Micronutrients in Health and Disease

Twenty-eight essential vitamins and minerals play key roles in the metabolism of protein, carbohydrate, and fat, as well as in the structure of the human body (e.g., vitamin K in bone matrix, calcium in bone tissue). Many micronutrients are also important antioxidants (e.g., vitamins C and E) or act as cofactors for antioxidant enzymes (e.g., selenium in glutathione peroxidase). Several trace minerals, though not considered essential, are being studied for their roles in human nutrition. Examples include silicon for bone health[1] and vanadium for stimulation of glucose transport.[2]

Although vitamin deficiency diseases (e.g., pellagra) are no longer widespread, suboptimal micronutrient intake is common. Governmental data show many people do not meet the recommended dietary allowance (RDA) for many micronutrients (e.g., zinc, riboflavin, iron, potassium, vitamin B 12,). While what constitutes sufficient intake is controversial for some nutrients, it is clear that many people would do well to take advantage of foods that improve their micronutrient intake.

Insufficient micronutrient intake has short-term and long-term implications for disease risk. Regarding potassium, for example, many people have less than optimal intake, which may be as important as too much sodium in hypertension,[3] a major risk factor for heart disease and stroke. Additionally, immune function is adversely affected by poor intakes of nearly every essential vitamin and mineral.[4]

The following sections address issues of greatest concern to clinicians: deficiency states, diet-drug interactions, and at-risk populations. Three reference tables are included at the end of this chapter: Table 1, Conditions That May Be Improved by Nutritional Supplements; Table 2, Vitamin Functions, Deficiency Diseases, Toxicity Symptoms, and Dietary Reference Intakes; and Table 3, Mineral Functions, Deficiency Diseases, Toxicity Symptoms, and Dietary Reference Intakes.

Vitamin Deficiency States

Vitamin B12. Vitamin B12 deficiency affects approximately 20% of the elderly population, mainly due to poor absorption.[5] (See Megaloblastic Anemia chapter.)

Vitamin C. Deficiency of vitamin C, which manifests as scurvy in its most severe form, is a condition most clinicians would presume to be long gone. Nevertheless, vitamin C deficiency or depletion was found in 5% to 17% of participants in the Third National Health and Nutrition Examination Survey,[6] in 30% of a sample of hospice patients,[7] in 68% of a population of hospitalized elderly patients,[8] and in individuals who eat meat-based diets and avoid fruits and vegetables.[9] In smokers, the risk for vitamin C deficiency is roughly 4 times greater than in nonsmokers.[7]

Vitamin D. Soft and deformed bones characterize rickets, a vitamin D deficiency disease that affects infants and children. Although rickets is presumed to be an infrequent problem in the United States due to vitamin D fortification of milk, these efforts have not been entirely successful, and resurgence of this disease has occurred for a number of reasons. The natural source of vitamin D is sun exposure. However, life in urban areas or at extremes of latitude makes sunlight a less predictable source. Vitamin D is naturally present in few foods (e.g., oily fish, egg yolk), many of which people do not eat for reasons of preference or health. This has prompted the American Academy of Pediatrics to recommend 400 international units (IU) of supplemental vitamin D for infants, children, and adolescents ingesting less than 500 mL per day of vitamin D-fortified formula or milk.[10]

Intakes that are considered either deficient or insufficient have also been found in young women and elderly persons who lack sun exposure.[11] These low intakes are a risk factor for autoimmune disease and some cancers.[12] Certain drugs (e.g., phenytoin, phenobarbital) can also decrease blood levels of vitamin D, resulting in both osteopenia and osteomalacia.[13]

Some evidence suggests that a “functional” vitamin D deficiency state may be caused by a high calcium intake due to dairy intake and calcium supplements and may influence the risk for prostate cancer. In one study, although higher calcium intake was not appreciably associated with total or nonadvanced prostate cancer, men with intakes of 1,500 to 1,999 mg per day of calcium had nearly double the risk for advanced and fatal prostate cancer. Men consuming 2,000 mg per day or more had a risk almost 2.5 times greater, compared with men whose long-term calcium intakes were 500 to 749 mg per day. These risks have been attributed to elevated blood calcium concentrations that decrease production of the active form of vitamin D (calcitriol). Under normal circumstances, vitamin D’s presumed anticancer differentiation, and regulation of the invasiveness, angiogenesis, and metastatic potential of prostate cancer cells.[14] Vitamin D adequacy reduces the risk of osteoporosis (see Osteoporosis chapter) and may also reduce risk of cardiovascular disease through inhibition of vascular smooth effects include inhibition of cellular proliferation, promotion of muscle proliferation, suppression of vascular calcification, changes in cytokine profile from pro- to anti-inflammatory types, and down-regulation of the renin-angiotensin system.[15]

Considerable evidence suggests that certain subgroups (e.g., elderly persons) do not meet vitamin D requirements due to lack of sun exposure.[16] Multiple vitamin formulas typically contain 400 IU of vitamin D, an amount that meets or exceeds the recommended intakes for all age groups except those over 70 years. Some evidence suggests, however, that current recommended intakes may be insufficient for elderly persons, as well as for individuals in other age groups, and these recommendations are being re-evaluated.[17]

Mineral Deficiencies

Iron. Iron deficiency anemia is common worldwide and can lead to immune dysfunction, gastrointestinal disturbances, and neurocognitive impairment.[18] Iron depletion is the most common cause of anemia in pregnancy.[19] (See Iron Deficiency Anemia chapter.)

