Nutrition Guide for Clinicians
Micronutrients in Health and Disease
Vitamins and minerals play essential roles in human biology, including the metabolism of protein, carbohydrate, and fat, maintenance of the structure of the human body (e.g., vitamin K in bone matrix, calcium in bone tissue), and antioxidant activity, among many others. 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 B12,). 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 signifcant 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
Folate (Vitamin B9). Folate deficiency typically manifests as megaloblastic anemia. However, inadequate intakes can lead to elevated serum homocysteine and increased risk of neural tube defects during gestation. Serum folate is also influenced by genetic polymorphisms affecting the function of an enzyme, 5,10‐methylenetetrahydrofolate reductase (MTHFR), that converts one form of folate to the main form of folate found in the blood. People with two copies the C677T MTHFR polymorphism, for instance, have reduced enzyme function, lower serum folate, and higher homocysteine levels.[5] Folate, derived from the word “foliage,” is found in significant amounts in dark green vegetables, as well as legumes. Folic acid, the oxidized form of folate, is also added to by law to all enriched grain products in the US.
Vitamin B12. Vitamin B12 deficiency can cause megaloblastic anemia and nerve damage. Vitamin B12 deficiency affects approximately 20% of the elderly population, mainly due to poor absorption.[6] (See Megaloblastic Anemia chapter.) The Institute of Medicine recommends that adults over age 50 get most of their vitamin B12 from supplements or fortified foods. Others at increased risk for deficiency include people consuming non-supplemented vegan diets, those taking metformin and/or certain acid-blocking medications, and those with gastrointestinal disorders or a history of gastrointestinal surgery.[7]
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 5-17% of participants in the Third National Health and Nutrition Examination Survey,[8] in 30% of a sample of hospice patients,[9] in 68% of a population of hospitalized elderly patients,[10] and in individuals who eat meat-based diets and avoid fruits and vegetables.[11] In smokers, the risk for vitamin C deficiency is roughly 4 times greater than in nonsmokers.[6]
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 US due to vitamin D fortification of milk, 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.[12]
Intakes that are considered either deficient or insufficient have also been found in young women and elderly persons who lack sun exposure. Individuals with darker skin are also at higher risk.[13] Low intakes are a risk factor for autoimmune disease and some cancers.[14] Certain drugs (e.g., phenytoin, phenobarbital) can also reduce blood levels of vitamin D, resulting in both osteopenia and osteomalacia.[15]
Some evidence suggests that a “functional” vitamin D deficiency state may be caused by a high calcium intake due to dairy products or calcium supplements and may increase the risk for prostate cancer. In one study, men with intakes of 1,500-1,999 mg per day of calcium had nearly double the risk for advanced and fatal prostate cancer, although higher calcium intake was not appreciably associated with total or nonadvanced 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 500-749 mg per day. The increased risk for advanced prostate cancer has been attributed to elevated blood calcium concentrations from high intake, which can decrease production of the active form of vitamin D (calcitriol). Under normal circumstances, vitamin D appears to play a role in reducing prostate cancer risk.[16] Vitamin D adequacy reduces the risk of osteoporosis (see Osteoporosis chapter) and may also reduce risk of cardiovascular disease.[17]
Considerable evidence suggests that certain subgroups (e.g., elderly persons) do not meet vitamin D requirements due to lack of sun exposure.[18] Typical multiple vitamin formulas 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; the Endocrine Society recommends that adults maintain a serum circulating 25 hydroxyvitamin D level of 30 ng/mL or higher. Supplementing with at least 1,500-2,000 IU of vitamin D may be required to attain this level.[19] More is not necessarily better, however, as a recent study of more than 5,000 adults showed no effect of high-dose vitamin D supplementation on cancer, cardiovascular disease, falls, respiratory infections, or non-vertebral fractures.[20]
Mineral Deficiencies
Iron. Iron deficiency anemia is common worldwide and can lead to immune dysfunction, gastrointestinal disturbances, and neurocognitive impairment.[21] Iron depletion is the most common cause of anemia in pregnancy.[22] (See Iron Deficiency Anemia chapter.)
