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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 20^th 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 - 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 20^th 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 20^th 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 20^th 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 USDA's FoodData Central.

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	3.75 ounces (1 can)	351
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., hydrochlorothiazide) 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 μg (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.

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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 supported by a grant from Pfizer Inc.

Copyright 2001-2024  Linus Pauling Institute

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Summary

• Chromium (Cr⁰) is a ubiquitous trace metal. The predominant chromium form in the body is trivalent chromium (Cr³⁺), which may potentiate insulin function when provided at pharmacological doses. (More information)
• The nutritional essentiality of chromium has been questioned, as a dietary deficiency has not been described. In 2001, the US Institute of Medicine set the adequate intake (AI) of chromium at 20-35 μg/day for adults. However, in 2014 the European Food Safety Authority concluded that requirements for chromium could not be established. (More information) 
• Results of randomized controlled trials of chromium supplementation in the prevention or treatment of impaired glucose tolerance and type 2 diabetes mellitus have been mixed, with few finding benefits that may be clinically meaningful. (More information)
• Evidence that supplemental chromium can help treat metabolic syndrome or polycystic ovary syndrome is largely lacking. (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 proposed function in the body remains poorly understood. In fact, in 2014 the European Food Safety Authority concluded that a dietary requirement — or even an Adequate Intake — cannot be set for trivalent chromium as no conclusive evidence exists that chromium is essential at any dietary intake (2). Trivalent chromium appears to have health effects only at pharmacological doses (reviewed in 3), and a dietary deficiency of the mineral has not been observed.

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 (4). 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 (5-7).

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 concentration, 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 (8). 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 (9).

Possible mechanism of action

The precise composition and structure of the biologically active form of chromium is not known. One model postulates that trivalent chromium might be the cofactor of a low-molecular-weight chromium-binding substance known as LMWCr or chromodulin (10). Chromodulin has been shown to play a role in the transport of chromium from the tissues to the bloodstream for ultimate elimination in the urine (11). When chromium is consumed at high levels, such as from dietary supplements, levels of chromodulin in tissues rise. At these high levels, chromodulin is proposed to enhance the cascade of signaling events induced by the binding of insulin to extracellular α-subunit of the insulin receptor (IR) (12). 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 (10). While this model is supported by in vitro studies, this mode of action for chromodulin has not been confirmed to date by in vivo studies.

Some, but not all, studies conducted in cell-based and animal models of insulin resistance and diabetes mellitus 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 10). A 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 (13). 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 10, 14).

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 (5).

Vitamin C

Chromium uptake is enhanced in animals when given at the same time as vitamin C (7). 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 (5).

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 (5).

Deficiency

Dietary chromium deficiency has not been observed in humans. Potential cases of chromium deficiency were thought to have been observed 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 (3, 14). However, the differences in symptoms among subjects, the range of doses of chromium utilized over varying windows of time, and the different reported outcomes are now realized to make interpretation of these results difficult, even in terms of any potential pharmacological effects from the chromium supplementation. 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 mellitus (5, 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).

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 (if chromium is nutritionally essential) (2).

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 (now the National Academy of Medicine) established an adequate intake (AI) based on the chromium content in healthy diets (Table 1; 5).

The case of trivalent chromium essentiality has been questioned in both animals and humans in the last decades, and in 2014 the European Food Safety Authority's Panel on Dietetic Products, Nutrition, and Allergies — which provides dietary guidelines for the EU community — concluded that requirements for chromium could not be established (2). The FNB, which sets dietary intake recommendations for the United States and Canada, is not currently reconsidering the AI level for chromium (22).

Disease Prevention

Impaired glucose tolerance and type 2 diabetes mellitus

Early controlled studies in subjects with impaired glucose tolerance 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 100-125 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 mellitus (25). Current estimates suggest that up to 70% of individuals with impaired glucose tolerance eventually develop type 2 diabetes (26).

In a randomized, double-blind, placebo-controlled study in 56 subjects at risk of developing 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 individuals without diabetes 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 individuals without diabetes (29).

Cardiovascular disease

Impaired glucose tolerance and type 2 diabetes mellitus 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 (6, 7, 30).

Moreover, a recent meta-analysis of 10 randomized controlled trials, mostly in patients with type 2 diabetes mellitus or metabolic syndrome, found chromium supplementation had no effect on either systolic or diastolic blood pressure (31). Yet, another meta-analysis of randomized controlled trials found chromium supplementation decreased circulating levels of two proinflammatory biomarkers associated with increased cardiovascular risk, hs-CRP and TNF-α, but not blood levels of IL-6 (32).

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 (8). 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 33). 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 (6, 30). In the US, the claim that chromium picolinate increases lean body mass is not allowed on supplement labels because it is not substantiated by the available research (34, 35).  

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 (36). A 2013 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 to 24 weeks (37). However, such a small change did not reach a clinically significant weight loss of ≥5% of the initial body weight (38). A 2019 meta-analysis of 19 clinical trials found similar results: chromium supplementation at doses between 20 μg/day and 1,000 μg/day for 4 to 24 weeks decreased body weight in overweight or obese subjects by only 0.75 kg, a clinically insignificant amount (39). Some reports have suggested that supplemental chromium may reduce food craving and intake in overweight or obese women (40, 41). Yet, current available data remain insufficient to support the use of chromium supplements as a weight-loss strategy (42). In the US, the claim that chromium picolinate promotes weight loss is not allowed on supplement labels because it is unsubstantiated (34, 35).  

Reduces insulin resistance

Despite stating that scientific evidence is severely limited, the US FDA allows a single claim on supplement labels: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain." (35, 43).

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 people with type 2 diabetes 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 (44). 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 (45). 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 (46). 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 over the past four months, 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 (47). Besides, the study was excluded from meta-analyses of randomized controlled trials due to insufficient data quality (29, 48).

In a recent systematic review and meta-analysis of randomized controlled trials in patients with type 2 diabetes, chromium supplementation (50-1,000 μg/day for 4 to 25 weeks) reduced concentrations of fasting plasma glucose (23 trials) and insulin (14 trials), and improved HbA1c values (18 trials) (49). These effects were not dose dependent (49). Yet, other meta-analyses in patients with type 2 diabetes did not find significant benefits of chromium supplementation on fasting glucose and insulin (50) or HbA1C (51). Moreover, a systematic review on 20 randomized controlled trials found that only a handful of chromium supplementation studies resulted in glycemic changes that are considered clinically meaningful, i.e., consistent with treatment goals of a 7.2-mmol/dL decrease in fasting glucose, a decrease of 0.5% in HbA1c, or reaching ≤7% HbA1c (52).   

Gestational diabetes

Few studies have examined the effects of chromium supplementation on gestational diabetes mellitus, a condition that is estimated to affect 5.8% to 9.2% of pregnant women in the US (53). The occurrence of gestational diabetes during pregnancy is associated with insufficient insulin secretion and glucose intolerance of variable severity (54). 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 (55). 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) (56, 57). The question also arises as to whether low chromium levels might be an effect rather than a contributing factor in gestational diabetes.

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 (58). 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 (59). 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 (6, 60).

Metabolic syndrome

Metabolic syndrome is a combination of medical conditions, including hypertension, dyslipidemia, central obesity, and insulin resistance, that places one at increased risk for cardiovascular disease and type 2 diabetes mellitus (see the page: Metabolic Syndrome). A prospective cohort study that followed 3,648 young US adults for 23 years found an inverse association between toenail chromium concentration measured at baseline and risk of developing metabolic syndrome (61). An inverse association between plasma chromium concentration and metabolic syndrome was also observed in a case-control study in 4,282 Chinese adults (62). However, low toenail and plasma chromium may be the result of metabolic syndrome, rather than suggesting a cause or contributing factor.

Only a few randomized controlled trials have examined whether chromium supplementation might benefit patients with metabolic syndrome. In a randomized, double-blind, placebo-controlled trial in 65 patients with metabolic syndrome, 300 μg/day of supplemental chromium (from chromium-enriched yeast) for 24 weeks had no effect on measured parameters of glucose, insulin, and lipid metabolism (63). While large-scale trials would be needed, there is presently no evidence that chromium can help treat metabolic syndrome.

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of childbearing age, with an estimated worldwide prevalence of 21% (64). The disorder has a multifactorial etiology and is characterized by menstrual irregularities, polycystic ovaries, and infertility. Similar to metabolic syndrome, women with PCOS often have various metabolic abnormalities, including dyslipidemia, obesity (especially abdominal obesity), impaired glucose tolerance, insulin resistance, and are at increased risk for developing type 2 diabetes mellitus (65).

Several randomized controlled trials have evaluated whether chromium supplementation might help treat PCOS, but the results are conflicting. A 2017 systematic review and meta-analysis of seven clinical trials found that chromium picolinate supplementation (of either 200 μg/day or 1,000 ug/day) for 8 to 24 weeks decreased BMI (3 studies), lowered free testosterone concentration (5 studies), and decreased fasting serum insulin concentration (5 studies) but had no effect on concentrations of fasting blood glucose (4 studies), total testosterone (3 studies), luteinizing hormone (3 studies), or follicle-stimulating hormone (2 studies) (66). However, other recent systematic reviews and meta-analyses have concluded that chromium supplementation in women with PCOS does not result in significant or clinically meaningful health benefits, including with respect to glucose and insulin metabolism (67-69).

