skeletal fluorosis are characterized by increased bone mass, detectable by x-ray. If very high fluoride intake persists over many years, joint pain and stiffness may result from the skeletal changes. The most severe form of skeletal fluorosis is known as "crippling skeletal fluorosis," which may result in calcification of ligaments, immobility, muscle wasting, and neurological problems related to spinal cord compression. While skeletal fluorosis is endemic in many world regions with naturally high fluoride concentrations in drinking water, crippling skeletal fluorosis may occur only when fluoride intake exceeds 10 mg/day for at least 10 years (7, 65). Rare cases of skeletal fluorosis in the US have been observed in consumers of large volumes of tea (66-69). Because of the potential risk for skeletal fluorosis, the EPA, which regulates water fluoridation under the Safe Drinking Water Act, is currently reviewing the maximum level of fluoride allowed in drinking water—a level currently set at 4 mg/L (44, 59).

Drug interactions

Calcium supplements, as well as calcium and aluminum-containing antacids, can decrease the absorption of fluoride. It is best to take these products two hours before or after fluoride supplements (70).

Linus Pauling Institute Recommendation

The safety and public health benefits of optimally fluoridated water for prevention of tooth decay in people of all ages have been well established. The Linus Pauling Institute supports the recommendations of the American Dental Association and the Centers for Disease Control and Prevention, which include optimally fluoridated water and the use of fluoride toothpaste, fluoride mouth rinse, fluoride varnish, and when necessary, fluoride supplementation. Due to the risk of fluorosis, any fluoride supplementation should be prescribed and closely monitored by a dentist or physician.


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2014 by:
John J. Warren, D.D.S., M.S.
Professor
Preventive & Community Dentistry
College of Dentistry
The University of Iowa

Last Updated 4/29/15  Copyright 2001-2017  Linus Pauling Institute


References

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36.  Murray TM, Ste-Marie LG. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 7. Fluoride therapy for osteoporosis. CMAJ.1996;155(7):949-954.  (PubMed)

37.  Alexandersen P, Riis BJ, Christiansen C. Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study. J Clin Endocrinol Metab. 1999;84(9):3013-3020.  (PubMed)

38.  National Center for Chronic Disease Prevention and Health Promotion, Division of Oral Health. Community water fluoridation: 2010 water fluoridation statistics.  Available at: http://www.cdc.gov/fluoridation/statistics/2010stats.htm. Accessed 1/15/14.

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40.  Quock RL, Chan JT. Fluoride content of bottled water and its implications for the general dentist. Gen Dent. 2009;57(1):29-33.  (PubMed)

41.  Van Winkle S, Levy SM, Kiritsy MC, Heilman JR, Wefel JS, Marshall T. Water and formula fluoride concentrations: significance for infants fed formula. Pediatr Dent. 1995;17(4):305-310.  (PubMed)

42.  Tate WH, Chan JT. Fluoride concentrations in bottled and filtered waters. Gen Dent. 1994;42(4):362-366.

43.  McGuire S. Fluoride content of bottled water. N Engl J Med. 1989;321(12):836-837.

44.  Palmer CA, Gilbert JA, Academy of N, Dietetics. Position of the Academy of Nutrition and Dietetics: the impact of fluoride on health. J Acad Nutr Diet. 2012;112(9):1443-1453.  (PubMed)

45.  Marshall TA, Levy SM, Warren JJ, Broffitt B, Eichenberger-Gilmore JM, Stumbo PJ. Associations between Intakes of fluoride from beverages during infancy and dental fluorosis of primary teeth. J Am Coll Nutr. 2004;23(2):108-116.  (PubMed)

46.  Pendrys DG. Risk of enamel fluorosis in nonfluoridated and optimally fluoridated populations: considerations for the dental professional. J Am Dent Assoc. 2000;131(6):746-755.  (PubMed)

47.  Levy SM, Broffitt B, Marshall TA, Eichenberger-Gilmore JM, Warren JJ. Associations between fluorosis of permanent incisors and fluoride intake from infant formula, other dietary sources and dentifrice during early childhood. J Am Dent Assoc. 2010;141(10):1190-1201.  (PubMed)

48.  Levy SM, Kohout FJ, Guha-Chowdhury N, Kiritsy MC, Heilman JR, Wefel JS. Infants' fluoride intake from drinking water alone, and from water added to formula, beverages, and food. J Dent Res. 1995;74(7):1399-1407.  (PubMed)

49.  Siew C, Strock S, Ristic H, et al. Assessing a potential risk factor for enamel fluorosis: a preliminary evaluation of fluoride content in infant formulas. J Am Dent Assoc. 2009;140(10):1228-1236.  (PubMed)

50. Fein NJ, Cerklewski FL. Fluoride content of foods made with mechanically separated chicken. J Agric Food Chem. 2001;49(9):4284-4286.  (PubMed)

51.  Kiritsy MC, Levy SM, Warren JJ, Guha-Chowdhury N, Heilman JR, Marshall T. Assessing fluoride concentrations of juices and juice-flavored drinks. J Am Dent Assoc. 1996;127(7):895-902.  (PubMed)

52.  Rozier RG, Adair S, Graham F, et al. Evidence-based clinical recommendations on the prescription of dietary fluoride supplements for caries prevention: a report of the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2010;141(12):1480-1489.  (PubMed)

53.  Centers for Disease Control and Prevention. Recommendations for using fluoride to prevent and control dental caries in the United States. MMWR Recomm Rep. 2001;50(RR-14):1-42.  Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5014a1.htm

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56.  Falcao A, Tenuta LM, Cury JA. Fluoride gastrointestinal absorption from Na2FPO3/CaCO3- and NaF/SiO2-based toothpastes. Caries Res. 2013;47(3):226-233.  (PubMed)

57.  Pollick HF. Salt fluoridation: a review. J Calif Dent Assoc. 2013;41(6):395-397, 400-394.  (PubMed)

58.  Marthaler TM, Petersen PE. Salt fluoridation--an alternative in automatic prevention of dental caries. Int Dent J. 2005;55(6):351-358.  (PubMed)

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Iodine

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Summary

  • Iodine is a key component of thyroid hormones, which are required throughout life for normal growth, neurological development, and metabolism. (More information)
  • Insufficient iodine intake impairs the production of thyroid hormones, leading to a condition called hypothyroidism. Iodine deficiency results in a range of adverse health disorders with varying degrees of severity, from thyroid gland enlargement (goiter) to severe physical and mental retardation known as cretinism. (More information)
  • Iodine deficiency-induced hypothyroidism has adverse effects in all stages of development but is most damaging to the developing brain. Maternal iodine deficiency during pregnancy can result in maternal and fetal hypothyroidism, as well as miscarriage, preterm birth, and neurological impairments in offspring. (More information)
  • Even in areas with voluntary/mandatory iodization programs and in iodine-replete countries, pregnant women, lactating mothers, and young infants are among the most vulnerable to iodine deficiency due to their special requirements during these life stages. (More information)
  • The recommended dietary allowance (RDA) for iodine intake is 150 micrograms (μg)/day in adults, 220 μg/day in pregnant women, and 290 μg/day in breast-feeding women. During pregnancy and lactation, the fetus and infant are entirely reliant on maternal iodine intake for thyroid hormone synthesis. (More information)
  • Thyroid accumulation of radioactive iodine (131I) increases the risk of developing thyroid cancer, especially in children. In case of radiation emergencies, current preventive measures include the distribution of pharmacologic doses of potassium iodide that would reduce the risk of significant uptake of 131I by the thyroid gland. (More information)
  • Seafood is an excellent source of dietary iodine. Dairy products, grains, eggs, and poultry contribute substantially to dietary iodine intakes in the US. (More information)
  • More than 120 countries worldwide have introduced programs of salt fortification with iodine in order to correct iodine deficiency in populations. (More information)
  • In iodine-deficient populations, a rapid increase in iodine intake may precipitate iodine-induced hyperthyroidism. The risk of iodine-induced hyperthyroidism is especially high in older people with multi-nodular goiter. (More information)
  • In iodine-sufficient adults, long-term iodine intake above the tolerable upper intake level (UL) of 1,100 μg/day may increase the risk of thyroid disorders, including iodine-induced goiter and hypothyroidism. (More information)

Iodine (I), a non-metallic trace element, is required by humans for the synthesis of thyroid hormones. Iodine deficiency is an important health problem throughout much of the world. Most of the Earth's iodine, in the form of the iodide ion (I-), is found in oceans, and iodine content in the soil varies with region. The older an exposed soil surface, the more likely the iodine has been leached away by erosion. Mountainous regions, such as the Himalayas, Atlas, Andes, and Alps; flooded river valleys, such as the Ganges River plain in India; and many inland regions, such as central Asia and Africa, central and eastern Europe, and the Midwestern region of North America are among the most severely iodine-deficient areas in the world (1)

Function

Iodine is an essential component of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), and is therefore essential for normal thyroid function. To meet the body's demand for thyroid hormones, the thyroid gland traps iodine from the blood and incorporates it into the large (660 kDa) glycoprotein thyroglobulin. The hydrolysis of thyroglobulin by lysosomal enzymes gives rise to thyroid hormones that are stored and released into the circulation when needed. In target tissues, such as the liver and the brain, T4 (the most abundant circulating thyroid hormone) can be converted to T3 by selenium-containing enzymes known as iodothyronine deiodinases (DIOs) (Figure 1; see also Nutrient interactions). T3 is the physiologically active thyroid hormone that can bind to thyroid receptors in the nuclei of cells and regulate gene expression. In this manner, thyroid hormones regulate a number of physiologic processes, including growth, development, metabolism, and reproductive function (2).

Figure 1. Iodine Intake and Thyroid Function. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH), which stimulates iodine trapping, thyroid hormone synthesis, and release of T3 (triiodothyronine) and T4 (thyroxine) by the thyroid gland. When dietary iodine intake is sufficient, the presence of adequate circulating T4 and T3 feeds back at the level of both the hypothalamus and pituitary, decreasing TRH and TSH production. When circulating T4 levels decrease, the pituitary increases its secretion of TSH, resulting in increased iodine trapping as well as increased production and release of both T3 and T4. Dietary iodine deficiency results in inadequate production of T4. In response to decreased blood levels of T4, the pituitary gland increases its output of TSH. Persistently elevated TSH levels may lead to hypertrophy of the thyroid gland, also known as goiter.

The regulation of thyroid function is a complex process that involves the hypothalamus and the pituitary gland. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH), which stimulates iodine trapping, thyroid hormone synthesis, and release of T4 and T3 by the thyroid gland. The presence of adequate circulating T4 and T3 feeds back at the level of both the hypothalamus and pituitary, decreasing TRH and TSH production (Figure 2). When circulating T4 levels decrease, the pituitary gland increases its secretion of TSH, resulting in increased iodine trapping, as well as increased production and release of both T3 and T4. Iodine deficiency results in inadequate production of T4. In response to decreased blood T4 concentrations, the pituitary gland increases its output of TSH. Persistently elevated TSH levels may lead to hypertrophy (enlargement) of the thyroid gland, also known as goiter (see Deficiency) (3).

Figure 2. The Hypothalamic-Pituitary-Thyroid Axis. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH). TSH stimulates iodine trapping and thyroid hormone synthesis by the thyroid gland and the release of T3 (triiodothyronine) and T4 (thyroxine) into the circulation. When dietary iodine intake is sufficient, the presence of adequate serum T4 and T3 concentrations feeds back at the level of both the hypothalamus and pituitary gland, decreasing TRH and TSH production. When circulating T4 concentrations decrease, the pituitary gland increases its secretion of TSH, stimulating iodine trapping and production and release of both T3 and T4. In the case of iodine deficiency, persistently elevated TSH levels may lead to hypertrophy of the thyroid gland, also known as goiter.

Deficiency

The thyroid gland of a healthy adult concentrates 70-80% of a total body iodine content of 15-20 mg and utilizes about 80 μg of iodine daily to synthesize thyroid hormones. In contrast, chronic iodine deficiency can result in a dramatic reduction of the iodine content in the thyroid well below 1 mg (1). Iodine deficiency is recognized as the most common cause of preventable brain damage in the world. The spectrum of iodine deficiency disorders (IDD) includes mental retardation, hypothyroidism, goiter, and varying degrees of other growth and developmental abnormalities (4). The World Health Organization (WHO) estimated that over 30% of the world’s population (2 billion people) have insufficient iodine intake as measured by median urinary iodine concentrations below 100 μg/L (5). Moreover, about one-third of school-age children (6-12 years old) worldwide (241 million children in 2011) have insufficient iodine intake (6, 7). Major international efforts have produced dramatic improvements in the correction of iodine deficiency in the 1990s, mainly through the use of iodized salt in iodine-deficient countries (4). Although about 70% of households in the world now have access to iodized salt (8), mild-to-moderate iodine deficiency remains a public health concern in at least 30 countries; there are no iodine excretion data available for 42 other countries, including Israel, Syria, and Sierra Leone (7). For more information on the international effort to eradicate iodine deficiency, visit the websites of the Iodine Global Network (formerly the International Council for the Control of Iodine Deficiency Disorders) and the WHO.

Biomarkers of iodine status

More than 90% of ingested iodine is excreted in the urine within 24-48 hours such that daily iodine intakes in a population can be extrapolated from measures of median spot urinary iodine concentrations (9, 10). According to WHO criteria, population iodine deficiency is defined by median urinary iodine concentrations lower than 150 micrograms (μg)/L for pregnant women and 100 μg/L for all other groups (Table 1). Adequate intakes correspond to median urinary iodine concentrations of 100-199 μg/L in school-age children and 150-249 μg/L in pregnant women (Table 1). While median urinary iodine concentration is a population indicator of recent dietary iodine intake, multiple collections of 24-hour urinary iodine are preferable to estimate intake in individuals (9-11).

Table 1. WHO Criteria for Assessment of Iodine Nutrition through Population-based Median Urinary Iodine Concentrations (4)
Population Group Median/Range of Urinary Iodine Concentrations (μg/L) Iodine Intake
Children (<2 years) <100 Insufficient
≥100 Adequate
Children (≥6 years), adolescents, and adults* <100 Insufficient
100-199 Adequate
200-299 More than adequate
>300 Excessive
Pregnant women <150 Insufficient
150-249 Adequate
250-499 More than adequate
≥500 Excessive
Breast-feeding women# <100 Insufficient
≥100 Adequate

*Excludes pregnant or lactating women.
#Given that iodine requirements are increased in breast-feeding women (see The RDA), the numbers for median urinary excretion concentrations are lower than one would expect because iodine is also excreted in breast milk.

In many countries, serum TSH concentration is used in the screening for congenital hypothyroidism in newborns. Newborn TSH can be used as an indicator of population iodine status. Yet, in older children and adults, serum TSH is not a sensitive indicator of iodine status as concentrations are usually maintained within a normal range despite frank iodine deficiency (12). Serum thyroglobulin concentration in school-age children is a sensitive marker of iodine status in populations (13). In areas of endemic goiter, changes in thyroid size reflect long-term iodine nutrition (months to years). Assessment of the goiter rate in a population is used to define the severity of iodine deficiency, as well as to monitor the long-term impact of sustained salt iodization programs (4, 10). Finally, serum thyroid hormone concentrations do not adequately reflect iodine nutrition in populations (1).

Iodine deficiency disorders

All the adverse effects of iodine deficiency in animals and humans are collectively termed iodine deficiency disorders (reviewed in 1). Thyroid enlargement, or goiter, is one of the earliest and most visible signs of iodine deficiency. It is a physiologic adaptation of the thyroid gland in response to persistent stimulation by TSH (see Function). In mild iodine deficiency, thyroid enlargement may be enough to maximize the uptake of available iodine and provide the body with sufficient thyroid hormones. Yet, large goiters can obstruct the trachea and esophagus and damage the recurrent laryngeal nerves.

More severe cases of iodine deficiency result in impaired thyroid hormone synthesis known as hypothyroidism. Adequate iodine intake will generally reduce the size of goiters, but the reversibility of the effects of hypothyroidism depends on an individual's life stage. Iodine deficiency-induced hypothyroidism has adverse effects in all stages of development but is most damaging to the developing brain. In addition to regulating many aspects of growth and development, thyroid hormones are important for the migration, proliferation, and differentiation of specific neuronal populations, the overall architecture of the brain’s cortex, the formation of axonal connections, and the myelination of the central nervous system, which occurs both before and shortly after birth (reviewed in 14).

The effects of iodine deficiency at different life stages are discussed below.

Pregnancy and lactation

Daily iodine requirements are significantly increased in pregnant and breast-feeding women because of (1) the increased thyroid hormone production and transfer to the fetus in early pregnancy before the fetal thyroid gland becomes functional, (2) iodine transfer to the fetus during late gestation, (3) increased urinary iodine excretion, and (4) iodine transfer to the infant via breast milk (see also The RDA) (12, 15).

During pregnancy, the size of the thyroid gland is increased by 10% in women residing in iodine-sufficient regions and increased by 20%-40% in those living in iodine-deficient regions (16). Iodine deficiency during pregnancy can result in hypothyroidism in women. Maternal hypothyroidism has been associated with increased risk for preeclampsia, miscarriage, stillbirth, preterm birth, and low-birth-weight infants (reviewed in 16). In addition, severe iodine deficiency during pregnancy may result in congenital hypothyroidism and neurocognitive deficits in the offspring (see Prenatal development) (12).

Iodine-deficient women who are breast-feeding may not be able to provide sufficient iodine to their infants who are particularly vulnerable to the effects of iodine deficiency (see Newborns and infants) (17). A daily prenatal supplement of 150 μg of iodine, as recommended by the American Thyroid Association (ATA) (16), will help to ensure that US pregnant and breast-feeding women consume sufficient iodine during these critical periods. In iodine-deficient areas where iodized salt is not available, the Iodine Global Network (IGN; formerly the International Council for the Control of Iodine Deficiency Disorders), the World Health Organization (WHO), and UNICEF recommend that lactating women receive a single annual dose of 400 mg of iodine (or 250 μg/day) and exclusively breast-feed for at least six months. When breast-feeding is not possible, direct supplementation of the infant (<2 years old) with a single annual dose of 200 mg of iodine (or 90 μg/day) is advised (4). A randomized and placebo-controlled trial recently demonstrated that maternal supplementation (with a single 400-mg dose of iodine) improved the iodine status of breast-fed infants more efficiently than direct infant supplementation (with a single 100 mg-dose of iodine) for a period of at least six months (18). Yet, supplementation of lactating women failed to increase maternal urinary iodine concentrations above 100 μg/L, suggesting that supplemented mothers remained deficient in iodine (18).

Prenatal development

Fetal iodine deficiency is caused by iodine deficiency in the mother (see Pregnancy and lactation). During pregnancy, before the fetal thyroid gland becomes functional at 16-20 weeks’ gestation, maternal thyroxine (T4) crosses the placenta to promote normal embryonic and fetal development. Hence, maternal iodine deficiency and hypothyroidism can result in adverse pregnancy complications, including fetal loss, placental abruption, preeclampsia, preterm delivery, and congenital hypothyroidism in the offspring (16). The effects of maternal hypothyroidism on the offspring depend on the timing and severity of in utero iodine deficiency. A severe form of congenital hypothyroidism may lead to cretinism, a condition associated with irreversible mental retardation. The clinical picture of neurological cretinism in the offspring includes severe mental and physical retardation, deafness, mutism, and motor spasticity.

A myxedematous form of cretinism has been associated with coexisting iodine and selenium deficiency in central Africa (see Nutrient interactions) and is characterized by a less severe degree of mental retardation than in neurological cretinism. Yet, affected individuals exhibit all the features of severe hypothyroidism, including severe growth retardation and delayed sexual maturation (12). Two longitudinal cohort studies (one in the UK and one in Australia) recently observed that even mild-to-moderate iodine deficiency during pregnancy was associated with reduced scores of IQ and various measures of literacy performance in children 8 to 9 years of age (19, 20)

Newborns and infants (up to one year of age)

Infant mortality is higher in areas of severe iodine deficiency than in iodine-replete regions, and several studies have demonstrated an increase in childhood survival upon correction of the iodine deficiency (8, 21, 22). Infancy is a period of rapid brain growth and development. Sufficient thyroid hormone, which depends on adequate iodine intake, is essential for normal brain development. Even in the absence of congenital hypothyroidism, iodine deficiency during infancy may result in abnormal brain development and, consequently, impaired intellectual development (23, 24).

Children and adolescents

Iodine deficiency in children and adolescents is often associated with goiter. The incidence of goiter peaks in adolescence and is more common in girls than boys. School-age children in iodine-deficient areas show poorer school performance, lower IQs, and a higher incidence of learning disabilities than matched groups from iodine-sufficient areas. Three meta-analyses of mainly cross-sectional studies concluded that chronic iodine deficiency was associated with reduced mean IQ scores by 7-13.5 points in participants (primarily children) (25-27). However, these observational studies did not distinguish between iodine deficiency during pregnancy and during childhood, and such observational studies may be confounded by social, economic, and educational factors that influence child development.

Adults

Inadequate iodine intake may also result in goiter and hypothyroidism in adults. Although the effects of hypothyroidism are more subtle in the brains of adults than children, research suggests that hypothyroidism results in poor social and economic achievements due to low educability, apathy, and reduced work productivity (28). Other symptoms of hypothyroidism in adults include fatigue, weight gain, cold intolerance, and constipation.

Finally, because iodine deficiency induces an increase in the iodine trapping capacity of the thyroid, iodine-deficient individuals of all ages are more susceptible to radiation-induced thyroid cancer (see Disease Prevention), as well as to iodine-induced hyperthyroidism after an increase in iodine intakes (see Safety) (2).

Individuals and populations at risk of iodine deficiency

While the risk of iodine deficiency for populations living in iodine-deficient areas without adequate iodine fortification programs is well recognized, concerns have been raised that certain subpopulations in countries considered iodine-sufficient may not consume adequate iodine (7, 29). The greater use of methods assessing iodine status (see Biomarkers of iodine status) has shown that iodine deficiency also occurs in areas where the prevalence of goiter is low, in coastal areas, in highly developed countries, and in regions where iodine deficiency was previously eliminated (4).

The US is currently considered to be iodine-sufficient. Yet, in recent years, dietary intakes of iodine in the US population have decreased. Data from the latest US National Health and Nutrition Examination Survey (NHANES 2009-2010) indicated that the median urinary iodine concentration for the general population was 144 μg/L compared to 164 μg/L reported in previous assessments (NHANES 2005-2006 and 2007-2008) (30, 31). In addition to regional differences across the US, ethnic variations have been found. In all age groups, median urinary iodine concentrations were shown to be lower in African Americans than in Hispanics and Caucasians.

In addition, median urinary iodine concentrations in nonpregnant women of childbearing age and pregnant women indicate that mild iodine deficiency has re-emerged in the US in recent years (31).

Nonpregnant women

Data from US NHANES 2007-2010 indicated that 37.3% of nonpregnant women (ages 15-44 years) had urinary iodine concentrations lower than 100 μg/L, reflecting potentially insufficient iodine intakes (see Biomarkers of iodine status) (31). Only one-fifth of nonpregnant women reported using iodine-containing supplements in an earlier NHANES (2001-2006) (32). Yet, adequate intakes of iodine in women of childbearing age (150 μg/day; see The RDA) are essential for optimum stores of iodine, especially if they are considering pregnancy. Some experts suggested a daily consumption of 250 μg of iodine before conception to ensure adequate thyroid hormone production and iodine supply to the embryo and fetus during pregnancy (see Pregnancy and lactation) (12).

Pregnant women

There are no statistics on the global burden of iodine deficiency in pregnant women, but national and regional data suggest that this group is especially vulnerable. Given the increased iodine requirements during pregnancy, the median urinary iodine concentration should be at least of 150 μg/L (see Biomarkers of iodine status). Pooled data from NHANES 2005-2010 reported that US pregnant women had a median urinary iodine concentration of 129 μg/L, and the lowest median concentration (109 μg/L) was observed during the first trimester of gestation, when the embryo/fetus relies exclusively on maternal thyroid hormones (31).

Breast-feeding women

While data regarding the iodine status of breast-feeding women in the US are limited, dietary intakes that were inadequate during pregnancy are likely to be insufficient in a significant fraction of breast-feeding women (33, 34). A systematic review of the literature recently reported suboptimal dietary iodine intakes in breast-feeding women in some countries with a mandatory fortification program, including Denmark, Australia, and India (35). The American Thyroid Association (ATA) recommends that all North American women who are pregnant or breast-feeding supplement their dietary iodine intake with 150 μg/day of iodine (36).

Breast-fed and weaning infants

The body of a healthy newborn contains only about 300 μg of iodine, which makes newborns extremely vulnerable to iodine deficiency (28), and breast-fed infants are entirely reliant on maternal iodine intakes for thyroid hormone synthesis. Even in areas covered by a salt iodization program, weaning infants are at high risk of iodine deficiency, especially if they are not receiving iodine-containing infant formula (17).

Individuals consuming special diets

Diets that exclude iodized salt, fish, and seaweed have been found to contain very little iodine (9). Individuals consuming branded weight-loss foods may also be at risk of inadequate intakes (37). A small US cross-sectional study in 78 vegetarians and 63 vegans reported median urinary iodine concentrations of 147 μg/L and 78.5 μg/L, respectively, suggesting inadequate iodine intakes among vegans (38). Two cases of goiter and/or hypothyroidism have also been recently reported in children following restrictive diets to control esophageal inflammation (eosinophilic esophagitis) (39) or allergies (40).

Patients requiring parenteral nutrition

Although iodine is usually not added to parenteral nutrition (PN) solutions, topical iodine-containing disinfectants and other adventitious sources provide substantial amounts of iodine to some PN patients such that the occurrence of iodine deficiency is unlikely. Yet, deficiency might occur, especially in preterm infants with limited body stores, if chlorhexidine-based antiseptics replace iodinated antiseptics (28, 41).

Nutrient interactions

Concurrent deficiencies in selenium, iron, or vitamin A may exacerbate the effects of iodine deficiency (reviewed in 42).

Selenium

While iodine is an essential component of thyroid hormones, the selenium-containing iodothyronine deiodinases (DIOs) are enzymes (or selenoenzymes) required for the conversion of T4 to the biologically active thyroid hormone, T3 (see the article on Selenium). DIO1 activity may also be involved in regulating iodine homeostasis (43). In addition, glutathione peroxidases are selenoenzymes that protect the thyroid gland from hydrogen peroxide-induced damage during thyroid hormone synthesis (44). A randomized, placebo-controlled study in 151 pregnant women at risk of developing autoimmune thyroid disease found that selenium supplementation (200 μg/day in the form of selenomethionine) at 12 weeks of gestation until 12 months’ postpartum reduced the risk of thyroid dysfunction and permanent hypothyroidism (45). However, another trial (the Selenium in Pregnancy Intervention Trial) found no benefit of selenium supplementation (60 μg/day from 12-14 weeks of gestation to delivery) over placebo on circulating autoantibody concentrations in pregnant women mildly deficient in iodine (46).

The epidemiology of coexisting iodine and selenium deficiencies in central Africa has been linked to the prevalence of myxedematous cretinism, a severe form of congenital hypothyroidism accompanied by mental and physical retardation. Selenium deficiency may be only one of several undetermined factors that might exacerbate the detrimental effects of iodine deficiency (42). Besides, results from randomized controlled intervention trials have shown that correcting only the selenium deficiency may have a deleterious effect on thyroid hormone metabolism in school-age children with co-existing selenium and iodine deficiency (47, 48). Finally, selenium deficiency in rodents was found to have little impact on DIO activities as it appears that selenium is being supplied in priority for adequate synthesis of DIOs at the expense of other selenoenzymes (44)

Iron

Severe iron-deficiency anemia can impair thyroid metabolism in the following ways: (1) by altering the TSH response of the pituitary gland; (2) by reducing the activity of thyroid peroxidase that catalyzes the iodination of thyroglobulin for the production of thyroid hormones; and (3) in the liver by limiting the conversion of T4 to T3, increasing T3 turnover, and decreasing T3 binding to nuclear receptors (49). It is estimated that goiter and iron-deficiency anemia coexist in up to 25% of school-age children in west and north Africa (42). A randomized controlled study in iron-deficient children with goiter showed a greater reduction in thyroid size following the consumption of iodized salt together with 60 mg/day of iron four times per week compared to placebo (50). Additional interventions have confirmed that correcting iron-deficiency anemia improved the efficacy of iodine supplementation to mitigate thyroid disorders (reviewed in 42, 49).

Vitamin A

In north and west Africa, vitamin A deficiency and iodine deficiency-induced goiter may coexist in up to 50% of children. Vitamin A status, like other nutritional factors, appears to influence the response to iodine prophylaxis in iodine-deficient populations (51). Vitamin A deficiency in animal models was found to interfere with the pituitary-thyroid axis by (1) increasing the synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary gland, (2) increasing the size of the thyroid gland, (3) reducing iodine uptake by the thyroid gland and impairing the synthesis and iodination of thyroglobulin, and (4) increasing circulating concentrations of thyroid hormones (reviewed in 52). A cross-sectional study of 138 children with concurrent vitamin A and iodine deficiencies found that the severity of vitamin A deficiency was associated with higher risk of goiter and higher concentrations of circulating TSH and thyroid hormones (51). These children received iodine-enriched salt together with vitamin A (200,000 IU at baseline and at 5 months) or a placebo in a randomized, double-blind, 10-month trial. Vitamin A supplementation significantly decreased TSH concentration and thyroid volume compared to placebo (51). In another trial, vitamin A supplementation alone (without iodine) to iodine-deficient children reduced the volume of the thyroid gland, as well as TSH and thyroglobulin concentrations (53). Yet, supplemental vitamin A had no additional effect on thyroid function/hormone metabolism when children were also given iodized oil.

Goitrogens

Some foods contain substances that interfere with iodine utilization or thyroid hormone production; these substances are called goitrogens. The occurrence of goiter in the Democratic Republic of Congo has been related to the consumption of cassava, which contains linamarin, a compound that is metabolized to thiocyanate and blocks thyroidal uptake of iodine (1). In iodine-deficient populations, tobacco smoking has been associated with an increased risk for goiter (54, 55). Cyanide in tobacco smoke is converted to thiocyanate in the liver, placing smokers with low iodine intake at risk of developing a goiter. Moreover, thiocyanate affects iodine transport into the lactating mammary gland, leading to low iodine concentrations in breast milk and impaired iodine supply to the neonates/infants of smoking mothers (2). Some species of millet, sweet potatoes, beans, and cruciferous vegetables (e.g., cabbage, broccoli, cauliflower, and Brussels sprouts) also contain goitrogens (1). Further, the soybean isoflavones, genistein and daidzein, have been found to inhibit thyroid hormone synthesis (56). Most of these goitrogens are not of clinical importance unless they are consumed in large amounts or there is coexisting iodine deficiency. Industrial pollutants, such as perchlorate (see Safety), resorcinol, and phthalic acid, may also be goitrogenic (1, 57).

The Recommended Dietary Allowance (RDA)

The RDA for iodine was reevaluated by the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) in 2001 (Table 2). The recommended amounts were calculated using several methods, including the measurement of iodine uptake in the thyroid glands of individuals with normal thyroid function (9). Similar recommendations have been made by several organizations, including the American Thyroid Association (ATA) (16, 58), the World Health Organization (WHO), the Iodine Global Network (IGN; formerly the International Council for the Control of Iodine Deficiency Disorders), and the United Nations Children’s Fund (UNICEF) (4). Of note, the WHO, IGN, and UNICEF recommend daily intakes of 250 μg of iodine for both pregnant and breast-feeding women (4).

Table 2. Recommended Dietary Allowance (RDA) for Iodine
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months 110 (AI) 110 (AI)
Infants  7-12 months   130 (AI)   130 (AI) 
Children  1-3 years  90  90 
Children 4-8 years  90  90 
Children  9-13 years  120  120 
Adolescents  14-18 years  150  150 
Adults  19 years and older 150  150 
Pregnancy  all ages  220
Breast-feeding  all ages  290

Disease Prevention

Radiation-induced thyroid cancer

Radioactive iodine, especially iodine 131 (131I), may be released into the environment as a result of nuclear reactor accidents, such as the 1986 Chernobyl nuclear accident in Ukraine and the 2011 Fukushima Daiichi nuclear accident in Japan. Thyroid accumulation of radioactive iodine increases the risk of developing thyroid cancer, especially in children (59). The increased iodine trapping activity of the thyroid gland in iodine deficiency results in increased thyroid accumulation of radioactive iodine (131I). Thus, iodine-deficient individuals are at increased risk of developing radiation-induced thyroid cancer because they will accumulate greater amounts of radioactive iodine. Potassium iodide administered in pharmacologic doses (up to 130 mg for adults) within 48 hours before or eight hours after radiation exposure from a nuclear reactor accident can significantly reduce thyroid uptake of 131I and decrease the risk of radiation-induced thyroid cancer (60). The prompt and widespread use of potassium iodide prophylaxis in Poland after the 1986 Chernobyl nuclear reactor accident may explain the lack of a significant increase in childhood thyroid cancer compared to fallout areas where potassium iodide prophylaxis was not widely used (61). In the US, the Nuclear Regulatory Commission (NRC) requires that consideration be given to potassium iodide as a protective measure for the general public in the case of a major release of radioactivity from a nuclear power plant (62). See also the US FDA’s Potassium Iodide Information.

Disease Treatment

Fibrocystic breast changes

Fibrocystic breast changes constitute a benign (non-cancerous) condition of the breasts, characterized by lumpiness and discomfort in one or both breasts. Cyst formation and fibrous changes in the appearance of breast tissue occur in at least 50% of premenopausal women and are not usually associated with an increased risk of breast cancer (63). The cause of fibrocystic changes is not known, but variations in hormonal stimulation during menstrual cycles may trigger changes in breast tissue (63).