Calcium. Intakes of calcium at levels significantly below dietary reference intakes (DRI) are common in a large segment of the U.S. population. After 10 years of age, both males and females get, on average, roughly half the recommended intake.[20] A significant body of evidence, however, indicates that a more moderate calcium intake may be adequate. While calcium intakes below 400 mg per day may reduce bone development, intakes above this level do not appear to correlate with bone mineral density or to reduce fracture risk. Other factors, particularly targeted physical activity, do appear to more precisely reflect bone density in this population.[21] Data from the Nurses’ Health Study do not support the hypothesis that a higher total calcium or dairy calcium intake in adults is protective against hip or forearm fracture.[22] ,[23]

Concerns about high calcium intakes have arisen from studies indicating a higher risk of prostate cancer among men consuming more dairy products or calcium (see Prostate Cancer chapter) and a higher risk of kidney stones under certain circumstances (see Kidney Stones chapter).

Magnesium. Clinical deficiency of blood magnesium is rare in the general population, but it should be suspected in individuals with chronic diarrhea, patients with hypocalcemia or refractory hypokalemia, and those given certain medications (see below).[23],[24] In the Third National Health and Nutrition Examination Survey (NHANES III), 68% of adults consumed less than the recommended daily allowance (RDA) for magnesium, and 19% consumed less than 50% of the RDA.[25]

One study with children aged 8-17 found hypomagnesemia rates twice as high in obese children compared to those who were lean,[26] and another with nonhospitalized adults showed those with type 2 diabetes have much higher rates.[27] Hypomagnesemia is strongly associated with more rapid disease progression and increased complications.[28] (See Diabetes chapter.) Magnesium deficiency may result from poor intake of foods rich in this mineral, such as green vegetables, nuts, seeds, dried beans, and whole grains.

Antioxidants and Phytochemicals

Antioxidant vitamins (vitamins C and E), carotenoids, and minerals that are constituents of antioxidant enzymes (e.g., zinc, magnesium, and manganese in superoxide dismutase; selenium in glutathione peroxidase) are essential for minimizing free-radical reactions and the resulting destruction of cellular structures. However, clinical trials indicate that simply adding supplemental antioxidant nutrients to a typical American diet does not reduce the risk for common diseases such as cardiovascular disease and cancer and may be harmful in well-nourished populations.[29] ,[30] Evidence suggests that a healthful overall diet is required—namely, a diet that is both low in factors that promote disease and high in antioxidant nutrients.

In addition, an increasing body of evidence indicates that the presence of nonvitamin, nonmineral antioxidants (e.g., phytochemicals) in foods is responsible for the majority of antioxidant effects.[31] In general, populations eating greater amounts of phytochemical-containing foods (e.g., fruits, vegetables, whole grains) have a significantly lower mortality risk[32] and a lower risk for cardiovascular disease, cancer, diabetes mellitus, hypertension, and arthritis.[33] ,[34] Population studies do not, however, typically isolate the effect of micronutrients, and they also involve significant macronutrient differences, compared with unmodified diets. Nevertheless, these studies suggest that any additional nutrients should be supplemental to, and not substituted for, a plant-based diet.

At-Risk Populations

Certain groups are likely to be deficient in micronutrients and to need dietary adjustments or supplementation. The following nutritional choices may result in poor or deficient intakes of essential nutrients:

Alcohol abuse. Lower blood concentrations of vitamins C and E, carotenoids, and selenium have been found in alcohol-dependent patients, compared with low-alcohol consumers.[35] ,[36] Alcohol abusers may miss B vitamins through poor food intake and may lose B vitamins due to the diuretic effect of alcohol; these (particularly thiamine) must be replaced to prevent neurologic sequelae, including Wernicke-Korsakoff syndrome.[37] Folate intake may be especially important for alcohol consumers. For example, individuals who consume as little as one-half of a serving of alcohol per day appear to be at twice the risk for breast cancer when folate intakes are below recommendations (i.e., at < 335 μ g/d), compared with those with higher intakes.[38]

A Western dietary pattern. Individuals who eat a Western diet generally have reduced intakes of several micronutrients, compared with individuals following plant-based diets, although these reduced intakes may not represent frank deficiencies. Vitamin C deficiency has been found in individuals who eat meat-based diets and shun fruits and vegetables.[10][36],[39] In the European Investigation into Cancer and Nutrition study of 65,429 men and women, individuals avoiding meat and other animal products had much higher intakes of fiber, folate, and vitamins C and E, compared with omnivores.[40] Other surveys of vegetarians also determined higher intake of vitamins C and E, in addition to potassium[41] and dietary fiber,[42] compared with omnivores. Pregnant vegetarian women had significantly lower risk for folate deficiency than omnivores had.[43]

According to the Institute of Medicine (IOM), only 26% and 34% of vitamin A activity, consumed by men and women, respectively, is from provitamin A carotenoids.[44] This results in lower blood levels of carotenoids, and these reduced levels are consistent with a greater risk for many chronic diseases, compared with the risk for individuals eating recommended amounts (i.e., 5 servings/day) of fruits and vegetables. The IOM states that existing recommendations for increased consumption of carotenoid-rich fruits and vegetables for their health-promoting benefits are strongly supported.[45]

Iron overload, although less common than iron deficiency, occurs in roughly 0.5% of whites and results from hereditary hemochromatosis (HHC), an autosomal recessive disorder caused in most cases by the C282Y and H63D mutation in the HFE gene on chromosome 6p21.3.[45] However, in spite of the frequency of this disorder, it is not solely responsible for HHC-related diseases, such as diabetes and liver disease.[46] Even in the absence of the gene for hemochromatosis, evidence shows that individuals in Western, meat-eating populations may have iron stores far in excess of those needed for health.[47] These individuals may be at greater risk for heart disease, cancer, and diabetes, risks that appear to be greatest among elderly persons.[48] Among elderly participants in the Framingham Heart Study, 13% had high iron stores, while approximately 3% were found to have iron deficiency.[49]