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. Whole-grain products, high-bran cereals, green beans, broccoli, nuts, and egg yolk are good sources of chromium. Processed meats may also be high in chromium, depending on the processing equipment and method (70). Foods high in simple sugars, such as sucrose and fructose, are usually low in chromium and may actually promote chromium excretion (6, 71). Estimated average chromium intakes in the US range from 23 μg/day-29 μg/day for adult women and 39-54 μg/day for adult men (5). The chromium content of some foods is listed in Table 2 and expressed in micrograms (μg) (72). Since chromium content varies significantly between different batches of the same food, the information provided in the table should serve only as a guide to the chromium content of food.

Supplements

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, including multivitamin/mineral supplements. Doses typically range from 100 to 300 μg of elemental chromium in single-nutrient supplements and from 10 to 180 μg in multivitamin/mineral supplements (73).

Much of the research on impaired glucose tolerance and type 2 diabetes mellitus uses chromium picolinate as the source of chromium, although investigations suggest that its bioavailability may not be greater than that of dietary chromium (74). 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, with inhalation causing lung, nasal, and sinus cancers (75). 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 (76). 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 (now the National Academy 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 (5).

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 (77-80). 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 (81).

Many studies have demonstrated the safety of daily doses of up to 1,000 μg of chromium for several months (46, 82). 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 (83), while kidney failure and impaired liver function were reported after the use of 1,200 to 2,400 μg/day of chromium in the form of chromium picolinate over a period of four to five months (84). Additionally, a 24-year old healthy male reportedly developed reversible, acute renal failure after taking chromium picolinate-containing supplements for two weeks (85). Individuals with pre-existing kidney or liver disease may be at increased risk of adverse effects and should limit supplemental chromium intake (5).

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 (7).

Linus Pauling Institute Recommendation

The lack of any known indicators of chromium nutritional status in humans makes it difficult to determine the level of chromium intake most likely to promote optimum health, if such exists. Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (DV) of most nutrients may provide 10 to 180 μg/day of chromium, which is generally considered safe.

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 (86). 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, type 2 diabetes mellitus, and metabolic syndrome are associated with serious health problems, individuals with any of these conditions should seek medical advice if considering the use of high-dose chromium supplements.

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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

Updated in November 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2024 by:
John B. Vincent, Ph.D.
Professor, Department of Chemistry
The University of Alabama
Tuscaloosa, Alabama

Copyright 2001-2024  Linus Pauling Institute

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References

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Summary

• Copper is an essential cofactor for oxidase enzymes that catalyze oxidation-reduction reactions in various metabolic pathways. These copper-dependent enzymes, or cuproenzymes, participate in, for example, energy (ATP) production, iron metabolism, connective tissue formation, and neurotransmission. (More information) 
• Dietary copper insufficiency in humans has been infrequently described; however, copper depletion may occur due to intestinal defects, high supplemental zinc intake, or in genetic conditions such as Menkes disease. Intestinal copper absorption is severely impaired in Menkes disease, leading to systemic copper deficiency. Symptoms of low body copper include anemia, bone and connective tissue abnormalities, and neurological dysfunction. (More information)
• Assessing copper status in humans is challenging, since no definitive biomarkers exist for detecting moderate, or subclinical, copper deficiency. The development of more precise and sensitive biomarkers of copper nutritional status is thus a critical area for future research. (More information)
• Copper imbalance in humans increases risks of bone demineralization and osteoporosis, fatty liver disease, liver disease mortality, and cardiovascular and neurodegenerative diseases. In certain pathological states, dysregulation of copper homeostasis may not be a primary outcome but could rather be secondary to some aspect of disease pathogenesis. (More information)
• Accurately assessing dietary copper intake is difficult since the copper content of many foods has not been firmly established. Organ meats, shellfish, nuts, seeds, wheat-bran cereals, and whole-grain products are, however, recognized as good sources of dietary copper. (More information)
• Copper toxicity is rare, being most frequently associated with Wilson disease, a rare inborn error of metabolism that causes copper overload initially in the liver and then subsequently in other tissues, particularly the brain. Toxic effects of copper overload in Wilson disease include disruption of lipid metabolism, as well as damage to mitochondria. Toxic copper accumulation is also observed in Indian Childhood Cirrhosis and Endemic Tyrolean Infantile Cirrhosis (or Idiopathic Copper Toxicosis). No causal genetic defects have been linked to these latter disorders, although increased susceptibility to excess copper has been proposed. (More information)

Copper (Cu) is an essential trace element for humans and other mammals. In biological systems, copper readily shifts between the cuprous (Cu¹⁺) and cupric (Cu²⁺) forms. The redox properties of copper underlie its important role in oxidation-reduction 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 critical for the function of several essential enzymes known as cuproenzymes, which are integral parts of various metabolic pathways (4, 5). Physiologic functions of these copper-dependent enzymes, and the biochemical pathways in which they function (6, 7), are outlined below. 

Energy production

The copper-dependent enzyme cytochrome c oxidase (CCO) plays a critical role in cellular energy production in mitochondria by catalyzing the reduction of molecular oxygen (O₂) to water (H₂O), thereby generating an electrical gradient that is required for ATP production (8). Redox-active copper contained within the CCO enzyme complex is required for the electron transfer reactions that are critical for its function.

Connective tissue formation

Another cuproenzyme, lysyl oxidase (LOX), is required for the cross-linking of collagen and elastin fibers, which is essential for the formation of strong and flexible connective tissue. LOX function is critical for bone formation and maintenance of connective tissue in the heart and blood vessels (2).

Iron metabolism

Multi-copper oxidases (MCOs) are copper-dependent ferroxidases that function in iron homeostasis. MCOs oxidize ferrous iron (Fe²⁺) to the ferric (Fe³⁺) form, which enables binding to transferrin (the main iron carrier) in the blood, thus allowing iron transport to sites of utilization (e.g., the bone marrow). The MCOs include: (1) ceruloplasmin (CP), which contains 60%-95% of plasma copper; (2) a membrane-bound form of CP (GPI-CP), expressed in brain and other tissues; and (3) the membrane-bound ferroxidases hephaestin (HEPH) and zyklopen, which function in the intestine and placenta, respectively (9, 10). CP knockout (Cp^-/-) mice accumulate excess hepatic iron but have normal copper status (11, 12). Similarly, humans with aceruloplasminemia, who lack functional CP, display iron overload in liver, brain, and retina but have no observable defects in copper homeostasis (13). Moreover, absorption of dietary iron and iron mobilization from storage sites (e.g., liver) are impaired in copper deficiency, when CP and HEPH activity is reduced, further supporting a role for the MCOs in iron metabolism (14).

Central nervous system

Several physiological processes within the brain and nervous system, including neurotransmitter synthesis and formation and maintenance of myelin, depend upon catalysis mediated by cuproenzymes. Dopamine β-hydroxylase, for example, catalyzes the conversion of dopamine to the neurotransmitter norepinephrine (15). Also, CCO is required for the biosynthesis of phospholipids, which are critical structural components of the myelin sheath (2).

Melanin biosynthesis

The cuproenzyme tyrosinase (TYR) is required for the biosynthesis of melanin in melanocytes, which is critical for normal pigmentation of hair, skin, and eyes (2). Low TYR activity most likely explains the achromotrichia seen in copper-deficient laboratory and agricultural animals, and the depigmentation noted in severely copper-depleted patients with Menkes disease.

Antioxidation

Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of reactive oxygen species, such as the superoxide anion (O^2-) and the hydroxyl radical (•OH), to hydrogen peroxide (H₂O₂), which is subsequently reduced to water by other antioxidant systems (16). Two forms of SOD contain copper: copper/zinc SOD (SOD1), which is expressed in most cells, including red blood cells; and extracellular SOD (EcSOD), which is highly expressed in the lungs and found at lower levels in plasma (2). Also, as outlined above, ceruloplasmin has antioxidant properties relating to iron metabolism. The ferroxidase activity of ceruloplasmin may prevent ferrous iron (Fe²⁺) from participating in harmful free-radical-generating reactions via Fenton chemistry (16).

Regulation of gene expression

Copper-related gene expression pathways seem to be mainly regulated at a post-translation level, in some cases via protein trafficking-related mechanisms that respond to intracellular copper levels (17). Cytosolic copper may also influence mRNA expression levels of specific genes, in a dose-dependent manner (18-20), implicating possible transcriptional regulation. For example, intracellular copper may alter the redox state of cells and thus induce oxidative stress, which can activate signal transduction pathways that increase the expression of genes encoding proteins involved in the detoxification of reactive oxygen species (21).