A few observational studies also suggested an association between benign breast diseases (including but not limited to fibrocystic changes) and thyroid disorders. Recently, a small case-control study (166 cases vs. 72 controls) showed that the frequency of benign breast diseases was greater in women with nodular goiter (54.9%) or Hashimoto thyroiditis (47.4%) than in euthyroid controls (29.2%) (64). Conversely, the prevalence of anti-thyroid autoimmunity and hypothyroidism was found to be significantly higher in women with benign breast diseases compared to controls (65, 66). Interestingly, correcting hypothyroidism with supplemental T4 was found to improve some of the benign breast disease symptoms, including breast pain (mastalgia) and nipple discharge (65).

In estrogen-treated rats, iodine deficiency leads to changes similar to those seen in fibrocystic breasts, while iodine repletion reverses those changes (67). An uncontrolled study of 233 women with fibrocystic changes found that treatment with aqueous molecular iodine (I2) at a dose of 0.08 mg of I2/kg of body weight daily over 6 to 18 months was associated with improvement in pain and other symptoms in over 70% of participants (68). About 10% of the study participants reported side effects that were described by the investigators as minor. A double-blind, placebo-controlled trial of aqueous molecular iodine (0.07-0.09 mg of I2/kg of body weight daily for six months) in 56 women with fibrocystic changes found that 65% of the women taking molecular iodine reported improvement compared to 33% of those taking the placebo (68). A double-blind, placebo-controlled trial in 87 women with documented breast pain reported that molecular iodine (1.5, 3, or 6 mg/day) for six months improved overall pain (69). In this study, 38.5% of the women receiving 1.5 mg/day, 37.9% of those receiving 3 mg/day, and 51.7% of those receiving 6 mg/day reported at least a 50% reduction in self-assessed breast pain compared to 8.3% in the placebo group.

Large-scale, controlled clinical trials are needed to determine the therapeutic value of molecular iodine in fibrocystic breasts. Besides, the doses of iodine used in these studies (1.5 to 6 mg/day for a 60 kg person) are higher than the tolerable upper intake level (UL) recommended by the Food and Nutrition Board of the Institute of Medicine and should only be used under medical supervision (see Safety).

Sources

Food sources

Data from the ongoing US Total Diet Study, which monitors the levels of some contaminants and nutrients in food products, indicates that dietary iodine intakes in adults range between 138 and 268 micrograms (μg)/day. Considerably higher average intakes (304-353 μg/day of iodine) were reported for boys 14 to 16 years of age (70).

Seafood is rich in iodine because marine animals can concentrate the iodine from seawater. Certain types of edible seaweed (e.g., wakame) are also very rich in iodine (71). The iodine content of food that is grown or raised on a particular soil depends on the iodine content of this soil. In the US, dairy products contribute up to 90% of total estimated iodine intakes in infants, at least 70% in children (ages, 2-10 years), 53%-63% in adolescents (ages, 14-16 years), and about 50% in adults (70). In the UK and northern Europe, iodine levels in dairy products tend to be lower in summer when cattle are allowed to graze in pastures with low soil iodine content (9).

Other good sources of dietary iodine include eggs, fruit, grain products, and poultry (70). Processed foods can contribute to iodine intake if iodized salt or food additives, such as calcium iodate and potassium iodate, are added during production. Yet, in the US, virtually no iodized salt is used in the manufacturing of processed food and fast food products, and the food industry is not required to list the iodine content on food packaging (72). Table 3 lists the iodine content of some iodine-rich foods in micrograms (μg). Because the iodine content of foods can vary considerably, these values should be considered approximate (73).

Table 3. Some Food Sources of Iodine
Food Serving Iodine (μg)
Salt (iodized) 1 gram 77
Cod 3 ounces* 99
Shrimp 3 ounces 35
Fish sticks 2 fish sticks 35
Tuna, canned in oil 3 ounces (½ can) 17
Milk (cow's) 1 cup (8 fluid ounces) 99
Egg, boiled 1 large 12
Navy beans, cooked ½ cup 32
Potato with peel, baked 1 medium 60
Turkey breast, baked 3 ounces 34
Seaweed ¼ ounce, dried Variable; may be greater than 4,500 μg (4.5 mg)
*A three-ounce serving of meat is about the size of a deck of cards.

Supplements

Over-the-counter iodine supplements

Potassium iodide is available as a nutritional supplement, typically in combination products, such as multivitamin/mineral supplements. Iodine makes up approximately 77% of the total weight of potassium iodide (56). A multivitamin/mineral supplement that contains 100% of the daily value (DV) for iodine provides 150 μg of iodine. Although most people in the US consume sufficient iodine in their diets (see Sources), an additional 150 μg/day is unlikely to result in excessive iodine intake. The American Thyroid Association (ATA) recommends prenatal supplementation with 150 μg/day of iodine and advises against the ingestion of ≥500 μg/day of iodine from iodine, potassium iodine, and kelp supplements for children and adults, and during pregnancy and lactation (see also Safety) (36, 74).

Iodine fortification programs

The fortification of salt with iodine is a feasible and inexpensive method to eliminate iodine deficiency, and salt iodization programs have been implemented in almost all countries. In North America, salt fortification with iodine is mandated in Canada and some parts of Mexico, but only voluntary in the US such that only 52% of US table salt is iodized and only one-fifth of the total salt consumed in the US is iodized (72, 75). Potassium iodide (KI), cuprous iodide (CuI), and potassium iodate (KIO3) are used to iodize salt. The US Food and Drug Administration (FDA) recommends between 46 and 76 μg of iodine per gram of salt in iodized salt. However, the recent analysis of 88 US iodized food-grade salt samples revealed that the iodine content was below the recommended range in 52% of the samples and above the range in 7% of the samples (76).

In other countries, salt commonly contains 20-50 μg of iodine per gram of salt, depending on local regulations (76). In countries like Denmark (77), Australia (78, 79), and New Zealand (80), the use of iodized salt in the bread-making process is mandated. Additional approaches have been explored, including sugar fortification (81), egg fortification (82), use of iodized salt in the preparation of fermented fish and fish sauce (83), and use of iodine-rich crop fertilizers (84). In addition, fortification of livestock feeds with iodine and the use of iodophors for sanitation during milking contribute to increasing iodine content in dairy products (85). Finally, annual doses of iodized vegetable oil are administered orally or intramuscularly to individuals in iodine-deficient populations who do not have access to iodized salt (4, 56).

Safety

Acute toxicity

Acute iodine poisoning is rare and usually occurs only with doses of many grams. Symptoms of acute iodine poisoning include burning of the mouth, throat, and stomach, fever, nausea, vomiting, diarrhea, a weak pulse, cyanosis, and coma (1).

Excessive iodine intakes

Risk of iodine-induced hyperthyroidism in iodine-deficient individuals

Iodine supplementation programs in iodine-deficient populations have been associated with an increased incidence of iodine-induced hyperthyroidism (IIH), especially in older people with multi-nodular goiter (86). Iodine intakes of 150-200 μg/day have been found to increase the incidence of IIH in iodine-deficient populations. Iodine deficiency increases the risk of developing autonomous thyroid nodules that are unresponsive to TSH control (see Function). These autonomous nodules may then overproduce thyroid hormones in response to sudden iodine supply. IIH symptoms include weight loss, tachycardia (high pulse rate), muscle weakness, and skin warmth. IIH can be dangerous in individuals with underlying heart disease. Yet, because the primary cause of nodular goiter and IIH is chronic iodine deficiency, the benefit of iodization programs largely outweighs the risk of IIH in iodine-deficient populations (1).

Risk of hypothyroidism in iodine-sufficient individuals

In iodine-sufficient individuals, excess iodine intake is most commonly associated with elevated blood concentrations of thyroid stimulating hormone (TSH) that inhibit thyroid hormone production, leading to hypothyroidism and goiter. A slightly elevated serum TSH concentration without a decrease in serum T4 or T3 is the earliest sign of abnormal thyroid function when iodine intake is excessive. In iodine-sufficient adults, elevated serum TSH has been found at chronic iodine intakes of ≥750 μg/day in children and ≥1,700 μg/day in adults. Because various edible seaweed species substantially contribute to traditional Asian meals, average Japanese dietary intakes are estimated to range between 1,000 and 3,000 μg of iodine/day (71). Iodine-induced goiter and hypothyroidism are not uncommon in Japan and can be reversed by restricting seaweed intake (71). Prolonged intakes of more than 18,000 μg/day (18 mg/day) increase the incidence of goiter in adults. In newborns, iodine-induced goiter and hypothyroidism can be due to either high maternal intakes or high exposure to iodized antiseptics (87). In order to minimize the risk of adverse health effects, the Food and Nutrition Board of the US Institute of Medicine set a tolerable upper intake level (UL) for iodine that is likely to be safe in almost all individuals. The UL values for iodine are listed in Table 4 by age group; the UL does not apply to individuals who are being treated with iodine under medical supervision (74).

Table 4. Tolerable Upper Intake Level (UL) for Iodine
Age Group UL (μg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 200
Children 4-8 years   300
Children 9-13 years   600
Adolescents 14-18 years 900
Adults 19 years and older 1,100
*Source of intake should be from food and formula only.
Individuals with increased sensitivity to excess iodine intake

Individuals with iodine deficiency and those with preexisting thyroid disease, including nodular goiter, autoimmune Hashimoto thyroiditis, Graves disease, and a history of partial thyroidectomy, may be sensitive to iodine intake levels considered safe for the general population and may not be protected by the UL for iodine (9). Infants, the elderly, and pregnant and lactating women may also be more susceptible to excess iodine (see Supplements) (74).

Do elevated and/or insufficient iodine intakes increase the risk of thyroid cancer?

Over the past decades, the incidence of thyroid cancer has increased worldwide. In the US, the incidence of thyroid cancer — representing 4% of all newly diagnosed cancers — has increased from 4.9 cases per persons in 1983 to 14.7 cases per 100,000 persons in 2011, but mortality rate from thyroid cancer has remained low (about 0.5 per 100,000 persons) (88). Accounting for over 80% of all thyroid cancers, thyroid papillary cancer is less aggressive and has a better prognosis than thyroid follicular cancer or anaplastic thyroid cancer. The increasing incidence of thyroid cancer worldwide is likely due at least in part to the improved screening and diagnosis activities. However, because it has coincided with the introduction of iodine fortification programs, a possible contribution of increased iodine intakes has been hypothesized. Yet, in the US, the increasing incidence of thyroid cancers (primarily papillary cancer) over the last few decades was paralleled with a reduction in average iodine intake (89).

Ecologic studies also suggested that iodine prophylaxis in populations that were previously iodine deficient was associated with an increased incidence of the papillary rather than the follicular cancer subtype, and with a reduced incidence of the more aggressive anaplastic thyroid cancer (89). While changes in iodine intakes appear to affect the histological type of thyroid cancer, it is not yet clear whether iodine deficiency and/or iodine excess increase the risk of thyroid cancer (88).

Drug interactions

Amiodarone, a medication used to prevent abnormal heart rhythms, contains high levels of iodine and may affect thyroid function (90). Antithyroid drugs used to treat hyperthyroidism, such as propylthiouracil (PTU), methimazole, and carbimazole, may increase the risk of hypothyroidism. Additionally, the long-term use of lithium to treat mood disorders may increase the risk of hypothyroidism (91). Further, the use of pharmacologic doses of potassium iodide may decrease the anticoagulant effect of warfarin (coumarin) (92).

Contaminants

Perchlorate is an oxidizing agent found in rocket propellants, airbags, fireworks, herbicides, and fertilizer. Mainly as a result of human activity, perchlorate has been found to contaminate drinking water and many foods (57). Chronic exposure to perchlorate concentrations at levels greater than 20 μg per kg body weight (bw) per day interferes with iodine uptake by the thyroid gland and may lead to hypothyroidism (93). The US Environment Protection Agency (EPA) recommends that daily oral exposure to perchlorate should not exceed 0.7 μg/kg bw to protect the most sensitive population, i.e., the fetuses of pregnant women who might be deficient in iodine and/or hypothyroid (94). Among all age groups, children aged two years have the highest estimated perchlorate intakes per day with 0.35-0.39 μg/kg bw/day. Average estimated intakes of perchlorate in US adults range between 0.08 and 0.11 μg/kg bw/day (70).

Linus Pauling Institute Recommendation

The RDA for iodine is sufficient to ensure normal thyroid function. There is presently no evidence that iodine intakes higher than the RDA are beneficial. Most people in the US consume sufficient iodine in their diets, making supplementation unnecessary.

Pregnant and breast-feeding women

Given the importance of sufficient iodine during prenatal development and infancy, pregnant and breast-feeding women should take a supplement that provides 150 μg of iodine per day (see Deficiency).

Older adults (>50 years)

Because aging has not been associated with significant changes in the requirement for iodine, the LPI recommendation for iodine intake is not different for older adults.


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2015 by:
Elizabeth N. Pearce, M.D., M.Sc.
Associate Professor of Medicine
Boston University School of Medicine

Copyright 2001-2017  Linus Pauling Institute 


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Iron

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Summary

  • Iron is an essential component of hundreds of proteins and enzymes that support essential biological functions, such as oxygen transport, energy production, and DNA synthesis. Hemoglobin, myoglobin, cytochromes, and peroxidases require iron-containing heme as a prosthetic group for their biological activities. (More information)
  • Because the body excretes very little iron, iron metabolism is tightly regulated. In particular, the iron regulatory hormone, hepcidin, blocks dietary iron absorption, promotes cellular iron sequestration, and reduces iron bioavailability when body iron stores are sufficient to meet requirements. (More information)
  • Iron status can be assessed in healthy men and nonpregnant women using laboratory tests that measure serum ferritin (iron-storage protein), serum iron, total iron binding capacity, saturation of transferrin (the main iron carrier in blood), and soluble transferrin receptor. (More information)
  • Iron deficiency results from an inadequate supply of iron to cells following depletion of the body’s reserves. Microcytic anemia occurs when body iron stores are so low that hemoglobin synthesis and red blood cell formation are severely impaired. (More information)
  • Iron deficiency is the most common nutritional deficiency worldwide, affecting primarily children, women of childbearing age, pregnant women, frequent blood donors, and individuals with certain medical conditions. (More information)
  • Much of our iron requirement is met through recycling iron from senescent red blood cells. The recommended dietary allowance (RDA) for iron is 8 mg/day for men and postmenopausal women, 18 mg/day for premenopausal women, and 27 mg/day for pregnant women. (More information)
  • Iron deficiency with or without anemia in children has been associated with poor cognitive development, poor school achievement, and abnormal behavior patterns. Limited evidence suggests that iron supplementation has no effect on psychomotor development and cognitive function of anemic iron-deficient infants younger than three years but may improve attention and concentration in older children, adolescents, and women with anemia and/or iron deficiency. (More information)
  • Heme iron comes from hemoglobin and myoglobin in animal food sources and represents 10%-15% of total dietary iron intake of meat eaters. Yet, because it is much better absorbed than nonheme iron found in both plant and animal food sources, heme iron contributes up to 40% of total absorbed iron. (More information)
  • Toxic iron deposition in vital organs in patients affected by hereditary hemochromatosis has been associated with numerous chronic conditions, including liver cancer and type 2 diabetes mellitus. Increased heme iron intake and/or loss of iron homeostasis might also increase the risk of chronic disease in individuals free of genetic disorders. (More information)
  • Iron supplementation may cause gastrointestinal irritation, nausea, vomiting, diarrhea, or constipation, and interfere with the absorption and efficacy of certain medications, including antibiotics and drugs used to treat osteoporosis, hypothyroidism, or Parkinson’s disease symptoms. (More information)


Iron is the fourth most abundant element of Earth’s crust and one of the best studied micronutrients in nutrition science (1, 2). It is a key element in the metabolism of all living organisms. Iron exists in two biologically relevant oxidation states: the ferrous form (Fe2+) and the ferric form (Fe3+). Iron is an essential component of hundreds of proteins and enzymes supporting essential biological functions, such as oxygen transport, energy production, DNA synthesis, and cell growth and replication.

Function

Heme is an iron-containing compound found in a number of biologically important molecules (Figure 1). Some, but not all, iron-dependent proteins are heme-containing proteins (also called hemoproteins). Iron-dependent proteins that carry out a broad range of biological activities may be classified as follows (1, 3):

  • Globin-heme: nonenzymatic proteins involved in oxygen transport and storage (e.g., hemoglobin, myoglobin, neuroglobin)
  • Heme enzymes involved in electron transfer (e.g., cytochromes a, b, f; cytochrome c oxidase) and/or with oxidase activity (e.g., sulfite oxidase, cytochrome P450 oxidases, myeloperoxidase, peroxidases, catalase, endothelial nitric oxide synthase, cyclooxygenase)
  • Iron-sulfur (Fe-S) cluster proteins with oxidoreductase activities involved in energy production (e.g., succinate dehydrogenase, isocitrate dehydrogenase, NADH dehydrogenase, aconitase, xanthine oxidase, ferredoxin-1) or involved in DNA replication and repair (DNA polymerases, DNA helicases)
  • Nonheme enzymes that require iron as a cofactor for their catalytic activities (e.g., phenylalanine, tyrosine, tryptophan, and lysine hydroxylases; hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases; ribonucleotide reductase)
  • Nonheme proteins responsible for iron transport and storage (e.g., ferritin, transferrin, haptoglobin, hemopexin, lactoferrin).

Iron-containing proteins support a number of functions, some of which are listed below.

Figure 1. Structure of Heme b.

Oxygen transport and storage

Globin-hemes are heme-containing proteins that are involved in the transport and storage of oxygen and, to a lesser extent, may act as free radical scavengers (1). Hemoglobin is the primary protein found in red blood cells and represents about two-thirds of the body's iron (3). The vital role of hemoglobin in transporting oxygen from the lungs to the rest of the body is derived from its unique ability to acquire oxygen rapidly during the short time it spends in contact with the lungs and to release oxygen as needed during its circulation through the tissues. Myoglobin functions in the transport and short-term storage of oxygen in muscle cells, helping to match the supply of oxygen to the demand of working muscles (1). A third globin called neuroglobin is preferentially expressed in the central nervous system, but its function is not well understood (4).

Electron transport and energy metabolism

Cytochromes are heme-containing enzymes that have important roles in mitochondrial electron transport required for cellular energy production and thus life. Specifically, cytochromes serve as electron carriers during the synthesis of ATP, the primary energy storage compound in cells. Cytochrome P450 (CYP) is a family of enzymes involved in the metabolism of a number of important biological molecules (including organic acids; fatty acids; prostaglandins; steroids; sterols; and vitamins A, D, and K), as well as in the detoxification and metabolism of drugs and pollutants. Nonheme iron-containing enzymes in the citric acid cycle, such as NADH dehydrogenase and succinate dehydrogenase, are also critical to energy metabolism (1)

Antioxidant and beneficial pro-oxidant functions 

Catalase and some peroxidases are heme-containing enzymes that protect cells against the accumulation of hydrogen peroxide, a potentially damaging reactive oxygen species (ROS), by catalyzing a reaction that converts hydrogen peroxide to water and oxygen. As part of the immune response, some white blood cells engulf bacteria and expose them to ROS in order to kill them. The synthesis of one such ROS, hypochlorous acid, by neutrophils is catalyzed by the heme-containing enzyme myeloperoxidase (1).

In addition, in the thyroid gland, heme-containing thyroid peroxidase catalyzes the iodination of thyroglobulin for the production of thyroid hormones such that thyroid metabolism can be impaired in iron deficiency and iron-deficiency anemia (see Nutrient Interactions).

Oxygen sensing

Inadequate oxygen (hypoxia), such as that experienced by those who live at high altitudes or those with chronic lung disease, induces compensatory physiologic responses, including increased red blood cell formation (erythropoiesis), increased blood vessel growth (angiogenesis), and increased production of enzymes utilized in anaerobic metabolism. Hypoxia is also observed in pathological conditions like ischemia/stroke and inflammatory disorders. Under hypoxic conditions, transcription factors known as hypoxia-inducible factors (HIF) bind to response elements in genes that encode various proteins involved in compensatory responses to hypoxia and increase their synthesis. Iron-dependent enzymes of the dioxygenase family, HIF prolyl hydroxylases and asparaginyl hydroxylase (factor inhibiting HIF-1 [FIH-1]), have been implicated in HIF regulation. When cellular oxygen tension is adequate, newly synthesized HIF-α subunits (HIF-1α, HIF-2α, HIF-3α) are modified by HIF prolyl hydroxylases in an iron/2-oxoglutarate-dependent process that targets HIF-α for rapid degradation. FIH-1-induced asparaginyl hydroxylation of HIF-α impairs the recruitment of co-activators to HIF-α transcriptional complex and therefore prevents HIF-α transcriptional activity. When cellular oxygen tension drops below a critical threshold, prolyl hydroxylase can no longer target HIF-α for degradation, allowing HIF-α to bind to HIF-1β and form a transcription complex that enters the nucleus and binds to specific hypoxia response elements (HRE) on target genes like the erythropoietin gene (EPO) (5)

DNA replication and repair

Ribonucleotide reductases (RNRs) are iron-dependent enzymes that catalyze the synthesis of deoxyribonucleotides required for DNA replication. RNRs also facilitate DNA repair in response to DNA damage. Other enzymes essential for DNA synthesis and repair, such as DNA polymerases and DNA helicases, are Fe-S cluster proteins. Although the underlying mechanisms are still unclear, depletion of intracellular iron was found to inhibit cell cycle progression, growth, and division. Inhibition of heme synthesis also induced cell cycle arrest in breast cancer cells (6).

Iron is required for a number of additional vital functions, including growth, reproduction, healing, and immune function.

Regulation

Systemic regulation of iron homeostasis

While iron is an essential mineral, it is potentially toxic because free iron inside the cell can lead to the generation of free radicals causing oxidative stress and cellular damage. Thus, it is important for the body to systemically regulate iron homeostasis. The body tightly regulates the transport of iron throughout various body compartments, such as developing red blood cells (erythroblasts), circulating macrophages, liver cells (hepatocytes) that store iron, and other tissues (7). Intracellular iron concentrations are regulated according to the body’s iron needs (see below), but extracellular signals also regulate iron homeostasis in the body through the action of hepcidin.

Hepcidin, a peptide hormone primarily synthesized by liver cells, is the key regulator of systemic iron homeostasis. Hepcidin can induce the internalization and degradation of the iron-efflux protein, ferroportin-1; ferroportin-1 regulates the release of iron from certain cells, such as enterocytes, hepatocytes, and iron-recycling macrophages, into plasma (8). When body iron concentration is low and in situations of iron-deficiency anemia, hepcidin expression is minimal, allowing for iron absorption from the diet and iron mobilization from body stores. In contrast, when there are sufficient iron stores or in the case of iron overload, hepcidin inhibits dietary iron absorption, promotes cellular iron sequestration, and reduces iron bioavailability. Hepcidin expression is up-regulated in conditions of inflammation and endoplasmic reticulum stress and down-regulated in hypoxia (9). In Type 2B hemochromatosis, deficiency in hepcidin due to mutations in the hepcidin gene, HAMP, causes abnormal iron accumulation in tissues (see Iron Overload). Of note, hepcidin is also thought to have a major antimicrobial role in the innate immune response by limiting iron availability to invading microorganisms (see Iron withholding defense during infection) (10).

Regulation of intracellular iron

Iron-responsive elements (IREs) are short sequences of nucleotides found in the messenger RNAs (mRNAs) that code for key proteins in the regulation of iron storage, transport, and utilization. Iron regulatory proteins (IRPs: IRP-1, IRP-2) can bind to IREs and control mRNA stability and translation, thereby regulating the synthesis of specific proteins, such as ferritin (iron storage protein) and transferrin receptor-1 (TfR; controls cellular iron uptake) (1, 2).

When the iron supply is low, iron is not available for storage or release into plasma. Less iron binds to IRPs, allowing the binding of IRPs to IREs. The binding of IRPs to IREs located in the 5’end of mRNAs coding for ferritin and ferroportin-1 (iron efflux protein) inhibits mRNA translation and protein synthesis. Translation of mRNA that codes for the key regulatory enzyme of heme synthesis in immature red blood cells is also reduced to conserve iron. In contrast, IRP binding to IREs in the 3’ end of mRNAs that code for TfR and divalent metal transporter-1 (DMT1) stimulates the synthesis of iron transporters, thereby increasing iron uptake into cells (1, 2).

When the iron supply is high, more iron binds to IRPs, thereby preventing the binding of IRPs to IREs on mRNAs. This allows for an increased synthesis of proteins involved in iron storage (ferritin) and efflux (ferroportin-1) and a decreased synthesis of iron transporters (TfR and DMT1) such that iron uptake is limited (2). In the brain, IRPs are also prevented from binding to the 5’end of amyloid precursor protein (APP) mRNA, allowing for APP expression. APP stimulates iron efflux from neurons through stabilizing ferroportin-1. In Parkinson’s disease (PD), APP expression is inappropriately suppressed, leading to iron accumulation in dopaminergic neurons (11, 12).

Iron withholding defense during infection

Iron is required by most infectious agents to grow and spread, as well as by the infected host in order to mount an effective immune response. Sufficient iron is critical for the differentiation and proliferation of T lymphocytes and the generation of reactive oxygen species (ROS) required for killing pathogens (13). During infection and inflammation, hepcidin synthesis is up-regulated, serum iron concentrations decrease, and concentrations of ferritin (the iron storage protein) increase, supporting the idea that sequestering iron from pathogens is an important host defense mechanism (2).

Recycling of iron

Total body content of iron in adults is estimated to be 2.3 g in women and 3.8 g in men (2). The body excretes very little iron; basal losses, menstrual blood loss, and the need of iron for the synthesis of new tissue are compensated by the daily absorption of a small proportion of dietary iron (1 to 2 mg/day). Body iron is primarily found in red blood cells, which contain 3.5 mg of iron per g of hemoglobin. Senescent red blood cells are engulfed by macrophages in the spleen, and about 20 mg of iron can be recovered daily from heme recycling. The released iron is either deposited to the ferritin of spleen macrophages or exported by ferroportin-1 (iron efflux protein) to transferrin (the main iron carrier in blood) that delivers iron to other tissues. Iron recycling is very efficient, with about 35 mg being recycled daily (1).

Assessment of iron status

Measurements of iron stores, circulating iron, and hematological parameters may be used to assess the iron status of healthy people in the absence of inflammatory disorders, parasitic infection, and obesity. Commonly used iron status biomarkers include serum ferritin (iron-storage protein), serum iron, total iron binding capacity (TIBC), and saturation of transferrin (the main iron carrier in blood; TSAT). Soluble transferrin receptor (sTfR) is also an indicator of iron status when iron stores are depleted. In iron deficiency and iron-deficiency anemia, the abundance of cell surface-bound transferrin receptors that bind diferric transferrin is increased in order to maximize the uptake of available iron. Therefore, the concentration of sTfR generated by the cleavage of cell-bound transferrin receptors is increased in iron deficiency. Hematological markers, including hemoglobin concentration, mean corpuscular hemoglobin concentration, mean corpuscular volume of red blood cells, and reticulocyte hemoglobin content can help detect abnormality if anemia is present (9, 14).

Of note, serum ferritin is an acute-phase reactant protein that is up-regulated by inflammation. Importantly, serum hepcidin concentration is also increased by inflammation to limit iron availability to pathogens. Therefore, it is important to include inflammation markers (e.g., C-reactive protein, fibrinogen) when assessing iron status to rule out inflammation (14).

Nutrient Interactions

Vitamin A

Vitamin A deficiency often coexists with iron deficiency and may exacerbate iron-deficiency anemia by altering iron metabolism (15). Vitamin A supplementation has been shown to have beneficial effects on iron-deficiency anemia and improve iron nutritional status among children and pregnant women (15, 16). The combination of vitamin A and iron seems to reduce anemia more effectively than either supplemental iron or vitamin A alone (17). Vitamin A may facilitate the mobilization of iron from storage sites to developing red blood cells for incorporation into hemoglobin (15, 16). Moreover, studies in rats have shown that iron deficiency alters plasma and liver levels of vitamin A (18, 19).

Copper

Adequate copper nutritional status is necessary for normal iron metabolism and red blood cell formation. Anemia is a clinical sign of copper deficiency, and iron has been found to accumulate in the livers of copper-deficient animals, indicating that copper (via copper-containing ceruloplasmin) is required for iron transport to the bone marrow for red blood cell formation (20). The connection between copper availability and iron metabolism has also been established in humans; copper deficiency can lead to secondary ceruloplasmin deficiency and hepatic iron overload and/or cirrhosis (21). Oral copper supplementation restored normal ceruloplasmin levels and plasma ferroxidase activity and corrected the iron metabolism disorder in a copper-deficient subject (22). Moreover, infants fed a high-iron formula absorbed less copper than infants fed a low-iron formula, suggesting that high iron intakes may interfere with copper absorption in infants (23).

Zinc

Zinc is essential to maintain adequate erythropoiesis. When zinc deficiency coexists with iron deficiency, it may exacerbate iron-deficiency anemia (24). On the other hand, high doses of iron supplements, taken together with zinc supplements on an empty stomach, may inhibit the absorption of zinc. When taken with food, supplemental iron does not appear to inhibit zinc absorption. Iron-fortified foods have not been found to impair zinc absorption (25, 26).

Calcium

The presence of calcium decreases iron absorption from both nonheme (i.e., most supplements and food sources other than meat, poultry, and seafood) and heme sources (27). However, calcium supplementation up to 12 weeks has not been found to change iron nutritional status, probably due to a compensatory increase in iron absorption (28). Individuals taking iron supplements should take them two hours apart from calcium-rich food or supplements to maximize iron absorption.

Iodine

Severe iron-deficiency anemia can impair thyroid metabolism in the following ways: (1) by altering the thyroid-stimulating hormone response of the pituitary gland; (2) by reducing the activity of thyroid peroxidase that catalyzes the iodination of thyroglobulin for the production of thyroid hormones; and (3) in the liver by limiting the conversion of T4 to T3, increasing T3 turnover, and decreasing T3 binding to nuclear receptors (29). It is estimated that goiter and iron-deficiency anemia coexist in up to 25% of school-age children in west and north Africa (30). A randomized controlled study in iron-deficient children with goiter showed a greater reduction in thyroid size following the consumption of iodized salt together with 60 mg/day of iron four times per week compared to placebo (31). Additional interventions have confirmed that correcting iron-deficiency anemia improved the efficacy of iodine supplementation to mitigate thyroid disorders (reviewed in 29, 30).

Deficiency

Levels of iron deficiency

Iron deficiency is the most common nutrient deficiency in the US and the world. Levels of iron deficiency are listed below from least to most severe.

Storage iron depletion

Iron stores are depleted, but the functional iron supply is not limited. 

Early functional iron deficiency

Before the development of frank anemia, the supply of functional iron to tissues, including bone marrow, is inadequate such as to impair erythropoiesis.  

Iron-deficiency anemia

By definition, anemia is present when individual hemoglobin concentrations fall below two standard deviations of the distribution mean for hemoglobin in a healthy population of the same gender and age and living at the same altitude (32). In 2013, iron-deficiency anemia was the leading cause of years lived with disability in children and adolescents in the 50 most populous countries. The countries with the highest prevalence of iron-deficiency anemia in individuals younger than 19 years were Afghanistan (41%) and Yemen (39.8%); India contributed the largest number of cases of anemia (147.9 million). The prevalence in the US was estimated to be 19.3% with nearly 16 million cases of iron-deficiency anemia in children and adolescents (33).

Iron-deficiency anemia occurs when there is inadequate iron to support normal red blood cell formation. The anemia of iron deficiency is usually characterized as microcytic and hypochromic, i.e., red blood cells are measurably smaller than normal and their hemoglobin content is decreased such that they are paler than normal. At this stage of iron deficiency, symptoms may be a result of inadequate oxygen delivery due to anemia and/or suboptimal function of iron-dependent enzymes. Changes in hematological parameters are used in the clinical diagnosis of iron-deficiency anemia (see Assessment of iron status). It is important to remember that iron deficiency is not the only cause of anemia, and that the diagnosis or treatment of iron deficiency solely on the basis of anemia may lead to misdiagnosis or inappropriate treatment of the underlying cause (34). See also the articles on Folate and Vitamin B12 for information on other nutritional causes of anemia.

Symptoms of iron deficiency

Most of the symptoms of iron deficiency are a result of the associated anemia and may include fatigue, rapid heart rate, palpitations, and rapid breathing on exertion. Iron deficiency impairs athletic performance and physical work capacity in several ways. In iron-deficiency anemia, the reduced hemoglobin content of red blood cells results in decreased oxygen delivery to active tissues. Decreased myoglobin levels in muscle cells limit the amount of oxygen that can be delivered to mitochondria for oxidative metabolism. Iron depletion also decreases the oxidative capacity of muscle by diminishing the mitochondrial content of cytochromes and other iron-dependent enzymes required for electron transport and ATP synthesis (see Function) (35).

Poor thyroid function and impaired thyroid hormone synthesis likely disrupt the ability to maintain a normal body temperature on exposure to cold in iron-deficient individuals (see Function). Iron deficiency may also impair neutrophil phagocytosis and microbicidal activity and T-lymphocyte proliferative responses to infection (1). Severe iron-deficiency anemia may result in brittle and spoon-shaped nails, sores at the corners of the mouth, taste bud atrophy, and a sore tongue. In rare cases, advanced iron-deficiency anemia may cause difficulty in swallowing due to the formation of webs of tissue in the throat and esophagus due to a degradation of the pharyngeal muscles (36). The development of esophageal webs, also known as Plummer-Vinson syndrome, may require a genetic predisposition in addition to iron deficiency. Iron deficiency and iron-deficiency anemia in early childhood have been shown to impair psychomotor development and induce short- and long-term behavioral and cognitive alterations (reviewed in 37). Further, pica, a behavioral disturbance characterized by the consumption of non-food items, may be a symptom and a cause of iron deficiency (38).