Calcium. The optimal level of calcium intake is a matter of controversy. Intakes of calcium at levels below dietary reference intakes (DRIs) are common in a large segment of the U.S. population. Forty-two percent of Americans do not consume the estimated average requirement (EAR) for calcium (the amount determined to meet the needs of half of healthy individuals).[23] 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 in children and young adults, 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 predict bone density in this population.[24] 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.[25],[26]
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] Individuals developing or having hypomagnesemia may show neuromuscular hyperexcitability,[27] and hypocalcemia is a sign of severe hypomagnesemia ( < 1.8 mg/L, 0.74 mmol/L).[28],[29] Hypomagnesemia occurs in up to 12% of hospitalized patients and in as many as 60-65% of patients in intensive care units.[26] 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.[30]
One study with children aged 8-17 found that obese children were twice as likely to have hypomagnesemia, compared with lean children,[31] and another with nonhospitalized adults showed those with type 2 diabetes have much higher rates.[32] Hypomagnesemia is strongly associated with more rapid disease progression and increased complications.[33] (See Diabetes chapter.) Magnesium deficiency may result from inadequate intake of 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 an other otherwise unhealthful diet does not reduce the risk for common diseases such as cardiovascular disease and cancer; it may be harmful in well-nourished populations.[34],[35] 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 (i.e., phytochemicals) in foods is responsible for the majority of antioxidant effects.[36] In general, populations eating greater amounts of phytochemical-containing foods (e.g., fruits, vegetables, whole grains) have a significantly lower mortality risk[37] and a lower risk for cardiovascular disease, cancer, diabetes mellitus, hypertension, and arthritis.[38],[39] 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 conditions are associated with 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 individuals, compared with low-alcohol consumers.[40],[41] Alcohol abusers may miss B vitamins through poor food intake and lose B vitamins due to the diuretic effect of alcohol; these (particularly thiamine) must be replaced to prevent neurologic sequelae, including Wernicke-Korsakoff syndrome.[42] 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 μg/day), compared with those with higher intakes.[43]
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.[9],[44] 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.[45] Other surveys of vegetarians also found higher intake of vitamins C and E, in addition to potassium[46] and dietary fiber,[47] compared with omnivores. Pregnant vegetarian women had significantly lower risk for folate deficiency than omnivores had.[48]
According to the Institute of Medicine (IOM), only 26% and 34% of active vitamin A , consumed by men and women, respectively, is from provitamin A carotenoids.[49] 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.[47]
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.[50] However, in spite of the frequency of this disorder, it is not solely responsible for HHC-related diseases, such as diabetes and liver disease.[51] 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.[52] These individuals may be at greater risk for heart disease, cancer, and diabetes, risks that appear to be greatest among elderly persons.[53] Among elderly participants in the Framingham Heart Study, 13% had high iron stores, while approximately 3% were found to have iron deficiency.[51]
Smokers. Smokers often have poorer diets in general than nonsmoking individuals, and they generally consume fewer fruits and vegetables and more saturated fat.[54] Moreover, even after adjustment for differences in diet, smokers have significantly lower blood levels of several carotenoids and vitamin C.[55]
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[56],[57] 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.[58]
Elderly persons, particularly those in hospitals or long-term care facilities are at risk for vitamin deficiencies. Individuals following unsupplemented vegan diets are at risk of vitamin B12 deficiency, although, with appropriate supplementation, a vegan diet has nutritional advantages, compared with unmodified diets.[59] Alcohol-dependent individuals are at risk for folate, B6, B12, and thiamine 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.[60] A disadvantage of such a strategy is overconsumption of certain minerals. Excess iron and copper intake have been linked to higher risk of Alzheimer’s disease (See Alzheimer’s Disease chapter).