Nutrient interactions

Iron

Adequate copper nutritional status is necessary for normal iron metabolism and red blood cell production and function. Copper depletion results in an iron deficiency-like anemia, and iron accumulates in the livers of copper-deficient animals. The development of anemia during copper deficiency may be linked to low CP activity, impaired iron release from stores in the liver, and reduced iron delivery to the erythroid marrow, thus leading to iron-restricted erythropoiesis (see Iron metabolism) (2). However, this may not be the whole story, as was recently suggested by longtime copper researcher, Dr. Joseph R. Prohaska (Univ. of Minnesota, Duluth) (22). Copper depletion also reduces CP activity in humans, leading to hepatic iron overload and thus increasing risk for oxidative damage and liver cirrhosis (14). Oral copper supplementation restored normal serum CP levels and plasma ferroxidase activity, and corrected iron metabolism defects in a copper-deficient subject (23). Moreover, infants fed a formula with a high-iron content absorbed less copper than infants fed a low-iron formulation, suggesting that high iron intakes may interfere with copper absorption in infants (24). This observation was also confirmed in rats and mice, where high dietary iron caused copper depletion, thus increasing the copper nutritional requirement (25, 26).

Zinc

Excess intake of supplemental zinc, at doses of 50 mg/day or more for extended periods of time, may result in copper depletion. The mechanism may relate to increased synthesis of metallothionein (MT), an intracellular zinc- and copper-binding protein. MT has a stronger affinity for copper than zinc, so high levels of MT induced by excess zinc may trap copper within enterocytes thus limiting its bioavailability. This postulate, however, was called into question by studies done in MT-deficient mice, in which high enteral zinc still decreased copper absorption, suggesting that high zinc may block a copper transporter (27). Conversely, elevated copper intakes have not been found to affect zinc nutritional status (2, 24). Moreover, zinc supplementation at 10 mg/day for eight weeks restored normal plasma copper/zinc ratios in 65 subjects on long-term hemodialysis who initially exhibited low serum zinc and high copper. Whether improving zinc and copper status of hemodialysis patients can impact clinical outcomes, however, needs to be assessed (28).

Fructose

Evidence of copper-fructose interactions comes mainly from studies using experimental animals. High-fructose diets exacerbated copper deficiency in male rats, but not in pigs whose gastrointestinal system is anatomically and functionally more like humans. Also, 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, 24). However, high fructose consumption and low copper availability may be risk factors for functional copper deficiency in patients with non-alcoholic fatty liver disease (29).  

Vitamin C

Although vitamin C supplements have produced copper deficiency in guinea pigs (30), the effect of vitamin C supplementation on copper nutritional status in humans is less clear. Two small studies in healthy, young adult men indicated that ceruloplasmin oxidase activity may be impaired by relatively high doses of supplemental vitamin C. In one study, vitamin C intakes of 1,500 mg/day for two months resulted in a significant decline in CP oxidase activity (31). In the other study, supplements of 605 mg/day of vitamin C for three weeks resulted in decreased CP oxidase activity, although copper absorption did not decline (32). 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 CP levels may fall to 30% of normal in cases of severe copper deficiency. Hypocupremia is also observed in genetic disorders of copper metabolism, including Wilson disease (WD) and aceruloplasminemia; however, neither disorder has been linked to low dietary copper intake. One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but is corrected by copper supplementation. It was hypothesized that this anemia could result from defective iron mobilization due to decreased CP activity, yet individuals with inherited aceruloplasminemia do not always develop overt anemia (33). Moreover, in copper-deficient swine, intestinal iron absorption is impaired but iron distribution among tissues/organs is normal (34-36). Low serum iron from reduced absorption is an unlikely cause of this anemia since intravenous provision of iron did not correct it. An alternative postulate is that copper-deficiency anemia is caused principally by impaired hemoglobin production and red blood cell proliferation, and a shortened erythrocyte lifespan. These physiological processes are thus likely to require copper. Copper deficiency may also lead to neutropenia, which can increase susceptibility to infection. Copper depletion studies demonstrated that low copper might affect erythroid and myeloid cell lineages, supporting a role for copper in the regulation of blood cell proliferation and maturation (37, 38). More research is clearly needed to further define the mechanisms underlying copper deficiency-induced anemia and neutropenia (4, 39). Furthermore, osteoporosis and other abnormalities of bone development have been described in copper-deficient, low-birth-weight infants and young children. Less common features of copper deficiency may include impaired growth, depigmentation, and development of neurological pathologies (2, 8). 

Biomarkers of copper status

Currently, there is not a sensitive and specific biomarker to detect copper inadequacy in humans (5, 40-42). Blood copper (43) and ceruloplasmin concentrations are reduced in severe copper deficiency (3, 6). However, both of these parameters are also influenced by pregnancy, inflammation, and infection (5), thus limiting the usefulness of these assays to estimate body copper status. Experimental work has recently identified other copper-related biomarkers, including erythrocyte copper Cu/Zn superoxide dismutase (SOD1) and copper chaperone for superoxide dismutase (44-46), but further experimental validation is required, including clinical testing in humans.  

Individuals at risk of deficiency

Bovine milk is relatively low in copper, and cases of copper deficiency have been reported in infants fed only cow's milk formula (47). Other individuals at elevated risk for copper deficiency include premature and low-birth-weight infants; individuals with severe burns (48) or prolonged diarrhea, which accelerate copper losses; infants and children recovering from malnutrition; and individuals with malabsorption syndromes, including celiac disease, Crohn’s disease, and short bowel syndrome, possibly due to surgical removal of large portions of the intestine (48-50). Also, gastric bypass surgery for morbid obesity significantly increases the risk for copper depletion (51-53). Individuals receiving intravenous total parenteral nutrition lacking copper or those on certain restricted diets may also require supplementation with copper (and other trace elements) (2, 8). Moreover, copper deficiency in infants with cholestasis has been linked to long-term parenteral nutrition lacking copper (54). Case reports indicated that cystic fibrosis patients may also be at increased risk of copper insufficiency (55, 56). And finally, excessive zinc intake has been associated with secondary copper deficiency in individuals taking zinc supplements or using zinc-enriched dental creams (57-59).

Acquired copper deficiency

Copper deficiency is atypical in the general population; however, it was recently suggested that copper deficiency may be more widespread than currently recognized, and that (covert) pathophysiological links exist between low copper nutritional status and Alzheimer’s disease, ischemic heart disease (60), myelodysplastic syndrome, and postmenopausal osteoporosis (61). Part of the rationale for such an assertion relates to the difficulty in clinically evaluating the copper status of humans, so moderate to even severe copper deficiency is unlikely to be detected in individuals with no notable risk factors (62). Firmly establishing links between low copper status and increased risk for these, and possibly other, chronic diseases awaits further epidemiological and clinical testing. Furthermore, a neurological syndrome associated with copper deficiency was recently described in adults (63). The symptoms included central nervous system demyelination, polyneuropathy, myelopathy, and inflammation of the optic nerve. The etiology is unknown and risk factors have not been established (see Individuals at risk of deficiency). Case reports suggested that copper malabsorption underlies this disorder, but mutations in the gene encoding the main intestinal copper exporter, ATP7A, were not detected in affected patients (see Inherited copper deficiency) (64). Oral copper supplementation (2 mg/day) normalized serum copper and CP concentrations, and stabilized individuals afflicted with the disease and significantly improved their quality of life. Optimal duration and dose of copper administration has not, however, been experimentally evaluated (63).

Inherited copper deficiency

ATPase copper transporting alpha, or ATP7A, is a dual function Cu¹⁺-transporting ATPase that is expressed in most cell types, except for, notably, hepatocytes. ATP7A transports copper from the cytosol into the trans-Golgi (TGN), where cuproenzymes are synthesized within the secretory pathway, and exports copper from cells. Mutations in ATP7A, which underlie Menkes disease (MD), critically block copper export from enterocytes and vascular endothelial cells (65). Impaired absorption of dietary copper results in systemic copper deficiency in MD. Decreased cuproenzyme expression/activity is caused by low intracellular copper, and defective copper transport into the TGN. Copper accumulation in microvascular endothelial cells in the blood-brain barrier reduces copper transport into the brain, leading to low brain copper and reduced cuproenzyme activity in neurons. Other mutations in ATP7A have been linked to a less severe neurological copper deficiency disorder called occipital horn syndrome (OHS). The clinical features of MD include intractable seizures, connective tissue disorders, subdural hemorrhage, and hair abnormalities (so called "kinky hair"). OHS patients exhibit muscular hypotonia and connective tissue abnormalities, including formation of exostoses on occipital bones. Subcutaneous injections of copper-histidine improve copper-related metabolic functions in MD and OHS patients. Copper entry into the brain, however, remains limited (reviewed in 66). Furthermore, gene therapy approaches have been recently validated in a pre-clinical mouse model of MD, with long-term goals of using such treatments in humans with the disease (67, 68). Recently, another inherited copper-deficiency disorder was described in identical twin male infants, who were homozygous for a novel missense variant in the gene encoding copper transporter 1 (CTR1) (69). This genetic aberration caused a distinctive autosomal recessive syndrome of infantile seizures and neurodegeneration, consistent with profound central nervous system copper deficiency. Disease pathology was most likely caused by defective intestinal copper transport which resulted in severe systemic copper deficiency. This outcome is supported by experimental laboratory studies which demonstrated that intestine-specific ablation (deletion) of CTR1 significantly impaired absorption of dietary copper in mice (70).   