Individuals at increased risk of iron deficiency

Life stage groups with increased requirements

Neonates and infants up to six months of age: Inadequate maternal iron body stores and anemia during pregnancy may reduce the duration of gestation and birth weight; preterm and/or low body-weight newborns are at increased risk of iron-deficiency anemia (14). Pregnancy complications, including preeclampsia and gestational diabetes mellitus, may also lead to low iron stores in preterm and term infants (14).

Most of the 150 to 250 mg of iron present in a full-term healthy newborn is accumulated during the third trimester of pregnancy and is sufficient for the first four to six months of life (34). Iron stores are essential for infants less than six months of age because breast milk is relatively poor in iron (0.2 mg/L-0.4 mg/L), and intestinal absorption of iron remains low until six months of age. High iron requirements during this period of sustained and rapid growth rate can worsen the deficit in body iron in preterm infants (14). Moreover, a review of randomized controlled trials suggested that infants with an early umbilical cord clamping (≤1 min after birth) are at least twice more likely to be iron-deficient at three to six months compared to those with delayed cord clamping (39). Yet, healthy full-term infants have little need for external sources of iron before six months of age (1).

Infants and children between the ages of 6 months and 3 years: A full-term infant's iron stores are usually sufficient to last for the early months of life, but there is an increased risk of iron deficiency for infants older than six months (1). Given the sustained need of iron for increasing tissue mass, blood volume, and replenishing iron stores, the recommended dietary allowance (RDA) for iron is 11 mg/day for infants aged seven to 12 months, as established by the US Institute of Medicine (see Table 1).

The RDA for iron is 7 mg/day for toddlers aged 1 to 3 years old. Based on the US National Health and Nutrition Examination Survey (NHANES) 1999-2002 data, the prevalence of iron deficiency in toddlers aged 12 to 35 months varies from 6.6%-15.2%, and the prevalence of iron-deficiency anemia is 0.9%-4.4%, depending on ethnicity and socioeconomic status (14).

Of note, the World Health Organization (WHO) and the American Academy of Pediatrics recommend universal screening for anemia at one year of age. Yet, a recent report by the US Preventive Services Task Force (USPSTF) stated there was insufficient evidence to assess the benefits versus harms of screening (34, 40).

Adolescents: Early adolescence is period of rapid growth. Blood loss that occurs with menstruation in adolescent girls adds to the increased iron requirement of adolescence (1). The RDA of iron is 11 mg/day and 15 mg/day for adolescent boys and girls, respectively (see Table 1).

Nonpregnant women of childbearing age: Based on data from NHANES 2003-2006, the percentage of US women with two out of three markers of iron status (i.e., hemoglobin, ferritin, and % transferrin saturation) below cutoff values for deficiency was 9.8% in nonpregnant women (41).

The use of oral contraceptives decreases menstrual blood losses and is thus associated with improved iron status compared to intrauterine devices (copper coil) (1).

Breast-feeding is associated with lower dietary iron needs, allowing for the repletion of iron stores depleted during pregnancy and delivery. However, iron repletion may be incomplete in high-parity women who are therefore at increased risk of iron deficiency (41).

Pregnant women: The requirement for iron is significantly increased during pregnancy due to increased iron utilization by the developing fetus and placenta, as well as maternal blood volume expansion (42). Analysis of data from NHANES 2005-2006 found that 18.1% of pregnant women (mean age, 27.5 years) were deficient in iron, as assessed by the log ratio of soluble transferrin receptor to serum ferritin (43). The prevalence of iron deficiency was greater during the second (20.7%) and third (29.7%) trimesters compared to the first trimester (4.5%) of gestation. Further, iron deficiency in pregnancy was found to be more prevalent in Mexican (23.6%) and Black Americans (29.6%) than in non-Hispanic White Americans (13.9%) (43).

Individuals with chronic blood losses

Chronic bleeding or acute blood loss may result in iron deficiency. One milliliter (mL) of blood with a hemoglobin concentration of 150 g/L contains 0.5 mg of iron. Thus, chronic loss of very small amounts of blood may result in iron deficiency.

Parasitic infestation: A common cause of chronic blood loss and iron deficiency in developing countries is intestinal parasitic infection (44).

Frequent blood donation: Individuals who donate blood frequently, especially menstruating women, may need to increase their iron intake to prevent deficiency because each 500 mL of blood donated contains between 200 and 250 mg of iron (45, 46)

Regular intense exercise: Daily iron losses have been found to be greater in athletes involved in intense endurance training. This may be due to expanding blood cell mass and muscle mass, increased microscopic bleeding from the gastrointestinal tract (with the regular use of anti-inflammatory drugs), or increased fragility and hemolysis of red blood cells (47). The Food and Nutrition Board estimates that the average requirement for iron may be 30% higher for those who engage in regular intense exercise (25).

Individuals with decreased iron absorption

Celiac disease: Celiac disease (celiac sprue) is an autoimmune disorder estimated to occur in 1% of the population. When people with celiac disease consume food or products that contain gluten, the immune system response damages the intestinal mucosa, which may result in nutrient malabsorption and iron-deficiency anemia (48).

Atrophic gastritis: This condition is usually associated with the presence of antibodies directed towards stomach cells and has been implicated in pernicious anemia (see the article on Vitamin B12). Atrophic gastritis simultaneously impairs the absorption of both vitamin B12 and iron; yet, in menstruating women, iron deficiency may occur years before the depletion of vitamin B12 body stores (47).

Helicobacter pylori infection: H. pylori infection is associated with iron-deficiency anemia, especially in children, even in the absence of gastrointestinal bleeding. Data from NHANES 2000-2001 in individuals older than three years showed that the presence of iron deficiency (based on serum ferritin concentrations) was 40% more prevalent in those infected with H. pylori than in H. pylori-free individuals (49). Occult gastrointestinal bleeding and competition for dietary iron by bacteria may explain iron deficiency in infected individuals. Moreover, Helicobacter pylori infection may also play a role in the pathogenesis of atrophic gastritis (47).

Inflammatory bowel diseases (IBD): Iron-deficiency anemia is commonly reported among patients with IBD (e.g., ulcerative colitis, Crohn’s disease), likely due to both impaired intestinal absorption of iron and blood loss from ulcerated mucosa (50).

Gastric bypass surgery: Some types of gastric bypass (bariatric) surgery increase the risk of iron deficiency by causing malabsorption of iron, among other nutrients (51).

Obesity: An inverse association between body weight and iron status has been reported in several observational studies in children and adults (52, 53). Higher hepcidin expression in obese people may impair iron absorption despite adequate dietary intake of iron. Weight loss might lower serum hepcidin concentration and improve iron status in obese individuals (9).

Anemia of chronic disease: Acute and chronic inflammation may lead to abnormally low circulating concentrations of iron and to the development of anemia. This type of anemia of inflammation, also known as anemia of chronic disease (ACD), is commonly observed in inflammatory disorders, cancer, critical illness, trauma, chronic infection, and parasitic infestation. It is thought that anemia develops because dietary iron absorption and iron mobilization from body stores are inhibited by inflammation-induced hepcidin up-regulation (see also Systemic regulation of iron homeostasis) (9).

Other causes of iron deficiency

Vegetarian diet with inadequate sources of iron: Because iron from plants (nonheme iron) is less efficiently absorbed than that from animal sources (see Sources), the US Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) estimated that the bioavailability of iron from a vegetarian diet was only 10% versus 18% from a mixed Western diet. Therefore, the recommended dietary allowance (RDA) of iron for individuals consuming a completely vegetarian diet may be 1.8 times higher than the RDA for non-vegetarians (25). Yet, a vegetarian diet does not appear to be associated with an increased risk of iron deficiency when it includes whole grains, legumes, nuts, seeds, dried fruit, iron-fortified cereal, and green leafy vegetables (see Sources) (54).

Chronic kidney disease (CKD): Iron losses in CKD patients are due to significant gastrointestinal blood loss (1.2 L blood loss/year corresponding to ~400 mg iron/year) compared to individuals with normal kidney function (0.83 mL blood loss/day corresponding to ~100 mg iron/year). Estimated blood losses are even larger in patients on hemodialysis, and iron losses may be 1,000 to 2,000 mg/year or higher. Persistent inflammation in CKD patients may also contribute to inadequate iron supply for red blood cell formation despite adequate body iron stores (55).

The Recommended Dietary Allowance (RDA)

The RDA for iron was revised in 2001 and is based on the prevention of iron deficiency and maintenance of adequate iron stores in individuals eating a mixed diet (Table 1; 25).

Table 1. Recommended Dietary Allowance (RDA) for Iron
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 0.27 (AI) 0.27 (AI)
Infants 7-12 months 11 11
Children 1-3 years 7 7
Children 4-8 years 10 10
Children 9-13 years 8 8
Adolescents 14-18 years 11 15
Adults 19-50 years 8 18
Adults 51 years and older 8 8
Pregnancy all ages - 27
Breast-feeding 18 years and younger - 10
Breast-feeding 19 years and older - 9

Disease Prevention

Prevention or alleviation of iron deficiency or iron-deficiency anemia can limit the impact of iron inadequacy and defective erythropoiesis on the following health conditions and diseases.

Impaired psychomotor, cognitive, and intellectual development in children

Iron is critical for the development of the central nervous system, and iron deficiency is thought to be especially detrimental during the prenatal and early postnatal periods. Iron-dependent enzymes are required for nerve myelination, neurotransmitter synthesis, and normal neuronal energy metabolism (56). Most observational studies have found relationships between iron deficiency — with or without anemia — in children and poor cognitive development, poor school achievement, and abnormal behavior patterns (reviewed in 37). Whether psychomotor and mental deficits may be attributed to the lack of iron, only, or to a combination effect of iron deficiency and low hemoglobin concentrations — like in iron-deficiency anemia and anemia of inflammation — in early childhood remains unclear (14).

A recent systematic review of six small placebo-controlled trials (published between 1978 and 1989) in children with iron-deficiency anemia younger than 27 months found no convincing evidence that iron therapy (for less than 11 days) had any consistent effect on measures of psychomotor and mental development within 30 days of treatment initiation (57). Only one randomized, double-blind trial in anemic, iron-deficient infants examined the impact of iron therapy for four months and found a significant benefit on indices of cognitive development that needs to be further confirmed (58). A review of five randomized controlled trials in non-anemic, iron-deficient infants (0-9 months old) suggested an improvement in psychomotor (but not mental) development throughout the first 18 months of life (59). Iron supplementation in early infancy (4 to 6 months) also failed to demonstrate any long-term effect on cognitive performance and school performance at the age of 9 years compared to placebo (60). At present, evidence supporting any benefits of iron therapy on neurodevelopment outcomes in infants with iron deficiency, with or without anemia, remains limited.

Iron therapy might be more effective at improving cognitive outcomes in older children with anemia and/or iron deficiency. A systematic review of 17 randomized controlled trials found that iron supplementation had no effect on mental development of children under the age of 27 months but modestly improved scores of mental development in children over seven years of age (61). A more recent meta-analysis of randomized controlled trials in children older than six years, adolescents, and women with iron deficiency, anemia, or iron-deficiency anemia suggested that supplemental iron could improve attention and concentration irrespective of participants’ iron status (62). A potential improvement in IQ measures with iron therapy was also reported in anemic participants regardless of their iron status. No additional benefits were observed regarding measures of memory performance, psychomotor function, and school achievements.

Alterations in brain functions due to iron deficiency are likely to be resistant to iron therapy when they occur in early childhood. Long-term consequences of early life iron deficiency may include poor socioeconomic achievements and increased risk of certain psychopathologies, including anxiety, depression, and schizophrenia (56).

Adverse pregnancy outcomes

Epidemiological studies provide strong evidence of an association between severe anemia in pregnant women and adverse pregnancy outcomes, such as low birth weight, preterm birth, and neonatal and maternal mortality (63). Although iron deficiency can be a major contributing factor to severe anemia, evidence that iron-deficiency anemia causes poor pregnancy outcomes is still lacking. In addition, iron supplementation during pregnancy was shown to improve iron status and hematological parameters in women but failed to significantly reduce adverse pregnancy outcomes, including low birth weight and/or prematurity, neonatal death, and congenital anomalies (64). Moreover, routine supplementation during pregnancy had no effect on the length of gestation or newborn Apgar scores (40). Nevertheless, most experts consider the control of maternal anemia to be an important part of prenatal health care, and the IOM recommends screening for anemia in each trimester of pregnancy (65).

The requirement for iron is greatly increased in the second and third trimesters, and the RDA for pregnant women is 27 mg/day of iron (see The Recommended Dietary Allowance) (25). The American College of Obstetricians and Gynecologists recommend screening all pregnant women for anemia and advise iron supplementation when required (66). Nonetheless, the US Preventive Services Task Force (40) and the American Academy of Family Physicians (67) consider that evidence is lacking to evaluate the harms and benefits of screening for iron-deficiency anemia and supplementing with iron during pregnancy.

In malaria-endemic regions, however, iron supplementation may improve pregnancy outcomes when provided in conjunction with measures of prevention and management of malaria. Two recent randomized, placebo-controlled trials failed to find an increased risk of malaria infection in both iron-deficient and iron-replete pregnant women supplemented with iron, supporting the use of universal iron supplementation in malaria-endemic countries that adopt malaria intermittent preventive treatment (IPT) (68, 69).

Lead toxicity

Children who are chronically exposed to lead, even in small amounts, are more likely to develop learning disabilities, behavioral problems, and have low IQs. Deficits in growth and neurologic development may occur in the infants of women exposed to lead during pregnancy and lactation. In adults, lead toxicity may result in kidney damage and high blood pressure. Although the use of lead in paint products, gasoline, and food cans has been discontinued in the US, lead toxicity continues to be a significant health problem, especially in children living in inner cities (70). In 2012, the US Centers for Disease Control and Prevention set the reference value for blood lead concentration at 5 micrograms per deciliter (μg/dL) to identify children at risk. Yet, there is no known blood lead concentration below which children are 100% safe (71).

Iron deficiency and lead poisoning share a number of the same risk factors, including low socioeconomic status, ethnic minority groups, and residence in urban areas. Iron deficiency may increase the risk of lead poisoning in children, especially by increasing the intestinal absorption of lead via the DMT1 intestinal transporter (72). However, the use of iron supplementation in lead poisoning might be reserved for children who are truly iron deficient or for iron-replete children with chronic lead exposure (e.g., living in lead-exposed housing) (72)

Disease Treatment

Restless legs syndrome

Restless legs syndrome (RLS; also called Willis-Ekbom disease) is a neurologic movement disorder of unknown etiology. People with RLS experience unpleasant sensations resulting in an irresistible urge to move their legs and transient relief with movement. These sensations are more common at rest and often interfere with sleep (73). The prevalence of RLS is higher in women than in men and increases with age (74). This syndrome appears to be inherited in about 50% of patients but has also been related to chronic kidney failure (73). Iron deficiency may be involved in RLS development, possibly by affecting the activity of tyrosine hydroxylase, a rate limiting iron-dependent enzyme in the synthesis of the neurotransmitter, dopamine (74). The management of RLS includes iron therapy and the use of drugs like dopamine agonists (73). Current clinical evidence is insufficient to evaluate whether iron therapy may help relieve some RLS symptoms (74). Yet, the Medical Advisory Board of the Willis-Ekbom Disease Syndrome Foundation suggests that iron status should be assessed in all patients with RLS, and iron therapy be attempted on a case-by-case basis in those who might benefit from it (73).     

Sources

Food sources

The amount of iron in food or supplements that is absorbed and used by the body is influenced by the iron nutritional status of the individual and whether or not the iron is in the form of heme. Because it is absorbed by a different mechanism than nonheme iron, heme iron is more readily absorbed and its absorption is less affected by other dietary factors (2). In an attempt to improve body iron status, iron absorption is enhanced in individuals who are anemic or iron deficient compared to iron-replete individuals.

Heme iron

Heme iron comes mainly from hemoglobin and myoglobin in meat, poultry, and fish. Although heme iron accounts for only 10%-15% of the iron found in the diet, it may provide up to one-third of total absorbed dietary iron (54). The absorption of heme iron is less influenced by other dietary factors than that of nonheme iron (27)

Nonheme iron

Plants, dairy products, meat, and iron salts added to food and supplements are all sources of nonheme iron. The absorption of nonheme iron is strongly influenced by enhancers and inhibitors present in the same meal (27).

Enhancers of nonheme iron absorption

  • Vitamin C (ascorbic acid): Vitamin C strongly enhances the absorption of nonheme iron by reducing dietary ferric iron (Fe3+) to ferrous iron (Fe2+) and forming an absorbable, iron-ascorbic acid complex (75)
  • Other organic acids: Citric, malic, tartaric, and lactic acids have some enhancing effects on nonheme iron absorption (1)
  • Meat, poultry, and fish: Aside from providing highly absorbable heme iron, meat, fish, and poultry also enhance nonheme iron absorption. The mechanism for this enhancement of nonheme iron absorption is not clear (1, 25)

Inhibitors of nonheme iron absorption

  • Phytic acid (phytate): Phytic acid, present in legumes, whole grains, nuts, and seeds, inhibits nonheme iron absorption, probably by binding to it. Small amounts of phytic acid (5 to 10 mg) can reduce nonheme iron absorption by 50%. The absorption of iron from legumes, such as soybeans, black beans, lentils, mung beans, and split peas, has been shown to be as low as 2% (25). Food preparation, including soaking, germination, fermentation, and cooking, can help remove or degrade phytic acid (27).
  • Polyphenolic compounds: Polyphenolic compounds in coffee, black tea, and herbal tea can markedly inhibit the absorption of nonheme iron (76). This effect may be reduced by the presence of vitamin C (27, 77).
  • Soy protein: Soy protein, such as that found in tofu, has an inhibitory effect on iron absorption that is only partly related to its phytic acid content (27, 77).
  • Calcium: Calcium appears to affect iron absorption from both heme and nonheme sources. Yet, its effect appears to be limited when one consumes a wide variety of food with varied levels of enhancers and inhibitors of iron absorption (27).

National surveys in the US have indicated that the average dietary intake of iron is 16 to 18 mg/day in men, 12 mg/day in pre- and postmenopausal women, and about 15 mg/day in pregnant women (25). Thus, the majority of premenopausal and pregnant women in the US consume less than the RDA for iron, and many men consume more than the RDA (see The Recommended Dietary Allowance). In the US, most grain products are fortified with nonheme iron. The iron content of some relatively iron-rich foods is listed in milligrams (mg) in Table 2. For more information on the nutrient content of specific foods, search the USDA food composition database.

Table 2. Some Food Sources of Iron
Food Serving Iron (mg)
Beef 3 ounces* 1.6
Chicken, liver, cooked, pan-fried 1 ounce 3.6
Oysters, Pacific, cooked 6 medium  13.8
Oysters, Eastern, cooked 6 medium   3.9
Clams, cooked, steamed 3 ounces   2.4
Tuna, light, canned in water 3 ounces   1.3
Mussels, cooked, steamed 3 ounces  5.7
Raisin bran cereal 1 cup  5.8-18.0
Raisins, seedless 1 small box (1.5 ounces)   0.8
Prune juice 6 fluid ounces  2.3
Prunes (dried plums) ~5 prunes (1.7 ounces)   0.4
Potato, with skin, baked 1 medium potato  1.8
Quinoa, cooked  ½ cup 1.4
Spinach, cooked 1 cup  6.4
Swiss chard, cooked, boiled ½ cup 2.0
Beans, white, cooked ½ cup 3.3
Lentils, cooked ½ cup 3.3
Tofu, regular, raw ½ cup  6.6
Hazelnuts, dry-roasted 1 ounce 1.3
Cashews 1 ounce 1.9
*A three-ounce serving of meat is about the size of a deck of cards.

Supplements

Iron supplements are indicated for the prevention and treatment of iron deficiency and iron deficiency anemia. Individuals who are not at risk of iron deficiency (e.g., adult men and postmenopausal women) should not take iron supplements without an appropriate medical evaluation. A number of iron supplements are available, and different forms provide different proportions of elemental iron. Ferrous sulfate heptahydrate is 20% elemental iron, ferrous sulfate monohydrate is 33% elemental iron, ferrous gluconate is 12% elemental iron, and ferrous fumarate is 33% elemental iron. If not stated otherwise, the iron discussed in this article is elemental iron.

Iron Overload

Deregulation of intestinal iron absorption will result in iron overload because the body cannot excrete excess iron (2). However, iron overload due to prolonged iron supplementation is very rare in healthy individuals without a genetic predisposition. Several genetic disorders may lead to pathological accumulation of iron in the body despite normal iron intake. Supplementation of individuals who are not iron deficient should be avoided due to the frequency of undetected inherited diseases and recent concerns about the more subtle effects of chronic excess iron intake (see Diseases associated with iron overload).

Inherited iron-overload diseases

Hereditary hemochromatosis

Hereditary hemochromatosis (HH) refers to late-onset, autosomal recessive disorders of iron metabolism that result in iron accumulation in the liver, heart, and other tissues. Disorders may lead to cirrhosis of the liver, diabetes mellitus, cardiomyopathy (heart muscle damage), hypogonadism, arthropathy (joint problems), and increased skin pigmentation (reviewed in 78). There are four main types of HH, which are classified according to the specific gene that is mutated. The most common type of HH, called Type 1 or HFE-related HH, results from mutations in the HFE gene (79, 80). The majority of Type 1 HH cases are homozygous for mutation C282Y G>A (rs1800560) in the HFE gene. Another mutation found in 4% of patients with Type 1 HH is H63D C>G (rs1799945) in the HFE gene. The protein encoded by the HFE gene is thought to play a role in regulating intestinal absorption of dietary iron and with sensing the body’s iron stores (81). HFE gene mutations are associated with an increased cellular uptake of iron. With a typical disease onset before age 30, juvenile hemochromatosis (HH Type 2) is much rarer than Type 1 HH and results from genetic mutations affecting either hemojuvelin (Type 2A) or hepcidin (Type 2B) function (82). HH Type 3 results from mutations in the transferrin receptor 2 gene (TFR2), and HH Type 4 (also called Ferroportin disease) results from mutations in the gene encoding ferroportin-1 (SLC40A1), a protein important in the export of iron from cells (see Regulation). Type 4 HH is the second most common inherited iron overload disorder after Type 1 HH (78).

Iron overload in HH is treated by phlebotomy, the removal of 500 mL of blood at a time, at intervals determined by the severity of the iron overload. Chelation therapy is an alternate option to deplete iron in HH patients who cannot undergo phlebotomy treatment. Individuals with HH are advised to avoid supplemental iron, but generally not told to avoid iron-rich food. High-dose vitamin C regimens may worsen iron overload in patients with HH (75). Alcohol consumption is strongly discouraged due to the increased risk of cirrhosis of the liver (83). Genetic testing, which requires a blood sample, is available for those who may be at risk for HH, for example, individuals with a family history of hemochromatosis. 

Other inherited conditions

Other genetic disorders leading to iron overload include aceruloplasminemia, hypotransferrinemia, Friedreich’s ataxia, and porphyria cutanea tarda (2)

Acquired iron-overload diseases

Iron overload may develop in individuals with severe hereditary anemias that are not caused by iron deficiency. Excessive dietary absorption of iron may occur in response to the body's continued efforts to form red blood cells. Beta-thalassemia is characterized by defective hemoglobin A synthesis due to mutations in the β-globin gene. Patients affected by thalassemia intermedia do not require blood transfusion as do those affected by the most severe form of the disease (called thalassemia major), yet they develop iron overload due to increased intestinal iron absorption (84). Other anemic patients at risk of iron overload include those with sideroblastic anemia, hemolytic anemia, pyruvate kinase deficiency, and thalassemia major, especially because they are treated with numerous transfusions. Patients with hereditary spherocytosis and thalassemia minor do not usually develop iron overload unless they are misdiagnosed as having iron deficiency and treated with large doses of iron over many years. Iron overload has also been associated with hemodialysis and chronic liver diseases (metabolic, viral, and alcoholic) (2).

Diseases associated with iron overload

Toxic iron deposition in vital organs in hereditary hemochromatosis (HH) has been associated with an increased incidence of liver cancer, type 2 diabetes mellitus, and neurodegenerative disease. Iron overload might also increase the risk of chronic disease in HH-free individuals. Nevertheless, whether iron tissue accumulation in those unaffected by genetic disorders is due to high dietary iron intakes is not yet fully understood (1).

Cancer

Hereditary hemochromatosis that is characterized by abnormal hepatic iron accumulation is a risk factor for liver cancer (hepatocellular carcinoma; HCC). Iron accumulation is thought to function as a carcinogen by increasing oxidative stress that causes damage to lipids, proteins, and DNA. A meta-analysis of nine observational studies found an increased HCC risk with the C282Y mutation in the HFE gene of healthy participants and patients with chronic liver disease (see Iron Overload) (85). Other meta-analyses have reported associations between HFE gene mutations C282Y and H63D and increased risks of overall cancer (86, 87). However, studies reporting on HFE gene mutations and risk of cancer at extra-hepatic sites are rather scarce and/or inconsistent. Some, but not all, observational studies found significant associations between the C282Y mutation and risk of colorectal (88), breast (88, 89), and epithelial ovarian cancer (90). The presence of the H63D mutation in the HFE gene was linked to an increased risk of leukemia (91, 92) and gastric cancer (93).

Whether high dietary iron could increase the risk of cancer in individuals without hemochromatosis has also been investigated. The consumption of red or processed meat (but not white meat), rich in heme iron, has been linked to an increased risk of colorectal cancer (CRC) (94). Exposure to carcinogenic compounds (called heterocyclic amines) generated when meat is cooked at high temperatures and to carcinogenic N-nitroso compounds formed in the gastrointestinal tract following consumption of red and processed meat may explain such an association (95). Several meta-analyses of observational studies have also suggested a potential association of heme iron in red meat with CRC (96-98). This has been explained by an increased exposure of colonic cells to potentially damaging N-nitroso compounds and lipid peroxidation end-products derived from heme iron-catalyzed reactions (99). Further, recent results from the large European Prospective Investigation into Cancer and Nutrition (EPIC) study suggested a higher risk of esophageal adenocarcinoma with high intakes of red/processed meat and heme iron (100).

Cardiovascular disease

Experimental studies have suggested a role for iron-induced oxidative stress in vessel wall damage and the development of atherosclerosis, which underlies most forms of cardiovascular disease (101). However, epidemiological studies of iron nutritional status and cardiovascular disease in humans have yielded conflicting results. A recent systematic review and meta-analysis of 17 prospective cohort studies in 156,427 participants (9,236 cases of coronary heart disease [CHD] or myocardial infarction [MI]) did not find evidence to support the existence of strong associations between a number of different measures of iron status and CHD/MI (102). Only individuals in the highest versus lowest tertile of serum transferrin saturation exhibited an 18% lower incidence of CHD/MI (102). Another meta-analysis of 21 prospective studies found serum transferrin saturation and serum iron to be inversely associated with the risk of CHD. However, the authors noted that most studies failed to adjust for the confounding effects of inflammation (103). The review also reported an inverse association between CHD incidence and total dietary iron intake, but dietary heme iron was positively associated with CHD incidence (103). Although the relationship between iron stores and CHD/MI requires further clarification, it would be prudent for those who are not at risk of iron deficiency (e.g., adult men and postmenopausal women) to avoid excess iron intake (see the LPI Rx for Health). 

Type 2 diabetes mellitus and metabolic syndrome

Individuals with hereditary hemochromatosis (HH) are known to be at a heightened risk of developing type 2 diabetes mellitus (104). Increasing evidence also suggests a role for iron excess in the pathogenesis of type 2 diabetes independent of hemochromatosis. Cross-sectional, case-control, and prospective cohort studies have reported an increased risk of type 2 diabetes (105) and metabolic syndrome (106) with high versus low ferritin concentrations (reflecting iron body stores) after adjustment for inflammation. It is currently unclear how other indices of iron status relate to the risk of type 2 diabetes (107-110). Iron overload-induced oxidative stress in patients with HH is thought to damage pancreatic β-cells and impair insulin secretion. In subjects free of HH, iron excess might damage the liver, interfering with glucose metabolism and triggering insulin resistance, rather than impair β-cell function (111, 112). Iron removal by phlebotomy has been shown to improve metabolic parameters in subjects with type 2 diabetes (113) and metabolic syndrome (114). Additional randomized controlled trials are needed to determine whether lowering body stores of iron will aid in the prevention of type 2 diabetes and metabolic syndrome.

Neurodegenerative disease

Iron is required for normal brain and nerve function through its involvement in cellular metabolism, as well as in the synthesis of neurotransmitters and myelin. Deregulation of iron homeostasis has been observed in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) (115-117). The abnormal accumulation of iron in the brain does not appear to be a result of increased dietary iron, but rather a disruption in the complex process of cellular iron regulation (117). Brain iron accumulation can result in increased oxidative stress, and the brain is particularly susceptible to oxidative damage. Mechanisms behind the disruption of iron homeostasis in the brain of patients affected by neurodegenerative disease are actively being investigated. For example, studies using genetically modified mouse models indicated that the suppression of amyloid precursor protein (APP) expression by upstream nitric oxide (NO) elevation (11) or loss of Tau protein (12) could impair neuronal export or iron and lead to iron accumulation in specific brain regions affected in Parkinson’s disease. A pilot, double-blind, placebo-controlled trial in patients with early-stage Parkinson’s disease demonstrated oral administration of the iron chelator, deferiprone, for 12 months reduced iron deposition in the part of the brain called substantia nigra and improved motor performance without compromising systemic iron homeostasis (118, 119).

Safety

Toxicity

Overdose

Accidental overdose of iron-containing products is the single largest cause of poisoning fatalities in children under six years of age. Although the oral lethal dose of elemental iron is approximately 180 to 250 mg/kg of body weight, considerably less has been fatal. Symptoms of acute toxicity may occur with iron doses of 20 to 60 mg/kg of body weight. Iron overdose is an emergency situation because the severity of iron toxicity is related to the amount of elemental iron absorbed. Acute iron poisoning produces symptoms in four stages: (1) Within one to six hours of ingestion, symptoms may include nausea, vomiting, abdominal pain, tarry stools, lethargy, weak and rapid pulse, low blood pressure, fever, difficulty breathing, and coma; (2) If not immediately fatal, symptoms may subside for about 24 hours; (3) Symptoms may return 12 to 48 hours after iron ingestion and may include serious signs of failure in the following organ systems: cardiovascular, kidney, liver, hematologic (blood), and central nervous system; and (4) Long-term damage to the central nervous system, liver (cirrhosis), and stomach may develop two to six weeks after ingestion (25, 120).

Adverse effects

At therapeutic levels used to treat iron deficiency, iron supplements may cause gastrointestinal irritation, nausea, vomiting, diarrhea, or constipation. Stools will often appear darker in color. Iron-containing liquids can temporarily stain teeth, but diluting the liquid helps to prevent this effect (120). Taking iron supplements with food instead of on an empty stomach may relieve gastrointestinal effects. The Food and Nutrition Board (FNB) of the Institute of Medicine based the tolerable upper intake level (UL) for iron on the prevention of gastrointestinal distress (Table 3). The UL for adolescents (14-18 years) and adults, including pregnant and breast-feeding women, is 45 mg/day. It should be noted that the UL is not meant to apply to individuals being treated with iron under close medical supervision. Individuals with hereditary hemochromatosis or other conditions of iron overload, as well as individuals with alcoholic cirrhosis and other liver diseases, may experience adverse effects at iron intake levels below the UL (25).

Table 3. Tolerable Upper Intake Level (UL) for Iron
Age Group UL (mg/day)
Infants 0-12 months 40
Children 1-13 years 40
Adolescents 14-18 years 45
Adults 19 years and older 45

Drug interactions

Medications that decrease stomach acidity, such as antacids, histamine (H2) receptor antagonists (e.g., cimetidine, ranitidine), and proton-pump inhibitors (e.g., omeprazole, lansoprazole), may impair iron absorption. Taking iron supplements at the same time as the following medications may result in decreased absorption and efficacy of the medication: carbidopa and levodopa (Sinemet), levothyroxine (Synthroid, Levoxyl), methyldopa (Aldomet), penicillamine (Cuprimine, Depen), quinolones, tetracyclines, and bisphosphonates (120). Therefore, it is best to take these medications two hours apart from iron supplements. Cholestyramine (Questran) and colestipol (Colestid), used to lower blood cholesterol concentrations, should also be taken at least four hours apart from iron supplements because they may interfere with iron absorption (121). Allopurinol (Zyloprim), a medication used to treat gout, may increase iron storage in the liver and should not be used in combination with iron supplements.

Does iron supplementation increase the risk of malaria in malaria-endemic regions?

Despite the critical functions of iron in the immune response, the nature of the relationship between iron status and susceptibility to infection, especially with respect to malaria, has been controversial. Because iron withholding is a recognized defense mechanism against pathogens (see Iron withholding defense during infection), concerns have beenraised regarding the safety of iron supplementation, especially in iron-replete children living in malaria-endemic regions (122).

Iron supplementation of children residing in the tropics has been associated with increased risk of clinical malaria and other infections like pneumonia (123, 124). A randomized controlled trial in 24,076 children (ages, 1-35 months) living in a malaria-endemic region of eastern Africa (Tanzania) investigated the effects of supplemental iron and folic acid, with or without zinc, compared to the effects of zinc alone or a placebo, on all-cause mortality and hospital admissions (125). The administration of iron, folic acid, and/or zinc was found to increase the risk of serious adverse effects, hospital admission, and death, and was therefore prematurely halted. Further analyses of the trial revealed that iron-replete children were more likely than iron deficient-children (with or without anemia) to be at risk of adverse effects following iron supplementation (125). Such a potential risk of adverse effects with routine iron supplementation was not observed in preschool children in settings without malaria (southern Nepal) (126).

A recent review of 35 trials indicated that iron supplementation did not increase the risk of clinical malaria or other parasitic diseases, infections, and all-cause mortality in children living in malaria-endemic regions in which prevention and management of malaria are available (127). Moreover, a pooled analysis of three high-quality trials demonstrated that supplemental iron combined with anti-malarial treatment protected children against clinical malaria and improved hematological parameters (127). The World Health Organization (WHO) currently recommends the provision of iron supplementation in infants and children, together with measures of malaria prevention, diagnosis, and treatment in malaria-endemic areas (128).