Smokers. Smokers often have poorer diets in general than nonsmoking individuals, and they generally consume fewer fruits and vegetables and more saturated fat.[50] Moreover, even after adjustment for differences in diet, smokers have significantly lower blood levels of several carotenoids and vitamin C.[51]

Inappropriately restricted diets. Nutritional deficiency can result from overly stringent dietary restrictions, particularly those that suggest elimination of the most nutrient-rich foods (e.g., vegetables, fruits, and whole grains). Such diets may be practiced by individuals who are dealing with what they suspect are problematic reactions to foods[52] ,[53] and who do not seek alternative sources of essential nutrients. Individuals who consume low-carbohydrate, high-meat diets may have vitamin C intakes that are nearly 50% lower than those of persons eating more plant-based diets.[54]

Elderly persons, particularly those in hospitals or long-term care facilities, and individuals following unsupplemented vegan diets are at risk for deficiency of vitamins B 12 and D. With appropriate supplementation, a vegan diet has nutritional advantages, compared with unmodified diets.[55] Alcohol-dependent in dividuals are at risk for folate, B 6, B 12, and thiam in deficiencies. Poor intakes and subclinical deficiencies in these and other groups, along with the increased risk for chronic diseases that may follow, have led to the suggestion that all adults take a multiple vitamin daily.[49]

Vitamin dependency disorders resulting from inborn errors of metabolism are rare, but they require lifelong treatment with certain vitamins. Examples of these include multiple carboxylase deficiencies that are biotin-responsive[56] and pyridoxine-dependent seizures.[57]

Drug-Diet Interactions

Drug-diet interactions can cause increased needs for certain micronutrients. Electrolyte imbalances are probably the most common micronutrient deficiency states and are often caused by medications.[14]

Folic acid deficiency may occur due to treatment with many anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, valproic acid) and may subsequently increase the risk for birth defects.[58] Through an antagonizing effect on folate, these same drugs also significantly increase certain indicators of cardiovascular risk, such as homocysteine and possibly lipoprotein(a).[59] Available data indicate that folic acid treatment can significantly reduce homocysteine in children on anticonvulsant medications.[60] Additional studies are needed to test the initial observation that B-vitamin supplements (folate, pyridoxine, and riboflavin) reduce certain other cardiovascular risk factors, including von Willebrand factor and lipoprotein, that are elevated in adults on anticonvulsant treatment.[61]

Many side effects of methotrexate treatment (gastrointestinal intolerance, stomatitis, alopecia, and cytopenia) are due to folate antagonism. However, it is thought that these effects may be avoided by combining a folate-rich diet with minimal folate supplementation (i.e., multiple vitamins) and by reducing the dose of methotrexate if necessary.[62] Although doses of 2.5 mg to 5.0 mg reduce the side effects of methotrexate without significantly altering effectiveness, higher amounts (e.g., 15 mg) have resulted in worsening of rheumatoid arthritis symptoms.[57]

Vitamin B12 absorption decreases as a result of long-term acid suppression therapy (e.g., proton pump inhibitors) and can exacerbate the already-declining absorption of this vitamin caused by atrophic gastritis.[63] Long-term treatment with metformin also decreases B12 absorption,[64] apparently as a result of inhibiting a calcium-dependent process that normally promotes ileal uptake of the B12-intrinsic factor complex. Preliminary data indicate that this effect is ameliorated by calcium supplementation.[65]

Hypokalemia frequently results from commonly used diuretics, amphotericin B, corticosteroids, antipseudomonal penicillins, and insulin, while hyperkalemia may result from heparin,[14] as well as from potassium-sparing diuretics and poor kidney function.[66]

Hypomagnesemia and thiamine deficiencies frequently result from treatment with diuretics, and the former can also occur due to administration of amphotericin B, aminoglycoside antibiotics, and cyclosporine.[14],[67] Cisplatin therapy may cause hypomagnesemia.
Hypocalcemia may result from foscarnet by forming a complex with ionized calcium.[14] It may also occur in patients given bisphosphonates who have unrecognized hypoparathyroidism, impaired renal function, or vitamin D deficiency.

Sodium imbalances may occur due to the ubiquitous presence of sodium and phosphorus in foods; deficiencies of these electrolytes are less common. Hyponatremia, however, can occur from carbamazepine and thiazide diuretics, while hypernatremia can result from drugs that cause diarrhea (e.g., lactulose).

Micronutrients in Clinical Practice

Certain diseases or conditions increase nutrient needs. For example, diseases that cause malabsorption (chronic cholestasis, abetalipoproteinemia, celiac disease, and cystic fibrosis) result in vitamin E deficiency and the need for supplementation.[68] Clinicians should encourage patients to obtain these nutrients primarily from foods, rather than supplements, due to the presence of other nutrients in whole foods and their potentially synergistic effects.[69] For example, vitamin E supplements only contain α-tocopherol, but food sources of vitamin E include γ-tocopherol (a scavenger of reactive oxygen and nitrogen radicals and inhibitor of cyclooxygenase)[70] and tocotrienols, which have both antioxidant and nonantioxidant benefits that alpha-tocopherol does not possess.[71]

Similarly, patients may be tempted to purchase dietary supplements containing carotenoids (e.g., lutein/zeaxanthin) to prevent or treat certain eye diseases (see Cataract chapter and Macular Degeneration chapter). Although some studies indicate a benefit for supplements, many have found a protective association with carotenoids in foods. The latter may be a preferable source, because macular pigment density increases to a greater degree (43%) when lutein is combined with other antioxidants, compared with lutein alone (36% increase).[72] Emerging evidence also suggests that higher lutein intake is associated with progression of macular degeneration in the context of diets higher in easily peroxidized polyunsaturated fat (i.e., linoleic acid).[73] Until further data are available, lutein and other micronutrients should be obtained from food primarily, and in supplement form only if recommended by a physician.