Copper Excess

Inherited copper overload

Patients with Wilson disease (WD) may have increased risk for copper toxicosis even at copper intakes in the normal range. WD is an autosomal recessive disorder that is typified by defective copper distribution and storage (71). The disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase that is highly expressed in liver and brain. Dysfunctional ATP7B disrupts copper flux in these organs. A recent review provides a nice summary of this devastating human disease (72). WD prevalence is ~1:30,000 individuals globally (73), although much higher prevalence rates have been reported. It was suggested that differences in the penetrance of disease-causing genetic variants explain the apparent discrepancy between epidemiological and genetic prevalence studies of WD (74).

In WD, redox-active copper accumulates in liver, brain, and cornea due to impaired ATP7B-mediated copper excretion, which increases oxidative stress leading to eventual tissue and organ damage. Untreated WD patients are likely to develop liver damage, cancer, and eventual hepatic failure, and severe hemolytic crisis. Elevated brain copper content can lead to neurological damage, and copper accumulation in the eye in so-called Kayser-Fleisher rings can result in abnormal eye movements. Blood concentrations of ceruloplasmin are characteristically low in WD patients, since hepatic ATP7B is required for its biosynthesis, and urinary copper losses may be enhanced. Early intervention can prevent development of some of the most severe pathophysiological outcomes. Treatments for WD include zinc supplementation, which attenuates enteral copper absorption, and/or copper chelation therapy with penicillamine or trientine (75).

Other genetic copper-overload disorders

Additional pathologies associated with liver copper loading include Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT). In ICC, notable liver copper loading and progressive liver failure are observed (76). In contrast to Wilson disease when ceruloplasmin is low, in ICC, ceruloplasmin is normal or elevated. ICC is most likely caused by inadvertent excess copper ingestion, possibly from the use of copper-lined, food/beverage storage containers in a genetically susceptible individual. It seems likely that the unknown genetic defect in ICC relates to the efficiency of excretion of excess copper in the bile, but this has not been definitively established. Also, about one-third of ICC patients have α-1-antitrypsin deficiency, which calls into question a primary role for copper in disease outcomes (77). ICT is another hepatic copper overload disorder that predominantly afflicts infants and children. ICT displays autosomal recessive inheritance, and an unidentified genetic aberration results in defective copper metabolism leading to an increased susceptibility to excess copper. Affected individuals are at increased risk for copper-related, hepatic toxicosis due to inadvertent consumption of excess copper. However, the source of extra copper remains unidentified in many ICT patients, perhaps suggesting a more complex disease pathogenesis (78).

The Recommended Dietary Allowance (RDA)

A variety of bioindicators 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 (24). However, whether these are accurate and sensitive biomarkers of copper nutritional status uncertain (40). Also, estimates of copper concentrations in various foods and water sources may not be accurate and reliable (40, 62). The RDA for copper reflects the results of depletion-repletion studies and is based on the prevention of deficiency (Table 1). For infants up to one year of age, an adequate intake (AI) was established due to the lack of experimental evidence to set a requirement.

Disease Prevention

Cardiovascular disease

Severe copper deficiency results in cardiomyopathy in some animal species (79); however, this pathology differs from the atherosclerotic cardiovascular disease that is prevalent in humans (24). Outcomes of cardiovascular disease (CVD)-related clinical studies in humans are inconsistent, possibly since the copper status of participants is uncertain given the lack of reliable biomarkers of copper nutritional status. Ionic copper is a pro-oxidant, and it can oxidize low-density lipoprotein (LDL) in the test tube. CP can also stimulate LDL oxidation in the laboratory setting (80). As such, some researchers have proposed that excess copper could increase the risk for developing atherosclerosis by promoting the oxidation of LDL in vivo. However, there is scant experimental evidence to support this possibility. Moreover, superoxide dismutase and ceruloplasmin have known antioxidant properties, leading some experts to propose that copper deficiency, rather than copper excess, increases the risk for cardiomyopathy (81, 82). Outcomes of observational and intervention studies relating copper nutritional status to relative risk for CVD are summarized below.  

Observational studies

Observational studies have linked elevated serum copper levels to an increased risk for developing CVD. For example, a prospective cohort study examined serum copper levels in more than 4,500 men and women 30 years of age and older in the United States (83). During the subsequent 16 years, 151 participants died from coronary heart disease (CHD). After adjusting for other risk factors, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from CHD. Case-control studies conducted in Europe also had similar outcomes. For example, a case-cohort study of 2,087 adults in Germany reported an association between higher serum copper concentrations and increased risk of incident CVD, including myocardial infarction and stroke (84). Another study in 60 patients with chronic heart failure or ischemic heart disease reported that serum copper was a predictor of short-term outcomes (85). Higher serum copper was also linked to an increased risk of heart failure in a prospective cohort study of 1,866 middle-aged and older men in Finland (86). Another prospective cohort study in 4,035 middle-aged men in France 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 CVD mortality in this study (87). Serum copper was also elevated in patients with rheumatic heart disease (88). In sum, these studies may indicate that high serum copper reflects elevated body copper content, which increases oxidative stress and accelerates tissue/organ damage and disease development. Importantly, however, most copper in the serum is contained within CP, up to 90% depending upon the species, with the remaining, smaller proportion of serum copper bound to albumin or α2-macroglobulin (89, 90). Serum CP is an acute-phase reactant protein, with levels increasing by up to 50% as a result of trauma or infection and during chronic inflammatory states. Changes in circulating CP are associated with proportional changes in serum copper levels, independent of body copper status. Therefore, elevated serum copper in CHD patients may simply reflect increased CP production due to the inflammation that typifies atherosclerosis. Collectively, these observations raise concerns about linking elevated serum copper to increased tissue copper content and chronic disease development in humans (91).

In contrast to the observational findings discussed above linking high serum copper levels to heart disease, two autopsy studies found copper levels in cardiac muscle were actually lower in patients who died of CHD than in those who died of other causes (92). Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients (93, 94). Further, patients with a history of myocardial infarction (MI) had lower concentrations of copper-dependent, extracellular superoxide dismutase than those without a history of MI (95). Thus, due to the lack of specific, reliable biomarkers of copper nutritional status, it is not clear whether copper is related to cardiovascular disease. It is also important to note that altered copper metabolism may be symptomatic of a cardiovascular condition, rather than a factor that primarily influences its development.

Studies examining dietary intake of copper are scarce. In a prospective cohort study in Japan, which included 58,646 participants followed for a median of 19 years, dietary copper intake — measured by a food frequency questionnaire — was not associated with CHD mortality (96). Yet, this study associated higher copper intakes with an increased risk of mortality from stroke and other cardiovascular diseases (96).

Notably, it was suggested that elevated plasma copper concentrations could be linked to high circulating homocysteine levels in individuals with cardiovascular disease (97-99). Increased blood homocysteine may precipitate development of arterial wall lesions and increase risk of CVD (100); however, this matter is currently open to debate (101). In animal models, copper-homocysteine interactions were linked to impaired vascular endothelial function (102, 103). Copper restriction in experimental animals decreased homocysteine levels and reduced incidence of atherogenic lesions (104, 105), but it is not known whether copper imbalance contributes to a possible atherogenic effect of homocysteine in humans (106).

Intervention studies

Small studies in adults deprived of dietary copper documented adverse changes in blood cholesterol, including increased total and LDL cholesterol concentrations and decreased HDL cholesterol concentrations (107), but these outcomes were not confirmed in other studies (108). For example, in one recent study, copper supplementation of 2 to 3 mg/day for 4 to 8 weeks did not result in clinically significant changes in blood cholesterol levels (81, 109, 110). Additionally, 8 mg/day of copper for six months had no effect on blood cholesterol levels (111). Interpretation of these outcomes is, however, challenging since the copper status of participants was presumably not well defined. Additional research failed to link increased copper intake to elevated oxidative stress. In a multi-center, placebo-controlled clinical trial, copper supplementation of 3 or 6 mg/day for six weeks did not result in increased susceptibility of LDL to oxidation by copper (112). Moreover, supplementation with 3 or 6 mg/day of copper did not increase oxidative damage to red blood cells (113). Collectively, these studies indicated that copper intakes several times above the RDA do not increase oxidative stress, at least as measured by these assays in these populations.

Summary: Copper and cardiovascular disease

Although free copper and CP can promote LDL oxidation in the laboratory, there is little evidence that high dietary copper increases oxidative stress in the human body. Increased serum copper levels have been associated with increased CVD risk, as outlined above, but the significance of these findings is unclear due to the complex association among serum copper, CP, and inflammatory mediators. Clarification of the relationships of copper intake, copper nutritional status, CP levels, and CVD risk thus requires further research.