Linus Pauling Institute Recommendation

Following the RDA for iron should provide sufficient iron to prevent deficiency without causing adverse effects in most individuals. Although sufficient iron can be obtained through a varied diet, a considerable number of people do not consume adequate iron to prevent deficiency. A multivitamin/mineral supplement containing 100% of the daily value (DV) for iron provides 18 mg of elemental iron. While this amount of iron may be beneficial for premenopausal women, it is well above the RDA for men and postmenopausal women.

Adult men and postmenopausal women

Since hereditary hemochromatosis is not uncommon and the effects of long-term dietary iron excess on chronic disease risk are not yet clear, men and postmenopausal women who are not at risk of iron deficiency should take a multivitamin/mineral supplement without iron. A number of multivitamins formulated specifically for men or those over 50 years of age do not contain iron.

Older adults (>50 years)

Moderately elevated iron stores might be much more common than iron deficiency in middle-age and older individuals (129). Thus, older adults should not generally take nutritional supplements containing iron unless they have been diagnosed with iron deficiency. Moreover, it is extremely important to determine the underlying cause of the iron deficiency, rather than simply treating it with iron supplements (see The Recommended Dietary Allowance).


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2006 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2016 by:
Marianne Wessling-Resnick, Ph.D.
Professor of Nutritional Biochemistry
Department of Genetics and Complex Diseases
Harvard T.H. Chan School of Public Health

The 2016 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2001-2017  Linus Pauling Institute


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Magnesium

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Summary

Magnesium plays important roles in the structure and the function of the human body. The adult human body contains about 25 grams of magnesium. Over 60% of all the magnesium in the body is found in the skeleton, about 27% is found in muscle, 6% to 7% is found in other cells, and less than 1% is found outside of cells (1).

Function

Magnesium is involved in more than 300 essential metabolic reactions, some of which are discussed below (2).

Energy production

The metabolism of carbohydrates and fats to produce energy requires numerous magnesium-dependent chemical reactions. Magnesium is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP) (3).

Synthesis of essential molecules

Magnesium is required for a number of steps during synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Several enzymes participating in the synthesis of carbohydrates and lipids require magnesium for their activity. Glutathione, an important antioxidant, requires magnesium for its synthesis (3).

Structural roles

Magnesium plays a structural role in bone, cell membranes, and chromosomes (3).

Ion transport across cell membranes

Magnesium is required for the active transport of ions like potassium and calcium across cell membranes. Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm (3).

Cell signaling

Cell signaling requires MgATP for the phosphorylation of proteins and the formation of the cell-signaling molecule, cyclic adenosine monophosphate (cAMP). cAMP is involved in many processes, including the secretion of parathyroid hormone (PTH) from the parathyroid glands (see the articles on Vitamin D and Calcium for additional discussions regarding the role of PTH) (3).

Cell migration

Calcium and magnesium levels in the fluid surrounding cells affect the migration of a number of different cell types. Such effects on cell migration may be important in wound healing (3).

Nutrient interactions

Zinc

High doses of zinc in supplemental form apparently interfere with the absorption of magnesium. One study reported that zinc supplements of 142 mg/day in healthy adult males significantly decreased magnesium absorption and disrupted magnesium balance (the difference between magnesium intake and magnesium loss) (4)

Fiber

Large increases in the intake of dietary fiber have been found to decrease magnesium utilization in experimental studies. However, the extent to which dietary fiber affects magnesium nutritional status in individuals with a varied diet outside the laboratory is not clear (2, 3).

Protein

Dietary protein may affect magnesium absorption. One study in adolescent boys found that magnesium absorption was lower when protein intake was less than 30 grams/day, and higher protein intakes (93 grams/day vs. 43 grams/day) were associated with improved magnesium absorption in adolescents (5).

Vitamin D and calcium

The active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium (6). However, it is not clear whether magnesium absorption is calcitriol-dependent as is the absorption of calcium and phosphate. High calcium intake has not been found to affect magnesium balance in most studies. Inadequate blood magnesium levels are known to result in low blood calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (2, 3).

Deficiency

Magnesium deficiency in healthy individuals who are consuming a balanced diet is quite rare because magnesium is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. The following conditions increase the risk of magnesium deficiency (1):

  • Gastrointestinal disorders: Prolonged diarrhea, Crohn's disease, malabsorption syndromes, celiac disease, surgical removal of a portion of the intestine, and intestinal inflammation due to radiation may all lead to magnesium depletion. 
  • Renal disorders (magnesium wasting): Diabetes mellitus and long-term use of certain diuretics (see Drug interactions) may result in increased urinary loss of magnesium. Multiple other medications can also result in renal magnesium wasting (3).
  • Chronic alcoholism: Poor dietary intake, gastrointestinal problems, and increased urinary loss of magnesium may all contribute to magnesium depletion, which is frequently encountered in alcoholics.
  • Age: Several studies have found that elderly people have relatively low dietary intakes of magnesium (7, 8). Intestinal magnesium absorption tends to decrease with age and urinary magnesium excretion tends to increase with age; thus, suboptimal dietary magnesium intake may increase the risk of magnesium depletion in the elderly (2).

Although severe magnesium deficiency is uncommon, it has been induced experimentally. When magnesium deficiency was induced in humans, the earliest sign was decreased serum magnesium levels (hypomagnesemia). Over time, serum calcium levels also began to decrease (hypocalcemia) despite adequate dietary calcium. Hypocalcemia persisted despite increased secretion of parathyroid hormone (PTH), which regulates calcium homeostasis. Usually, increased PTH secretion quickly results in the mobilization of calcium from bone and normalization of blood calcium levels. As the magnesium depletion progressed, PTH secretion diminished to low levels. Along with hypomagnesemia, signs of severe magnesium deficiency included hypocalcemia, low serum potassium levels (hypokalemia), retention of sodium, low circulating levels of PTH, neurological and muscular symptoms (tremor, muscle spasms, tetany), loss of appetite, nausea, vomiting, and personality changes (3).

The Recommended Dietary Allowance (RDA)

In 1997, the Food and Nutrition Board of the Institute of Medicine increased the recommended dietary allowance (RDA) for magnesium, based on the results of recent, tightly controlled balance studies that utilized more accurate methods of measuring magnesium (2; Table 1). Balance studies are useful for determining the amount of a nutrient that will prevent deficiency; however, such studies provide little information regarding the amount of a nutrient required for chronic disease prevention or optimum health.

Table 1. Recommended Dietary Allowance (RDA) for Magnesium
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months 30 (AI) 30 (AI)
Infants  7-12 months  75 (AI) 75 (AI)
Children  1-3 years  80 80
Children 4-8 years 130 130
Children  9-13 years  240 240
Adolescents  14-18 years  410 360
Adults  19-30 years  400 310
Adults  31 years and older  420 320
Pregnancy  18 years and younger  - 400
Pregnancy  19-30 years - 350
Pregnancy  31 years and older - 360
Breast-feeding  18 years and younger - 360
Breast-feeding  19-30 years - 310
Breast-feeding  31 years and older - 320

Disease Prevention

Metabolic syndrome

Low magnesium intakes have been associated with the diagnosis of metabolic syndrome. The concomitant presentation of several metabolic disorders in an individual, including dyslipidemia, hypertension, insulin resistance, and obesity, increases the risk for type 2 diabetes mellitus and cardiovascular disease. Systemic inflammation, which contributes to the development of metabolic disorders, has been inversely correlated with magnesium intakes in a cross-sectional study of 11,686 middle-aged women; the lowest prevalence of metabolic syndrome was found in the group of women with the highest quintile of magnesium intakes (median intake, 422 mg/day) (9).

Hypertension (high blood pressure)

Large epidemiological study studies suggest a relationship between magnesium and blood pressure. However, the fact that foods high in magnesium (fruit, vegetables, whole grains) are frequently high in potassium and dietary fiber has made it difficult to evaluate the independent effects of magnesium on blood pressure. A prospective cohort study of more than 30,000 male health professionals found an inverse association between dietary fiber, potassium, and magnesium and the development of hypertension over a four-year period (10). In a similar study of more than 40,000 female registered nurses, dietary fiber and dietary magnesium were each inversely associated with systolic and diastolic blood pressures in those who did not develop hypertension over the four-year study period, but neither dietary fiber nor magnesium was related to the risk of developing hypertension (11). The Atherosclerosis Risk in Communities (ARIC) study examined dietary magnesium intake, magnesium blood levels, and risk of developing hypertension in 7,731 men and women over a six-year period (12). The risk of developing hypertension in both men and women decreased as serum magnesium levels increased, but the trend was statistically significant only in women.

However, circulating magnesium represents only 1% of total body stores and is tightly regulated; thus, serum magnesium levels might not best reflect magnesium status. A recent prospective study that followed 5,511 men and women for a median period of 7.6 years found that the highest levels of urinary magnesium excretion corresponded to a 25% reduction in risk of hypertension, but plasma magnesium levels were not correlated with risk of hypertension (13). In cohort of 28,349 women followed for 9.3 years, the risk of hypertension was 7% lower for those with the highest magnesium intakes (434 mg/day vs. 256 mg/day) (14). The relationship between magnesium intake and risk of hypertension suggests that magnesium supplementation might play a role in preventing hypertension; however, randomized controlled trials are needed to assess whether supplemental magnesium might help prevent hypertension in high-risk individuals.

Diabetes mellitus

Public health concerns regarding the epidemics of obesity and type 2 diabetes mellitus and the prominent role of magnesium in glucose metabolism have led scientists to investigate the relationship between magnesium intake and type 2 diabetes mellitus. A prospective study that followed more than 25,000 individuals, 35 to 65 years of age, for seven years found no difference in incidence of diabetes mellitus when comparing the highest (377 mg/day) quintile of magnesium intake to the lowest (268 mg/day) (15). However, inclusion of this study in a meta-analysis of eight cohort studies showed that risk of type 2 diabetes was inversely correlated with magnesium intake (15). A second meta-analysis found that an increase of 100 mg/day in magnesium intake was associated with a 15% decrease in the risk of developing type 2 diabetes (16). The most recent meta-analysis of 13 observational studies, published in the last 15 years and including almost 540,000 individuals and 24,500 new cases of diabetes, found higher magnesium intakes were associated with a lower risk of diabetes (17).

Insulin resistance, which is characterized by alterations in both insulin secretion by the pancreas and insulin action on target tissues, has been linked to magnesium deficiency. An inverse association between magnesium intakes and fasting insulin levels was evidenced in a meta-analysis of 11 cohort studies that followed more than 36,000 participants without diabetes (18). It is thought that pancreatic β-cells, which regulate insulin secretion and glucose tolerance, could become less responsive to changes in insulin sensitivity in magnesium-deficient subjects (19). A randomized, double-blind, placebo-controlled trial, which enrolled 97 individuals (without diabetes and with normal blood pressure) with significant hypomagnesemia (serum magnesium level ≤0.70 mmoles/L), showed that daily consumption of 638 mg of magnesium (from a solution of magnesium chloride) for three months improved the function of pancreatic β-cells, resulting in lower fasting glucose and insulin levels (20). Increased insulin sensitivity also accompanied the correction of magnesium deficiency in patients diagnosed with insulin resistance but not diabetes (21). Another study found that supplementation with 365 mg/day of magnesium (from magnesium aspartate hydrochloride) for six months reduced insulin resistance in 47 overweight individuals even though they displayed normal values of serum and intracellular magnesium (22). This suggests that magnesium might have additive effects on glucose tolerance and insulin sensitivity that go beyond the normalization of physiologic serum concentrations in deficient individuals.

Cardiovascular disease

A number of studies have found decreased mortality from cardiovascular disease in populations who routinely consume "hard" water. Hard (alkaline) water is generally high in magnesium but may also contain more calcium and fluoride than "soft" water, making the cardioprotective effects of hard water difficult to attribute to magnesium alone (23). One large prospective study (almost 14,000 men and women) found a significant trend for increasing serum magnesium levels to be associated with decreased risk of coronary heart disease (CHD) in women but not in men (24). However, the risk of CHD in the lowest quartile of dietary magnesium intake was not significantly higher than the risk in the highest quartile in men or women. This prospective study was included in a meta-analysis of 14 studies that found a 22% lower risk of CHD (but not fatal CHD) per 200 mg/day incremental intake in dietary magnesium (25). In another prospective study, which followed nearly 90,000 female nurses for 28 years, women in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal myocardial infarction) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day) (26). Higher magnesium intakes were associated with an 8%-11% reduction in stroke risk in two meta-analyses of prospective studies, each including over 240,000 participants (27, 28). Additionally, a meta-analysis of 13 prospective studies in over 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium (29). Finally, a meta-analysis of six prospective studies found no association between magnesium intake and cardiovascular mortality risk (30). However, a recent prospective study that followed 3,910 subjects for 10 years found significant correlations between hypomagnesemia and all-cause mortality, including cardiovascular-related mortality (31). Presently, well-controlled intervention trials are required to assess the benefit of magnesium supplementation in the prevention of cardiovascular disease.

Stroke

Occurrence of hypomagnesemia has been reported in patients who suffered from a subarachnoid hemorrhage caused by the rupture of a cerebral aneurysm (32). Poor neurologic outcomes following an aneurysmal subarachnoid hemorrhage (aSAH) have been linked to inappropriate calcium-dependent contraction of arteries (known as cerebral arterial vasospasm), leading to delayed cerebral ischemia (33). Magnesium sulfate is a calcium antagonist and potent vasodilator that has been considered in the prevention of vasospasm after aSAH. Several randomized controlled trials have assessed the effect of intravenous (IV) magnesium sulfate infusions. A meta-analysis of nine randomized controlled trials found that magnesium therapy after aSAH significantly reduced vasospasm but failed to prevent neurologic deterioration or decrease the risk of death (34). The most recent meta-analysis of 13 trials in 2,413 aSAH patients concluded that the infusion of magnesium sulfate had no benefits in terms of neurologic outcome and mortality, despite a reduction in the incidence of delayed cerebral ischemia (35). At present, the data advise against the use of intravenous magnesium in clinical practice for aSAH patients after normalization of their magnesium status.

Complications of heart surgery

Atrial arrhythmia is a condition defined as the occurrence of persistent heart rate abnormalities that often complicate the recovery of patients after cardiac surgery. The use of magnesium in the prophylaxis of postoperative atrial arrhythmia after coronary artery bypass grafting has been evaluated as a sole or adjunctive agent to classical antiarrhythmic molecules (namely, β-blockers and amiodarone) in several prospective, randomized controlled trials. A meta-analysis of 21 intervention studies showed that intravenous magnesium infusions could significantly reduce postoperative atrial arrhythmia in treated compared to untreated patients (36). However, a meta-analysis of five randomized controlled trials concerned with rhythm-control prophylaxis showed that intravenous magnesium added to β-blocker treatment did not decrease the risk of atrial arrhythmia compared to β-blocker alone and was associated with more adverse effects (bradycardia and hypotension) (37). Presently, the findings support the use of β-blockers and amiodarone, but not magnesium, in patients with contraindications to first-line antiarrhythmics.

Osteoporosis

Although decreased bone mineral density (BMD) is the primary feature of osteoporosis, other osteoporotic changes in the collagenous matrix and mineral components of bone may result in bones that are brittle and more susceptible to fracture. Magnesium comprises about 1% of bone mineral and is known to influence both bone matrix and bone mineral metabolism. As the magnesium content of bone mineral decreases, apatite crystals of bone become larger and more brittle. Some studies have found lower magnesium content and larger apatite crystals in bones of women with osteoporosis compared to women without the disease (38). Inadequate serum magnesium levels are known to result in low serum calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (calcitriol), all of which can lead to increased bone loss (see the articles on Vitamin D and Calcium). A study of over 900 elderly men and women found that higher dietary magnesium intakes were associated with increased BMD at the hip in both men and women. However, because magnesium and potassium are present in many of the same foods, the effect of dietary magnesium could not be isolated (39). A cross-sectional study in over 2,000 elderly individuals reported that magnesium intake was positively associated with total-body BMD in white men and women but not in black men and women (40). More recently, a large cohort study conducted in almost two-thirds of the Norwegian population found the level of magnesium in drinking water was inversely correlated with risk of hip fracture (41).

Few studies have addressed the effect of magnesium supplementation on BMD or osteoporosis in humans. In a small group of postmenopausal women with osteoporosis, magnesium supplementation of 750 mg/day for the first six months followed by 250 mg/day for 18 more months resulted in increased BMD at the wrist after one year, with no further increase after two years of supplementation (42). A study in postmenopausal women who were taking estrogen replacement therapy and also a multivitamin found that supplementation with an additional 500 mg/day of magnesium and 600 mg/day of calcium resulted in increased BMD at the heel compared to postmenopausal women receiving only estrogen replacement therapy (43). Evidence is not yet sufficient to suggest that supplemental magnesium could be recommended in the prevention of osteoporosis unless normalization of serum magnesium levels is required. Moreover, it appears that high magnesium levels could be harmful to skeletal health by interfering with the action of the calciotropic hormones, PTH and calcitriol (44). Presently, the potential for increased magnesium intake to influence calcium and bone metabolism warrants more research with particular attention to its role in the prevention and treatment of osteoporosis.

Disease Treatment

The use of pharmacologic doses of magnesium to treat specific diseases is discussed below. Although many of the cited studies utilized supplemental magnesium at doses considerably higher than the tolerable upper intake level (UL), which is 350 mg/day set by the Food and Nutrition Board (see Safety), it is important to note that these studies were all conducted under medical supervision. Because of the potential risks of high doses of supplemental magnesium, especially in the presence of impaired kidney function, any disease treatment trial using magnesium doses higher than the UL should be conducted under medical supervision.

Pregnancy complications

Preeclampsia and eclampsia

Preeclampsia and eclampsia are pregnancy-specific conditions that may occur anytime after 20 weeks of pregnancy through six weeks following birth. Approximately 7% of pregnant women in the US develop preeclampsia-eclampsia. Preeclampsia (sometimes called toxemia of pregnancy) is defined as the presence of elevated blood pressure (hypertension), protein in the urine, and severe swelling (edema) during pregnancy. Eclampsia occurs with the addition of seizures to the triad of symptoms and is a significant cause of perinatal and maternal death (45). Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of eclamptic women do not initially exhibit preeclamptic symptoms (46). For many years, high-dose intravenous magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with preeclampsia-eclampsia late in pregnancy or during labor (47, 48). A systematic review of seven randomized trials compared the administration of magnesium sulfate with diazepam (a known anticonvulsant) treatment on perinatal outcomes in 1,396 women with eclampsia. Risks of recurrent seizures and maternal death were significantly reduced by the magnesium regimen compared to diazepam. Moreover, the use of magnesium for the care of eclamptic women resulted in newborns with higher Apgar scores; there was no significant difference in the risk of preterm birth and perinatal mortality (46). Additional research has confirmed that infusion of magnesium sulfate should always be considered in the management of preeclampsia and eclampsia to prevent initial and recurrent seizures (49).

Perinatal neuroprotection

While intravenous magnesium sulfate is included in the medical care of preeclampsia and eclampsia, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support its use in two additional situations: specific conditions of short-term prolongation of pregnancy and neuroprotection of the fetus in anticipated premature delivery (50). The relationship between magnesium sulfate and risk of cerebral damage in premature infants has been assessed in observational studies. A meta-analysis of six case-control and five prospective cohort studies showed that the use of magnesium significantly reduced the risk of cerebral palsy, as well as mortality (51). However, the high degree of heterogeneity among the cohort studies and the fact that corticosteroid exposure (which is known to decrease antenatal mortality) was higher in the cases of children exposed to magnesium compared to controls imply a cautious interpretation of the results. However, a meta-analysis of five randomized controlled trials, which included a total of 6,145 babies, found that magnesium therapy given to mothers delivering before term decreased the risk of cerebral palsy and gross motor dysfunction, without modifying the risk of other neurologic impairments or mortality in early childhood (52). Another meta-analysis conducted on five randomized controlled trials found that intravenous magnesium administration to newborns who suffered from perinatal asphyxia could be beneficial in terms of short-term neurologic outcomes, although there was no effect on mortality (53). Nevertheless, additional trials are needed to evaluate the long-term benefits of magnesium in pediatric care.

Cardiovascular disease

Hypertension (high blood pressure)

While results from intervention studies have not been entirely consistent (2), the latest review of the data highlighted a therapeutic benefit of magnesium supplements in treating hypertension. A recent meta-analysis examined 22 randomized, placebo-controlled trials of magnesium supplementation conducted in 1,173 individuals with either a normal blood pressure (normotensive) or hypertension, both treated or untreated with medications. Oral supplementation with magnesium (mean dose of 410 mg/day; range of 120 to 973 mg/day) for a median period of 11.3 months significantly reduced systolic blood pressure by 2-3 mm Hg and diastolic blood pressure by 3-4 mm Hg (54); a greater effect was seen at higher doses (≥370 mg/day). The results of 19 of the 22 trials included in the meta-analysis were previously reviewed together with another 25 intervention studies (55). The systematic examination of these 44 trials suggested a blood pressure-lowering effect associated with supplemental magnesium in hypertensive but not in normotensive individuals. Magnesium doses required to achieve a decrease in blood pressure appeared to depend on whether subjects with high blood pressure were treated with antihypertensive medications, including diuretics. Intervention trials on treated subjects showed a reduction in hypertension with magnesium doses from 243 mg/day to 486 mg/day, whereas untreated patients required doses above 486 mg/day to achieve a significant decrease in blood pressure. While oral magnesium supplementation may be helpful in hypertensive individuals who are depleted of magnesium due to chronic diuretic use and/or inadequate dietary intake (56), several dietary factors play a role in hypertension. For example, adherence to the DASH diet — a diet rich in fruit, vegetables, and low-fat dairy and low in saturated and total fats — has been linked to significant reductions in systolic and diastolic blood pressures (57). See the article in the Spring/Summer 2009 Research Newsletter, Dietary and Lifestyle Strategies to Control Blood Pressure.

Myocardial infarction (heart attack)

Results of a meta-analysis of randomized, placebo-controlled trials indicated that an intravenous (IV) magnesium infusion given early after suspected myocardial infarction (MI) could decrease the risk of death. The most influential study included in the meta-analysis was a randomized, placebo-controlled trial in 2,316 patients that found a significant reduction in mortality (7.8% all-cause mortality in the experimental group vs. 10.3% all-cause mortality in the placebo group) in the group of patients given intravenous magnesium sulfate within 24 hours of suspected myocardial infarction (58). Follow-up from one to five years after treatment revealed that the mortality from cardiovascular disease was 21% lower in the magnesium treated group (59). However, a larger placebo-controlled trial that included more than 58,000 patients found no significant reduction in five-week mortality in patients treated with intravenous magnesium sulfate within 24 hours of suspected myocardial infarction, resulting in controversy regarding the efficacy of the treatment (60). A US survey of the treatment of more than 173,000 patients with acute MI found that only 5% were given IV magnesium in the first 24 hours after MI, and that mortality was higher in patients treated with IV magnesium compared to those not treated with magnesium (61). The most recent systematic review of 26 clinical trials, including 73,363 patients, concluded that IV magnesium likely does not reduce mortality following MI and thus should not be utilized as a treatment (62). Thus, the use of IV magnesium sulfate in the therapy of acute MI remains controversial.

Endothelial dysfunction

Vascular endothelial cells line arterial walls where they are in contact with the blood that flows through the circulatory system. Normally functioning vascular endothelium promotes vasodilation when needed, for example, during exercise, and inhibits the formation of blood clots. Conversely, endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. In cardiovascular disease, chronic inflammation is associated with the formation of atherosclerotic plaques in arteries. Atherosclerosis impairs normal endothelial function, increasing the risk of vasoconstriction and clot formation, which may lead to heart attack or stroke (reviewed in 63). Research studies have indicated that pharmacologic doses of oral magnesium may improve endothelial function in individuals with cardiovascular disease. A randomized, double-blind, placebo-controlled trial in 50 men and women with stable coronary artery disease found that six months of oral magnesium supplementation (730 mg/day) resulted in a 12% improvement in flow-mediated vasodilation compared to placebo (64). In other words, the normal dilation response of the brachial (arm) artery to increased blood flow was improved. Magnesium supplementation also resulted in increased exercise tolerance during an exercise stress test compared to placebo. In another study of 42 patients with coronary artery disease who were already taking low-dose aspirin (an inhibitor of platelet aggregation), three months of oral magnesium supplementation (800 to 1,200 mg/day) resulted in an average 35% reduction in platelet-dependent thrombosis, a measure of the propensity of blood to clot (65). Additionally, a study in 657 women participating in the Nurses' Health Study reported that dietary magnesium intake was inversely associated with E-selectin, a marker of endothelial dysfunction (66). In vitro studies using human endothelial cells have provided mechanistic insights into the association of low magnesium concentrations, chronic inflammation, and endothelial dysfunction (67). Finally, since magnesium can function as a calcium antagonist, it has been suggested that it could be utilized to slow down or reverse the calcification of vessels observed in patients with chronic kidney disease. The atherosclerotic process is often accelerated in these subjects, and patients with chronic kidney disease have higher rates of cardiovascular-related mortality compared to the general population (68). Additional studies are needed to assess whether magnesium may be of benefit in improving endothelial function in individuals at high risk for cardiovascular disease.

Diabetes mellitus

Magnesium depletion is commonly associated with both insulin-dependent (type 1) and non-insulin dependent (type 2) diabetes mellitus. Reduced serum levels of magnesium (hypomagnesemia) have been reported in 13.5% to 47.7% of individuals with type 2 diabetes (69). One cause of the depletion may be increased urinary loss of magnesium, which results from increased urinary excretion of glucose that accompanies poorly controlled diabetes. Magnesium depletion has been shown to increase insulin resistance in a few studies and may adversely affect blood glucose control in diabetes (70). One study reported that dietary magnesium supplements (390 mg/day of elemental magnesium for four weeks) improved glucose tolerance in elderly individuals (71). Another small study in nine patients with type 2 diabetes reported that supplemental magnesium (300 mg/day for 30 days), in the form of a liquid, magnesium-containing salt solution, improved fasting insulin levels but did not affect fasting glucose levels (72). Yet, the most recent meta-analysis of nine randomized, double-blind, controlled trials concluded that oral supplemental magnesium may lower fasting plasma glucose levels in individuals with diabetes (73). One randomized, double-blind, placebo-controlled study in 63 individuals with type 2 diabetes and hypomagnesemia found that those taking an oral magnesium chloride solution (638 mg/day of elemental magnesium) for 16 weeks had improved measures of insulin sensitivity and glycemic control compared to those taking a placebo (74). Large-scale, well-controlled studies are needed to determine whether magnesium supplementation has any long-term therapeutic benefit in patients with type 2 diabetes. However, correcting existing magnesium deficiencies may improve glucose metabolism and insulin sensitivity in those with diabetes.

Migraine headaches

Individuals who suffer from recurrent migraine headaches have lower intracellular magnesium levels (demonstrated in both red blood cells and white blood cells) than individuals who do not experience migraines (75). Additionally, the incidence of ionized magnesium deficiency has been found to be higher in women with menstrual migraine compared to women who don't experience migraines with menstruation (76). Oral magnesium supplementation has been shown to increase intracellular magnesium levels in individuals with migraines, leading to the hypothesis that magnesium supplementation might be helpful in decreasing the frequency and severity of migraine headaches. Two early placebo-controlled trials demonstrated modest decreases in the frequency of migraine headaches after supplementation with 600 mg/day of magnesium (75, 77). Another placebo-controlled trial in 86 children with frequent migraine headaches found that oral magnesium oxide (9 mg/kg body weight/day) reduced headache frequency over the 16-week intervention (78). However, there was no reduction in the frequency of migraine headaches with 485 mg/day of magnesium in another placebo-controlled study conducted in 69 adults suffering migraine attacks (79). The efficiency of magnesium absorption varies with the type of oral magnesium complex, and this might explain the conflicting results. Although no serious adverse effects were noted during these migraine headache trials, 19% to 40% of individuals taking the magnesium supplements have reported diarrhea and gastric (stomach) irritation.

The efficacy of magnesium infusions was also investigated in a randomized, single-blind, placebo-controlled, cross-over trial of 30 patients with migraine headaches (80). The administration of 1 gram of intravenous (IV) magnesium sulfate ended the attacks, abolished associated symptoms, and prevented recurrence within 24 hours in nearly 90% of the subjects. While this promising result was confirmed in another trial (81), two additional randomized, placebo-controlled studies found that magnesium sulfate was less effective than other molecules (e.g., metoclopramide) in treating migraines (82, 83). The most recent meta-analysis of five randomized, double-blind, controlled trials reported no beneficial effect of IV magnesium for migraine in adults (84). However, the effect of magnesium should be examined in larger studies targeting primarily migraine sufferers with hypomagnesemia (85).

Asthma

The occurrence of hypomagnesemia may be greater in patients with asthma than in individuals without asthma (86). Several clinical trials have examined the effect of intravenous (IV) magnesium infusions on acute asthmatic attacks. One double-blind, placebo-controlled trial in 38 adults with acute asthma, who did not respond to initial treatment in the emergency room, found improved lung function and decreased likelihood of hospitalization when IV magnesium sulfate was infused compared to a placebo (87). However, another placebo-controlled, double-blind study in 48 adults reported that IV infusion of magnesium sulfate did not improve lung function in patients experiencing an acute asthma attack (88). A systematic review of seven randomized controlled trials (five adult and two pediatric) concluded that IV magnesium sulfate is beneficial in patients with severe, acute asthma (89). In addition, a meta-analysis of five randomized placebo-controlled trials, involving 182 children with severe asthma, found that IV infusion of magnesium sulfate was associated with a 71% reduction in the need for hospitalization (90). In the most recent meta-analysis of 16 randomized controlled trials (11 adult and 5 pediatric), IV magnesium sulfate treatment was associated with a significant improvement of respiratory function in both adults and children with acute asthma treated with β2-agonists and systemic steroids (91). At present, available evidence indicates that IV magnesium infusion is an efficacious treatment for severe, acute asthma; however, oral magnesium supplementation is of no known value in the management of chronic asthma (92-94). Nebulized, inhaled magnesium for treating asthma requires further investigation. A meta-analysis of eight randomized controlled trials in asthmatic adults showed that nebulized, inhaled magnesium sulfate had benefits with respect to improved lung function and decreased hospital admissions (91). However, a recent systematic review of 16 randomized controlled trials, including adults, children, or both, found little evidence that inhaled magnesium sulfate, along with a β2-agonist, improved pulmonary function in patients with acute asthma (95).

Sources

Food sources

A large US national survey indicated that average magnesium intake is about 350 mg/day for men and about 260 mg/day for women — significantly below the current recommended dietary allowance (RDA). Magnesium intakes were even lower in men and women over 50 years of age (8). Such findings suggest that marginal magnesium deficiency may be relatively common in the US.

Since magnesium is part of chlorophyll, the green pigment in plants, green leafy vegetables are rich in magnesium. Unrefined grains (whole grains) and nuts also have high magnesium content. Meats and milk have an intermediate content of magnesium, while refined foods generally have the lowest. Water is a variable source of intake; harder water usually has a higher concentration of magnesium salts (2). Some foods that are relatively rich in magnesium are listed in Table 2, along with their magnesium content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Magnesium
Food Serving Magnesium (mg)
Cereal, all bran ½ cup 112
Cereal, oat bran ½ cup dry 96
Brown rice, medium-grain, cooked 1 cup 86
Fish, mackerel, cooked 3 ounces 82
Spinach, frozen, chopped, cooked ½ cup 78
Almonds 1 ounce (23 almonds) 77
Swiss chard, chopped, cooked ½ cup 75
Lima beans, large, immature seeds, cooked ½ cup 63
Cereal, shredded wheat 2 biscuits 61
Peanuts 1 ounce 48
Molasses, blackstrap 1 tablespoon 48
Hazelnuts 1 ounce (21 hazelnuts) 46
Okra, frozen, cooked ½ cup 37
Milk, 1% fat 8 fluid ounces 34
Banana 1 medium 32

Supplements

Magnesium supplements are available as magnesium oxide, magnesium gluconate, magnesium chloride, and magnesium citrate salts, as well as a number of amino acid chelates, including magnesium aspartate. Magnesium hydroxide is used as an ingredient in several antacids (96).

Safety

Toxicity

Adverse effects have not been identified from magnesium occurring naturally in food. However, adverse effects from excess magnesium have been observed with intakes of various magnesium salts (i.e., supplemental magnesium) (6). The initial symptom of excess magnesium supplementation is diarrhea — a well-known side effect of magnesium that is used therapeutically as a laxative. Individuals with impaired kidney function are at higher risk for adverse effects of magnesium supplementation, and symptoms of magnesium toxicity have occurred in people with impaired kidney function taking moderate doses of magnesium-containing laxatives or antacids. Elevated serum levels of magnesium (hypermagnesemia) may result in a fall in blood pressure (hypotension). Some of the later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac rhythm, and deterioration of kidney function, are related to severe hypotension. As hypermagnesemia progresses, muscle weakness and difficulty breathing may occur. Severe hypermagnesemia may result in cardiac arrest (2, 3). The Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper intake level (UL) for magnesium at 350 mg/day (Table 3); this UL represents the highest level of daily supplemental magnesium intake likely to pose no risk of diarrhea or gastrointestinal disturbance in almost all individuals. The FNB cautions that individuals with renal impairment are at higher risk for adverse effects from excess supplemental magnesium intake. However, the FNB also notes that there are some conditions that may warrant higher doses of magnesium under medical supervision (2).

Table 3. Tolerable Upper Intake Level (UL) for Supplemental Magnesium
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 65 
Children 4-8 years   110 
Children 9-13 years   350 
Adolescents 14-18 years 350 
Adults 19 years and older 350 
*Source of intake should be from food and formula only.