Certain individuals may require nutrients in amounts that exceed RDAs for healthy adults. Such individuals may also benefit from supplementation with nonessential or conditionally essential micronutrients (e.g., carnitine, coenzyme Q10).

The following three tables show the relationship between micronutrients and health.

Disease

Nutrient(s)

Rationale

Table 1: Conditions That May Be Improved by Nutrient Supplementation

Anemia, microcytic

Iron

Increased need in high-risk groups (e.g., pregnant adolescents).

Anemia, pernicious

Vitamin B12

Risk for deficiency in elderly individuals, post-gastrectomy patients.

Burn injury

Vitamins A, D & E; carotenoids; selenium, zinc, copper

Burns reduce blood levels; increases are needed to support immune function.

Celiac sprue

Vitamins D, E & K;B-vitamins; iron, calcium, zinc, magnesium

Restricted diet increases risk of deficiency.

Congestive heart failure

Thiamine, magnesium

Loss due to diuretics may further compromise cardiac function.

Cystic fibrosis(CF)

Vitamins A, D, E, K &C; selenium, zinc

Malabsorption of fat-soluble vitamins is common. CF patients have lower blood levels of antioxidants and greater oxidative stress.

Eating disorders

Multivitamin/mineral, calcium, vitamin D

Poor intake; evidence of deficiency; reversal of osteoporosis in patients with anorexia nervosa.

End-stage kidney disease

B-vitamins, vitamin C

Losses due todialysis treatment.

Inflammatory bowel disease

Beta-carotene, vitamins C, D, & E; selenium, zinc

Malabsorption.

Macular degeneration

C, E, beta-carotene; zinc, copper, lutein

Antioxidants reduce oxidative stress in the macula.

Osteoporosis

Calcium, vitamin D

At-risk populations include elderly individuals and persons on long-term corticosteroid treatment.

Vitamin

Functions/Roles in Metabolism

Deficiency Symptoms

Toxicity Symptoms

Recommended Dietary Allowance or AI*

Table 2: Vitamin Functions, Deficiency Diseases, Toxicity Symptoms, and Dietary Reference Intakes

Vitamin A

Bone growth, reproduction, cell division, immunity, cell differentiation

Clinical: Night blindness; total blindness (rare in the United States.)Subclinical: May increase risk for respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness

Birth defects, liver abnormalities, reduced bone mineral density; central nervous system disorders (e.g., pseudotumor cerebri)

Adults: Age 19+:
Males: 900 μ g
Females: 700 μ g

Infants/children:
0-6 months: * 400 μ g
6-12 months:* 500 μ g
1-3 years: 300 μ g
4-8 years: 400 μ g
9-13 years: 600 μ g
14-18 years (boys): 900 μ g
14-18 years (girls): 700 μ g


Pregnancy:
Age 14-18 750 μ g
Age 19-50 770 μ g

Lactation:
Age 14-18 1,200 μ g
Age 19-50 1,300 μ g

Vitamin D

Maintenance of normal blood levels of calcium and phosphorus; promotes bone mineralization; regulates cell growth, differentiation, immune function

In children: ricketsIn adults: osteomalacia

Nausea, vomiting, poor appetite, constipation, weakness, and weight loss; mental status changes; hypercalcemia; calcinosis

Adults:*
Ages19-50: 15 μ g/600 IU
Ages 51-70: 15 μ g/600 IU
Ages 70+: 20 μ g/800 IU

Infants /children:*
0-12 months: 10 μ g/400 IU
1-18 years: 15 μ g/600 IU

Pregnancy/lactation:*
15 μ g/600 IU

Vitamin E

Antioxidant (protects cells against free radicals); plays role in immune function and in DNA repair; inhibits cell proliferation, platelet aggregation, and monocyte adhesion 1

Nerve degeneration in hands and feet

Can influence coagulation in some persons with drug-induced vitamin K deficiency; anti-platelet effect

Adults:19+ years: 15 mg

Infants/children:
0-6 months:* 4 mg
6-12 months:* 5 mg
1-3 years: 6 mg
4-8 years: 7 mg
9-13 years: 11 mg
14-18 years: 15 mg

Pregnancy: 15 mg
Lactation: 19 mg

Vitamin K

Coenzyme for synthesis of proteins involved in blood coagulation and bone metabolism

Increase in prothrombin time; in severe cases, hemorrhagic events

None currently known

Adults: 19+ years: *
Males: 120 μ g
Females: 90 μ g

Infants/children/adolescents:*
0-6 months: 2 μ g
6-12 months: 2.5 μ g
1-3 years: 30 μ g
4-8 years: 55 μ g
9-13 years: 60 μ g
14-18 years: 75 μg

Pregnancy/lactation:*
Girls 14-18 years: 75 μ g
Adults 19-50 years: 90 µ g

Sources: National Institutes of Health, Office of Dietary Supplements Web site (http://dietary-supplements.info.nih.gov…)

1 see Zingg JM, Azzi A. Non-antioxidant activities of vitamin E. Curr Med Chem. 2004;11:1113-1133.

of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001.

Institute of Medicine, D ietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academies Press; 2000. Dietary Reference Intakes for Calcium and Vitamin D, Washington, DC: National Academy Press; 2011.