Immune system function

Copper is known to play several important roles in the development and maintenance of immune system function, including innate and adaptive immunity (reviewed in 114). Neutropenia is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune system function appear most pronounced in infants. For example, infants with Menkes disease, a genetic copper-deficiency disorder, suffer from frequent and severe infections (115, 116). Moreover, in a study of 11 malnourished infants with evidence of copper deficiency, the ability of white blood cells to engulf pathogens increased significantly after one month of copper supplementation (117). Moreover, 11 men on a low-copper diet (0.66 mg/day of copper for 24 days and 0.38 mg/day for another 40 days) showed an impaired monocyte proliferative response in an ex vivo immune challenge assay (118). Mechanistic studies also support a role for copper in the innate immune response to bacterial and viral infections (reviewed in 119, 120). Severe copper deficiency thus has adverse effects on immune system function; however, whether marginal copper insufficiency impairs immunity in humans has not been established.

Osteoporosis

Progressive decrease of bone mineral density (BMD) is commonly observed in the elderly, frequently leading to development of osteopenia (pre-osteoporosis) and osteoporosis. Women are more often affected by osteoporosis than men, (e.g., prevalence ratio is 5:1 in non-Hispanic whites) (121), primarily due to the postmenopausal reduction in the production of estrogen, which is essential for maintaining strength of muscle, bone, and connective tissue (122). Osteoporosis is associated with an increased risk of falls, bone fracture, and mortality in individuals over 65 years of age (123).

Osteoporosis has been reported in infants with severe copper deficiency (124, 125), but how copper depletion affects bone and connective tissue health in adults is less certain. One recent investigation documented bone resorption (breakdown) in 11 healthy adult males consuming marginal copper for six weeks (0.7 mg/day) (126). Also, 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 (127, 128). An effect of copper deficiency on bone integrity seems likely, since a copper-dependent enzyme, lysyl oxidase (LOX), is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. In individuals with marginal copper intake and less efficient copper absorption, such as the elderly, it seems plausible that LOX activity is decreased, possibly increasing risk for bone and connective tissue effects.  

Observational studies

Collectively, research examining 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 age-matched controls (129). Another study, however, found no differences in serum copper levels among postmenopausal women with normal BMD (N=40), osteopenia (N=40), or osteoporosis (N=40) (130). A cross-sectional study showed that blood copper concentrations were lower than the normal reference range in postmenopausal women with osteopenia (N=28) and osteoporosis (N=23) (131). In another cross-sectional study in 728 postmenopausal women, 491 of which had confirmed osteoporosis, lower serum copper concentrations were associated with osteoporosis in the younger women (ages 40-59 years) but not the older women (ages 60-80 years) (132). Furthermore, in a national survey in the US, including 8,224 adults (compiling data from NHANES 2007-2010, 2013-2014, and 2017-2018), higher daily copper intakes (from diet and supplements) were associated with higher BMD at the femur and lumbar spine and a lower risk of osteoporosis (133).

Intervention studies

Limited studies of copper supplementation and bone health outcomes have been undertaken. A small study in perimenopausal women, who consumed ~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 (134). Additionally, a two-year, double-blind, placebo-controlled trial in 59 postmenopausal women found that daily intake of supplemental calcium plus trace minerals, including 2.5 mg of copper, resulted in maintenance of spinal BMD.  Supplemental calcium or trace minerals, alone, were not as effective at preventing loss of bone density (135). Another randomized, double-blind, placebo-controlled study in 224 healthy, postmenopausal women ages 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. Another trial showed that BMD was reduced in subjects with dietary copper intakes below the RDA (0.9 mg/day), but copper supplementation did not prevent the progressive loss of BMD as well as a calcium regimen alone (136). Finally, several studies have suggested that tooth loss might be related to defects in the maintenance of BMD (137, 138). When compared with 20 healthy-matched controls, 50 patients (mean age, 47.5 years) with low spinal BMD and advanced tooth wear were found to have significantly lower copper content in tooth enamel. However, despite evidence of bone demineralization, serum copper levels in this population were similar to those of the healthy group (139). In sum, additional research is required to draw meaningful conclusions regarding the effects of marginal copper depletion and copper supplementation on bone metabolism and risk for developing 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 under investigation. A recent meta-analysis of case-control studies described higher blood concentrations of copper in AD patients (N=2,929) as compared to healthy subjects (N=3,547), from a total of 46 studies reviewed (140). Also, ‘free’ serum copper (i.e., not bound to CP) was higher in AD patients (N=1,595) than in healthy control subjects (N=2,399), representing 18 total studies. These observations were confirmed in another recent review of published studies (141). An additional meta-analysis of 12 case-control studies revealed AD patients had lower copper concentrations in various brain regions compared to healthy controls (142), further exemplifying dysregulation of copper homeostasis in Alzheimer’s disease.

Among the many hypotheses supporting a role for copper in AD onset or progression includes copper involvement in the formation of senile plaques through hypermetallation of the β-amyloid peptides, possibly leading to zinc depletion, enhanced oxidative stress, and brain damage (143-145). Recent research has also identified polymorphisms in the ATP7B gene that may be associated with the risk of developing copper imbalance and AD (140, 142). ATP7B is a copper-transporting ATPase expressed in the liver and brain. Impairment of ATP7B function causes Wilson disease, which is typified by elevated ‘free’ copper level in blood and copper accumulation in liver and brain.

Additional research is required to determine whether genetic variation could influence individual susceptibility to environmental exposure of high copper levels. Copper administered in drinking water was associated with development of enhanced pathological features in animal models of AD (146, 147). One study in a rabbit model reported that combining a high-cholesterol diet and copper (0.12 mg/L in drinking water) impaired cognition (146). A prospective cohort study in 3,718 elderly participants in the Chicago Health and Aging Project, followed for 5.5 years, evaluated the impact of fat and copper intakes using food frequency questionnaires on cognitive function. 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 copper per day) (148).

Although dysfunctional copper metabolism is suggested as a risk factor for AD, it could also be symptomatic of the disease, rather than causative. 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 (149). This delay, however, was not associated with improved cognitive performance (150). Relating to the use of zinc supplementation to block copper absorption in Wilson disease, slow-release zinc acetate administration (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 (143). A specific role for copper was not, however, determined in these notable outcomes. In summary, additional human studies are needed to clarify the role of copper in AD prevention, development, and progression.

Parkinson's disease

Neurologically presenting Wilson disease and inherited aceruloplasminemia are characterized by copper accumulation in the brain and development of neurological symptoms, including dystonia and cognitive impairment, that resemble Parkinson’s disease (PD) (151). Disruption of copper homeostasis has been documented in PD (152). Copper depletion occurs in brain regions with loss of neurons in PD patients (153, 154). Moreover, some studies have documented lower serum copper and/or CP concentrations in PD patients compared to healthy controls (155-157). Dietary copper intake did not, however, relate to the risk of developing PD in two small case-control studies (158, 159). As in AD, further research is required to elucidate whether copper imbalance contributes to the pathogenesis of PD.

Nonalcoholic fatty liver disease

Similar to findings from animal models (160), human studies have documented low circulating copper (161, 162) or low hepatic copper content (161, 163, 164) in adults and children with nonalcoholic fatty liver disease. An inverse association between hepatic copper content and liver disease severity has also been observed (163, 165). However, it is not known whether low dietary intake of copper might be a contributor to disease pathogenesis or whether dysregulated copper metabolism is only a manifestation of liver disease.

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 (NHANES), the mean dietary intake of copper in the US is 1.1 mg/day for adult women and 1.3 mg/day for adult men (166), levels that exceed the established RDA for copper for adults of 900 µg/day (see Table 1). The estimated copper content of some foods that are relatively rich in copper is listed in Table 2. For more information on the nutrient content of foods, search USDA's FoodData Central.

Supplements

Identification of those at risk for copper depletion is challenging since sensitive and specific, copper nutrition-related bioindicators have yet to be identified. Nonetheless, a range of copper supplements are available for purchase, including cupric oxide, copper gluconate, copper sulfate, and copper amino acid chelates (167). The relative bioavailability of these different chemical forms of copper, however, has not yet been established in humans (168). Copper supplements may contain a few µg up to 15 mg of elemental copper, which exceeds the UL for copper by 1.5 fold (169). Moreover, copper is typically included in multivitamin/mineral supplements (169) and added to fortified breakfast cereals. Supplementation of adults with 10 mg/day of cupric gluconate for 12 weeks did not cause copper toxicity (170). Importantly, however, higher copper intakes could be detrimental in some at-risk (unknown) individuals. Copper supplementation of infants should be approached with caution since homeostatic regulators of copper absorption and excretion are not fully developed, thus increasing the potential for copper toxicosis. From a clinical perspective, copper overload most frequently presents in biliary atresia, biliary cirrhosis and in WD patients, and as such, individuals suffering from these conditions should avoid taking supplemental copper.