Drug interactions

Magnesium interferes with the absorption of digoxin (a heart medication), nitrofurantoin (an antibiotic), and certain anti-malarial drugs, which could potentially reduce drug efficacy. Bisphosphonates (e.g., alendronate and etidronate), which are drugs used to treat osteoporosis, and magnesium should be taken two hours apart so that the absorption of the bisphosphonate is not inhibited. Magnesium has also been found to reduce the efficacy of chlorpromazine (a tranquilizer), penicillamine, oral anticoagulants, and the quinolone and tetracycline classes of antibiotics. Because intravenous magnesium has increased the effects of certain muscle-relaxing medications used during anesthesia, it is advisable to let medical staff know if you are taking oral magnesium supplements, laxatives, or antacids prior to surgical procedures. High doses of furosemide (Lasix) and some thiazide diuretics (e.g., hydrochlorothiazide), if taken for extended periods, may result in magnesium depletion (96, 97). Moreover, long-term use (three months or longer) of proton-pump inhibitors (drugs used to reduce the amount of stomach acid) may increase the risk of hypomagnesemia (98, 99). Many other medications may also result in renal magnesium loss (3).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the latest RDA for magnesium intake (400-420 mg/day for men and 310-320 mg/day for women). Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement may ensure an intake of at least 100 mg of magnesium/day. Few multivitamin/mineral supplements contain more than 100 mg of magnesium due to its bulk. Because magnesium is plentiful in foods, eating a varied diet that provides green vegetables, whole grains, and nuts daily should provide the rest of an individual's magnesium requirement.

Older adults (>50 years)

Older adults are less likely than younger adults to consume enough magnesium to meet their needs and should therefore take care to eat magnesium-rich foods in addition to taking a multivitamin/mineral supplement daily. Since older adults are more likely to have impaired kidney function, they should avoid taking more than 350 mg/day of supplemental magnesium without medical consultation (see Safety).


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2014 by:
Stella L. Volpe, Ph.D., R.D., L.D.N., F.A.C.S.M.
Professor and Chair
Department of Nutrition Sciences
Drexel University

Copyright 2001-2017  Linus Pauling Institute


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Manganese

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Manganese is a mineral element that is both nutritionally essential and potentially toxic. The derivation of its name from the Greek word for magic remains appropriate, because scientists are still working to understand the diverse effects of manganese deficiency and manganese toxicity in living organisms (1).

Function

Manganese (Mn) plays an important role in a number of physiologic processes as a constituent of multiple enzymes and an activator of other enzymes (2).

Antioxidant function

Manganese superoxide dismutase (MnSOD) is the principal antioxidant enzyme in the mitochondria. Because mitochondria consume over 90% of the oxygen used by cells, they are especially vulnerable to oxidative stress. The superoxide radical is one of the reactive oxygen species produced in mitochondria during ATP synthesis. MnSOD catalyzes the conversion of superoxide radicals to hydrogen peroxide, which can be reduced to water by other antioxidant enzymes (3).

Metabolism

A number of manganese-activated enzymes play important roles in the metabolism of carbohydrates, amino acids, and cholesterol (4). Pyruvate carboxylase, a manganese-containing enzyme, and phosphoenolpyruvate carboxykinase (PEPCK), a manganese-activated enzyme, are critical in gluconeogenesis — the production of glucose from non-carbohydrate precursors. Arginase, another manganese-containing enzyme, is required by the liver for the urea cycle, a process that detoxifies ammonia generated during amino acid metabolism (3). In the brain, the manganese-activated enzyme, glutamine synthetase, converts the amino acid glutamate to glutamine. Glutamate is an excitotoxic neurotransmitter and a precursor to an inhibitory neurotransmitter, γ-aminobutyric acid (GABA) (5, 6).

Bone development

Manganese deficiency results in abnormal skeletal development in a number of animal species. Manganese is the preferred cofactor of enzymes called glycosyltransferases; these enzymes are required for the synthesis of proteoglycans that are needed for the formation of healthy cartilage and bone (7).

Wound healing

Wound healing is a complex process that requires increased production of collagen. Manganese is required for the activation of prolidase, an enzyme that functions to provide the amino acid, proline, for collagen formation in human skin cells (8). A genetic disorder known as prolidase deficiency results in abnormal wound healing among other problems, and is characterized by abnormal manganese metabolism (7). Glycosaminoglycan synthesis, which requires manganese-activated glycosyltransferases, may also play an important role in wound healing (9).

Nutrient interactions

Iron

Although the specific mechanisms for manganese absorption and transport have not been determined, some evidence suggests that iron and manganese can share common absorption and transport pathways (10). Absorption of manganese from a meal decreases as the meal's iron content increases (7). Iron supplementation (60 mg/day for four months) was associated with decreased blood manganese levels and decreased MnSOD activity in white blood cells, indicating a reduction in manganese nutritional status (11). Additionally, an individual's iron status can affect manganese bioavailability. Intestinal absorption of manganese is increased during iron deficiency, and increased iron stores (ferritin levels) are associated with decreased manganese absorption (12). Men generally absorb less manganese than women; this may be related to the fact that men usually have higher iron stores than women (13). Further, iron deficiency has been shown to increase the risk of manganese accumulation in the brain (14).

Magnesium

Supplemental magnesium (200 mg/day) has been shown to slightly decrease manganese bioavailability in healthy adults, either by decreasing manganese absorption or by increasing its excretion (15).

Calcium

In one set of studies, supplemental calcium (500 mg/day) slightly decreased manganese bioavailability in healthy adults. As a source of calcium, milk had the least effect, while calcium carbonate and calcium phosphate had the greatest effect (15). Several other studies have found minimal effects of supplemental calcium on manganese metabolism (16).

Deficiency

Manganese deficiency has been observed in a number of animal species. Signs of manganese deficiency include impaired growth, impaired reproductive function, skeletal abnormalities, impaired glucose tolerance, and altered carbohydrate and lipid metabolism. In humans, demonstration of a manganese deficiency syndrome has been less clear (2, 7). A child on long-term total parenteral nutrition (TPN) lacking manganese developed bone demineralization and impaired growth that were corrected by manganese supplementation (17). Young men who were fed a low-manganese diet developed decreased serum cholesterol levels and a transient skin rash (18). Blood calcium, phosphorus, and alkaline phosphatase levels were also elevated, which may indicate increased bone remodeling as a consequence of insufficient dietary manganese. Young women fed a manganese-poor diet developed mildly abnormal glucose tolerance in response to an intravenous (IV) infusion of glucose (16). Overall, manganese deficiency is not common, and there is more concern for toxicity related to manganese overexposure (see Safety).

The Adequate Intake (AI)

Because there was insufficient information on manganese requirements to set a Recommended Dietary Allowance (RDA), the Food and Nutrition Board (FNB) of the Institute of Medicine set an adequate intake (AI). Since overt manganese deficiency has not been documented in humans eating natural diets, the FNB based the AI on average dietary intakes of manganese determined by the Total Diet Study — an annual survey of the mineral content of representative American diets (4). AI values for manganese are listed in Table 1 in milligrams (mg)/day by age and gender. Manganese requirements are increased in pregnancy and lactation (4).

Table 1. Adequate Intake (AI) for Manganese
Life Stage Age Males
(mg/day)
Females
(mg/day)
Infants  0-6 months 0.003 0.003
Infants  7-12 months   0.6  0.6
Children  1-3 years  1.2 1.2
Children  4-8 years  1.5 1.5
Children  9-13 years  1.9 1.6
Adolescents  14-18 years  2.2 1.6
Adults  19 years and older 2.3 1.8
Pregnancy  all ages  2.0
Breast-feeding  all ages  2.6

Disease Prevention

Low dietary manganese or low levels of manganese in blood or tissue have been associated with several chronic diseases. Although manganese insufficiency is not currently thought to cause the diseases discussed below, more research may be warranted to determine whether suboptimal manganese nutritional status contributes to certain disease processes.

Osteoporosis

Women with osteoporosis have been found to have decreased plasma or serum levels of manganese and also an enhanced plasma response to an oral dose of manganese (19, 20), suggesting they may have lower manganese status than women without osteoporosis. Yet, a more recent study in postmenopausal women with and without osteoporosis did not find any differences in plasma levels of manganese (21). A study in healthy postmenopausal women found that a supplement containing manganese (5 mg/day), copper (2.5 mg/day), and zinc (15 mg/day) in combination with a calcium supplement (1,000 mg/day) was more effective than the calcium supplement alone in preventing spinal bone loss over a two-year period (22). However, the presence of other trace elements in the supplement makes it impossible to determine whether manganese supplementation was the beneficial agent for maintaining bone mineral density.

Diabetes mellitus

Manganese deficiency results in glucose intolerance similar to diabetes mellitus in some animal species, but studies examining the manganese status of diabetic humans have generated mixed results. In one study, whole blood manganese levels did not differ significantly between 57 diabetics and 28 non-diabetic controls (23). However, urinary manganese excretion tended to be slightly higher in 185 diabetics compared to 185 non-diabetic controls (24). A case-control study of 250 diabetic and non-diabetic individuals found that type 2 diabetic individuals had higher serum manganese levels than non-diabetics (25). However, a more recent study in 257 type 2 diabetics and 166 non-diabetic controls found lower blood levels of manganese in the diabetic patients (26). Additionally, a study of functional manganese status found the activity of the antioxidant enzyme, MnSOD, was lower in the white blood cells of diabetics than in non-diabetics (27). Neither 15 mg nor 30 mg of oral manganese improved glucose tolerance in diabetics or non-diabetic controls when given at the same time as an oral glucose challenge (28). Although manganese appears to play a role in glucose metabolism, there is little evidence that manganese supplementation improves glucose tolerance in diabetic or non-diabetic individuals.  

Epilepsy (seizure disorders)

Manganese deficient rats are more susceptible to seizures than manganese sufficient rats, and rats that are genetically prone to epilepsy have lower than normal brain and blood manganese levels. Certain subgroups of humans with epilepsy reportedly have lower whole blood manganese levels than non-epileptic controls. One study found blood manganese levels of individuals with epilepsy of unknown origin were lower than those of individuals whose epilepsy was induced by trauma (e.g., head injury) or disease, suggesting a possible genetic relationship between epilepsy and abnormal manganese metabolism. While manganese deficiency does not appear to be a cause of epilepsy in humans, the relationship between manganese metabolism and epilepsy deserves further research (7, 29).

Sources

Food sources

In the US, estimated average dietary manganese intakes range from 2.1 to 2.3 mg/day for men and 1.6 to 1.8 mg/day for women. People eating vegetarian diets and Western-type diets may have manganese intakes as high as 10.9 mg/day (4). Rich sources of manganese include whole grains, nuts, leafy vegetables, and teas. Foods high in phytic acid, such as beans, seeds, nuts, whole grains, and soy products, or foods high in oxalic acid, such as cabbage, spinach, and sweet potatoes, may slightly inhibit manganese absorption. Although teas are rich sources of manganese, the tannins present in tea may moderately reduce the absorption of manganese (15). Intake of other minerals, including iron, calcium, and phosphorus, have been found to limit retention of manganese (4). The manganese content of some manganese-rich foods is listed in milligrams (mg) in Table 2. For more information on the nutrient content of foods, search the USDA food composition database (30).

Table 2. Some Food Sources of Manganese
Food Serving Manganese (mg)
Pineapple, raw ½ cup, chunks 0.77
Pineapple juice ½ cup (4 fl. oz.) 0.63
Pecans 1 ounce (19 halves) 1.28
Almonds 1 ounce (23 whole kernels) 0.65
Peanuts 1 ounce 0.55
Instant oatmeal (prepared with water) 1 packet 0.99
Raisin bran cereal 1 cup 0.78-3.02
Brown rice, cooked ½ cup 1.07
Whole wheat bread 1 slice 0.60
Pinto beans, cooked ½ cup 0.39
Lima beans, cooked ½ cup 0.49
Navy beans, cooked ½ cup 0.48
Spinach, cooked ½ cup 0.84
Sweet potato, cooked ½ cup, mashed 0.44
Tea (green) 1 cup (8 ounces) 0.41-1.58
Tea (black) 1 cup (8 ounces) 0.18-0.77

Breast milk and infant formulas

Infants are exposed to varying amounts of manganese depending on their source of nutrition. Manganese concentrations in breast milk, cow-based formula, and soy-based formula range from 3 to 10 micrograms/liter (μg/L), 30 to 50 μg/L, and 200 to 300 μg/L, respectively. However, bioavailability of manganese from breast milk is higher than from infant formulas, and manganese deficiencies in breast-fed infants or toxicities in formula-fed infants have not been reported (31).

Water

Manganese concentrations in drinking water range from 1 to 100 μg/L, but most sources contain less than 10 μg/L (32). The US Environmental Protection Agency (EPA) recommends 0.05 mg (50 μg)/L as the maximum allowable manganese concentration in drinking water (33).

Supplements

Several forms of manganese are found in supplements, including manganese gluconate, manganese sulfate, manganese ascorbate, and amino acid chelates of manganese. Manganese is available as a stand-alone supplement or in combination products (34). Relatively high levels of manganese ascorbate may be found in a bone/joint health product containing chondroitin sulfate and glucosamine hydrochloride (see Safety).

Safety

Toxicity

Inhaled manganese

Manganese toxicity may result in multiple neurologic problems and is a well-recognized health hazard for people who inhale manganese dust, such as welders and smelters (1, 4). Unlike ingested manganese, inhaled manganese is transported directly to the brain before it can be metabolized in the liver (35). The symptoms of manganese toxicity generally appear slowly over a period of months to years. In its worst form, manganese toxicity can result in a permanent neurological disorder with symptoms similar to those of Parkinson's disease, including tremors, difficulty walking, and facial muscle spasms. This syndrome, often called manganism, is sometimes preceded by psychiatric symptoms, such as irritability, aggressiveness, and even hallucinations (36, 37). Additionally, environmental or occupational inhalation of manganese can cause an inflammatory response in the lungs (38). Clinical symptoms of effects to the lung include cough, acute bronchitis, and decreased lung function (39).

Methylcyclopentadienyl manganese tricarbonyl (MMT)

MMT is a manganese-containing compound used in gasoline as an anti-knock additive. Although it has been used for this purpose in Canada for more than 20 years, uncertainty about adverse health effects from inhaled exhaust emissions kept the US EPA from approving its use in unleaded gasoline. In 1995, a US court decision made MMT available for widespread use in unleaded gasoline (35). A study in Montreal, where MMT had been used for more than 10 years, found airborne manganese levels to be similar to those in areas where MMT was not used (40). A more recent Canadian study found higher concentrations of respirable manganese in an urban versus a rural area, but average concentrations in both areas were below the safe level set by the US EPA (41). The impact of long-term exposure to low levels of MMT combustion products, however, has not been thoroughly evaluated and will require additional study (42).

Ingested manganese

Limited evidence suggests that high manganese intakes from drinking water may be associated with neurological symptoms similar to those of Parkinson's disease. Severe neurological symptoms were reported in 25 people who drank water contaminated with manganese, and probably other contaminants, from dry cell batteries for two to three months (43). Water manganese levels were found to be 14 mg/liter (mg/L) almost two months after symptoms began and may have already been declining (1). A study of older adults in Greece found a high prevalence of neurological symptoms in those exposed to water manganese levels of 1.8 to 2.3 mg/L (44), while a study in Germany found no evidence of increased neurological symptoms in people drinking water with manganese levels ranging from 0.3 to 2.2 mg/L compared to those drinking water containing less than 0.05 mg/L (45). Manganese in drinking water may be more bioavailable than manganese in food. However, none of the studies measured dietary manganese, so total manganese intake in these cases is unknown. In the US, the EPA recommends 0.05 mg/L as the maximum allowable manganese concentration in drinking water (33).

Additionally, more recent studies have shown that children exposed to high levels of manganese through drinking water experience cognitive and behavioral deficits (46). For instance, a cross-sectional study in 142 10-year old children, who were exposed to a mean manganese water concentration of 0.8 mg/L, found that children exposed to higher manganese levels had significantly lower scores on three tests of intellectual function (47). Another study associated high levels of manganese in tap water with hyperactive behavioral disorders in children (48). These and other recent reports have raised concern over the neurobehavioral effects of manganese exposure in children (46).

A single case of manganese toxicity was reported in a person who took large amounts of mineral supplements for years (49), while another case was reported as a result of a person taking a Chinese herbal supplement (36). Manganese toxicity resulting from foods alone has not been reported in humans, even though certain vegetarian diets could provide up to 20 mg/day of manganese (4, 32).

Intravenous manganese

Manganese neurotoxicity has been observed in individuals receiving total parenteral nutrition, both as a result of excessive manganese in the solution and as an incidental contaminant (50). Neonates are especially vulnerable to manganese-related neurotoxicity (51). Infants receiving manganese-containing TPN can be exposed to manganese concentrations about 100-fold higher than breast-fed infants (31). Because of potential toxicities, some argue against including manganese in parenteral nutrition (52).

Individuals with increased susceptibility to manganese toxicity

  • Chronic liver disease: Manganese is eliminated from the body mainly in bile. Thus, impaired liver function may lead to decreased manganese excretion. Manganese accumulation in individuals with cirrhosis or liver failure may contribute to neurological problems and Parkinson's disease-like symptoms (1, 34).
  • Newborns: The newborn brain may be more susceptible to manganese toxicity due to a greater expression of receptors for the manganese transport protein (transferrin) in developing nerve cells and the immaturity of the liver's bile elimination system (4).
  • Children: Compared to adults, infants and children have higher intestinal absorption of manganese, as well as lower biliary excretion of manganese (46). Thus, children are especially susceptible to any negative, neurotoxic effects of manganese. Indeed, several recent studies in school-aged children have reported deleterious cognitive and behavioral effects following excessive manganese exposure (47, 48, 53).
  • Iron-deficient populations: Iron deficiency has been shown to increase the risk of manganese accumulation in the brain (14).

Due to the severe implications of manganese neurotoxicity, the Food and Nutrition Board (FNB) of the Institute of Medicine set very conservative tolerable upper intake levels (UL) for manganese; the ULs are listed in Table 3 according to age (4).

Table 3. Tolerable Upper Intake Level (UL) for Manganese
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 2
Children 4-8 years 3
Children 9-13 years 6
Adolescents 14-18 years 9
Adults 19 years and older 11
*Source of intake should be from food and formula only.

Drug interactions

Magnesium-containing antacids and laxatives and the antibiotic medication, tetracycline, may decrease the absorption of manganese if taken together with manganese-containing foods or supplements (34).

High levels of manganese in supplements marketed for bone/joint health

Two studies have found that supplements containing a combination of glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate are beneficial in relieving pain due to mild or moderate osteoarthritis of the knee when compared to a placebo (54, 55). The dose of elemental manganese supplied by the supplements was 30 mg/day for eight weeks in one study (55) and 40 mg/day for six months in the other (54). No adverse effects were reported during either study, and blood manganese levels were not measured. Neither study compared the treatment containing manganese ascorbate to a treatment containing glucosamine hydrochloride and chondroitin sulfate without manganese ascorbate, so it is impossible to determine whether the supplement would have resulted in the same benefit without high doses of manganese.

Linus Pauling Institute Recommendation

The adequate intake (AI) for manganese (2.3 mg/day for adult men and 1.8 mg/day for adult women) appears sufficient to prevent deficiency in most individuals. The daily intake of manganese most likely to promote optimum health is not known. Following the Linus Pauling Institute recommendation to take a multivitamin/multimineral supplement containing 100% of the daily values (DV) of most nutrients will generally provide 2 mg/day of manganese in addition to that in foods. Because of the potential for toxicity and the lack of information regarding benefit, manganese supplementation beyond 100% of the DV (2 mg/day) is not recommended. There is presently no evidence that the consumption of a manganese-rich plant-based diet results in manganese toxicity.

Older adults (>50 years)

The requirement for manganese is not known to be higher for older adults. However, liver disease is more common in older adults and may increase the risk of manganese toxicity by decreasing the elimination of manganese from the body (see Toxicity). Manganese supplementation beyond 100% of the DV (2 mg/day) is not recommended. 


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2010 by:
Michael Aschner, Ph.D.
Chair, Department of Nutrition
Gray E.B. Stahlman Professor of Neuroscience
Professor of Pediatrics
Professor of Pharmacology
Vanderbilt University Medical Center

Copyright 2001-2017  Linus Pauling Institute


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24.  el-Yazigi A, Hannan N, Raines DA. Urinary excretion of chromium, copper, and manganese in diabetes mellitus and associated disorders. Diabetes Res. 1991;18(3):129-134.  (PubMed)

25.  Ekin S, Mert N, Gunduz H, Meral I. Serum sialic acid levels and selected mineral status in patients with type 2 diabetes mellitus. Biol Trac Elem Res. 2003;94:193-201.  (PubMed)

26.  Kazi TG, Afridi HI, Kazi N, et al. Copper, chromium, manganese, iron, nickel, and zinc levels in biological samples of diabetes mellitus patients. Biol Trace Elem Res. 2008;122(1):1-18.  (PubMed)

27.  Nath N, Chari SN, Rathi AB. Superoxide dismutase in diabetic polymorphonuclear leukocytes. Diabetes. 1984;33(6):586-589.  (PubMed)

28.  Walter RM, Aoki TT, Keen CL. Acute oral manganese does not consistently affect glucose tolerance in non diabetic and type II diabetic humans. J Trace Elem Exp Med. 1991;4:73-79.

29.  Carl GF, Gallagher BB. Manganese and epilepsy. In: Klimis-Tavantzis DL, ed. Manganese in health and disease. Boca Raton: CRC Press, Inc; 1994:133-157.

30.  US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 22. 2009. Available at: http://ndb.nal.usda.gov//. Accessed 3/3/10.

31.  Aschner JL, Aschner M. Nutritional aspects of manganese homeostasis. Mol Aspects Med. 2005;26(4-5):353-362.  (PubMed)

32. Keen CL, Zidenberg-Cherr S. Manganese toxicity in humans and experimental animals. In: Klimis-Tavantzis DL, ed. Manganese in health and disease. Boca Raton: CRC Press, Inc; 1994:193-205.

33. EPA Office of Water. Current Drinking Water Standards. Environmental Protection Agency, [Web page]. Available at: http://www.epa.gov/safewater/mcl.html. Accessed 9/14/06.

34.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

35.  Davis JM. Methylcyclopentadienyl manganese tricarbonyl: health risk uncertainties and research directions. Environ Health Perspect. 1998;106 Suppl 1:191-201.  (PubMed)

36.  Pal PK, Samii A, Calne DB. Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology. 1999;20(2-3):227-238.  (PubMed)

37.  Aschner M, Aschner JL. Manganese neurotoxicity: cellular effects and blood-brain barrier transport. Neurosci Biobehav Rev. 1991;15(3):333-340.  (PubMed)

38.  Han J, Lee JS, Choi D, et al. Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: implication in manganese-induced pulmonary inflammation. Toxicol Appl Pharmacol. 2009;235(3):261-267.  (PubMed)

39.  Roels H, Lauwerys R, Buchet JP, et al. Epidemiological survey among workers exposed to manganese: effects on lung, central nervous system, and some biological indices. Am J Ind Med. 1987;11(3):307-327.  (PubMed)

40.  Zayed J, Thibault C, Gareau L, Kennedy G. Airborne manganese particulates and methylcyclopentadienyl manganese tricarbonyl (MMT) at selected outdoor sites in Montreal. Neurotoxicology. 1999;20(2-3):151-157.  (PubMed)

41.  Bolte S, Normandin L, Kennedy G, Zayed J. Human exposure to respirable manganese in outdoor and indoor air in urban and rural areas. J Toxicol Environ Health A. 2004;67(6):459-467.  (PubMed)

42.  Aschner M. Manganese: brain transport and emerging research needs. Environ Health Perspect. 2000;108 Suppl 3:429-432.  (PubMed)

43. Kawamura R. Intoxication by manganese in well water. Kisasato Archives of Experimental Medicine. 1941;18:145-169.

44. Kondakis XG, Makris N, Leotsinidis M, Prinou M, Papapetropoulos T. Possible health effects of high manganese concentration in drinking water. Arch Environ Health. 1989;44(3):175-178.  (PubMed)

45. Vieregge P, Heinzow B, Korf G, Teichert HM, Schleifenbaum P, Mosinger HU. Long term exposure to manganese in rural well water has no neurological effects. Can J Neurol Sci. 1995;22(4):286-289.  (PubMed)

46.  Ljung K, Vahter M. Time to re-evaluate the guideline value for manganese in drinking water? Environ Health Perspect. 2007;115(11):1533-1538.  (PubMed)

47.  Wasserman GA, Liu X, Parvez F, et al. Water manganese exposure and children's intellectual function in Araihazar, Bangladesh. Environ Health Perspect. 2006;114(1):124-129.  (PubMed)

48.  Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D. Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water. Environ Health Perspect. 2007;115(1):122-127.  (PubMed)

49.  Keen C, Zidenberg-Cherr S. Manganese toxicity in humans and experimental animals. In: Klimis-Tavantzis D (ed). Manganese in health and disease. Boca Raton: CRC Press, Inc.; 1994.

50.  Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann NY Acad Sci. 2004;1012:115-128.  (PubMed)

51.  Erikson KM, Thompson K, Aschner J, Aschner M. Manganese neurotoxicity: a focus on the neonate. Pharmacol Ther. 2007;113(2):369-377.  (PubMed)

52.  Hardy IJ, Gillanders L, Hardy G. Is manganese an essential supplement for parenteral nutrition? Curr Opin Clin Nutr Metab Care. 2008;11(3):289-296.  (PubMed)

53.  Wright RO, Amarasiriwardena C, Woolf AD, Jim R, Bellinger DC. Neuropsychological correlates of hair arsenic, manganese, and cadmium levels in school-age children residing near a hazardous waste site. Neurotoxicology. 2006;27(2):210-216.  (PubMed)

54.  Das A, Jr., Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage. 2000;8(5):343-350.  (PubMed)

55.  Leffler CT, Philippi AF, Leffler SG, Mosure JC, Kim PD. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med. 1999;164(2):85-91.  (PubMed)

Molybdenum

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Summary

  • The molybdenum atom is part of the molybdenum cofactor in the active site of four enzymes in humans: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime reducing component. (More information)
  • Excess molybdenum intake causes fatal copper deficiency diseases in grazing animals. Their rumen is the site of high sulfide generation, and the interaction of molybdenum with sulfur results in the formation of thiomolybdates. Tetrathiomolybdate, a thiomolybdate with four sulfur atoms, can form complexes with copper preventing its absorption and blocking the activity of copper-dependent enzymes. (More information)
  • In humans, tetrathiomolybdate therapy has been developed for Wilson's disease, a genetic disease in which the accumulation of copper in tissues leads to liver and brain damage. More recently, tetrathiomolybdate use has been explored for the treatment of cancer and inflammatory diseases. (More information)
  • Mutations in the molybdenum cofactor biosynthetic pathway lead to the combined deficiency of all molybdenum-dependent enzymes. Molybdenum cofactor deficiency Type A is due to mutations in the MOCS1 gene, while Type B deficiency is caused by mutations in MOCS2. Both Type A and Type B deficiencies result in the loss of sulfite oxidase activity, also observed in isolated sulfite oxidase deficiency and characterized by severe neurologic abnormalities in affected patients. (More information)
  • New treatment options for molybdenum cofactor deficiency are being considered. Cyclic pyranopterin monophosphate supplementation to patients with Type A deficiency could correct the metabolic disorder and prevent neurologic deterioration. Patients with Type B deficiency do not lack this molecule and therefore cannot benefit from this treatment. However, a recent study showed that pyridoxine supplementation in these patients could alleviate suffering by abolishing seizures. (More information)
  • The molybdenum content of foods depends on the molybdenum content of soils, which can vary considerably. Variation in esophageal cancer incidence worldwide has been linked to the molybdenum content in soils and food. Similar observations have been made in order to identify the factors associated with a population's extended lifespan. (More information)

 

Molybdenum is an essential trace element for virtually all life forms. It functions as a cofactor for a number of enzymes that catalyze important chemical transformations in the global carbon, nitrogen, and sulfur cycles (1). Thus, molybdenum-dependent enzymes are not only required for human health, but also for the health of our ecosystem.

Function

The biological form of the molybdenum atom is an organic molecule known as the molybdenum cofactor (Moco) present in the active site of Moco-containing enzymes (molybdoenzymes) (2). In humans, molybdenum is known to function as a cofactor for four enzymes:

  • Sulfite oxidase catalyzes the transformation of sulfite to sulfate, a reaction that is necessary for the metabolism of sulfur-containing amino acids (methionine and cysteine).
  • Xanthine oxidase catalyzes the breakdown of nucleotides (precursors to DNA and RNA) to form uric acid, which contributes to the plasma antioxidant capacity of the blood.
  • Aldehyde oxidase and xanthine oxidase catalyze hydroxylation reactions that involve a number of different molecules with similar chemical structures. Xanthine oxidase and aldehyde oxidase also play a role in the metabolism of drugs and toxins (3).
  • Mitochondrial amidoxime reducing component (mARC) was described only recently (4), and its precise function is under investigation. Initial studies showed that mARC forms a three-component enzyme system with cytochrome b5 and NADH cytochrome b5 reductase that catalyzes the detoxification of mutagenic N-hydroxylated bases (5).

Of these enzymes, sulfite oxidase is known to be crucial for human health. Hereditary xanthinuria, characterized by a deficiency in xanthine oxidase (Type 1) or by a deficiency in both xanthine oxidase and aldehyde oxidase (Type 2), can be asymptomatic (6). However, in less than half of the cases, affected individuals exhibit a range of health issues of variable severity (7, 8).

Nutrient interactions

Copper

An early study reported that molybdenum intakes of 500 μg/day and 1,500 μg/day from sorghum increased urinary copper excretion (2). However, the results of a more recent, well-controlled study indicated that very high dietary molybdenum intakes (up to 1,500 μg/day) did not adversely affect copper nutritional status in eight, healthy young men (9).

Tetrathiomolybdate

Excess dietary molybdenum has been found to result in copper deficiency in grazing animals (ruminants). In the digestive tract of ruminants, the formation of compounds containing sulfur and molybdenum, known as thiomolybdates, prevents the absorption of copper and can cause fatal copper-dependent disorders (10). Tetrathiomolybdate (TM) is a molecule that can form high-affinity complexes with copper, controlling free copper (copper that is not bound to ceruloplasmin), and inhibiting copper chaperones and copper-containing enzymes (11, 12). TM's ability to lower free copper levels is exploited in the treatment of Wilson's disease, a genetic disorder characterized by copper accumulation in tissues responsible for hepatic and neurologic disorders. Neurologic worsening has been linked with toxic levels of free copper in the serum of neurologically presenting patients. TM therapy seems able to stabilize neurologic status and prevent neurologic deterioration in these patients, as opposed to the standard initial treatment of choice (13).

Copper is also a required cofactor for enzymes involved in inflammation and angiogenesis, known to accelerate cancer progression and metastasis. Copper depletion studies employing TM have been initiated in patients with advanced malignancies with the aim of preventing disease progression or relapse. These pilot trials showed promising results in individuals with metastatic kidney cancer (14), metastatic colorectal cancer (15), and breast cancer with high risk of relapse (16). TM was relatively well-tolerated and stabilized disease or prevented relapse in correlation with copper depletion. TM's efficacy is also investigated in animal models of inflammatory and immune-related diseases (17, 18) and, at this point, clinical studies are needed to evaluate whether copper depletion could stabilize diseases and improve survival in humans, as suggested by a trial of TM therapy with patients with biliary cirrhosis (19).

Deficiency

Dietary molybdenum deficiency has never been observed in healthy people (2).

Acquired molybdenum deficiency

The only documented case of acquired molybdenum deficiency occurred in a patient with Crohn's disease on long-term total parenteral nutrition (TPN) without molybdenum added to the TPN solution (20). The patient developed rapid heart and respiratory rates, headaches, and night blindness, and ultimately became comatose. The patient was diagnosed with defects in uric acid production and sulfur amino acid metabolism. The patient's clinical condition improved and the amino acid intolerance disappeared when the TPN solution was discontinued and instead supplemented with molybdenum in the form of ammonium molybdate (160 μg/day) (20).

Inherited molybdenum cofactor deficiency

Because molybdenum functions only in the form of the Moco in humans, any disturbance of Moco metabolism can disrupt the function of all molybdoenzymes. Current understanding of the essentiality of molybdenum in humans is based largely on the study of individuals with very rare inborn metabolic disorders caused by a deficiency in Moco. Moco is synthesized de novo by a multistep metabolic pathway involving four genes: MOCS1, MOCS2, MOCS3, and GPHN (Figure 1). To date, more than 60 mutations affecting mostly MOCS1 and MOCS2 have been identified (21).

Figure 1. Molybdenum Cofactor Biosynthesis. Molybdenum cofactor (Moco) is synthesized de novo by a multistep metabolic pathway involving four genes: MOCS1, MOCS2, MOCS3, and GPHN.

The absence of a functional Moco has a direct impact on the activity of the molybdoenzymes. Metabolic disorders specifically associated with deficiency in sulfite oxidase activity include an accumulation of sulfite, taurine, S-sulfocysteine, and thiosulfate (see Figure 2 below). This metabolic profile is identical to that observed in isolated sulfite oxidase deficiency (ISOD), an inherited condition caused by mutations in SUOX gene that codes for sulfite oxidase (22). Compared with ISOD, Moco deficiency (MocoD) also affects the xanthine pathway and leads to an accumulation of hypoxanthine and xanthine, and low to undetectable uric acid levels in blood (see Figure 3 below). MocoD and ISOD have been diagnosed in more than 100 individuals worldwide. However the global incidence of MocoD is likely to be underestimated as a result of a failure to diagnose or to report (21, 23, 24). Both disorders result from recessive traits, meaning that only individuals who inherit two copies of the abnormal gene (one from each parent) develop the disease. Individuals who inherit only one copy of the abnormal gene are known as carriers of the trait but do not exhibit any symptoms. ISOD and MocoD can be diagnosed relatively early in pregnancy (10-14 weeks' gestation) by enzyme activity assays using amniotic cell and chorionic villus sampling and by genetic testing (23, 25).