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[61] and pyridoxine-dependent seizures.[62]
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.[13]
Folate 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.[63] Through an antagonizing effect on folate, these same drugs also increase certain indicators of cardiovascular risk, such as homocysteine and possibly lipoprotein(a).[64] Available data indicate that folic acid treatment can reduce homocysteine in children on anticonvulsant medications.[65] Additional studies are needed to test the 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.[66]
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 modest folate supplementation (i.e., multivitamins) and by reducing the dose of methotrexate if necessary.[67] Although doses of 2.5-5.0 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.[66]
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.[68] Long-term treatment with metformin also decreases B12 absorption, 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.[69][70]
Hypokalemia frequently results from commonly used diuretics, amphotericin B, corticosteroids, antipseudomonal penicillins, and insulin, while hyperkalemia may result from heparin,[13] as well as from potassium-sparing diuretics and poor kidney function.[71]
Hypomagnesemia and thiamine deficiency frequently result from treatment with diuretics, and the former can also occur due to administration of amphotericin B, aminoglycoside antibiotics, and cyclosporine.[13],[26]Cisplatin therapy may also cause hypomagnesemia.[72]
Hypocalcemia may result from foscarnet by forming a complex with ionized calcium.[13] It may also occur in patients given bisphosphonates who have unrecognized hypoparathyroidism, impaired renal function, or vitamin D deficiency.[73]
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, gastric bypass procedures necessitate lifelong multivitamin and mineral supplementation.[74] For example, diseases that cause malabsorption (chronic cholestasis, abetalipoproteinemia, celiac disease, and cystic fibrosis) result in vitamin E deficiency and the need for supplementation.[75] Clinicians should encourage patients to obtain these nutrients from foods in addition to supplements, due to the presence of other nutrients in whole foods and their potentially synergistic effects.[76] For example, vitamin E supplements may contain only α-tocopherol, but food sources of vitamin E include γ-tocopherol (a scavenger of reactive oxygen and nitrogen radicals and inhibitor of cyclooxygenase)[77] and tocotrienols, which have both antioxidant and nonantioxidant benefits that α-tocopherol does not possess.[78]
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).[79] 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).[80] 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 or supplementation with nonessential or conditionally essential micronutrients (e.g., carnitine, coenzyme Q10).
The following three tables summarize key relationships between micronutrients and health.
Disease | Nutrient(s) | Rationale |
Anemia, microcytic | Iron | Increased need in high-risk groups (e.g., pregnant people, adolescents). |
Anemia, pernicious | Vitamin B12 | Risk for deficiency in elderly individuals, post-gastrectomy patients. |
Burn injury | Vitamins A, C, D, & E; carotenoids; selenium, zinc, copper | Burns reduce blood levels; increases are needed to support immune function. |
Celiac sprue | Vitamins D, E, & K; | 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 supplement, 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* |
Vitamin A | Bone growth, reproduction, cell division, immunity, cell differentiation | Clinical: Night blindness; total blindness (rare in the US) | Birth defects, liver abnormalities, reduced bone mineral density; central nervous system disorders (e.g., pseudotumor cerebri) | Adults: Age 19+: Infants/children: Pregnancy: RDA/AI units: retinoic acid equivalents |
Vitamin D | Maintenance of normal blood levels of calcium and phosphorus; promotes bone mineralization; regulates cell growth, differentiation, immune function | In children: rickets | Nausea, vomiting, poor appetite, constipation, weakness, and weight loss; mental status changes; hypercalcemia; calcinosis; polyuria; heart arrhythmias | Adults: Infants /children: |
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 | Peripheral neuropathy, ataxia, skeletal myopathy, retinopathy, impairment of the immune response | Can influence coagulation in some persons with drug-induced vitamin K deficiency; anti-platelet effect | Adults:19+ years: 15 mg Pregnancy: 15 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 Note: potentially dangerous interaction with anticoagulants such as warfarin | Adults: 19+ years:* Infants/children/adolescents:* Pregnancy/lactation:* |
Sources: National Institutes of Health, Office of Dietary Supplements Web site (https://ods.od.nih.gov/)