* IOM did not set an RDA for vitamins in this age group. Instead, an Adequate Intake (AI) is used. According to IOM, “ The AI is a recommended average daily nutrient intake level, based on experimentally derived intake levels or approximations of observed mean nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is established when there is insufficient scientific evidence to determine an Estimated Average Requirement (EAR).”

Vitamin

Functions/Roles in Metabolism

Deficiency Symptoms

Toxicity Symptoms

Recommended Dietary Allowance or AI*

Vitamin C

Antioxidant; biosynthesis of connective tissue components (collagen, elastin, fibronectin, proteoglycans, bone matrix, and elastin-associated fibrillin); carnitine, and neurotransmitters

Scurvy (involves deterioration of elastic tissue); follicular hyperkeratosis, petechiae, ecchymoses, coiled hairs, inflamed and bleeding gums, perifollicular hemorrhages, joint effusions, arthralgia, and impaired wound healing; dyspnea, edema, Sjögren syndrome, weakness, fatigue, depression

Nausea, abdominal cramps, and diarrhea (from supplements)

Adults ( > 19 years):
Males: 90 mg
Females: 75 mg

Infants/children:
0-6 months:* 40 mg
6-12 months:* 50 mg
1-3 years: 15 mg
4-8 years: 25 mg
9-13 years: 45 mg
14-18 years (boys): 75 mg
14-18 years (girls): 65 mg

Pregnancy:
Age 14-18: 80 mg
Age 19-50: 85 mg

Lactation:
Age 14- 18: 115 mg
Age 19-50: 120 mg

Thiamine (B1)

Coenzyme in the metabolism of carbohydrates and branched-chain amino acids

Anorexia; weight loss; mental changes such as apathy, decrease in short-term memory, confusion, and irritability; muscle weakness; cardiomegaly; beriberi (polyneuritis)

Oral forms: None currently known

Parenteral: Pruritus (rare: 1% of patients); extremely rare anaphylactic reaction

IOM conclusion: Even high-dose IV use is relatively safe

Adults ( > 19 years):
Males: 1.2 mg
Females: 1.1 mg

Infants/children:
0-6 months:* 0.2 mg
7-12 months:* 0.3 mg
1-3 years: 0.5 mg
4-8 years: 0.6 mg
9-13 years: 0.9 mg
14-18 years (boys): 1.2 mg
14-18 years (girls): 1.0 mg

Pregnancy/lactation: 1.4 mg

Riboflavin (B2)

Coenzyme in numerous redox reactions

Ariboflavinosis; sore throat; hyperemia and edema of pharyngeal and oral mucous membranes; cheilosis; angular stomatitis; glossitis (magenta tongue); seborrheic dermatitis; normochromic, normocytic anemia

None currently known

Adults (ages 19+):
Males: 1.3 mg
Females: 1.1 mg

Infants/children:
0-6 months:* 0.3 mg
6-12 months:* 0.4 mg
1-3 years: 0.5 mg
4-8 years: 0.6 mg
9-13 years: 0.9 mg
14-18 years (boys): 1.3 mg
14-18 years (girls): 1.0 mg

Pregnancy: 1.4 mg
Lactation: 1.6 mg

Niacin (B3)

Coenzyme in numerous redox reactions

Pellagra (pigmented rash, vomiting, constipation or diarrhea, bright red tongue; neurological symptoms, including depression, apathy, headache, fatigue, and loss of memory)

From nicotinamide: nausea, vomiting, and signs and symptoms of liver toxicity (at intakes of 3 g/d); from nicotinic acid: same signs at 1.5 g/d (most toxicity related to pharmacologic use); hepatotoxicity (at doses of 3-9 g/d); blurred vision, toxic amblyopia, macular edema (doses of 1.5-5g/d)

Adult males and males
≥ age 14: 16 mg
Adult females and females
≥ age 14: 14 mg

Infants/children:
0-6 months:* 2.0 mg
6-12 months:* 4.0 mg
1-3 years: 6.0 mg
4-8 years: 8.0 mg
9-13 years: 12.0 mg

Pregnancy: 18 mg
Lactation: 17 mg

Pantothenic acid (B5)

Component of coenzyme A; cofactor and acyl group carrier for many enzymatic processes, and acyl carrier protein, a component of the fatty acid synthase complex

Extremely rare; irritability and restlessness; fatigue; apathy; malaise; sleep disturbances; gastro-intestinal complaints such as nausea, vomiting, and abdominal cramps; neurobiological symptoms such as numbness, paresthesias, muscle cramps, staggering gait

None currently known

Adults ages 19+:* 5.0 mg

Infants/children/adolescents:*
0-6 months: 1.7 mg
6-12 months: 1.8 mg
1-3 years: 2.0 mg
4-8 years: 3.0 mg
9-13 years: 4.0 mg
14-18 years: 5.0 mg

Pregnancy:* 6.0 mg
Lactation:* 7.0 mg

Pyridoxine (B6)

Coenzyme in the metabolism of amino acids, glycogen, and sphingoid bases

Seborrheic dermatitis, microcytic anemia, epileptiform convulsions

Sensory neuropathy with high ( ≥ 100 mg) supplementary intake

Adults:
Ages 19-50: 1.3 mg
Age 51+ (males): 1.7 mg
Age 51+ (females): 1.5 mg

Infants/children:
0-6 months:* 0.1 mg
6-12months: * 0.3 mg
1-3 years: 0.5 mg
4-8 years: 0.6 mg
9-13 (boys/girls): 1.0 mg
14-18 years (boys): 1.3 mg
14-18 years (girls): 1.2 mg

Pregnancy: 1.9 mg
Lactation: 2.0 mg

Folate

Coenzymes are involved in DNA synthesis; amino acid interconversions; single-carbon metabolism; methylation reactions