Figure 2. Sulfur Amino Acid Metabolism.

Figure 3. Figure 3. Uric Acid Production. Adenine is converted to hypoxanthine; hypoxanthine is converted to xanthine via the enzymes, xanthine oxidase and aldehyde oxidase. Xanthine can be further metabolized to uric acid via xanthine oxidase.

MocoD and ISOD typically occur in the first days of life, although a few cases of MocoD with late presentation have been described (26-28). The loss of sulfite oxidase activity in ISOD and MocoD leads to severe neurological dysfunction characterized by cerebral atrophy, mental retardation, intractable seizures, and dislocation of ocular lenses. At present, it is not clear whether the neurologic effects are a result of the accumulation of a toxic metabolite, such as sulfite, or inadequate sulfate production. Patients with ISOD and MocoD were also found with elevated excretion of α-amino adipic semialdehyde (α-AASA) (29). α-AASA accumulation is the metabolic signature of a deficiency in α-AASA dehydrogenase observed in patients with pyridoxine-dependent epilepsy. The enzymatic deficiency in these individuals causes an increase in α-AASA and its cyclic form piperideine-6-carboxylate (P6C). P6C can trap pyridoxal-5-phosphate (PLP), the active form of vitamin B6 (pyridoxine), leading to a deficiency in PLP, which is corrected with supplemental pyridoxine. A decrease in PLP has also been observed in the cerebrospinal fluid from ISOD and MocoD patients (30). It is not clear whether sulfite is responsible for the accumulation of α-AASA and the deficiency in PLP in ISOD and MocoD patients. Nevertheless, pyridoxine and folic acid supplementation in patients with MocoD successfully normalized the PLP level and abolished seizures in two patients with mutations in MOCS2 (MocoD Type B) (31). Although anti-seizure medications and dietary restriction of sulfur-containing amino acids may be beneficial in some cases (32), there are no treatment options for patients with mutations in the MOCS2, GPHN (MocoD Type C), or SUOX genes. Pyridoxine supplementation is a new option being considered to alleviate specific clinical features in patients.

A successful treatment using cyclic pyranopterin monophosphate (cPMP) has been described for patients with mutations in the MOCS1 gene, and a clinical trial using a retrospective approach is under way to assess its safety. The MOCS1 gene controls the initial step in the Moco biosynthetic pathway, catalyzing the conversion of guanosine triphosphate into cPMP. Therefore, patients with mutations in the MOCS1 gene lack cPMP. Daily administration of cPMP to patients resolved all metabolic abnormalities associated with defective sulfite oxidase and xanthine pathways and prevented further signs of neurologic deterioration (33, 34). Early diagnosis and initiation of treatment are essential to ensure success (34). Since cPMP replacement therapy can only benefit MocoD Type A, additional treatment methods are required.

The Recommended Dietary Allowance (RDA)

The recommended dietary allowance (RDA) for molybdenum was most recently revised in January 2001 (2). It was based on the results of nutritional balance studies conducted in eight, healthy young men under controlled laboratory conditions (35, 36). The RDA values for molybdenum are listed in Table 1 in micrograms (μg)/day by age and gender. Adequate intake (AI) levels were set for infants based on mean molybdenum intake from human milk, exclusively.

Table 1. Recommended Dietary Allowance (RDA) for Molybdenum
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months 2 (AI) 2 (AI)
Infants  7-12 months   3 (AI)  3 (AI)
Children  1-3 years  17 17
Children 4-8 years  22 22
Children  9-13 years  34 34
Adolescents  14-18 years  43 43
Adults  19 years and older 45 45
Pregnancy  all ages  50
Breast-feeding  all ages  50

Disease Prevention

Esophageal cancer

Linxian is a small region in northern China where the incidence of cancer of the esophagus and stomach is very high (10 times higher than the average in China and 100 times higher than the average in the US). The soil in this region is low in molybdenum and other mineral elements; therefore, dietary molybdenum intake is also low. Studies conducted in other areas of low and high incidence of esophageal cancer showed that content of molybdenum and zinc in hair and nails is significantly lower in inhabitants of high-risk regions compared to cold spots. Moreover, esophageal cancer patients display reduced content of the trace elements compared to healthy relatives (37, 38).

Increased intake of nitrosamines, which are known carcinogens, may be one of a number of dietary and environmental factors that contributes to the development of esophageal cancer in residents of high-risk regions. Adding ammonium molybdate to the soil may help decrease the risk of esophageal cancer by limiting nitrosamine exposure. It is not clear whether dietary molybdenum supplementation is beneficial in decreasing the risk of esophageal cancer. Intervention trials conducted in Linxian area using dietary supplementation of minerals and vitamins, including molybdenum (30 μg/day), failed to decrease incidence and mortality rates of esophageal cancer or other cancers over a five-year period (reviewed in 39).

Longevity

Rugao is a county in Jiangsu province (China) renowned for the longevity of its residents. Extended longevity can hardly be attributed to significant differences in traditions, lifestyles, or dietary habits among the residents, and most longevous people are not related to one another, limiting the possible influence of genetics. However, the county has a large number of different soils whose compositions could affect the distribution of trace elements in water and crops and ultimately be linked with human health and longevity. Significant correlations were found between the ratio of people over 90 years old per 100,000 inhabitants and trace elements, including molybdenum, in soils, drinking water, and rice, which constitute key elements of their natural environment (40). The percentage of long-lived people (>80 years old) in Zhongxiang (Hubei province) was also positively linked to the content of molybdenum in their staple food, rice (41). In these regions, it is likely that combinations of trace elements contribute to optimum health and longevity as opposed to the sole effect of molybdenum.

Sources

Food sources

The Total Diet Study, an annual survey of the mineral content in the typical American diet, indicates that the dietary intake of molybdenum averages 76 μg/day for women and 109 μg/day for men. Thus, usual molybdenum intakes are well above the RDA for molybdenum. Legumes, such as beans, lentils, and peas, are the richest sources of molybdenum. Grain products and nuts are considered good sources, while animal products, fruit, and many vegetables are generally low in molybdenum (2). Because the molybdenum content of plants depends on the soil molybdenum content and other environmental conditions, the molybdenum content of foods can vary considerably (38, 42).

Supplements

Molybdenum in nutritional supplements is generally in the form of sodium molybdate or ammonium molybdate (43).

Safety

Toxicity

The toxicity of molybdenum compounds appears to be relatively low in humans. Increased serum levels of uric acid and ceruloplasmin (an iron-oxidizing enzyme) have been reported in occupationally exposed workers in a molybdenite roasting plant (44). Gout-like symptoms have also been reported in an Armenian population consuming 10 to 15 milligrams (mg) of molybdenum from food daily (45). In other studies, blood and urinary uric acid levels were not elevated by molybdenum intakes up to 1.5 mg/day (2). There has been only one report of acute toxicity related to molybdenum from a dietary supplement: an adult male reportedly consumed a total of 13.5 mg of molybdenum over a period of 18 days (300-800 μg/day) and developed acute psychosis with hallucinations, seizures, and other neurologic symptoms (46). However, a controlled study in four, healthy young men found that molybdenum intakes, ranging from 22 μg/day to 1,490 μg/day (almost 1.5 mg/day), elicited no serious adverse effects when molybdenum was given for 24 days (35).

The Food and Nutrition Board (FNB) of the Institute of Medicine found little evidence that molybdenum excess was associated with adverse health outcomes in generally healthy people. To determine the tolerable upper intake level (UL), the FNB selected adverse reproductive effects in rats as the most sensitive index of toxicity and applied a large uncertainty factor because animal data were used (2). The UL for molybdenum is listed by age group in Table 2.

Table 2. Tolerable Upper Intake Level (UL) for Molybdenum
Age Group UL (μg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 300
Children 4-8 years 600
Children 9-13 years 1,100 (1.1 mg/day)
Adolescents 14-18 years 1,700 (1.7 mg/day)
Adults 19 years and older 2,000 (2.0 mg/day)
*Source of intake should be from food and formula only.

Drug interactions

High doses of molybdenum have been found to inhibit the metabolism of acetaminophen in rats (47); however, it is not known whether this occurs at clinically relevant doses in humans.

Linus Pauling Institute Recommendation

The RDA for molybdenum (45 μg/day for adults) is sufficient to prevent deficiency. Although the intake of molybdenum most likely to promote optimum health is not known, there is presently no evidence that intakes higher than the RDA are beneficial. Most people in the US consume more than sufficient molybdenum in their diets, making supplementation unnecessary. Following the Linus Pauling Institute's general recommendation to take a multivitamin/mineral supplement that contains 100% of the daily values (DV) for most nutrients is likely to provide 75 μg/day of molybdenum because the DV for molybdenum has not been revised to reflect the most recent RDA. Although the amount of molybdenum presently found in most multivitamin/mineral supplements is higher than the RDA, it is well below the tolerable upper intake level (UL) of 2,000 μg/day and should be safe for adults.

Older adults (>50 years)

Because aging has not been associated with significant changes in the requirement for molybdenum (2), our recommendation for older adults is the same as that for adults 50 and younger.


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2013 by:
Ralf R. Mendel, Ph.D.
Professor of Plant Biology and Head
Department of Plant Biology
Braunschweig University of Technology
Braunschweig, Germany

Copyright 2001-2017  Linus Pauling Institute


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22.  Tan WH, Eichler FS, Hoda S, et al. Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature. Pediatrics. 2005;116(3):757-766.  (PubMed)

23.  Shalata A, Mandel H, Dorche C, et al. Prenatal diagnosis and carrier detection for molybdenum cofactor deficiency type A in northern Israel using polymorphic DNA markers. Prenat Diagn. 2000;20(1):7-11.  (PubMed)

24.  Kikuchi K, Hamano S, Mochizuki H, Ichida K, Ida H. Molybdenum cofactor deficiency mimics cerebral palsy: differentiating factors for diagnosis. Pediatr Neurol. 2012;47(2):147-149.  (PubMed)

25.  Johnson JL. Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. Prenat Diagn. 2003;23(1):6-8.  (PubMed)

26.  Hughes EF, Fairbanks L, Simmonds HA, Robinson RO. Molybdenum cofactor deficiency-phenotypic variability in a family with a late-onset variant. Dev Med Child Neurol. 1998;40(1):57-61.  (PubMed)

27.  Vijayakumar K, Gunny R, Grunewald S, et al. Clinical neuroimaging features and outcome in molybdenum cofactor deficiency. Pediatr Neurol. 2011;45(4):246-252.  (PubMed)

28.  Alkufri F, Harrower T, Rahman Y, et al. Molybdenum cofactor deficiency presenting with a parkinsonism-dystonia syndrome. Mov Disord. 2013;28(3):399-401.  (PubMed)

29.  Mills PB, Footitt EJ, Ceyhan S, et al. Urinary AASA excretion is elevated in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. J Inherit Metab Dis. 2012;35(6):1031-1036.  (PubMed)

30.  Footitt EJ, Heales SJ, Mills PB, Allen GF, Oppenheim M, Clayton PT. Pyridoxal 5'-phosphate in cerebrospinal fluid; factors affecting concentration. J Inherit Metab Dis. 2011;34(2):529-538.  (PubMed)

31.  Struys EA, Nota B, Bakkali A, Al Shahwan S, Salomons GS, Tabarki B. Pyridoxine-dependent epilepsy with elevated urinary α-amino adipic semialdehyde in molybdenum cofactor deficiency. Pediatrics. 2012;130(6):e1716-1719.  (PubMed)

32.  Johnson JL, Duran M. Molybdenum cofactor deficiency and isolated sulfite deficiency. In: Scriver RC, ed. Metabolic and molecular bases of inherited disease. New York: μgraw-Hill; 2001:3163-3177.

33.  Veldman A, Santamaria-Araujo JA, Sollazzo S, et al. Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics. 2010;125(5):e1249-1254.  (PubMed)

34.  Hitzert MM, Bos AF, Bergman KA, et al. Favorable outcome in a newborn with molybdenum cofactor type A deficiency treated with cPMP. Pediatrics. 2012;130(4):e1005-1010.  (PubMed)

35.  Turnlund JR, Keyes WR, Peiffer GL. Molybdenum absorption, excretion, and retention studied with stable isotopes in young men at five intakes of dietary molybdenum. Am J Clin Nutr. 1995;62(4):790-796.  (PubMed)

36.  Turnlund JR, Keyes WR, Peiffer GL, Chiang G. Molybdenum absorption, excretion, and retention studied with stable isotopes in young men during depletion and repletion. Am J Clin Nutr. 1995;61(5):1102-1109.  (PubMed)

37.  Nouri M, Chalian H, Bahman A, et al. Nail molybdenum and zinc contents in populations with low and moderate incidence of esophageal cancer. Arch Iran Med. 2008;11(4):392-396.  (PubMed)

38.  Ray SS, Das D, Ghosh T, Ghosh AK. The levels of zinc and molybdenum in hair and food grain in areas of high and low incidence of esophageal cancer: a comparative study. Glob J Health Sci. 2012;4(4):168-175.  (PubMed)

39.  Goodman M, Bostick RM, Kucuk O, Jones DP. Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radic Biol Med. 2011;51(5):1068-1084.  (PubMed)

40.  Huang B, Zhao Y, Sun W, et al. Relationships between distributions of longevous population and trace elements in the agricultural ecosystem of Rugao County, Jiangsu, China. Environ Geochem Health. 2009;31(3):379-390.  (PubMed)

41.  Lv J, Wang W, Krafft T, Li Y, Zhang F, Yuan F. Effects of several environmental factors on longevity and health of the human population of Zhongxiang, Hubei, China. Biol Trace Elem Res. 2011;143(2):702-716.  (PubMed)

42.  Mills CF, Davis GK. Molybdenum. In: Mertz W, ed. Trace elements in human and animal nutrition. 5th ed. San Diego: Academic Press; 1987:429-463.

43.  Molybdenum. In: Hendler S, Rorvik D, eds. PDR for Nutritional Supplements. 2nd ed. Montvale: Physicians' Desk Reference Inc.; 2008:425-429.

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45.  Vyskocil A, Viau C. Assessment of molybdenum toxicity in humans. J Appl Toxicol. 1999;19(3):185-192.  (PubMed)

46.  Momcilovic B. A case report of acute human molybdenum toxicity from a dietary molybdenum supplement--a new member of the "Lucor metallicum" family. Arh Hig Rada Toksikol. 1999;50(3):289-297.  (PubMed)

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Phosphorus

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Summary

  • Phosphorus is an essential structural component of cell membranes and nucleic acids but is also involved in several biological processes, including bone mineralization, energy production, cell signaling through phosphorylation reactions, and regulation of acid-base homeostasis. (More information)
  • Dietary phosphorus deficiency is uncommon and often only observed in cases of near-total starvation or in rare inherited disorders involving renal phosphorus wasting. Symptoms include loss of appetite, muscle weakness, bone fragility, numbness in the extremities, and rickets in children. (More information)
  • The recommended dietary allowance (RDA), 700 mg/day of phosphorus for healthy adults, is meant to sustain serum phosphorus concentrations within the physiologic range of 2.5 to 4.5 mg/dL. (More information)
  • Phosphorus is found in most food sources and is a component of many commonly used food additives. The bioavailability of phosphorus from food is usually very high with the exception of phytate phosphorus in plant sources, such as grains, legumes, and seeds, which is poorly digested. (More information)
  • Estimates of dietary phosphorus intakes in the US population are likely to be inaccurate because the amounts of phosphorus-based food additives used in processed foods are not always included in the nutrient content database used to compute nutrient intakes. (More information)
  • High serum phosphorus concentrations have been associated with increased rates of cardiovascular disease and mortality in subjects with or without kidney disease. Abnormal deposition of calcium phosphate in soft tissues may predispose individuals to vascular dysfunction and cardiovascular disease. (More information)
  • Hyperphosphatemia, which is common in individuals with impaired kidney function, characterizes a condition in which there is an abnormally high accumulation of phosphorus in blood, because the kidneys are not able to effectively excrete it. (More information)
  • The tolerable upper intake level (UL) for phosphorus is 4,000 mg/day for generally healthy adults. Yet, daily phosphorus intakes in excess of the RDA have been linked to an increased risk of all-cause mortality in healthy individuals. (More information)
  • Observational studies suggest that a low calcium-to-phosphorus intake ratio may be detrimental to bone health, especially in women at increased risk for osteoporosis. (More information)

Phosphorus is an essential mineral that is required by every cell in the body for normal function (1). Bound to oxygen in all biological systems, phosphorus is found as phosphate (PO43-) in the body. Approximately 85% of the body's phosphorus is found in bones and teeth (2).

Function

Phosphorus is a major structural component of bone in the form of a calcium phosphate salt called hydroxyapatite. Phospholipids (e.g., phosphatidylcholine) are major structural components of cell membranes. All energy production and storage are dependent on phosphorylated compounds, such as adenosine triphosphate (ATP) and creatine phosphate. Nucleic acids (DNA and RNA), which are responsible for the storage and transmission of genetic information, are long chains of phosphate-containing molecules. A number of enzymes, hormones, and cell-signaling molecules depend on phosphorylation for their activation. Phosphorus also helps maintain normal acid-base balance (pH) by acting as one of the body's most important buffers. Additionally, the phosphorus-containing molecule 2,3-diphosphoglycerate (2,3-DPG) binds to hemoglobin in red blood cells and regulates oxygen delivery to the tissues of the body (1).

Regulation

Parathyroid hormone-vitamin D and FGF-23-endocrine axis

Dietary phosphorus is readily absorbed in the small intestine, and in healthy individuals, excess phosphorus is excreted by the kidneys under the regulatory action of the endocrine hormones: parathyroid hormone (PTH), vitamin D, and fibroblast growth factor-23 (FGF-23). The acute regulation of blood calcium and phosphorus concentrations is controlled through the actions of PTH and the active form of vitamin D. A slight drop in blood calcium levels (e.g., in the case of inadequate calcium intake) is sensed by the parathyroid glands, resulting in their increased secretion of PTH, which rapidly decreases urinary excretion of calcium but increases urinary excretion of phosphorus and stimulates bone resorption. This results in the release of bone mineral (calcium and phosphate) — actions that restore serum calcium concentrations. Although the action is not immediate, PTH also stimulates conversion of vitamin D to its active form (1,25-dihydroxyvitamin D; calcitriol) in the kidneys. Increased circulating 1,25-dihydroxyvitamin D in turn stimulates increased intestinal absorption of both calcium and phosphorus. A third hormone, FGF-23, plays a central role in phosphorus homeostasis. FGF-23 is secreted by bone-forming cells (osteoblasts/osteocytes) in response to increases in phosphorus intake. In a negative feedback loop, FGF-23 inhibits the production and stimulates the degradation of 1,25-dihydroxyvitamin D, as well as promotes an increase in urinary phosphorus excretion independently of PTH and 1,25-dihydroxyvitamin D (3).

Deficiency

Inadequate phosphorus intake rarely results in abnormally low serum phosphorus levels (hypophosphatemia) because renal reabsorption of phosphorus increases to compensate for decreased intake. The effects of moderate to severe hypophosphatemia may include loss of appetite, anemia, muscle weakness, bone pain, rickets (in children), osteomalacia (in adults), increased susceptibility to infection, numbness and tingling of the extremities, difficulty walking, and respiratory failure. Severe hypophosphatemia may occasionally be life threatening. Since phosphorus is so widespread in food, dietary phosphorus deficiency is usually seen only in cases of near-total starvation. Other individuals at risk of hypophosphatemia include alcoholics, diabetics recovering from an episode of diabetic ketoacidosis, patients with respiratory alkalosis, and starving or anorexic patients on refeeding regimens that are high in calories but too low in phosphorus (reviewed in 4). Hypophosphatemia caused by inherited disorders of phosphorus homeostasis (phosphorus wasting disorders) has been linked to elevated urinary excretion or impaired renal reabsorption of phosphorus in affected subjects (reviewed in 5).

The Recommended Dietary Allowance (RDA)

The recommended dietary allowance (RDA) for phosphorus is based on the maintenance of normal serum phosphorus levels in adults (2.5-4.5 milligrams/deciliter [mg/dL]) and is believed to represent adequate phosphorus intakes to meet cellular and bone formation needs (6; Table 1). The RDA, which is the average daily intake that meets the requirements of 97.5% of healthy individuals in a specific life stage and gender group, is based on the estimated average requirement (EAR; 580 mg/day of phosphorus for adults) — the nutrient intake that meets the requirements of 50% of healthy individuals in a particular life stage and gender group.

Table 1. Recommended Dietary Allowance (RDA) for Phosphorus
Life Stage Age Males
(mg/day)
Females
(mg/day)
Infants  0-6 months 100 (AI) 100 (AI)
Infants  7-12 months  275 (AI) 275 (AI)
Children  1-3 years  460 460
Children  4-8 years  500 500
Children  9-13 years   1,250 1,250
Adolescents  14-18 years  1,250 1,250
Adults  19 years and older 700 700
Pregnancy 18 years and younger 1,250
Pregnancy  19 years and older 700
Breast-feeding  18 years and younger 1,250
Breast-feeding 19 years and older 700

Sources

Food sources

Phosphorus is found in most food because it is a critical constituent of all living organisms. Dairy foods, cereal products, meat, and fish are particularly rich sources of phosphorus (7). Phosphorus is also a component of many food additives that are used in food processing and is present in cola soft drinks as phosphoric acid (8). In the nationally representative NHANES survey, phosphorus intakes were well above the EAR and RDA, with average daily intakes of 1,602 mg in men and 1,128 mg in women (8). Dietary phosphorus derived from food additives is not always included in food nutrient composition databases, so the total amount of phosphorus consumed by the average person in the US can be underestimated by more than 20% (9). Segments of the US population who consume more highly processed foods and whose phosphorus intakes approach the tolerable upper intake level of 4,000 mg/day are thought by some to be at high risk of developing adverse health outcomes (see Safety) (7, 9).

Bioavailability

The phosphorus in plant seeds (beans, peas, cereals, and nuts) is present in a storage form of phosphate called phytic acid or phytate. Only about 50% of the phosphorus from phytate is available to humans because we lack enzymes (phytases) that liberate phosphorus from phytate (10). Yeasts possess phytases, so whole grains incorporated into leavened breads have more bioavailable phosphorus than whole grains incorporated into breakfast cereals or flat breads (6). Because reducing dietary phosphorus absorption may benefit individuals with impaired kidney function who are at risk of hyperphosphatemia (serum phosphorus at or above the high-normal range), protein sources of phosphorus in grain-based vegetarian diets may be preferred over meat-based diets (11). Table 2 lists a number of phosphorus-rich foods, along with their phosphorus content in milligrams (mg). For more information on the nutrient content of food, search USDA food composition database.

Table 2. Some Food Sources of Phosphorus
Food Serving Phosphorus (mg)
Salmon (chinook, cooked) 3 ounces* 315
Yogurt (plain, nonfat) 8 ounces 306
Milk (skim) 8 ounces 247
Halibut (Atlantic or Pacific, cooked) 3 ounces 244
Turkey (light meat, cooked) 3 ounces 217
Chicken (light meat, cooked) 3 ounces 135-196
Beef (chuck eye steak, cooked) 3 ounces 179
Lentils# (cooked) ½ cup 178
Almonds# 1 ounce (23 nuts) 136
Cheese, mozzarella (part skim) 1 ounce 131
Peanuts# 1 ounce 108
Egg (hard-boiled) 1 large 86
Bread, whole-wheat 1 slice 68
Carbonated cola drink 12 ounces 41
Bread, enriched white 1 slice 25
*A three-ounce serving of meat or fish is about the size of a deck of cards.
#Phosphorus from nuts, seeds, and grains is about 50% less bioavailable than phosphorus from other sources (12).

Supplements

Phosphorus content of multivitamin/mineral (MVM) supplements varies; a US national survey found that MVM supplements contributed an average of 108 mg to daily phosphorus intake (10). Sodium phosphate and potassium phosphate salts are used for the treatment of hypophosphatemia that occurs in hereditary disorders of phosphate wasting, and their use requires medical supervision. Calcium phosphate salts are sometimes used as calcium supplements (13). Commonly used over-the-counter and prescription drugs also contribute to phosphorus intakes at levels yet to be defined (10).

Safety

Toxicity

Several disorders characterized by serum phosphorus levels above normal (hyperphosphatemia) have been described, including those resulting from increased intestinal absorption of phosphate salts taken by mouth or by colonic absorption of the phosphate salts in enemas (1). Yet, the disruption of phosphorus homeostasis is most often associated with excretion failure in patients with chronic kidney disease (CKD) or end-stage renal disease (advanced CKD). When kidney function is only 20% of normal, even phosphorus intakes within the recommended range may lead to hyperphosphatemia. Hyperphosphatemia may also affect individuals with inappropriately low parathyroid hormone (PTH) levels (hypoparathyroidism) as they lack PTH stimulation of renal phosphate excretion and fail to stimulate synthesis of 1,25-dihydroxyvitamin D (the active form of vitamin D). These individuals cannot excrete excess phosphorus in the absence of both hormones (14). Elevated serum phosphorus concentrations have been associated with accelerated disease progression in individuals with impaired kidney function and have been linked to increased risk of adverse health outcomes in the general population (9, 15).

High serum phosphorus concentrations in the general population

High serum phosphorus within the normal range (2.5-4.5 mg/dL) has recently been associated with increased incidence of cardiovascular disease (CVD) in individuals with normal kidney function. Two studies conducted in the general population and in individuals with prior CVD have linked high-normal serum phosphorus concentrations (≥3.5 mg/dL) to a greater cardiovascular risk (16, 17). Additional observational studies found that serum phosphorus concentrations equal to or above 4 mg/dL were associated with a doubling of the risk of developing incident CKD and end-stage renal disease in individuals free of renal disease at study inception (18). In a prospective cohort study, which followed 4,005 healthy young adults for more than 15 years, higher serum phosphorus within the normal range was also associated with left ventricular hypertrophy, a condition often linked to adverse cardiovascular outcomes (19). In another study of 3,088 middle-aged healthy participants followed for over 17 years, serum phosphorus concentrations in the top quartile of the normal range were associated with a two-fold higher risk of heart failure compared to the lowest quartile (≥3.5 mg/dL vs. <2.9 mg/dL) (16). It is thought that vascular calcification, which may explain the relationship between high phosphorus and cardiovascular disease risk in CKD patients (see Hyperphosphatemia in subjects with kidney disease), contributes to this association in individuals with normal kidney function, even when their serum phosphorus is within the normal range and their intakes are below the tolerable upper intake level (UL) (20, 21).

Phosphorus homeostasis is tightly regulated by the PTH/vitamin D/FGF-23 axis in individuals with normal kidney function (see Regulation). Increased secretion of PTH and FGF-23 helps maintain phosphorus serum concentrations in the normal range (2.5-4.5 mg/dL) even in the setting of high phosphorus intake (9). This contributes to serum phosphorus being only weakly correlated to phosphorus consumption (22). Of note, sustained increases in FGF-23 and PTH are commonly observed during CKD in order to maintain normal serum phosphorus concentrations despite a reduction in urinary phosphorus excretion (23). Elevated FGF-23, rather than serum phosphorus, appears to be an early marker of disordered phosphorus homeostasis and a predictor of adverse health outcomes in patients with early-stage CKD (23, 24). Thus, it is reasonable to assume that measuring serum phosphorus in people with normal renal function cannot adequately reflect early disturbances in phosphorus metabolism due to high phosphorus consumption.

Hyperphosphatemia in subjects with kidney disease

Observational studies have reported high rates of mortality and cardiovascular events in association with high blood phosphorus levels in subjects with CKD. A meta-analysis of 13 prospective cohort studies, conducted in over 90,000 CKD patients, found an 18% increase in all-cause mortality per 1 mg/dL increase in serum phosphorus concentration above 3.5 mg/dL. A 10% increased risk in cardiovascular disease (CVD)-related death was also calculated for each 1 mg/dL higher concentration in the meta-analysis of three studies (25).

Although no causality has been established between vitamin D deficiency and CVD risk, it has been suggested that failure to produce 1,25-dihydroxyvitamin D in hyperphosphatemic individuals may modify the risk of developing cardiovascular and renal disease, as well as worsen kidney insufficiency in CKD patients (26). Another plausible mechanism for hyperphosphatemia-induced cardiovascular dysfunction is the deposition of calcium phosphate in non-skeletal tissues, especially the vasculature (27). Indeed, high phosphorus concentrations may stimulate the expression of bone specific markers in blood vessel-forming cells, resulting in a shift in their functions; this process, called osteochondrogenic differentiation, transforms vascular smooth muscle cells (VSMCs) into bone-like cells. The culture of human aortic VSMCs in hyperphosphatemic conditions was found to result in the mineralization of the extracellular media, mimicking in vivo vascular calcification (28). Vascular calcification has been associated with at least a three-fold increase in risk for cardiovascular events and mortality; the risk for cardiovascular events is twice as high (i.e., six-fold increased risk) in individuals with kidney insufficiency (29).

In CKD patients, disorders in bone remodeling may result in excess release of phosphorus and calcium into the blood, which exacerbates hyperphosphatemia and vascular calcification and accelerates the decline of kidney function. Currently, dietary phosphorus restriction is recommended to normalize serum concentrations in CKD patients, although the impact on CVD and mortality risks is not known.

The Tolerable Upper Intake Level (UL)

To avoid the adverse effects of hyperphosphatemia, the US Food and Nutrition Board set a tolerable upper intake level (UL) for oral phosphorus in generally healthy individuals (6; Table 3). The lower UL for individuals over 70 years of age, compared to younger age groups, reflects the increased likelihood of impaired kidney function in elderly individuals. The UL does not apply to individuals with significantly impaired kidney function or other health conditions known to increase the risk of hyperphosphatemia.

Table 3. Tolerable Upper Intake Level (UL) for Phosphorus
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 3,000 (3.0 g)
Children 4-8 years   3,000 (3.0 g)
Children 9-13 years   4,000 (4.0 g)
Adolescents 14-18 years 4,000 (4.0 g)
Adults 19-70 years 4,000 (4.0 g)
Adults 71 years and older 3,000 (3.0 g)
Pregnancy 3,500 (3.5 g)
Breast-feeding 4,000 (4.0 g)
*Source of intake should be from food and formula only.

Adverse health outcomes have been associated with normal serum phosphorus concentrations, suggesting that in individuals with adequate kidney function, the measurement of tightly controlled serum phosphorus levels may misrepresent the detrimental effect of high dietary phosphorus intake (see High serum phosphorus concentrations in the general population). While phosphorus intakes below the UL of 4,000 mg/day should not result in hyperphosphatemia or cardiovascular risk in healthy adults ages 19-70 years, a recent study found that daily phosphorus intakes more than twice the RDA (i.e., >1,400 mg/day) were significantly associated with an increased risk of all-cause mortality (30).

Is high phosphorus intake detrimental to bone health?

Some investigators are concerned about the increasing amounts of phosphates in the diet, which they largely attribute to phosphoric acid in some soft drinks and the increasing use of phosphate additives in processed foods (31, 32). High serum phosphorus has been shown to impair synthesis of the active form of vitamin D (1,25-dihydroxyvitamin D) in the kidneys, reduce blood calcium, and lead to increased PTH release by the parathyroid glands (8). PTH stimulation then results in decreased urinary calcium excretion and increased bone resorption; both contribute to serum calcium concentrations returning to normal (8). If sustained, elevated PTH levels could have an adverse effect on bone mineral content, but this effect appears to be observed with diets that are high in phosphorus and low in calcium, underscoring the importance of a balanced dietary calcium-to-phosphorus ratio. In a small cross-sectional study, which enrolled 147 premenopausal women with adequate calcium intakes, participants with lower calcium-to-phosphorus (Ca:P) intakes (ratios ≤0.5) had significantly higher serum PTH levels and urinary calcium excretion than those with higher Ca:P ratios (ratios >0.5) (33). A controlled trial in 10 young women found no adverse effects of a phosphorus-rich diet (3,000 mg/day) on bone-related hormones and biochemical markers of bone resorption when dietary calcium intakes were maintained at almost 2,000 mg/day (Ca:P = 0.66), again demonstrating the importance of the balance between dietary calcium and phosphorus (34).

A cross-sectional study conducted in 2,344 Brazilian men and women (median age, 58 years) showed an association between higher phosphorus intakes and increased risk of fracture. Yet, intakes of other minerals and vitamins relevant to bone health, such as calcium, magnesium, and vitamin D, were below the RDA in this population, whereas phosphorus intakes were close to the RDA (35). While it appears that hormonal and calcium disorders might be prevented by an adequate calcium-to-phosphorus intake ratio, there is no convincing evidence that the dietary phosphorus levels experienced in the US adversely affect bone mineral density. Nevertheless, the substitution of phosphate-containing soft drinks and snack foods for milk and other calcium-rich food may represent a serious risk to bone health (see the article on Calcium) (36).

Drug interactions

Aluminum-containing antacids reduce the absorption of dietary phosphorus by forming aluminum phosphate, which is unabsorbable. When consumed in high doses, aluminum-containing antacids can produce abnormally low blood phosphorus levels (hypophosphatemia), as well as aggravate phosphorus deficiency due to other causes (37). The reduction of stomach acidity by proton-pump inhibitors may also limit the efficacy of phosphate-binder therapy in patients with kidney failure (38). Excessively high doses of 1,25-dihydroxyvitamin D, the active form of vitamin D, or its analogs, may result in hyperphosphatemia (6).

Potassium supplements or potassium-sparing diuretics taken together with phosphorus supplements may result in high blood levels of potassium (hyperkalemia). Hyperkalemia can be a serious problem, resulting in life-threatening heart rhythm abnormalities (arrhythmias). People taking such a combination must inform their health care provider and have their serum potassium levels checked regularly (37).