Safety

Toxicity

Copper toxicity is rare in the general population. Acute copper poisoning has occurred by storing beverages in copper-containing containers, as well as from contaminated water supplies (171). 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) (172). 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, daily doses of up to 10,000 μg (10 mg) have not resulted in liver damage. The US Food and Nutrition Board has thus set the tolerable upper intake level (UL) in adults at 10 mg/day of copper from food and supplements combined (Table 3) (24). It should be noted that individuals with genetic disorders affecting copper metabolism (e.g., Wilson 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. For example, one study in adult men who consumed 7.8 mg/day of copper for 147 days showed that they loaded excess 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 (173, 174). However, another study did not report any adverse effects in individuals supplemented with 8 mg/day of copper for six months (150).

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 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 dietary copper requirement. Additionally, antacids may interfere with copper absorption when used in very high amounts (2). Also, the anti-tuberculosis drug ethambutol may chelate copper in mitochondria and reduce cytochrome c oxidase activity specifically in optic nerve axons, possibly contributing to optic neuropathy which is a documented side-effect of this drug (175).

Linus Pauling Institute Recommendation

The RDA for copper (900 μg/day for adults) is sufficient to prevent deficiency, but the lack of clear biomarkers 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 (176).

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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

Updated in October 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed and updated in July 2024 by:
James F. Collins, Ph.D.
Food Science & Human Nutrition department
University of Florida

Reviewed in July 2023 by:
Jason Burkhead, Ph.D.
Biological Sciences department
University of Alaska, Anchorage

Copyright 2001-2024  Linus Pauling Institute

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References

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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. In 2015, 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 studies did find a relationship between water intake and outdoor air temperature. This recommendation was made in an effort to reduce the risk of dental fluorosis (see below) and in light of the widespread availability of fluoride from other sources, including fluoride-containing oral-care products (5). 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 (6).

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) (Table 1; 6). See the section below on Safety for a discussion of dental fluorosis.

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). Dental caries — both treated and untreated — contribute to diminished overall oral health, which, in turn, may affect systemic health. For example, some observational studies have suggested a link between systemic inflammation in individuals with periodontal (gum) infection and insulin resistance (8), type 2 diabetes mellitus (9), hypertension (10), and coronary heart disease (11). Moreover, the bacterium causing periodontitis, Porphyromonas gingivalis, may be linked to rheumatoid arthritis (12, 13). Poor oral health in general may constitute a risk factor for coronary heart disease (14) and other cardiovascular diseases (15, 16). 

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 (17, 18). 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 (19). A 2015 review and meta-analysis of prospective observational studies found a 35% and 26% reduction in number of decayed, missing, and filled primary and permanent teeth with consumption of fluoridated versus non-fluoridated water, respectively (20). While fluoride’s prevention of dental caries is primarily through topical action, 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 (7, 17).

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 (21). A 2013 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, and 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 (22). A recent (2021) meta-analysis of topical fluoride reviewed 15 clinical trials with 9,541 participants. Specifically, the meta-analysis evaluated 14 trials of fluoride varnish compared to placebo or no fluoride and one trial of fluoride foam, and found that topical fluoride reduced dental caries increment by about one tooth surface over a two-year period (23). The same meta-analysis also found that fluoride varnish significantly prevented any incident dental caries, but only for children who were younger than 2 years of age (23). 

The effects of fluoride-containing toothpaste has been more extensive. A 2017 meta-analysis of 96 randomized controlled trials, including more than 65,000 participants, found tooth brushing with a fluoridated toothpaste reduced caries in primary teeth of children and in permanent teeth of adults compared to brushing with non-fluoridated toothpaste (24). In participants overall, use of toothpastes containing 1,000 to 1,500 ppm of fluoride had a caries-preventative effect compared to use of toothpastes with lower fluoride concentrations or with non-fluoridated toothpastes (24). A systematic review of 17 clinical trials found use of fluoridated toothpaste effectively reduced dental caries in primary teeth of children younger than 6 years who were at high risk of developing dental caries (25).

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 (26). The protective effect of fluoridated agents against dental erosion has mainly been observed in in vitro studies (reviewed in 26). Nevertheless, a 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 (27). 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 (28,  29). 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 (30). 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 (31). Another community-based study in 1,300 women found that elevated serum fluoride concentrations were not related to BMD or to osteoporotic fracture incidence (32). Finally, a nationwide cohort study in Sweden found no association between chronic exposure to fluoridated water and incidence of hip fracture (33). A 2015 meta-analysis, which pooled results of 13 prospective cohort studies and one case-control study, found that fluoride exposure in drinking water was not associated with risk of hip fracture (34).

Moreover, because bone mineral accretion early in life affects risk for osteoporosis in later adulthood, studies have examined the association of fluoride intake during adolescence and bone outcomes. Reports from the Iowa Bone Development Study, an ongoing prospective cohort study, indicate little to no association of fluoride intake during childhood and adolescence with measures of bone microstructure throughout adolescence (35-37) and into early adulthood (38).

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 (39). 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 (40). 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 (41, 42). 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) (43). 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 (39, 44).

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 (45). 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 (46). Additionally, a 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 (47). 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 (45). 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 (39). 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 (48). Combinations of lower doses of fluoride with antiresorptive agents, such as estrogen or bisphosphonates, may improve therapeutic results while minimizing side effects (49, 50). Yet, randomized studies have shown that the risk of fractures remained unchanged whether treatments include fluoride, antiresorptives, or both (45, 46). 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 prevent dental caries. Originally, an optimal range of 0.7 to 1.2 milligrams (mg) per liter (corresponding to 0.7-1.2 ppm) was established, which was shown to decrease the incidence of dental caries while minimizing the risk of dental fluorosis and other adverse effects. In 2015, the US Department of Health and Human Services recommended that the optimal concentration in drinking water be set at 0.7 ppm (see Safety) (51). Approximately 73% of the US population receives water with sufficient fluoride for the prevention of dental caries (52). 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 (6). 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 carbon-charcoal filters do not remove fluoride (6, 48).

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 (53). 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 (54). Several other studies have reported similar findings, with most bottled waters relatively low in fluoride, but a few in the optimal range or higher (55-57). The FDA-approved claim that "drinking fluoridated water may reduce the risk of tooth decay" is only used by bottlers when the water contains greater than 0.6 ppm of fluoride but no more than 1.0 ppm of fluoride. However, bottlers are not required to provide the fluoride concentration in bottled water unless fluoride was added (58).

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 (59-61). One study found that, on average, at least half of all fluoride ingested by infants 6 months and younger was from water mixed with formula concentrates (62). 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 (63). 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 (UL) 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 (58). 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 (63).

For additional information on fluoride and infant formulas, see the CDC website.

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, 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 (64). In addition, certain fruit juices, particularly grape juices, often have relatively high fluoride concentrations (65). 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 mg/day-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. 

Fluoride supplements

Fluoride supplements — available only by prescription in the US — are intended for infants 6 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 (6). The American Dental Association Council on Scientific Affairs recommends the prescription of fluoride supplements only to children at high risk of developing dental caries (66). 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 (66, 67). 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. 

Toothpaste

Fluoridated toothpastes (1,000-1,100 ppm of fluoride) 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 6 years of age may ingest an average of 0.3 mg of fluoride from toothpaste with each brushing. Children under the age of 6 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 (see Safety section below). 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 6 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; size equivalent to a grain of rice) for children younger than 3 years, and no more than a pea-sized application of toothpaste for children 3 to 6 years of age (25, 68-70). 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  (71).

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. Observational studies have shown that the incidence of teeth with caries dramatically decreased in the regions where salt fluoridation programs were developed (reviewed in 72). 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 73). 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 (74).

Mouth rinses

Mouth rinses that contain fluoride are available over-the-counter in the US. Such products often contain 0.05% sodium fluoride, which translates to about 1 mg of fluoride per 5 mL (one teaspoon) (70). Due to the risk of accidental ingestion, fluoride-containing mouth rinses are not recommended for young children (70). 

Professionally applied fluoride products

Professionally applied fluoride products, including fluoride foams, gels, varnish, and silver diamine fluoride, are highly concentrated (9,000 to 44,800 ppm of fluoride) and applied topically to the teeth by dentists, dental hygienists, or other healthcare professionals (75). Because of their high concentrations, they are potential sources of fluoride; however, due to their infrequent use (every 3-6 months) and small amounts used per application, professionally applied fluoride products are not significant sources of fluoride when used as directed (75). 

Safety

Adverse effects

Fluoridation of public drinking water in the US was initiated more than 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 (51, 76, 77).

A number of observational studies, mostly published in Chinese journals, have investigated the association between fluoride content in drinking water and children’s neurodevelopment. Two meta-analyses of observational studies, mainly conducted in China, found lower intelligence quotients (IQs) in children exposed to higher fluoride concentrations in drinking water (78, 79). Serious limitations, including substantial heterogeneity among studies and co-occurrence of neurotoxicants in drinking water, hinder the strength of these findings and their application to US settings. The Academy of Nutrition and Dietetics has estimated that only limited evidence supports an association between fluoride content in water and the IQs of children (58). A 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 age 38 years (80). A series of recent studies by a research group in Canada have raised concern over a possible link between higher maternal fluoride exposures during pregnancy and lower IQ (81-83), cognitive delay (84), and attention-deficit/hyperactivity disorder (85) in offspring. However, these studies have been widely criticized for shortcomings in measuring fluoride intake, only reporting significant relationships among subgroups, and being observational and subject to residual confounding. Thus, high-quality prospective studies with more definitive fluoride intake measures and better control of confounders are needed to determine whether fluoride might have neurotoxic effects at usual intake levels.   