Early sign: hypersegmented neutrophilsLate sign:macrocytic anemia (weakness, fatigue, difficulty concentrating, irritability, headache, palpitations, shortness of breath)

None in healthy individuals; may decrease phenytoin levels and trigger seizures in patients with seizure disorder; may precipitate or exacer-bate neuropathy in vitamin B12-deficient individuals

Adults (ages 19+): 400 µ g

Infants/children:
0-6 months:* 65 µ g
6-12months:* 80 µ g
1-3 years: 150 µ g
4-8 years: 200 µ g
9-13 years: 300 µ g
14-18 years: 400 µ g

Pregnancy: 600 µ g
Lactation: 500 µ g

Vitamin B12

Cofactor for methionine synthase and L-methyl-malonyl-CoA mutase; essential for normal blood formation and neurologic function

Pernicious anemia; neuro-logic manifestations (sensory disturbances in the extremities; motor disturbances, including abnormalities of gait); cognitive changes (loss of concentration; memory loss, disorientation and frank dementia); visual disturbances, insomnia, impotency, and impaired bowel and bladder control

None currently known

Adults ( ages 19+): 2.4 µ g

Infants/children:
0-6 months:* 0.4 µ g
6-12months:* 0.5 µ g
1-3 years: 0.9 µ g
4-8 years: 1.2 µ g
9-13 years: 1.8 µ g
4-18 years: 2.4 µ g

Pregnancy: 2.6 µ g
Lactation: 2.8 µ g

Biotin

Coenzyme in bicarbonate-dependent carboxylation reactions (e.g., acetyl-CoA carboxylase, pyruvate carboxylase)

Dermatitis, conjunctivitis, alopecia, and central nervous system abnormalities (depression, lethargy, hallucinations, and paresthesia of the extremities)

None currently known

Adults (ages 19+)*: 30 µ g

Infants/children:*
0-6 months: 5 µ g
6-12 months: 6 µ g
1-3 years: 8 µ g
4-8 years: 12 µ g
9-13 years: 20 µ g
14-18 years: 25 µ g

Pregnancy:* 30 µ g
Lactation:* 35 µ g

Source: Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline ( 1998) and Institute of Medicine (IOM). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academies Press; 2000.

* IOM did not set an RDA for vitamins in this age group. Instead, an Adequate Intake (AI) is used. According to IOM, “ The AI is a recommended average daily nutrient intake level, based on experimentally derived intake levels or approximations of observed mean nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is established when there is insufficient scientific evidence to determine an Estimated Average Requirement (EAR).”

Mineral

Biochemical Role/Function

Deficiency Symptoms

Toxicity Symptoms

Recommended Dietary Allowance or AI*

Table 3: Mineral Functions, Deficiency Diseases, Toxicity Symptoms, and Dietary Reference Intakes*

Calcium

Component of teeth and bones; mediates vascular contraction and vasodilation, muscle contraction, nerve transmission, and glandular secretion

Reduced bone mass and osteoporosis

Hypercalcemia; increased risk for kidney stones (with supplements); milk-alkali syndrome; possible increase in risk for prostate cancer (see Prostate Cancer chapter)

Adults:*
Ages 19-50: 1,000 mg
Age 51-70:
Males: 1000 mg
Females: 1200mg
Ages 70+: 1,200mg

Infants/children/adolescents:*
0-6 months: 200 mg
6-12months: 260 mg
1-3 years: 700 mg
4-8 years: 1000 mg
9-18 years: 1,300 mg

Pregnancy/lactation:*
Age 14- 18: 1,300 mg
Age 19-50: 1,000 mg

Phosphorus

Component of most biological membranes and nucleotides and nucleic acids; buffering of acid or alkali excesses; temporary storage and transfer of the energy derived from metabolic fuels; activation of many catalytic proteins through phosphorylation

Anorexia, anemia, muscle weakness, bone pain, rickets and osteomalacia, general debility; may be seen in persons recovering from alcoholic bouts; in diabetic keto-acidosis; in refeeding with calorie-rich sources without paying attention to phosphorus needs; & with AL-containing antacids

Metastatic calcification,skeletal porosity, interferencewith calcium absorption

Adults (ages 19+): 700 mg

Infants/children:
0-6 months:* 100 mg
6-12months:* 275 mg
1-3 years: 460 mg
4-8 years: 500 mg
9-18 years: 1,250 mg

Pregnancy/lactation:
Age 14- 18: 1,250 mg
Age 19-50: 700 mg

Magnesium

Required cofactor for more than 300 enzymes, including ones involved in anaerobic and aerobic energy generation, glycolysis, and oxidative phosphorylation; DNA and RNA synthesis; activation of adenylate cyclase; sodium, potassium-ATPase activity; has a calcium channel-blocking effect

Hypocalcemia; neuro-muscular hyperexcitability & latent tetany; insulin resistance and impaired insulin secretion

GI disturbance (diarrhea, nausea, abdominal cram-ping, paralytic ileus); more likely to occur with impaired renal function

Adults:
Ages 19-30
males: 400 mg
females: 310 mg
Ages 31+
males: 420 mg
females: 320 mg

Infants/children:
0-6 months:* 30 mg
6-12months:* 75 mg
1-3 years: 80 mg
4-8 years: 130 mg
9-13 years: 240 mg
14-18 years: (males) 410 mg
(females) 360 mg

Pregnancy:
Ages 14- 18: 400 mg
Ages 19-30: 350 mg
Ages 31-50: 360 mg

Lactation:
Ages 14- 18: 360 mg
Ages 19-30: 310 mg
Ages 31-50: 320 mg

Source: Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academies Press; 1997. Dietary Reference Intakes for Calcium and Vitamin D, Washington, DC: National Academy Press; 2011.