Additionally, prevention of bone demineralization by hormone replacement therapy in postmenopausal women is associated with higher urinary phosphorus excretion and lower serum phosphorus levels in treated compared to untreated women (39, 40).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the RDA for phosphorus (700 mg/day for adults). Although some multivitamin/mineral supplements contain more than 15% of the current RDA for phosphorus, a varied diet should easily provide adequate phosphorus for most people.

Older adults (>50 years)

At present, there is no evidence that phosphorus requirements of older adults differ from that of younger adults, and a varied diet should easily provide the RDA (700 mg/day) of phosphorus for those over 50 years of age.


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in June 2014 by:
Mona S. Calvo, Ph.D.
Office of Applied Research and Safety Assessment
Center for Food Safety and Applied Nutrition
US Food and Drug Administration

The findings and conclusions of this reviewer do not necessarily represent the views and opinions of the US Food and Drug Administration.

Copyright 2001-2017  Linus Pauling Institute 


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22.  de Boer IH, Rue TC, Kestenbaum B. Serum phosphorus concentrations in the third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis. 2009;53(3):399-407.  (PubMed)

23.  Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79(12):1370-1378.  (PubMed)

24.  Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305(23):2432-2439.  (PubMed)

25.  Palmer SC, Hayen A, Macaskill P, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 2011;305(11):1119-1127.  (PubMed)

26.  Li YC. Vitamin D: roles in renal and cardiovascular protection. Curr Opin Nephrol Hypertens. 2012;21(1):72-79.  (PubMed)

27.  Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74(2):148-157.  (PubMed)

28.  Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res. 2000;87(7):E10-17.  (PubMed)

29.  Rennenberg RJ, Kessels AG, Schurgers LJ, van Engelshoven JM, de Leeuw PW, Kroon AA. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manag. 2009;5(1):185-197.  (PubMed)

30.  Chang AR, Lazo M, Appel LJ, Gutierrez OM, Grams ME. High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am J Clin Nutr. 2014;99(2):320-327.  (PubMed)

31.  Calvo MS, Park YK. Changing phosphorus content of the US diet: potential for adverse effects on bone. J Nutr. 1996;126(4 Suppl):1168S-1180S.  (PubMed)

32.  Calvo MS. Dietary considerations to prevent loss of bone and renal function. Nutrition. 2000;16(7-8):564-566.  (PubMed)

33.  Kemi VE, Karkkainen MU, Rita HJ, Laaksonen MM, Outila TA, Lamberg-Allardt CJ. Low calcium:phosphorus ratio in habitual diets affects serum parathyroid hormone concentration and calcium metabolism in healthy women with adequate calcium intake. Br J Nutr. 2010;103(4):561-568.  (PubMed)

34.  Grimm M, Muller A, Hein G, Funfstuck R, Jahreis G. High phosphorus intake only slightly affects serum minerals, urinary pyridinium crosslinks and renal function in young women. Eur J Clin Nutr. 2001;55(3):153-161.  (PubMed)

35.  Pinheiro MM, Schuch NJ, Genaro PS, Ciconelli RM, Ferraz MB, Martini LA. Nutrient intakes related to osteoporotic fractures in men and women--the Brazilian Osteoporosis Study (BRAZOS). Nutr J. 2009;8:6.  (PubMed)

36.  Calvo MS, Tucker KL. Is phosphorus intake that exceeds dietary requirements a risk factor in bone health? Ann N Y Acad Sci. 2013; 1301:29-35.  (PubMed)

37.  Minerals. Drug Facts and Comparisons. St. Louis: Facts and Comparisons; 2000:27-51.

38.  Cervelli MJ, Shaman A, Meade A, Carroll R, McDonald SP. Effect of gastric acid suppression with pantoprazole on the efficacy of calcium carbonate as a phosphate binder in haemodialysis patients. Nephrology (Carlton). 2012;17(5):458-465.  (PubMed)

39.  Zhang D, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K. Effects of sex and postmenopausal estrogen use on serum phosphorus levels: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2003-2006. Am J Kidney Dis. 2014;63(2):198-205.  (PubMed)

40.  Bansal N, Katz R, de Boer IH, et al. Influence of estrogen therapy on calcium, phosphorus, and other regulatory hormones in postmenopausal women: the MESA study. J Clin Endocrinol Metab. 2013;98(12):4890-4898.  (PubMed)

Potassium

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Potassium is an essential dietary mineral and electrolyte. The term electrolyte refers to a substance that dissociates into ions (charged particles) in solution, making it capable of conducting electricity. Normal body function depends on tight regulation of potassium concentrations both inside and outside of cells (1).

Function

Maintenance of membrane potential

Potassium is the principal positively charged ion (cation) in the fluid inside of cells, while sodium is the principal cation in the fluid outside of cells. Potassium concentrations are about 30 times higher inside than outside cells, while sodium concentrations are more than ten times lower inside than outside cells. The concentration differences between potassium and sodium across cell membranes create an electrochemical gradient known as the membrane potential. A cell's membrane potential is maintained by ion pumps in the cell membrane, especially the sodium, potassium-ATPase pumps. These pumps use ATP (energy) to pump sodium out of the cell in exchange for potassium (Figure 1). Their activity has been estimated to account for 20%-40% of the resting energy expenditure in a typical adult. The large proportion of energy dedicated to maintaining sodium/potassium concentration gradients emphasizes the importance of this function in sustaining life. Tight control of cell membrane potential is critical for nerve impulse transmission, muscle contraction, and heart function (2, 3).

Figure 1. A Simplified Model of the Sodium (Na+), Potassium (K+) ATPase Pump. The concentration differences between K+ and Na+ across cell membranes create an electrochemical gradient known as the membrane potential. Adenosine triphosphate (ATP) provides the energy to pump 3 Na+ ions out of the cell in exchange for 2 K+ ions, thus maintaining the membrane potential.

Cofactor for enzymes

A limited number of enzymes require the presence of potassium for their activity. The activation of sodium, potassium-ATPase requires the presence of sodium and potassium. The presence of potassium is also required for the activity of pyruvate kinase, an important enzyme in carbohydrate metabolism (2).

Deficiency

An abnormally low plasma potassium concentration is referred to as hypokalemia. Hypokalemia is most commonly a result of excessive loss of potassium, e.g., from prolonged vomiting, the use of some diuretics, some forms of kidney disease, or metabolic disturbances. The symptoms of hypokalemia are related to alterations in membrane potential and cellular metabolism. They include fatigue, muscle weakness and cramps, and intestinal paralysis, which may lead to bloating, constipation, and abdominal pain. Severe hypokalemia may result in muscular paralysis or abnormal heart rhythms (cardiac arrhythmias) that can be fatal (2, 4).

Conditions that increase the risk of hypokalemia (5):

  • The use of potassium-wasting diuretics (e.g., thiazide diuretics or furosemide)
  • Alcoholism
  • Severe vomiting or diarrhea
  • Overuse or abuse of laxatives
  • Anorexia nervosa or bulimia
  • Magnesium depletion
  • Congestive heart failure (CHF)


In rare cases, habitual consumption of large amounts of black licorice has resulted in hypokalemia (6, 7). Licorice contains a compound (i.e., glycyrrhizic acid) with similar physiologic effects to those of aldosterone, a hormone that increases urinary excretion of potassium. Low dietary intakes of potassium do not generally result in hypokalemia (5). However, research indicates that insufficient dietary potassium increases the risk of a number of chronic diseases (see Disease Prevention).

The Adequate Intake (AI)

In 2004, the Food and Nutrition Board of the Institute of Medicine established an adequate intake level (AI) for potassium based on intake levels that have been found to lower blood pressure, reduce salt sensitivity, and minimize the risk of kidney stones (4; Table 1).

Table 1. Adequate Intake (AI) for Potassium
Life Stage Age Males
(mg/day)
Females
(mg/day)
Infants  0-6 months 400 400
Infants  7-12 months  700 700
Children  1-3 years  3,000 3,000
Children 4-8 years  3,800 3,800
Children  9-13 years  4,500 4,500
Adolescents  14-18 years  4,700 4,700
Adults  19 years and older 4,700 4,700
Pregnancy 14-50 years - 4,700
Breast-feeding 14-50 years - 5,100

Disease Prevention

The diets of Western industrialized cultures are quite different from those of prehistoric cultures and the few remaining isolated primitive cultures. Among other differences, the daily intake of sodium chloride (salt) in Western industrialized cultures is about three times higher than the daily intake of potassium on a molar basis, whereas salt intake in primitive cultures is about seven times lower than potassium intake (8). The relative deficiency of dietary potassium in the modern diet may play a role in the pathology of some chronic diseases.

Stroke

Several large epidemiological studies have suggested that increased potassium intake is associated with decreased risk of stroke. A prospective study of more than 43,000 men followed for eight years found that men in the top quintile (1/5) of dietary potassium intake (median intake, 4,300 mg/day) were only 62% as likely to have a stroke than those in the lowest quintile of potassium intake (median intake, 2,400 mg/day) (9). The inverse association was especially high in men with hypertension. However, a similar prospective study of more than 85,000 women followed for 14 years found a much more modest association between potassium intake and the risk of stroke (10). Another large study that followed more than 9,000 people for an average of 16 years found that potassium intake was inversely related to stroke only in black men and men with hypertension (11). However, black men and women reported significantly lower potassium intakes than white men and women (1,606 mg/day vs. 2,178 mg/day). More recent data from the same population indicate that those with potassium intakes higher than 1,352 mg/day were only 72% as likely to have a stroke as those with potassium intakes lower than 1,352 mg/day (12). A prospective study in 5,600 men and women older than 65 years found that low potassium intake was associated with a significantly increased incidence of stroke in individuals not taking diuretics (13). More recently, a prospective study in a cohort of 26,556 male smokers reported that higher intake of potassium was associated with a nonsignificant reduction in risk of cerebral infarction (14). Taken together, the epidemiological data suggest that a modest increase in fruit and vegetable intake (rich sources of dietary potassium), especially in those with hypertension and/or relatively low potassium intakes, could significantly reduce the risk of stroke.

Osteoporosis

At least four cross-sectional studies have reported significant positive associations between dietary potassium intake and bone mineral density (BMD) in populations of premenopausal, perimenopausal, and postmenopausal women as well as elderly men (15-17). The average dietary potassium intakes of the study participants ranged from about 3,000 to 3,400 mg/day, while the highest potassium intakes exceeded 6,000 mg/day and the lowest intakes ranged from 1,400 to 1,600 mg/day. In all of these studies, BMD was also positively and significantly associated with fruit and vegetable intake. One study that examined changes in BMD over time found that higher dietary potassium intakes (and fruit and vegetable intakes) were associated with significantly less decline in BMD at the hip in men, but not in women, over a four-year period (17). However, a prospective study that followed 266 elderly women found that women in the highest quartile of potassium excretion had higher BMD measures after five years compared to women in the lowest quartile of potassium excretion (18), suggesting that eating potassium-rich foods may help to prevent osteoporosis.

Potassium-rich foods, such as fruit and vegetables, are also rich in precursors to bicarbonate ions, which buffer acids in the body. The modern Western diet tends to be relatively low in sources of alkalai (fruit and vegetables) and high in sources of acid (fish, meats, and cheeses). When the quantity of bicarbonate ions is insufficient to maintain normal pH, the body is capable of mobilizing alkaline calcium salts from bone in order to neutralize acids consumed in the diet and generated by metabolism (19). Increased consumption of fruit and vegetables reduces the net acid content of the diet and may preserve calcium in bones, which might otherwise be mobilized to maintain normal pH. Support for this theory was provided by a study of 18 postmenopausal women, which found that potassium bicarbonate supplementation decreased urinary acid and calcium excretion, resulting in increased biomarkers of bone formation and decreased biomarkers of bone resorption (20). Other studies have reported that short-term (<3 months) supplementation with potassium citrate decreased urinary acid excretion and biomarkers of bone resorption in postmenopausal women (21) and also ameliorated the negative effects of a high-salt diet on bone metabolism (22). However, a recent two-year randomized controlled trial found potassium citrate supplementation did not reduce bone turnover or increase BMD in postmenopausal women (23). Overall, consumption of potassium-rich fruit and vegetables may improve BMD and help lower the risk of osteoporosis.

Kidney stones

Abnormally high urinary calcium (hypercalciuria) increases the risk of developing kidney stones. In individuals with a history of developing calcium-containing kidney stones, increased dietary acid load was significantly associated with increased urinary calcium excretion (24). Increasing dietary potassium (and alkalai) intake by increasing fruit and vegetable intake or by taking potassium bicarbonate supplements has been found to decrease urinary calcium excretion. Additionally, potassium deprivation has been found to increase urinary calcium excretion (25, 26). A large prospective study of more than 45,000 men followed for four years found that men whose potassium intake averaged more than 4,042 mg/day were only half as likely to develop symptomatic kidney stones as men whose intake averaged less than 2,895 mg per day (27). A similar study that followed more than 90,000 women over a period of 12 years found that women in the highest quintile of potassium intake (averaging 3,458 mg/day) were only 65% as likely to develop symptomatic kidney stones as women in the lowest quintile of potassium intake (averaging 2,703 mg/day) (28). In both of these prospective studies, dietary potassium intake was derived almost entirely from potassium-rich foods, such as fruit and vegetables.

Disease Treatment

High blood pressure (hypertension)

A number of studies indicate that groups with relatively high dietary potassium intakes have lower blood pressures than comparable groups with relatively low potassium intakes (29). Data on more than 17,000 adults who participated in the Third National Health and Nutrition Examination Survey (NHANES III) indicated that higher dietary potassium intakes were associated with significantly lower blood pressures (30). The results of the Dietary Approaches to Stop Hypertension (DASH) trial provided further support for the beneficial effects of a potassium-rich diet on blood pressure (31). Compared to a control diet providing only 3.5 servings/day of fruit and vegetables and 1,700 mg/day of potassium, consumption of a diet including 8.5 servings/day of fruit and vegetables and 4,100 mg/day of potassium lowered blood pressure by an average of 2.8/1.1 mm Hg (systolic BP/diastolic BP) in all subjects and by an average of 7.2/2.8 mm Hg in those with hypertension. More information about the DASH trial is included in the article on Sodium.

In 1997, a meta-analysis of 33 randomized controlled trials including 2,609 individuals assessed the effects of increased potassium intake, mostly in the form of potassium chloride (KCl) supplements, on blood pressure (32). Increased potassium intake (2,300-3,900 mg/day) resulted in slight but significant blood pressure reductions that averaged 1.8/1.0 mm Hg in people with normal blood pressure and 4.4/2.5 mm Hg in people with hypertension. Subgroup analysis indicated that the blood pressure-lowering effect of potassium was more pronounced in individuals with higher salt intakes and in trials where black individuals were a majority of the participants. A clinical trial in 150 Chinese men and women with borderline to mild hypertension found that moderate supplementation with 500 mg/day of potassium chloride for 12 weeks resulted in a significant 5 mm Hg reduction in systolic BP compared to placebo; no changes in diastolic BP were observed in this study (32). Like many Western diets, the customary diet of this population was high in sodium and low in potassium. A cross-over trial in 14 hypertensive individuals reported that supplementation with potassium citrate was equally as effective in lowering blood pressure as potassium chloride (33). A more recent cross-over trial in 42 adults with mild, untreated high blood pressure compared the effects of supplemental potassium chloride or potassium bicarbonate with a placebo (34). Supplementation with potassium chloride slightly decreased ambulatory systolic BP but had no effect on office systolic BP, while supplementation with potassium bicarbonate did not affect blood pressure measurements. Both supplements resulted in improved endothelial function and other cardiovascular benefits (34). However, a cross-over trial in 48 adults with early hypertension (defined as a diastolic BP of greater than 80 mm Hg but less than 100 mg Hg), who were not taking anti-hypertensive medication, reported that increased potassium intake through dietary or supplemental (potassium citrate) means did not improve blood pressure or vascular function (35). Increasing potassium intake by consuming a diet rich in fruit and vegetables may help lower blood pressure and may have other health benefits (see the article on Fruit and Vegetables). Supplemental potassium might help lower blood pressure in some individuals, but potassium supplements should only be used in consultation with a medical provider (see Supplements).

Sources

Food sources

The richest sources of potassium are fruit and vegetables. A dietary survey in the US indicated that the average dietary potassium intake is about 2,300 mg/day for adult women and 3,100 mg/day for adult men (30). The potassium content of some relatively potassium-rich foods is listed in milligrams (mg) in Table 2 (36). For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Potassium
Food Serving Potassium (mg)
Banana 1 medium 422
Potato, baked with skin 1 medium 926
Prune juice 6 fluid ounces 528
Plums, dried (prunes) ½ cup 637
Orange juice 6 fluid ounces 372
Orange 1 medium 237
Tomato juice 6 fluid ounces 417
Tomato 1 medium 292
Raisins ½ cup 598
Raisin bran cereal 1 cup 362
Artichoke, cooked 1 medium 343
Lima beans, cooked ½ cup 485
Acorn squash, cooked ½ cup (cubes) 448
Spinach, cooked ½ cup 420
Sunflower seeds 1 ounce 241
Almonds 1 ounce 200
Molasses 1 tablespoon 293

Supplements

Multivitamin-mineral supplements in the US do not contain more than 99 mg of potassium per serving. Higher doses of supplemental potassium are generally prescribed to prevent and treat potassium depletion and hypokalemia. The use of more potent potassium supplements in potassium deficiency requires close monitoring of serum potassium concentrations. Potassium supplements are available as a number of different salts, including potassium chloride, citrate, gluconate, bicarbonate, aspartate and orotate (37). Because of the potential for serious side effects, the decision to use a potent potassium supplement should be made in collaboration with one's health care provider (see Safety).

Safety

Toxicity (excess)

Abnormally elevated serum potassium concentrations are referred to as hyperkalemia. Hyperkalemia occurs when potassium intake exceeds the capacity of the kidneys to eliminate it. Acute or chronic renal (kidney) failure, the use of potassium-sparing diuretics, and insufficient aldosterone secretion (hypoaldosteronism) may result in the accumulation of excess potassium due to decreased urinary potassium excretion. Oral doses greater than 18 grams taken at one time in individuals not accustomed to high intakes may lead to severe hyperkalemia, even in those with normal kidney function (4). Hyperkalemia may also result from a shift of intracellular potassium into the circulation, which may occur with the rupture of red blood cells (hemolysis) or tissue damage (e.g., trauma or severe burns). Symptoms of hyperkalemia may include tingling of the hands and feet, muscular weakness, and temporary paralysis. The most serious complication of hyperkalemia is the development of an abnormal heart rhythm (cardiac arrhythmia), which can lead to cardiac arrest (38). The Food and Nutrition Board of the Institute of Medicine did not set a tolerable upper intake level (UL) for potassium because adverse effects from high dietary intakes of potassium have not been reported in healthy individuals (4). See Drug interactions for a discussion of the medications that increase the risk of hyperkalemia.

Adverse reactions to potassium supplements

Gastrointestinal symptoms are the most common side effects of potassium supplements, including nausea, vomiting, abdominal discomfort, and diarrhea. Intestinal ulceration has been reported after the use of enteric-coated potassium chloride tablets. Taking potassium with meals or taking a microencapsulated form of potassium may reduce gastrointestinal side effects. The most serious adverse reaction to potassium supplementation is hyperkalemia (see Toxicity). Individuals with abnormal kidney function and those on potassium-sparing medications (see Drug interactions) should be monitored closely to prevent hyperkalemia (5, 37).

Drug interactions

The classes of medication known to increase the risk of hyperkalemia (elevated serum potassium) are listed in Table 3 (38), and medications known to increase the risk of hypokalemia (low serum potassium) are listed in Table 4 (5). Individuals are encouraged to consult their physicians regarding any dietary restriction that may apply when taking such medications.

Table 3. Medications Associated with Hyperkalemia
Medication Family Specific Medications
Potassium-sparing agents Spironolactone, triamterene, amiloride
Angiotensin converting enzyme (ACE) inhibitors  Captopril, enalapril, fosinopril
Nonsteroidal anti-inflammatory agents (NSAID) Indomethacin, ibuprofen, ketorolac
Anti-infective agents Trimethoprim-sulfamethoxazole, pentamidine
Anticoagulant Heparin
Cardiac glycoside Digitalis
Anti-hypertensive agents β-blockers, α-blockers
Angiotensin receptor blockers Losartan, valsartan, irbesartan, candesartan 
Table 4. Medications Associated with Hypokalemia
Medication Family Specific Medications
β-adrenergic agonists Epinephrine
Decongestants Pseudoephedrine, phenylpropanolamine
Bronchodilators Albuterol, terbutaline, pirbuterol, isoetharine, fenoterol, ephedrine, isoproterenol, metaproterenol, theophylline
Tocolytic (labor suppressing) agents Ritodrine, nylidrin
Diuretics Acetazolamide, thiazides, chlorthalidone, indapamide, metolazone, quinethazone, bumetanide, ethacrynic acid, furosemide, torsemide
Mineralocorticoids Fludrocortisone
Substances with mineralocorticoid effects Licorice, carbenoxolone, gossypol
High-dose glucocorticoids  
High-dose antibiotics Penicillin, nafcillin, carbenicillin
Other Caffeine, phenolphthalein, sodium polystyrene sulfonate

Linus Pauling Institute Recommendation

There is considerable evidence that a diet supplying at least 4.7 grams/day of potassium is associated with decreased risk of stroke, hypertension, osteoporosis, and kidney stones. Fruit and vegetables are among the richest sources of dietary potassium, and a large body of evidence supports the association of increased fruit and vegetable intakes with reduced risk of cardiovascular disease (39, 40). Consequently, the Linus Pauling Institute recommends increasing potassium intake to at least 4.7 grams/day by increasing consumption of potassium-rich foods (see Sources), especially fruit, vegetables, and nuts.

Older adults (>50 years)

A diet supplying at least 4.7 grams/day of potassium is also appropriate for healthy older adults since such diets are associated with decreased risk of stroke, hypertension, osteoporosis, and kidney stones. This recommendation does not apply to individuals who have been advised to limit potassium consumption by a health care professional (see Safety).


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in February 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2010 by
Pao-Hwa Lin, Ph.D.
Associate Research Professor
Division of Nephrology
Duke University Medical Center

Copyright 2001-2017  Linus Pauling Institute


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40.  Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA. 1999;282(13):1233-1239.  (PubMed)

Selenium

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Summary

  • Selenium exerts various biological functions mainly as part of the amino acid, selenocysteine, which is found in at least 25 selenocysteine-containing proteins (selenoproteins). (More information)
  • Five glutathione peroxidases, three thioredoxin reductases, three iodothyronine deiodinases, and one methionine sulfoxide reductase B1 are among the best characterized selenoproteins with known functions. (More information)
  • Impaired antioxidant protection in selenium-deficient individuals may affect physiological responses to stress. Keshan cardiomyopathy and Kashin-Beck osteoarthropathy are diseases occurring specifically in areas of selenium deficiency in Asia. (More information)
  • The current recommended dietary allowance (RDA) set by the US Institute of Medicine is 55 μg/day for adolescents and adults of all ages. (More information)
  • Early observational studies have found either null or inverse associations between selenium exposure and risk of site-specific cancers. However, current evidence from intervention trials in selenium-replete participants does not support a protective effect of selenium supplementation against cancer. (More information)
  • Preliminary evidence from randomized controlled trials suggests that selenium supplementation may prevent viral load progression and increase immune cell count in HIV-positive patients. (More information)
  • The levels and chemical forms of selenium in plant-based food vary according to the composition and selenium content of soil in which the plants are grown. Selenium-rich food sources include Brazil nuts, grains, seafood, organ meats, poultry, and dairy products. (More information)
  • The tolerable upper intake level (UL) for selenium is 400 μg/day for adolescents and adults and includes both selenium obtained from food, which averages about 100 μg/day for adults in the US, and selenium from supplements. (More information)
  • Because some evidence suggests that high serum selenium concentrations may have adverse effects on glycemic control, individuals with high selenium status and/or those at risk for type 2 diabetes mellitus should avoid taking selenium supplements. (More information)

Selenium is a trace element that is essential in small amounts, but like all essential elements, selenium can be toxic at high levels. Unlike plants, most animals — including humans — require selenium for the appropriate functioning of a number of selenium-dependent enzymes known as selenoproteins. During protein synthesis (translation), the amino acid selenocysteine is incorporated into elongating proteins at very specific locations in the amino acid sequence in order to form functional selenoproteins. Although higher plants do not appear to require selenium for survival, they can incorporate it non-specifically into sulfur-containing molecules when the mineral is present in the soil (1). Of note, in animals, the amino acid selenomethionine can be nonspecifically incorporated into proteins in place of methionine (2). However, only selenocysteine-containing proteins are regarded as selenoproteins (Figure 1).

Figure 1. Cysteine, Methionine, and Selenium-containing Analogs. Chemical structures of cysteine, selenocysteine, methionine, and selenomethionine.

Function

Selenoproteins 

Twenty-five genes coding for selenoproteins have been identified in humans (3). The insertion of selenocysteine into selenoproteins during translation is directed by the presence of a selenocysteine-insertion sequence (SECIS) within selenoprotein mRNAs. Briefly, the recognition of SECIS by the translational machinery results in the recruitment of specific translational factors that decode in-frame UGA codons by inserting selenocysteine into elongating selenoproteins (4).

Research is gradually uncovering the metabolic functions of all human selenoproteins, including splicing variants (3). Some of the selenoproteins with an identified function include: 

Glutathione peroxidases

Five selenium-containing glutathione peroxidases (GPx1-4 and GPx6) have been identified: GPx1 (cytosolic GPx), GPx2 (epithelial cell-specific GPx expressed in intestinal lining and lungs), GPx3 (highly expressed in thyroid gland and kidneys), GPx4 (phospholipid-hydroperoxide GPx; PHGPx), and GPx6 (expressed in the olfactory epithelium) (4). GPx isoenzymes are all antioxidant enzymes that reduce potentially damaging reactive oxygen species (ROS), such as hydrogen peroxide and lipid hydroperoxides, to harmless products like water and alcohols by coupling their reduction with the oxidation of glutathione (Figure 2). Spermatogenesis and male fertility are highly dependent on GPx4 and selenoprotein P (SEPP1; see below). In the testes, GPx4 reduces phospholipid hydroperoxides, hence protecting immature spermatozoa cells against oxidative stress. GPx4 is also a major structural protein of the capsule embedding mature sperm mitochondrial helix involved in sperm motility. SEPP1 is essential for selenium supply to the testes, and animal models lacking the SEPP1 gene are infertile due to poor selenium tissue bioavailability, defective GPx4 synthesis, and impaired sperm maturation (5).

Figure 2. Selenoproteins in Thiol-based Antioxidant Systems: the thioredoxin antioxidant system and glutathione antioxidant system.

Thioredoxin reductases

In mammals, three selenocysteine-containing thioredoxin reductase (TrxR) isoenzymes have been identified in the thioredoxin system: cytosolic TrxR1, mitochondrial TrxR3, and testes-specific thioredoxin glutathione reductase TGR. TrxRs are homodimeric enzymes, and each monomer contains FAD- and NADPH-binding domains and a selenocysteine-containing catalytic site. TrxRs catalyze the reduction of a wide range of substrates, including thioredoxin and protein disulfide isomerase (PDI) (see Figure 2 above). TrxRs also serve as electron donors for the regeneration of small antioxidants, possibly recycling ascorbic acid (vitamin C), α-lipoic acid, α-tocopherol (vitamin E), and coenzyme Q10 from their oxidized forms (6). The maintenance of thioredoxin in a reduced form by TrxRs is important for regulating cell growth and survival. The protein thioredoxin, together with TrxR1 (or TrxR3), NADPH, and FAD, constitute the thioredoxin antioxidant system involved in the reduction of antioxidant enzymes (e.g., peroxiredoxins, methionine sulfoxide reductases, and ribonucleotide reductase) and of many oxidation/reduction (redox)-sensitive signaling proteins (7). TrxR1 is one of the most investigated selenoproteins and regarded as one of the major antioxidant enzymes and redox regulators in mammalian cells.

Iodothyronine deiodinases (thyroid hormone deiodinases)

The thyroid gland releases very small amounts of biologically active thyroid hormone (triiodothyronine or T3) and larger amounts of an inactive form of thyroid hormone (T3 precursor: thyroxine or T4) into the circulation. Most of the biologically active T3 in the circulation and inside cells is generated by the removal of one iodine atom from T4 in a reaction catalyzed by selenium-dependent iodothyronine deiodinase enzymes. Two different selenium-dependent iodothyronine deiodinases (DIOs type 1 and 2) can deiodinate T4, thus increasing circulating T3, while a third iodothyronine deiodinase (DIO type 3) can convert both T3 and T4 to inactive metabolites (Figure 3) (8). Of note, inactivation of the genes encoding DIOs in rodent models has revealed a role for DIO type 1 in iodine homeostasis and the importance of DIOs type 2 and 3 in the maturation of auditory and visual systems during fetal development (8). Thus the importance of selenium in normal development, growth, and metabolism is not limited to its role in the regulation of thyroid gland function.

Figure 3. Deiodination of Thyroid Hormones. Iodothyronine deiodinases (DIOs) are selenoenzymes that catalyze the deiodination (removal of iodine) from iodothyronines. Specifically, DIO1 and DIO2 catalyze the deiodination of thyroxine (T4) that generates the biologically active triiodothyronine (T3). DIO3 inactivates T3 and T4 by removing iodine atoms from the inner ring.

Selenoprotein P

Selenoprotein P (SEPP1) is predominantly produced by the liver, a major storage site for selenium, and secreted in the plasma. The full-length glycoprotein contains a selenium-rich domain with nine selenocysteine residues, as well as a thioredoxin-like catalytic site with one selenocysteine residue. SEPP1 constitutes the major form of selenium transport to peripheral tissues (9). SEPP1 also functions as an antioxidant that protects cells from oxidative damage by enabling full activity of thioredoxin reductases and glutathione peroxidases through adequate supply of selenium to extrahepatic tissues (see Glutathione peroxidases). SEPP1 appears to be especially critical for selenium homeostasis in the brain and testes where apolipoprotein E receptor 2 (apoER2) facilitates the uptake of SEPP1. Megalin is another SEPP1-specific lipoprotein receptor that helps limit urinary selenium loss through SEPP1 re-uptake by the kidneys (10). Moreover, SEPP1 has been recently implicated in the regulation of glucose metabolism and insulin sensitivity (11).

Selenoprotein W

Selenoprotein W (SEPW or SelW) exists in different isoforms (homologues) and is highly conserved across species. In humans, SEPW is expressed in numerous tissues, with highest levels found in skeletal muscle and heart (12). SEPW contains a selenocysteine residue and a cysteine residue that binds to a glutathione molecule, suggesting a role in redox regulation (13). The expression of SEPW is correlated with selenium status and appears to be sensitive to low-selenium supply (14, 15). SEPW expression in the brain has been found to confer protection against oxidative stress-induced neuronal cell death (16). SEPW also appears to be a negative regulator for 14-3-3 proteins. Indeed, 14-3-3 inhibition by SEPW in breast cancer cells was found to increase cell proliferation and cell survival through increasing resistance to genotoxic stress (17). In skeletal muscle cells, SEPW was shown to reduce the binding of 14-3-3 to TAZ, allowing TAZ translocation to the nucleus and subsequent activation of muscle cell differentiation genes (18). Finally, SEPW was found to prevent the degradation of the epidermal growth factor receptor (EGFR) in breast and prostate epithelial cells in culture. EGFR is constitutively activated in many tumors, and evidence of a role for SEPW in EGFR activation and signaling may help shed light on the relationship between selenium status and cancer risk (19).

Selenophosphate synthetase 2

There is no free pool of the amino acid selenocysteine in cells such that selenocysteine synthesis takes place on a specialized tRNA during the translation of selenoprotein mRNAs. The reaction is catalyzed by pyridoxal 5’-phosphate (PLP)-dependent L-seryl-tRNASec selenium transferase and uses selenophosphate (monoselenium phosphate) as the selenium donor (Figure 4) (20). Selenophosphate synthetase 2 is a selenoenzyme that catalyzes the ATP-dependent synthesis of selenophosphate from hydrogen selenide (Figure 4) (3).

Figure 4. Synthesis of Selenocysteine. See text for description.

Methionine-R-sulfoxide reductase B1 (formerly selenoprotein R)

The methionine sulfoxide reduction system is involved in the protection against oxidative stress and is especially critical for the regeneration of proteins damaged by reactive oxygen species (ROS). Indeed, ROS can oxidize methionine residues (methionine sulfoxides) within proteins and potentially impair their activities. In humans, two stereospecific families of methionine sulfoxide reductases (MsrA and MsrB) are encoded by a single MSRA gene and three MSRB genes (MSRB1-3). MsrA catalyzes the reduction of the S-form of methionine sulfoxide; the R-form of methionine sulfoxide is reduced by MsrB1, 2, or 3. Only MsrB1 has been characterized as a selenoprotein with one selenocysteine residue in its catalytic site. MsrB1 appears to be involved in the redox regulation of certain proteins. In macrophages, reorganization of the actin cytoskeleton necessary for chemotaxis and phagocytosis requires MsrB1-dependent reduction of methionine-R-sulfoxide residues within actin (21). Studies using MSR gene inactivation in mice have also shown that methionine sulfoxide reduction is implicated in the regulation of the methionine cycle (reviewed in 22). Both the thioredoxin (Trx) and GSH-dependent glutaredoxin (Grx) antioxidant systems have been found to reduce methionine sulfoxide reductases in vitro and/or in vivo (see Figure 2 above) (22).