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 (77). 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 (48). 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

Dental fluorosis, also called enamel fluorosis, is a result of excess fluoride intake during the period of tooth formation, with the critical window of susceptibility being the first eight years of life, as this corresponds to the eruption of the permanent teeth (86). Once the tooth enamel has formed, dental fluorosis cannot develop (87). 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 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 (61). According to a US national survey, the National Health and Nutrition Examination Survey (NHANES) 1999-2004, 23% of people aged 6 to 49 years (n=16,051) had some degree of dental fluorosis (88). National data from NHANES 2011-2012 found that the prevalence of fluorosis among children and adolescents (n=2,283), ages 6 to 19 years, was much higher at 57% (89); however, a quality assessment of these data raised concerns about their validity and suggested such results were not biologically plausible (90). 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 (Table 4) (6).

The current US EPA maximum allowable level of fluoride in drinking water is 4 mg/L; the EPA also has a non-enforceable standard fluoride level of 2 mg/L to prevent moderate dental fluorosis (91). The EPA recently conducted a six-year review of drinking water standards and concluded that the limit of fluoride in drinking water is not a candidate for regulatory revision at this time (92).

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 (6, 93). Rare cases of skeletal fluorosis in the US have been observed in consumers of large volumes of tea (94-97). Because of the potential risk for skeletal fluorosis, as well as the risks for pitting of tooth enamel and bone fracture, the US EPA set the maximum level of fluoride allowed in drinking water at 4 mg/L (98). The agency also recommended limiting fluoride in drinking water at 2 mg/L to prevent dental fluorosis in children; however, this is only a guideline and not enforceable by law (see the US EPA website).

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 (99).

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.

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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

Updated in November 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2021 by:
John J. Warren, D.D.S., M.S.
Professor
Preventive & Community Dentistry
College of Dentistry
The University of Iowa

Copyright 2001-2024  Linus Pauling Institute

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References
 

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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 growth retardation and intellectual impairment 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 and certain types of edible seaweed are excellent sources of dietary iodine. Dairy products, grains, and eggs contribute substantially to dietary iodine intakes in the US. (More information)
• More than 140 countries worldwide have introduced programs of salt fortification with iodine in order to correct iodine deficiency in populations. An estimated 89% of the world’s population consumes iodized salt. (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 several physiological processes, including growth, development, metabolism, and reproductive function (2).

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). 

 

Deficiency

The thyroid gland of a healthy adult concentrates 70%-80% of a total body iodine content of 15 to 20 mg and utilizes about 80 μg of iodine daily to synthesize thyroid hormones. 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 includes intellectual impairment, hypothyroidism, goiter, and varying degrees of other growth and developmental abnormalities (4). Nearly 30% of the world’s population (i.e., almost 1.9 billion people) have insufficient iodine intake as measured by median urinary iodine concentrations below 100 μg/L (5). As of 2019, an estimated 4.8 million newborns are affected by iodine deficiency disorders each year (6). Moreover, about one-third of school-age children (6-12 years old) worldwide (241 million children in 2011) have insufficient iodine intake (5, 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 an estimated 89% 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 21 countries (9). For more information on iodine status in specific nations and the international effort to eradicate iodine deficiency, visit the website of the Iodine Global Network (formerly the International Council for the Control of Iodine Deficiency Disorders).

Biomarkers of iodine status

More than 90% of ingested iodine is excreted in the urine within 24 to 48 hours such that daily iodine intakes in a population can be extrapolated from measures of median spot urinary iodine concentrations (10, 11). 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 (10-12).

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 (14, 15). Serum thyroglobulin concentration in school-age children is a sensitive marker of iodine status in populations (16, 17). In areas of endemic goiter, changes in thyroid size reflect long-term iodine nutrition (months to years). Assessment of the goiter prevalence 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, 11). Finally, serum thyroid hormone concentrations do not adequately reflect iodine nutrition in populations (1), as they only decrease in states of severe deficiency (18).

Iodine deficiency disorders

All the adverse effects of iodine deficiency in animals and humans are collectively termed iodine deficiency disorders (reviewed in 19). 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 20). 

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 embryo/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) (14, 21).

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 (22). 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 12). In addition, severe iodine deficiency during pregnancy may result in congenital hypothyroidism and neurocognitive deficits in the offspring (see Prenatal development) (23).

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) (24). A daily prenatal supplement of 150 μg of iodine will help to ensure that US pregnant and breast-feeding women consume sufficient iodine during these critical periods. The American Thyroid Association recommends that women planning a pregnancy start taking a daily supplement containing 150 μg of potassium iodide preconceptionally (ideally 3 months before conception) and all pregnant women have a daily intake of 250 μg of iodine — total combined from diet and supplements (12). Additionally, the American Academy of Pediatrics recommends that women planning a pregnancy, pregnant women, and breast-feeding mothers take a daily supplement containing at least 150 μg of potassium iodide (25). In severely iodine-deficient areas where iodized salt and daily iodine supplements are not available, the Iodine Global Network, the World Health Organization (WHO), and the United Nations Children’s Fund (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, placebo-controlled trial demonstrated that maternal iodine 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 (26). Yet, supplementation of lactating women failed to increase maternal urinary iodine concentrations above 100 μg/L, suggesting that supplemented mothers still had insufficient iodine status (26). For information on the recommended iodine intake during lactation, please see the section on Breast-feeding women.

Prenatal development

Fetal iodine deficiency is caused by iodine deficiency in the pregnant person (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 (23). 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 intellectual impairment. The clinical picture of neurological cretinism in the offspring includes severe mental impairment, 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 intellectual impairment than in neurological cretinism. Yet, affected individuals exhibit all the features of severe hypothyroidism, including severe growth retardation and delayed sexual maturation (14). Two longitudinal cohort studies (one in the UK and one in Australia) 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 (27, 28). Other observational studies have found associations between mild iodine deficiency during pregnancy and neurocognitive deficits in offspring (29, 30). However, a meta-analysis of two randomized controlled trials (31, 32) found no effect of maternal iodine supplementation during pregnancy on cognitive, language, or motor scores in the children (33). Yet, well-designed randomized controlled trials are needed to inform whether maternal iodine supplementation throughout pregnancy might benefit neurocognitive development of the offspring.

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 (34-36). 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 (37, 38).

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 to 13.5 points in participants (primarily children) (39-41). 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 (42). 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, 43). 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 (44). Yet, in recent years, dietary intakes of iodine in the US population have decreased (45, 46). US National Health and Nutrition Examination Survey (NHANES 2011-2014) indicated that the median urinary iodine concentration for the general population was 133 μg/L compared to 164 μg/L reported in previous assessments (NHANES 2005-2006 and 2007-2008) (47, 48). In addition to regional differences across the US, ethnic variations have been found. For instance, in an analysis of data from NHANES 2011-2014, the median urinary iodine concentration of non-Hispanic Asian women was significantly lower in that of Hispanic women (48).

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 (49, 50).

Nonpregnant women

Data from US NHANES 2007-2014 indicated that 42.3% 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) (51). Additionally, only one-fifth of nonpregnant women reported using iodine-containing supplements in an earlier NHANES (2001-2006) (52). 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. The American Thyroid Association recommends that women planning a pregnancy take a daily supplement containing 150 μg of potassium iodide preconceptionally, ideally starting at three months before conception (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). An analysis of pooled data from NHANES 2005-2014 found pregnant women in the US had a median urinary iodine concentration of 144 μg/L (51), below the cutoff for nutritional adequacy (see Table 1). In an earlier analysis of pooled data from NHANES 2005-2010, the lowest median urinary iodine concentration during pregnancy (109 μg/L) was observed during the first trimester of gestation, when the embryo/fetus relies exclusively on maternal thyroid hormones (49). The American Thyroid Association recommends that pregnant women achieve a total daily intake of 250 μg of iodine (12). Supplementation with iodine (e.g., an iodine-containing multivitamin/mineral or prenatal supplement) may be necessary to reach this intake level.

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 (53, 54). A systematic review of the literature reported suboptimal dietary iodine intakes in breast-feeding women in some countries with a mandatory fortification program, including Denmark, Australia, and India (55). The American Thyroid Association recommends that women who are breast-feeding take a supplement containing 150 μg/day of iodine; potassium iodide (included in a multivitamin/mineral supplements) is the recommended form because iodine content of seaweed varies considerably (12). Moreover, the American Academy of Pediatrics recommends that all breast-feeding women use iodized salt and take a daily 150-μg supplement of iodide to achieve a daily intake of at least 290 μg (25).  

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 (42), 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 (56).

Individuals consuming special diets

Diets that exclude iodized salt, fish, dairy, and seaweed have been found to contain very little iodine (10). Individuals consuming branded weight-loss foods may also be at risk of inadequate intakes (57). 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 (58). Cases of goiter and/or hypothyroidism have also been reported in children and adolescents following very restrictive diets (59), including restrictive diets to control esophageal inflammation (eosinophilic esophagitis) 60 or allergies (61, 62).