* IOM did not set an RDA for vitamins in this age group. Instead, an Adequate Intake (AI) is used. According to IOM, “ The AI is a recommended average daily nutrient intake level, based on experimentally derived intake levels or approximations of observed mean nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is established when there is insufficient scientific evidence to determine an Estimated Average Requirement (EAR).”

Mineral

Biochemical Role/Function

Deficiency Symptoms

Toxicity Symptoms

Recommended Dietary Allowance or AI*

Potassium

Neural transmission;muscle contraction, vascular tone

Cardiac arrhythmias; muscle weakness; leg discomfort; extreme thirst; frequent urination; confusion; glucose intolerance, increased blood pressure, increased salt sensitivity, increased risk for kidney stones, increased bone turnover

Fatigue, weakness, tingling, numbness, or other unusual sensations; paralysis, palpitations, difficulty breathing; cardiac arrhythmias; GI distress

Adults & children:
≥ 14 years of age:* 4,700 mg

Infants/children:*
0-6 months: 400 mg
6-12months: 700 mg
1-3 years: 3,000 mg
4-8 years: 3,800 mg
9-13 years: 4,500 mg

Pregnancy:* 4,700 mg
Lactation:* 5,100 mg

Sodium

Maintenance of extra-cellular volume and plasma osmolality; is an important determinant of the membrane potential of cells and the active transport of molecules across cell membranes

Brain swelling, resulting in loss of appetite, nausea, vomiting, headache, mental status changes (confusion, irritability, fatigue, hallucinations); muscle weakness, convulsions

Elevated blood pressure; increased risk for cardiovascular disease and stroke; neurologic symptoms (confusion, coma, paralysis of the lung muscles)

Adults:*
19-50 years: 1,500 mg
51-70 years: 1,300 mg
70+ years: 1,200 mg

Infants/children:*
0-6 months: 120 mg
6-12months: 370 mg
1-3 years: 1,000 mg
4-8 years: 1,200 mg
9-18 years: 1,500 mg

Pregnancy:* 1,500 mg
Lactation:* 2,300 mg

Chloride

Important component of gastric juice as hydrochloric acid

Hypochloremic metabolic alkalosis; in infants, hypochloremia results in growth failure, lethargy, irritability, anorexia, gastrointestinal symptoms, and weakness; may also result in hypokalemia, metabolic alkalosis, hematuria, hyperaldosteronism, and increased plasma renin

Dehydration, fluid loss, hypernatremia

Adults:*
19-50 years: 2,300 mg
51-70 years: 2,000 mg
>70 years: 1,800 mg

Infants/children:*
0-6 months: 180 mg
6-12months: 570 mg
1-3 years: 1,500 mg
4-8 years: 1,900 mg9-18 years: 2,300 mg

Pregnancy:* 2,300 mg
Lactation:* 2,300 mg

Source: Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: National Academies Press; 2004.

* IOM did not set an RDA for vitamins in this age group. Instead, an Adequate Intake (AI) is used. According to IOM, “ The AI is a recommended average daily nutrient intake level, based on experimentally derived intake levels or approximations of observed mean nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is established when there is insufficient scientific evidence to determine an Estimated Average Requirement (EAR).”

Mineral

Biochemical Role/Function

Deficiency Symptoms

Toxicity Symptoms

Recommended Dietary Allowance or AI*

Iron

Component of enzymes necessary for oxidative metabolism; heme proteins (hemoglobin, myoglobin, cytochromes); partici-pates in electron transfer

Impaired physical work performance, developmental delay, cognitive impairment, anemia

Fatigue, anorexia, dizziness, nausea, vomiting, headache, weight loss, shortness of breath

Adults:
Males 19+ 8.0 mg
Females (age 19-50): 18.0 mg
Females 51+: 8.0 mg

Infants/children:
0-6 months:* 0.27 mg
7-12 months: 11 mg
1-3 years: 7 mg
4-8 years: 10 mg
9-13 years: 8 mg
14-18 years (boys): 11 mg
14-18 years (girls): 15 mg

Pregnancy 14-50 years:
27 mg
Lactation:14-18 years: 10 mg
19-50 years: 9 mg

Zinc

Component of enzymes (RNA polymerase, alkaline phosphatase); structural role for some enzymes and in protein folding; antioxidant function as part of zinc-copper superoxide dismutase

Growth retardation, hair loss, diarrhea, delayed sexual maturation and impotence, eye and skin lesions, loss of appetite, delayed wound healing

GI symptoms (epi-gastric pain, nausea, vomiting, abdominal cramps, diarrhea); impaired immune response; reduced copper status

Adults (ages 19+):
Men: 11.0 mg
Women: 8.0 mg

Infants/children:
0-6 months:* 2 mg
6 months to 3 years: 3 mg
4-8 years: 5 mg
9-13 years: 8 mg
14-18 years (boys): 11 mg
14-18 years (girls): 9 mg

Pregnancy:
14-18 years: 12 mg
19+ years: 11 mg

Lactation:
14- 18 years: 13 mg
19-50 years: 12 mg

Copper

Component of metalloenzymes (oxidases; e.g., monoamine oxidase; lysyl oxidase used for collagen and elastin production; cytochrome c oxidase; dopamine β mono-oxygenase); part of zinc-copper SOD

Defects in connective tissue; anemia; immune and cardiac dysfunction

GI symptoms (abdominal pain, nausea, vomiting, cramps, diarrhea)

Adults (ages 19+): 900 µ g

Infants/children:
0-6 months:* 200 µ g
6-12 months:* 220 µ g
1-3 years: 340 µ g
4-8 years: 440 µ g
9-13 years: 700 µ g
14-18 years: 890 µ g