15 kDa selenoprotein

15 kDa selenoprotein (selenoprotein 15; SEP15) is highly expressed in several tissues, including prostate, kidney, testes, liver, and brain (23). Although its function is not known, SEP15 was found to interact with the endoplasmic reticulum UDP-glucose:glycoprotein glucosyltransferase (UGGT), an enzyme involved in the quality control of glycoprotein folding (24, 25). Because SEP15 has a thioredoxin-like catalytic site, SEP15 is thought to either regulate UGGT activity or the redox state of UGGT substrates (26). Mice lacking a functional SEP15 were found to develop nuclear cataract (lens opacification) at a very early age suggesting that SEP15 may be critical to the quality control system of protein folding in the lens (27). SEP15 may also be implicated in anticancer mechanisms (reviewed in 28).

Selenoprotein S

The mammalian selenoprotein S (known as SEPS1, SelS, or VCP-interacting membrane selenoprotein [VIMP]) is an endoplasmic reticulum (ER) membrane protein. SEPS1 is involved in the cellular response to ER stress (ER-associated degradation; ERAD) activated by the detection of misfolded proteins. SEPS1 contributes to the removal and transfer (retrotranslocation) of misfolded proteins from the ER lumen to the cytosol where proteins are tagged with ubiquitin before being degraded. A polymorphism or variation in the sequence within an ER-response element located in the SEPS1 promoter was found to result in reduced SEPS1 promoter activity and gene expression (29). The polymorphism corresponding to the substitution of a guanine (G) by an adenine (A) at nucleotide -105 (-105G>A) has been associated with increased plasma levels of pro-inflammatory cytokines. In addition, a case-control study recently reported that the A allele was more prevalent in individuals affected by Hashimoto thyroiditis (HT) — a T-cell-mediated autoimmune disease resulting in the destruction of thyroid cells — than in healthy controls (30). Other associations between SEPS1 polymorphism (including -105G>A) and susceptibility to various conditions, such as preeclampsia, coronary artery disease, or gastrointestinal cancers, strongly suggest a role for this selenoprotein in the regulation of inflammatory and immune responses (31-34).

Other less well-characterized selenoproteins, which are also localized in the ER lumen and/or membrane, include selenoproteins K, M, N, and T (35).

Nutrient interactions

Antioxidant nutrients

The importance of selenium to biological systems, and specifically to the cellular redox (pro-oxidant/antioxidant) balance, is derived from its presence as selenocysteine in the catalytic site of selenoproteins (see Function). Other minerals that are critical components of antioxidant enzymes include copper (as superoxide dismutase), zinc (as superoxide dismutase), and iron (as catalase). Selenium acts in synergy with the antioxidant vitamins, vitamin C (ascorbic acid) and vitamin E (α-tocopherol), by regenerating them from their oxidized forms and promoting maximal antioxidant protection (36-38).

Iodine

While iodine is an essential component of thyroid hormones, the selenium-containing iodothyronine deiodinases (DIOs) are enzymes required for the conversion of thyroxine (T4) to the biologically active thyroid hormone, triiodothyronine (T3) (see Function). DIO1 activity may also be involved in regulating iodine homeostasis (39). The selenoenzymes, glutathione peroxidases, also play a critical role in thyroid function because they catalyze the degradation of peroxides generated during thyroid hormone synthesis (8). The epidemiology of coexisting iodine and selenium deficiencies in central Africa, but not in China, has been linked to the prevalence of myxedematous cretinism, a severe form of congenital hypothyroidism accompanied by mental and physical retardation. Selenium deficiency may be only one of several undetermined factors that might exacerbate the detrimental effects of iodine deficiency (40). Interestingly, selenium deficiency in rodents was found to have little impact on DIO activities as it appears that selenium is being supplied in priority for adequate synthesis of DIOs at the expense of other selenoenzymes (8).  

Deficiency

Insufficient selenium intake may negatively affect the activity of several selenium-responsive enzymes, including glutathione peroxidases (GPx1 and GPx3), iodothyronine deiodinases, selenoprotein W, and methionine-R-sulfoxide reductase B1 (MsrB1). Even when severe, isolated selenium deficiency does not usually result in obvious clinical illness. Yet, compared to subjects with adequate selenium status, selenium-deficient individuals might be more susceptible to additional physiological stresses (41). Prolonged selenium deficiency may likely contribute to Keshan and Kashin-Beck diseases (see below).

Individuals at increased risk of selenium deficiency

Selenium deficiency has been reported in chronically ill patients who were receiving total parenteral nutrition (TPN) without added selenium for prolonged periods of time. Muscular weakness, muscle wasting, and cardiomyopathy (inflammation and damage to the heart muscle) have been observed in these patients. Nowadays, TPN solutions are routinely supplemented with selenium. The risk of selenium deficiency may be increased following bariatric surgery or in severe gastrointestinal conditions, such as Crohn's disease. Some specialized medical diets like those used to treat certain metabolic disorders, including phenylketonuria, homocystinuria, and maple syrup urine disease, need to be supplemented with selenium to ensure optimum selenium status in patients (42).

Keshan disease

Keshan disease is a fatal form of dilated cardiomyopathy that was first described in young women and children in a selenium-deficient region in China. The acute form of the disease is characterized by the sudden onset of cardiac insufficiency, while the chronic form results in moderate-to-severe heart enlargement with varying degrees of cardiac insufficiency (43). The incidence of Keshan disease is closely associated with very low dietary intakes of selenium and poor selenium nutritional status. Selenium supplementation (in the form of sodium selenite; Na2SeO3) was found to protect people from developing Keshan disease but could not reverse heart muscle damage once it had occurred (43). A recent case-control study reported that selenium-responsive glutathione peroxidase 1 (GPx1) activity was significantly lower in Keshan patients compared to healthy individuals. Interestingly, a specific GPX1 polymorphism resulting in a proline-to-leucine transition at position 198 (Pro198Leu) is associated with a reduction in GPx1 activity and found to be more prevalent in Keshan patients. This GPX1 polymorphism might confer a greater susceptibility to Keshan disease in carriers with low selenium nutritional status (44).

While selenium deficiency is a major etiological factor of Keshan disease, the seasonal and annual variation in disease occurrence suggested that other factors, especially an infectious agent, might be involved in addition to selenium deficiency (45). Coxsackie virus B3 is one virus type that has been isolated from Keshan patients, and animal studies have shown that this virus was capable of causing an inflammation of the heart (myocarditis) in selenium-deficient mice. Studies in mice also indicated that oxidative stress induced by selenium deficiency could result in changes in the viral genome, such as to convert a relatively harmless strain of coxsackie virus B3 into a myocarditis-causing strain (43). Although not proven in Keshan disease, it is possible that selenium deficiency may increase the virulence of viruses with the potential to invade and damage the heart muscle (46)

Kashin-Beck disease

Kashin-Beck disease (KBD) is another endemic condition that affects an estimated 2.5 million people in Tibet, northern and central China, North Korea, and southeastern Siberia (47). KBD is characterized by the degeneration of articular cartilage between joints (osteoarthritis) that can result in joint deformities and dwarfism in the most severe forms of the disease. The disease affects children as young as two years old. As with Keshan disease, KBD is prevalent in selenium-deficient provinces and thus generally affects people with very low selenium intakes (47). Recent studies have suggested that increased susceptibility to KBD in selenium-deficient populations might result from a reduced antioxidant protection associated with polymorphisms in GPX genes (48, 49). Yet, the etiology appears to be multifactorial, as a number of other causative factors have been suggested for KBD, including fungal toxins in grain, iodine deficiency, and contaminated drinking water (43).

Recent meta-analyses of a few small trials and prospective cohort studies have indicated that improving selenium nutritional status in children living in endemic areas may help reduce KBD incidence (50). Also, there is limited evidence to suggest that selenium supplementation could be useful in the treatment of patients with KBD. A meta-analysis of 10 randomized controlled trials reported a significant increase in the repairing rate of bone lesions in KBD children supplemented with sodium selenite for at least one year (51). Larger trials of higher quality are needed to assess whether selenium supplementation could result in disease remission.

The Recommended Dietary Allowance (RDA)

The dietary reference intakes (DRIs) for selenium were last revised in 2000 by the Food and Nutrition Board (FNB) of the US Institute of Medicine. The most recent RDA is based on the estimated average requirement (EAR) needed to maximize antioxidant enzyme glutathione peroxidase (GPx) activity in plasma (52).

Table 1. Recommended Dietary Allowance (RDA) for Selenium
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months  15 (AI 15 (AI) 
Infants  7-12 months  20 (AI)  20 (AI) 
Children  1-3 years  20  20
Children  4-8 years  30  30
Children  9-13 years  40  40
Adolescents  14-18 years  55  55
Adults  19 years and older  55  55
Pregnancy  all ages  60
Breast-feeding  all ages  70

Of note, the third National Health and Nutrition Examination Survey (NHANES III) reported that over 99% of the US participants had serum selenium concentrations consistent with selenium requirements being met (52), suggesting selenium supplementation is not needed for Americans.

Disease Prevention

Cancer

Animal studies

There has been considerable research on the effect of selenium supplementation on the incidence of cancer in animals. More than two-thirds of over 100 published studies in 20 different animal models of spontaneous, viral, and chemically induced cancers found that selenium supplementation (to at least adequate intake levels) significantly reduces tumor incidence, especially in comparison to selenium-deficient diets (53). Evidence of cancer-inhibiting effects of selenium has provided a strong rationale for investigating potential associations between selenium intake and cancer risk in humans.

Observational studies

Most of the early epidemiological evidence from case-control and nested case-control studies suggested either null or inverse associations between selenium exposure and risk of site-specific cancers (54). Markers of selenium exposure include toenail and blood selenium content, as well as plasma glutathione peroxidase (GPx) activity. However, it is not clear whether they adequately reflect selenium exposure from dietary and supplemental sources (see Sources) or selenium distribution in tissues and organs that may be affected by cancer. In the Danish Prospective Diet, Cancer, and Health prospective study that followed over 57,000 men and women for 14 years, the risk of rectal cancer was found to be 42% higher in current smokers compared to nonsmokers. No difference between smokers and nonsmokers regarding supplemental and dietary intakes of antioxidant micronutrients, including selenium, was found to contribute to the association of smoking and rectal cancer (55). Yet, because studies have consistently reported lower blood selenium concentrations and GPx activities in smokers compared to nonsmokers (reviewed in 56), estimation of selenium intakes might not be a reliable marker of selenium exposure in this population. Also, the chemical forms of selenium found in food are varied (see Sources) and may have very different biological and toxicological effects (57, 58).

A recent Cochrane review included 55 completed observational studies — mostly with a nested case-control design — published over three decades (54). A meta-analysis of 16 of these observational studies, including over 144,000 individuals, reported that higher versus lower selenium status was associated with a 31% lower risk of cancer at any site and a 40% lower risk of cancer-related mortality. A significantly lower risk was reported for bladder cancer (5 studies) and prostate cancer (17 studies); however, higher selenium status was not inversely associated with risks of breast cancer (8 studies), lung cancer (12 studies), colorectal cancer (5 studies), and gastric cancer (5 studies) (54). Another meta-analysis of 16 observational studies reported an inverse relationship between breast cancer and serum selenium concentrations (59). Gender differences in cancer susceptibility have been reported in some studies, although consistent evidence of different effects in men and women appears to be lacking.

Single nucleotide variations (polymorphisms) in the sequence of genes can modify gene expression level and the stability and activity of the synthesized proteins. For example, a proline-to-leucine transition caused by a specific polymorphism in the GPX1 gene (rs1050450 C>T) is associated with reduced GPx1 enzymatic activity. The description of several polymorphisms in genes encoding selenoproteins has led to evaluation of possible associations with selenium status and cancer incidence. Notably, certain polymorphisms in genes coding for selenoproteins have been associated with increased risks of gastric and colorectal cancers (reviewed in 60). Additionally, a number of studies have investigated the effect of selenoprotein polymorphisms on the relationship between selenium status and prostate cancer risk. A nested case-control study within the EPIC-Heidelberg cohort has combined genotyping for several selenoprotein variants with markers of selenium status (61). Briefly, the study showed that a GPX1 gene polymorphism (rs1050450 C>T) affected the association between selenium concentrations and prostate cancer risk. Specifically, selenium concentrations were found to be inversely associated with prostate cancer risk only among carriers of the GPX1 T allele. Additional variants in selenoprotein genes may mitigate the effect of selenium status on the risk of prostate cancer (62, 63). In another nested case-control study within the Physicians’ Health Study (PHS), individuals in the highest versus lowest quartile of selenium concentrations were found to have a reduced risk of prostate cancer-related mortality except if carrying a specific variant in 15kDa selenoprotein gene (SEP15 rs561104 G>A) (64). More research is needed to further unravel the mechanisms underlying the influence of gene-diet interactions on the risk of developing cancer.

Intervention trials

Community-based studies: A very early intervention study of selenium supplementation was undertaken in China among a general population of 130,471 individuals living in a high-risk area for viral hepatitis B infection and liver cancer. The trial provided table salt enriched with sodium selenite to the population of one township (20,847 people) using four other townships as controls. During an eight-year follow-up period, the average incidence of liver cancer was reduced by 35% in the selenium-supplemented population, while no reduction was found in the control populations. In a clinical trial in the same region, 226 individuals with evidence of chronic hepatitis B infection were supplemented daily with either 200 μg of selenium in the form of a selenium-enriched yeast tablet or a placebo yeast tablet. During the 4-year follow-up period, 7 out of 113 individuals on the placebo developed primary liver cancer, while none of the 113 subjects supplemented with selenium developed liver cancer (65).

Randomized controlled trials: The double-blind, placebo-controlled Nutritional Prevention of Cancer (NPC) study in 1,312 older adults with a history of nonmelanoma skin cancer found that supplementation with 200 μg/day of selenium-enriched yeast (selenized yeast) for an average of 7.4 years resulted in a 52% decrease in prostate cancer incidence in men (reviewed in 66). The protective effect of selenium supplementation was greatest in men with lower baseline plasma selenium and prostate-specific antigen (PSA) levels. A reduced incidence in lung, colorectal, and total cancer was also associated with supplementation with 200 μg/day (67) but not with 400 μg/day of selenium-enriched yeast (68). Besides, selenium supplementation increased the risk of one type of skin cancer (squamous cell carcinoma) by 25%. A larger randomized, placebo-controlled intervention trial (the SELECT study) in more than 35,000 middle-aged and selenium-replete men, randomized to receive selenium (in the form of selenomethionine, 200 μg/day) and/or vitamin E supplementation, was halted because of concerns regarding an increased risk of type 2 diabetes with selenium and increased risk of prostate cancer with vitamin E (69, 70). In addition, the supplementation of selenium, alone or together with vitamin E, did not show any benefits regarding the risk of prostate, lung, or colorectal cancers after 5.5 years of follow-up (71, 72). Outcomes from other smaller trials (reviewed in 66) also suggested either a lack of an effect or the possibility of an increased risk of cancer. The lack of a beneficial effect of selenium supplementation was supported in a recent meta-analysis of randomized controlled trials (54).

Cardiovascular disease

Low activity levels of the selenoenzymes, glutathione peroxidases (GPx), have been reported in oxidative stress-related diseases, including cardiovascular disease (CVD) (73). Theoretically, the maintenance of an optimal selenium status has the potential to protect against oxidative stress (including lipid peroxidation) and could eventually prevent chronic inflammation and cardiovascular disorders. Yet, analyses of cross-sectional data from 13,887 US adults included in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) failed to show any significant associations between serum selenium concentrations and mortality from CVD, coronary artery/heart disease (CAD), or stroke (74). In addition, while individuals with renal insufficiency are at higher risk of developing CAD compared to those with normal kidney function, that risk was not found to be greater with low rather than normal selenium concentrations in serum (≤98 ng/mL vs. >98 ng/mL) (75).

A cross-sectional study based on NHANES 2003-2004 data from 2,638 participants ages 40 years and over found that the risk of high blood pressure (hypertension), a major contributing factor for CVD, was 73% higher in individuals in the upper versus lowest quintile of serum selenium concentrations (≥150 ng/mL vs. <122 ng/mL) (76). Yet, a recent systematic review of the literature failed to find enough evidence to support any relationship between serum selenium concentrations and hypertension (77). Besides, a few observational studies have also reported associations between normal-to-high selenium status and elevated serum lipid levels in selenium-replete populations, speculating that selenium might interfere with lipid metabolism and adversely affect cardiovascular health (78, 79). At present, randomized controlled trials have not provided consistent results regarding the effect of selenium supplementation on lipid levels nor have they demonstrated any additional cardiovascular benefits of selenium in individuals with suboptimal or optimal selenium intakes (80).

Disease Treatment

Immune dysfunction

Selenium deficiency has been associated with impaired immunity and chronic inflammation (81). A considerable amount of research conducted in cell culture and animal models indicates that selenium plays essential roles in regulating the migration, proliferation, differentiation, activation, and optimal function of immune cells, thus influencing innate immunity, B-cell dependent antibody production, and T-cell immunity (reviewed in 82). Recent evidence on the role of selenium and selenoproteins in the production of lipid mediators (called eicosanoids) involved in inflammatory responses suggests that selenium supplementation might mitigate dysfunctional inflammatory responses that contribute to the pathogenesis of many chronic health conditions (83). At present, randomized controlled trials are needed to evaluate the potential benefits of selenium supplementation in inflammatory disorders, such as asthma (84) and inflammatory bowel disease (85).

Infectious diseases

HIV/AIDS

In areas of widespread malnutrition, deficiencies in micronutrients (including selenium) are common in individuals infected by the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS). Before antiretroviral therapy (ART) became the standard for HIV treatment, observational studies had consistently reported associations between low serum selenium concentrations and HIV infection in well-nourished subjects (86). Poor selenium status has been linked to increased risks of dilated cardiomyopathy and mortality in HIV-infected children and adults, as well as mother-to-child HIV transmission and perinatal mortality (reviewed in 87. Early laboratory studies have suggested that HIV might disrupt normal antioxidant defenses in infected T-cells by reducing the levels of selenoproteins, i.e., thioredoxine reductases and glutathione peroxidases (87). Interestingly, a recent cross-sectional study found that HIV-seropositive individuals receiving ART for more than two years had undetectable plasma viral loads, higher CD4 lymphocyte T-cell counts, and adequate serum selenium concentrations compared to ART-naïve subjects (88). Because the antioxidant activity of selenoproteins may interfere with viral replication in HIV-infected immune cells (89,90), it has been suggested that selenium supplementation might serve as a potential adjunct to ART for HIV patients.

A few trials of selenium supplementation in HIV-infected individuals have been conducted. A randomized, double-blind, placebo-controlled trial in 186 HIV-positive adults initially found that selenium supplementation at 200 μg/day for two years significantly decreased the rate of hospital admissions (91). Another randomized, double-blind, placebo-controlled trial in 174 HIV-positive individuals reported that 200 μg/day of selenium supplementation (in the form of selenium-enriched yeast) for nine months increased serum selenium concentrations, improved CD4 lymphocyte T-cell count, and prevented any progression of the HIV viral load (92). In a third double-blind trial in Tanzania, 913 pregnant women between 12 and 27 weeks’ gestation were randomized to receive 200 μg/day of selenium (as selenomethionine) or a placebo until six months after birth. Selenium supplementation had no effect on maternal CD4, CD8, and CD3 T-cell counts and on HIV viral load, but it significantly decreased the risk of acute or persistent diarrhea (93, 94). In addition, the risk of death between six weeks and six months postpartum was significantly reduced in infants of mothers supplemented with selenium compared to placebo (94).

A recent four-armed trial in Botswana randomized 878 HIV-positive adults at an early stage of the infection to receive either a placebo treatment, multivitamins (vitamins B, C, and E), 200 μg/day of selenium, or both multivitamins and selenium for 24 months (95). Unlike selenium alone, supplementation with multivitamins (with or without selenium) reduced the risk of immune decline by significantly increasing the time before ART initiation became necessary (i.e., when CD4 T-cell count fell below 251 cells/mcL) compared to placebo. In the study, a combined outcome of (1) CD4 T-cell count falling below 251 cells/mcL; (2) occurrence of AIDS-defining conditions; and (3) AIDS-related death — whichever happened first — was used to evaluate disease progression in the different arms of treatment. Compared to placebo, there was a longer period of time from randomization to the date of the composite outcome in individuals supplemented with multivitamins plus selenium, but not in those who received multivitamins or selenium alone (95). More research is needed to replicate these preliminary results, especially in settings and communities where malnutrition hastens the progression of HIV infection and access to antiretroviral therapy may be limited.

Sepsis

The systemic inflammatory response syndrome (SIRS) results from a systemic inflammatory response that can be due to an infection (sepsis) (96). Severe sepsis and septic shock — defined as persistent sepsis-induced low blood pressure — are associated with elevated mortality rates in critically ill patients (96, 97). Because systemic inflammatory responses involve excessive oxidative stress, it has been suggested that providing antioxidant nutrients like selenium may improve the outcome of critically ill patients in intensive care units. Two recent meta-analyses of randomized controlled trials found that intravenous selenium supplementation (as sodium selenite) in critically ill patients with SIRS, sepsis, or septic shock resulted in significantly reducing the risk of mortality by 17% to 27% (98, 99). More trials are needed to identify the appropriate schedule of selenium administration (in terms of dose, route, and treatment duration) and to assess additional outcomes (e.g., infectious complications and length of hospital stay).

Autoimmune thyroid diseases

Hashimoto thyroiditis (HT; chronic autoimmune thyroiditis) is an autoimmune disease characterized by T-cell infiltration in the thyroid gland and circulating autoantibodies (predominantly raised against thyroid peroxidase), causing prolonged inflammation, tissue damage, and hypothyroidism (8). While the function of the thyroid gland of healthy individuals is usually protected from variations in selenium supply, selenium deficiency and genetic polymorphisms affecting the activity of selenoproteins might be potential contributing factors to autoimmune thyroid diseases. A recent systematic review (100) identified four randomized controlled trials that evaluated the effect of selenium supplementation as an adjunct treatment to T4 replacement therapy (levothyroxine) in HT patients (101-104). While three out of four studies suggested a reduction in levels of circulating autoantibodies, none of them provided information on whether selenium may improve mood- and health-related symptoms to allow for a decreased dosage of levothyroxine. Another randomized controlled trial found that selenium supplementation improved the well being of patients affected by another autoimmune thyroid disease leading to hyperthyroidism (Graves disease) (105). The results of two ongoing, randomized, placebo-controlled trials — the CATALYST in HT patients and the GRASS trial in patients with Graves disease — may provide insight into an effect of selenium on thyroid-specific quality-of-life criteria and inform clinical decision making (106, 107).

Sources

Food sources

The richest food sources of selenium are organ meats and seafood, followed by muscle meats. Drinking water is not considered to be a significant source of selenium in North America. However, in areas, where high levels of selenium in soil contribute to the selenium content of the water, higher levels of selenium may be found in wells used for drinking water (108). In general, there is wide variation in the selenium content of plants and grains, especially because some plants, including garlic, Brazil nuts, and multiple Brassica species, tend to accumulate selenium (‘selenium accumulators’), while other assimilate selenium to a lesser extent (‘non-accumulators’). The assimilation of selenium by plants also depends on soil selenium content. Brazil nuts grown in areas of Brazil with selenium-rich soil may provide more than 100 μg of selenium in one nut, while those grown in selenium-poor soil provide 10 times less (109). In the US, grains are a good source of selenium, but fruit and vegetables tend to be relatively poor in selenium.

Various chemical forms (species) of selenium are found in selenium accumulators, including selenate (inorganic selenium), selenomethionine, selenocysteine, selenium-methyl-selenocysteine, and γ-glutamyl-selenium-methyl-selenocysteine. Although the two latter compounds are predominant in plants of the Allium and Brassicaceae families (which include garlic, onion, and broccoli), wheat, other grains (including Brazil nuts), and soy are rich in selenomethionine and contain smaller amounts of selenocysteine and selenate. Less is known about selenium species and distribution in dietary sources of animal origin. Animal nutrition and growth conditions certainly contribute to the selenium species formed and their relative quantities, and it is assumed that the metabolic pathway of dietary selenium in animals is similar to that in humans. Selenocysteine is predominantly formed in animals fed inorganic selenium, while selenomethionine is derived from dietary sources of plant origin (reviewed in 110).

In the US, the national survey NHANES III reported mean dietary intakes ranging between 100.5 μg/day and 158.5 μg/day in adults ages 19-50 years (52). Table 2 lists some good food sources of selenium and their selenium content in micrograms (μg). For more information on the selenium content of specific foods, search the USDA food composition database.

Table 2. Some Common Food Sources of Selenium
Food Serving Selenium (μg)
Brazil nuts (from selenium-rich soil) 1 ounce (6 kernels) 543.5*
Tuna (yellowfin, cooked, dry heat) 3 ounces 92.0
Oysters (Pacific, raw) 3 ounces 65.4
Clams (mixed, cooked, steamed) 3 ounces 54.4
Halibut (Atlantic and Pacific, cooked, dry heat) 3 ounces 47.1
Shrimp (cooked, steamed) 3 ounces 42.1
Salmon (Chinook, cooked, dry heat) 3 ounces 39.8
Noodles (egg, cooked, enriched) 1 cup 38.2
Crab (queen, cooked, steamed) 3 ounces 37.7
Pork (lean, tenderloin, cooked, roasted) 3 ounces 32.5
Beef (lean, plate steak, cooked, grilled) 3 ounces 30.6
Chicken (light-meat, cooked, roasted) 3 ounces 25.8
Rice (brown, long-grain, cooked) 1 cup 19.1
Sunflowers seed kernels (dried) ¼ cup 18.6
Whole-wheat bread 2 slices 16.4
Milk (fat free or skim) 8 fluid ounces (1 cup) 7.6
*Above the tolerable upper intake level (UL) of 400 μg/day.

Supplements

Selenium supplements are available in several forms. Sodium selenite and sodium selenate are inorganic forms of selenium. Sodium selenate is almost completely absorbed, but a significant amount is excreted in the urine before it can be incorporated into proteins. Sodium selenite is only about 50% absorbed but is better retained than selenate once it is absorbed. Selenomethionine is about 90% absorbed (52); however, only about 34% may then actually be converted to free selenomethionine (111). Selenomethionine and selenium-enriched yeast, which mainly supply selenomethionine, are also available as supplements. The consumer should be aware that some forms of selenium-enriched yeast on the market contain yeast plus mainly inorganic forms of selenium.

Although both inorganic and organic forms of selenium can be metabolized to selenocysteine by the body and incorporated into selenoenzymes, they may not equally contribute to the maintenance of an adequate selenium status. In intervention trials, supplementation with an organic form of selenium (selenomethionine) more effectively increased blood selenium concentrations compared to supplementation with inorganic forms (i.e., sodium selenite and sodium selenate) (110). Yet, inorganic forms may increase plasma glutathione peroxidase (GPx) activity more effectively than organic forms (reviewed in 112). It has also been suggested that the incorporation of selenomethionine in place of methionine into tissue proteins may ensure that selenium is available upon protein turnover (110).

Selenium-enriched foods

Selenium-enriched foods have been of interest to scientists, especially because of the suggestion that some of the chemical forms of selenium produced by plants might be more potent modifiers of cancer risk than those currently available in supplements. Although there is currently no evidence of long-term health benefits associated with the consumption of selenium-enriched foods, results from animal studies and intervention trials suggest that protein-based sources of selenium are more effective at increasing GPx activity than selenium-enriched yeast and selenomethionine (112). Food fortification may also represent a cost-effective strategy to improve selenium nutritional status in populations at risk of inadequacy (113).

Safety

Toxicity

Although selenium is required for health, high doses of selenium can be toxic. Acute and fatal toxicities have occurred with accidental or suicidal ingestion of gram quantities of selenium. Clinically significant selenium toxicity was reported in 13 individuals after taking supplements that contained 27.3 mg (27,300 μg) per tablet due to a manufacturing error. Chronic selenium toxicity (selenosis) may occur with smaller doses of selenium over long periods of time. The most frequently reported symptoms of selenosis are hair and nail brittleness and loss. Other symptoms may include gastrointestinal disturbances, skin rashes, a garlic breath odor, fatigue, irritability, and neurologic disorders. In an area of China with a high prevalence of selenosis, toxic effects occurred with increasing frequency when blood selenium concentrations reached a level corresponding to an intake of 850 μg/day.

The Food and Nutrition Board (FNB) of the US Institute of Medicine set the tolerable upper intake level (UL) for selenium at 400 μg/day in adults based on the prevention of hair and nail brittleness and loss and early signs of chronic selenium toxicity (52). The UL of 400 μg/day for adults includes both selenium obtained from food and selenium from supplements (Table 3).

Table 3. Tolerable Upper Intake Level (UL) for Selenium
Age Group UL (μg/day)
Infants 0-6 months  45
Infants 6-12 months  60
Children 1-3 years  90
Children 4-8 years  150
Children 9-13 years  280
Adolescents 14-18 years  400
Adults 19 years and older  400

Do selenium supplements increase the risk for type 2 diabetes mellitus?

A few studies have examined the relationship between selenium status and type 2 diabetes mellitus. In the cross-sectional analysis of NHANES III (1988-1994) data from 8,876 adult participants, the highest versus lowest quintile of serum selenium concentrations (≥137 ng/mL vs. <111 ng/mL) was associated with an increased risk of type 2 diabetes (114). Data analyses from 917 participants (≥40 years of age) of NHANES 2003-2004 also indicated an increased prevalence of type 2 diabetes in the highest versus lowest quartile of serum selenium concentrations (≥147 ngm/L vs. <124 ng/mL). Individuals in the highest versus lowest quartile of serum selenium concentrations also had higher levels of plasma glucose and glycated hemoglobin, suggestive of poor glycemic control (115). The randomized, double-blind, placebo-controlled study in 1,312 participants in the Nutritional Prevention of Cancer (NPC) trial found that selenium supplementation (200 μg/day; mean follow-up of 7.7 years) significantly increased the risk for type 2 diabetes in participants in the highest tertile of baseline plasma selenium concentrations (116). In addition, in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), more cases of type 2 diabetes were found in the selenium group (200 μg/day; median follow-up of 5.5 years) than in the placebo group, but this was only a trend and not statistically significant (72).

At present, the mechanisms behind these observations are not well understood. An increase in insulin sensitivity has been reported in individuals with congenital (inborn) deficiency of most selenoproteins (117). Results from several animal studies also indicated that selenium supplementation and selenoproteins may interfere with insulin action and glucose homeostasis (reviewed in 118). On the other hand, recent studies have found that impaired glucose metabolism in patients with type 2 diabetes may affect SEPP1 expression and selenium homeostasis (11, 119, 120). While more research is needed to fully understand the interplay between carbohydrate metabolism and selenium homeostasis, the use of selenium supplements is considered unlikely to increase the risk of type 2 diabetes in healthy individuals but should be discouraged in those with high selenium status and/or at increased risk for developing type 2 diabetes (118).

Drug interactions

At present, few interactions between selenium and medications have been reported (121). For example, the anticonvulsant drug valproic acid and the chemotherapeutic agent cisplatin may lower circulating selenium concentrations in treated subjects (122, 123). Also, supplemental sodium selenite was found to reduce the toxicity of the antibiotic nitrofurantoin and the herbicide paraquat in animal studies (124).

Antioxidant supplements and statins

A three-year randomized controlled trial in 160 patients with documented coronary artery disease (CAD) and low high-density-lipoprotein (HDL) levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 subfraction levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events (125). Surprisingly, when an antioxidant combination (1,000 mg of vitamin C, 800 IU of vitamin E (d-α-tocopherol), 100 μg of selenium, and 25 mg of β-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. However, the individual contribution of selenium cannot be established, and other studies have reported that antioxidant vitamins alone could interfere with the action of HDL-raising drugs, including statins (126).

Linus Pauling Institute Recommendation

The average American diet is estimated to provide about 100 μg/day of selenium, an amount that is well above the current RDA (55 μg/day) and appears sufficient to optimize plasma and cellular glutathione peroxidase (GPx) activity. A recent 10-week randomized controlled study in healthy British adults (ages, 50-64 years) estimated that about 105 μg/day of total selenium intake was required to maximize the plasma concentrations of selenoprotein P (SEPP1), another useful biomarker of selenium status (127). However, a similar trial in an American cohort with higher baseline plasma selenium concentrations found no effect of selenium supplementation on SEPP1 concentrations (128). While the amount of selenium in multivitamin/mineral (MVM) supplements varies considerably, MVM supplements rarely provide more than the Daily Value (DV) of 70 μg. Eating a varied diet and taking a daily MVM supplement should provide sufficient selenium for most people in the US and help improve selenium status in populations with lower selenium intakes outside the US.

Men

At present, the effect of selenium supplementation on cancer risk is not clear enough to support a general recommendation for an extra selenium supplement, especially in men with serum selenium concentrations consistent with adequate selenium intakes. The SELECT trial found that 200 μg/day of selenium did not reduce the risk of prostate cancer (72), refuting the results of the NPC trial (see Cancer). Another recent multicenter, randomized, double-blind, placebo-controlled trial (the Negative Biopsy Trial) in 699 men at high risk of prostate cancer found no effect of either 200 μg/day or 400 μg/day of selenium on prostate cancer risk during a mean follow-up of 36 months (129). In addition, because current evidence suggests a U-shaped relationship between selenium status and prostate cancer risk (130), men should avoid taking supplemental selenium that would exceed 200 μg/day.

Women

At present, there is no clinical evidence showing that selenium supplementation above recommended levels decreases the risk of breast cancer although some, but not all, observational studies have found an inverse relationship between selenium status and breast cancer in women (59).

Older adults (>50 years)

Aging has not been associated with significant changes in the requirement for selenium. A five-year, randomized, double-blind, placebo-controlled trial in healthy Danish older people (ages at inclusion, 60-74 years) found that selenium supplementation (100-300 μg/day) had little-to-no impact on circulating levels of antioxidant enzymes, including GPx (131).


Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in June 2015 by:
Petra A. Tsuji, Ph.D., M.P.H.
Assistant Professor
Department of Biological Sciences
Towson University

Copyright 2001-2017  Linus Pauling Institute


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