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 (42, 63).

Nutrient interactions

Concurrent deficiencies in selenium, iron, or vitamin A may exacerbate the effects of iodine deficiency (reviewed in 64).

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 (65). In addition, glutathione peroxidases are selenoenzymes that protect the thyroid gland from hydrogen peroxide-induced damage during thyroid hormone synthesis (66). 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 (67). 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 (68). The current guidelines of the American Thyroid Association advise against routine selenium supplementation in pregnant women with thyroid autoimmunity (12).

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 physical retardation and intellectual impairment. Selenium deficiency may be one of several undetermined factors that might exacerbate the detrimental effects of iodine deficiency (64). Results of 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 (69, 70). 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 (66).  

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 (71). It is estimated that goiter and iron-deficiency anemia coexist in up to 25% of school-age children in west and north Africa (64). 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 (72). Additional interventions have confirmed that correcting iron-deficiency anemia improved the efficacy of iodine supplementation to mitigate thyroid disorders (reviewed in 64, 71).

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 (73). 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 74). 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 (73). 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 (73). 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 (75). 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 (76, 77). 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, kale, and Brussels sprouts) also contain goitrogens (1). Further, the soybean isoflavones, genistein and daidzein, have been found to inhibit thyroid hormone synthesis (78). 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, 25).

The Recommended Dietary Allowance (RDA)

The RDA for iodine was reevaluated by the Food and Nutrition Board of the US National Academy of Medicine 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 (10). Similar recommendations have been made by several organizations, including the American Thyroid Association (ATA) (22, 79), the World Health Organization (WHO), the Iodine Global Network (IGN), 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). 

Disease Prevention

Radiation-induced thyroid cancer

Radioactive iodine, especially iodine 131 (¹³¹I), may be released into the environment because 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 (80). 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 (81). 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 (82). In the US, the Nuclear Regulatory Commission 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 (83). See also the guidance of the US FDA, the American Thyroid Association, and the World Health Organization.

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 (84). The cause of fibrocystic changes is not known, but variations in hormonal stimulation during menstrual cycles may trigger changes in breast tissue (84).

A few observational studies have suggested an association between benign breast diseases (including but not limited to fibrocystic changes) and thyroid disorders. 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%) (85). Conversely, the prevalence of anti-thyroid autoimmunity and hypothyroidism was found to be significantly higher in women with benign breast diseases compared to controls (86, 87). Interestingly, correcting hypothyroidism with supplemental thyroxine was found to improve some of the benign breast disease symptoms, including breast pain (mastalgia) and nipple discharge (86).

In estrogen-treated rats, iodine deficiency leads to changes like those seen in fibrocystic breasts, while iodine repletion reverses the changes (88). 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 (89). 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 (89). 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 (90). 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 (90).

Large-scale, controlled clinical trials are needed to determine the therapeutic value of molecular iodine in fibrocystic breasts. It is important to note that 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 National Academy 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, indicate that dietary iodine intakes in adults range between 174 and 243 micrograms (μg)/day (91). Higher average intakes were reported for children ages 2 years (250 μg/day), 6 years (257 μg/day), and 10 years (253 μg/day), as well as boys ages 14 to 16 years (296 μg/day) (91).

Seafood is rich in iodine because marine animals can concentrate the iodine from seawater. Certain types of edible seaweed (e.g., wakame, nori, kelp) are also very rich in iodine (92, 93). The iodine content of food grown or raised on a particular soil depends on the iodine content of the soil. In the US, dairy products contribute 33% of total estimated iodine intakes in infants 6 to 11 months of age, 56%-76% in children (ages, 2, 6, and 10 years), 51%-53% in adolescents (ages, 14-16 years), and 40%-54% in adults (91). 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 (10, 94).

Other important dietary sources of iodine for Americans include eggs and grains (91). Processed foods could 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 most food packaging (95). Table 3 lists the iodine content of some iodine-rich foods in micrograms (μg); see the USDA, FDA, and ODS-NIH Database of Iodine Content of Foods (93). Because the iodine content of foods can vary considerably (96, 97), the values listed below should be considered approximate.

Supplements

Over-the-counter iodine supplements

Potassium iodide is available as a nutritional supplement, typically in combination products, such as multivitamin/mineral supplements (98). Iodine makes up approximately 77% of the total weight of potassium iodide (78). 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 recommends supplementation with 150 μg/day of iodine during pregnancy and lactation and advises against the ingestion of ≥500 μg/day of iodine from iodine, potassium iodide, and kelp supplements for children and adults, and during pregnancy and lactation (see also Safety) (94, 99, 100). For information about the iodine content of supplements marketed in the US, see the Office of Dietary Supplements’ Dietary Supplement Label Database.

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. Such programs have dramatically reduced the prevalence of iodine deficiency globally (6, 101). An estimated 89% of the global population currently consumes iodized salt (8). In North America, salt fortification with iodine is mandated in Canada and 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 (95, 102). Potassium iodide (KI) and cuprous iodide (CuI) are used to iodize salt in the US (103). The US Food and Drug Administration (FDA) recommends between 46 and 76 μg of iodine per gram of salt in iodized salt. However, the 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 (104).

In other countries, salt commonly contains 20-50 μg of iodine per gram of salt (ppm), depending on local regulations (104); fortification at 15-40 ppm is recommended to achieve sufficient iodine status of a population (9). In countries like Denmark (105), Australia (106, 107), and New Zealand (108), the use of iodized salt in the bread-making process is mandated. Additional approaches have been explored, including sugar fortification (109), egg fortification (110), use of iodized salt in the preparation of fermented fish and fish sauce (111), and use of iodine-rich crop fertilizers (112). 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 (113). Finally, annual doses of iodized vegetable oil are administered orally or intramuscularly to individuals in severely iodine-deficient populations who do not have access to iodized salt (4, 78).

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 (114). 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 (92). Iodine-induced goiter and hypothyroidism are not uncommon in Japan and can be reversed by restricting seaweed intake (92). 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 (115). To minimize the risk of adverse health effects, the Food and Nutrition Board of the US National Academy 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 (100). The American Thyroid Association advises against consuming iodine (or kelp) supplements containing 500 μg/day or more of iodine (116, 117). 

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 (10). Infants, the elderly, pregnant people, and lactating people may also be more susceptible to excess iodine (see Supplements) (100).

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

Over the past several decades, the incidence of thyroid cancer has increased worldwide. In the US, the incidence of thyroid cancer — representing 2% of all newly diagnosed cancers (118) — has increased from 4.6 cases per 100,000 persons in 1974-1977 to 14.4 cases per 100,000 persons in 2010-2013 (119). However, the mortality rate from thyroid cancer has remained low (about 0.5 per 100,000 persons) (120). Accounting for about 84% of all thyroid cancers, papillary thyroid cancer is less aggressive and has a better prognosis than follicular thyroid cancer or anaplastic thyroid cancer (120). The increasing incidence of thyroid cancer worldwide is likely due at least in part to changes in screening and diagnosis strategies. 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 (121).

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 (121). 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 (122).  

A meta-analysis of five case-control studies found excessive iodine intake, defined as a urinary iodine concentration greater than 300 μg/L, to be associated with an increased risk of papillary thyroid cancer (OR, 4.05; 95% CI, 1.64, 10.02) and adequate iodine intake (i.e., urinary iodine concentration of at least 100 μg/L but less than 200 μg/L) to be associated with protection against papillary thyroid cancer (OR, 0.36; 95% CI, 0.14-0.91) (123). Yet, it is important to note that the observational studies included in this pooled analysis were highly heterogenous (123).

Drug interactions

Amiodarone, a medication used to prevent abnormal heart rhythms, contains high levels of iodine and may affect thyroid function (124). 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 (125). Further, the use of pharmacologic doses of potassium iodide may decrease the anticoagulant effect of warfarin (coumarin) (126).

Contaminants

Perchlorate is an oxidizing agent found in rocket propellants, airbags, fireworks, herbicides, and fertilizer. Perchlorate has been found to contaminate drinking water and many foods, primarily because of human activity (25). 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 (127). 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 have hypothyroidism (128). Among all age groups, children two years of age have the highest estimated perchlorate intakes with average daily intakes of 0.43 μg/kg bw. Average daily intakes of perchlorate among US adults range between 0.09 and 0.10 μg/kg bw (91).

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 throughout prenatal development and infancy, pregnant and breast-feeding women should take a supplement that provides 150 μg of iodine per day (see Deficiency). Many multivitamin/mineral supplements and prenatal supplements contain at least this amount (98).

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.

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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

Updated in May 2024 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in June 2024 by:
Elizabeth N. Pearce, M.D., M.Sc.
Professor of Medicine
Boston University School of Medicine

Copyright 2001-2024  Linus Pauling Institute 

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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.

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).

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 USDA's FoodData Central.

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 of 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).

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). 

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 been raised 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).

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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 2001-2024  Linus Pauling Institute

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References