Pregnancy: 1000 µ g
Lactation: 1300 µ g

Chromium

Potentiates insulin action; mobilizes the glucose transporter GLUT4 to the plasma membrane; enhances tyrosine phosphorylation of the insulin receptor

Rare; found in patients on TPN prior to inclusion of Cr+3; symptoms included weight loss, neuropathy, and impaired glucose tolerance

None for Cr+3; Cr+6 is a known carcinogen when inhaled, and oral ingestion (20 mg/L) causes GI symptoms (abdominal pain, nausea, vomiting, diarrhea)

Adults:*
Men (age 19-50): 35 µ g
Women (age 19-50): 25 µ g
Males (age 50+): 30 µ g
Females (age 50+): 20 µ g

Infants/children/adolescents:*
0-6 months: 0.2 µ g
6-12 months: 5.5 µ g
1-3 years: 11 µ g
4-8 years: 15 µ g
9-13 years (males): 25 µ g
9-13 years (females): 21 µ g
14-18 years (males): 35 µ g
14-18 years (females): 24 µg

Pregnancy:* 30 µ g
Lactation:* 45 µ g

Sources: Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001;

National Institutes of Health, Office of Dietary Supplements Web site (http://dietary-supplements.info.nih.gov…)

* IOM did not set an RDA for vitamins in this age group. Instead, an Adequate Intake (AI) is used. According to IOM, “ The AI is a recommended average daily nutrient intake level, based on experimentally derived intake levels or approximations of observed mean nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is established when there is insufficient scientific evidence to determine an Estimated Average Requirement (EAR).”

Mineral

Biochemical Role/Function

Deficiency Symptoms

Toxicity Symptoms

Recommended Dietary Allowance or AI*

Selenium

Defense against oxidative stress, regulation of thyroid hormone action, and regulation of the redox status of vitamin C and other molecules, throughselenoproteins; e.g., oxidant defense enzymes like glutathione peroxidase; iodothyronine deiodinases

Keshan disease (cardiomyopathy in pediatric population); skeletal muscle disorders manifested by muscle pain, fatigue, proximal weakness, and serum creatine kinase (CK) elevation

Selenosis (gastrointestinal upset, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage); hair and nail brittleness and loss

Adults (ages 19+): 55 µ g

Infants/children:
0-6 months:* 15 µ g
6-12 months: 20 µ g
1-3 years: 20 µ g
4-8 years: 30 µ g
9-13 years: 40 µ g
14-18 years: 55 µ g

Pregnancy: 60 µ g
Lactation: 70 µ g

Iodine

Component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3)

Mental retardation, hypothyroidism, goiter, cretinism, and varying degrees of other growth and developmental abnormalities

Burning of the mouth, throat, and stomach, abdominal pain, fever, nausea, vomiting, diarrhea, weak pulse, cardiac irritability, coma, cyanosis; thyroid enlargement (goiter) from increased TSH stimulation; increased risk of thyroid papillary cancer; iodermia; hyperthyroidism

Adults (ages 19+): 1 50 µg

Infants/children:
0-6 months:* 110 µ g
6-12 months:* 130 µ g
1-3 years: 90 µ g
4-8 years: 90 µ g
9-13 years: 120 µ g
14-18 years: 150 µ g

Pregnancy: 220 µ g
Lactation: 290 µ g

Manganese

Component of metalloenzymes (arginase, manganese superoxide dismutase, pyruvate carboxylase)

Dermatitis, hypocholesterolemia

Neurotoxicity

Adults (ages 19+):*
Men: 2.3 mg
Women: 1.8 mg

Infants/children:*
0-6 months: 3 µ g
6-12 months: 0.6 mg
1-3 years: 1.2 mg
4-8 years: 1.5 m g
9-13 years (boys): 1.9 mg
9-18 years (girls): 1.6 mg
14-18 years (boys): 2.2 mg

Pregnancy:* 2 mg
Lactation:* 2.6 mg

Molybdenum

Component of sulfite oxidase, xanthine oxidase, aldehyde oxidase, enzymes involved in catabolism of sulfur-containing amino acids, purines, and pyridines

Rare; initially seen in patients on TPN, before addition of MO to standard TPN regimes; resulted in tachycardia, headache, night blindness, low serum uric acid

Reproductive effects asobserved in animal studies;with occupational exposure, hyperuricemia, and gout symptoms

Adults (ages 19+): 45 µ g

Infants/children:
0-6 months: (*) 2 µ g
6-12 months: (*) 3 µ g
1-3 years: 17 µ g
4-8 years: 22 µ g
9-13 years: 34 µ g
14-18 years 43 µ g

Pregnancy/lactation: 50 µ g

Sources: Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001;

National Institutes of Health, Office of Dietary Supplements Web site (http://dietary-supplements.info.nih.gov…)

1 see Chariot P, Bignani O. Skeletal muscle disorders associated with selenium deficiency in humans. Muscle Nerve. 2003;27:662-668.

* IOM did not set an RDA for vitamins in this age group. Instead, an Adequate Intake (AI) is used. According to IOM, “ The AI is a recommended average daily nutrient intake level, based on experimentally derived intake levels or approximations of observed mean nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is established when there is insufficient scientific evidence to determine an Estimated Average Requirement (EAR).”

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Last updated: November 27, 2017

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TY - ELEC T1 - Micronutrients in Health and Disease ID - 1342057 Y1 - 2017/11/27/ PB - Nutrition Guide for Clinicians UR - https://nutritionguide.pcrm.org/nutritionguide/view/Nutrition_Guide_for_Clinicians/1342057/all/Micronutrients_in_Health_and_Disease ER -