1 see Zingg JM, Azzi A. Non-antioxidant activities of vitamin E. Curr Med Chem. 2004;11:1113-1133; Institute of Medicine, DietaryReference 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 and can include follicular hyperkeratosis, petechiae, ecchymoses, coiled hairs, inflamed and bleeding gums, perifollicular hemorrhages, joint effusions, arthralgia, and impaired wound healing), dyspnea, edema, Sjogren syndrome, weakness, fatigue, depression | Nausea, abdominal cramps, and diarrhea (from supplements) | Adults ( > 19 years): Infants/children: Pregnancy: Lactation: |
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, rarely congestive heart failure); Wernicke-Korsakoff syndrome | 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): Infants/children: Pregnancy/lactation: 1.4 mg |
Riboflavin (B2) | Coenzyme in numerous redox reactions | 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+): Infants/children: Pregnancy: 1.4 mg |
Niacin (B3) | Coenzyme in numerous redox reactions | Pellagra (pigmented rash; “sunburned” appearance; 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/day) | Adult males and males RDA/AI unit: niacin equivalents |
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; hypoglycemia | Mild diarrhea and gastrointestinal distress | Adults ages 19+:* 5.0 mg Infants/children/adolescents:* Pregnancy:* 6.0 mg |
Pyridoxine (B6) | Coenzyme in the metabolism of amino acids, glycogen, and sphingoid bases | Seborrheic dermatitis, microcytic anemia, epileptiform convulsions, electroencephalographic abnormalities, glossitis, depression and confusion, weakened immune function | Sensory neuropathy with high ( > 100 mg) supplementary intake | Adults: Infants/children: Pregnancy: 1.9 mg |
Folate | Folate coenzymes are involved in DNA synthesis; amino acid interconversions including conversion of homocysteine to methionine; single-carbon metabolism; methylation reactions | Hypersegmented neutrophils, macrocytic anemia (weakness, fatigue, difficulty concentrating, irritability, headache, palpitations, shortness of breath), elevated homocysteine, increased risk of neural tube defects in offspring of women deficient during the periconceptual period | None in healthy individuals Supplements 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 µg Infants/children: Pregnancy: 600 µg |
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 µg Infants/children: Pregnancy: 2.6 µg |
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, seizures), ketolactic acidosis, aciduria, skin infection, brittle nails | None currently known | Adults (ages 19+)*: 30 µg Infants/children:* Pregnancy:* 30 µg |
Sources: National Institutes of Health, Office of Dietary Supplements Web site (https://ods.od.nih.gov/)
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* |
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:* Infants/children/adolescents:* Pregnancy/lactation:* |
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, | Adults (ages 19+): 700 mg Infants/children: Pregnancy/lactation: |
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: Pregnancy: Lactation: |
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; | 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: Pregnancy:* 4,700 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:* Pregnancy:* 1,500 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:* Pregnancy:* 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- | Impaired physical work performance, developmental delay, cognitive impairment, anemia | Fatigue, anorexia, dizziness, nausea, vomiting, headache, weight loss, shortness of breath | Adults: Infants/children: Pregnancy 14-50 years: 27 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+): Infants/children: Pregnancy: Lactation: |
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 µg Infants/children: Pregnancy: 1,000 µg |
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:* Pregnancy:* 50 µg |
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 (https://ods.od.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* |
Molybdeum | 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 | Occupational exposure, hyperuricemia, and gout symptoms | Adults (ages 19+): 45 µg |
Selenium | Defense against oxidative stress, regulation of thyroid hormone action, and regulation of the redox status of vitamin C and other molecules, through | 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 µg |
Iodine | Component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) | Intellectual disability, hypothyroidism, goiter, congenital hypothyroidism, 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+): 150 µg |
Manganese | Component of metalloenzymes (arginase, manganese superoxide dismutase, pyruvate carboxylase) | Dermatitis, hypocholesterolemia | Neurotoxicity | Adults (ages 19+):* Infants/children:* Pregnancy:* 2 mg |
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 (https://ods.od.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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