Several different factors can contribute to suboptimal micronutrient status and place certain groups of the population at increased risk for micronutrient deficiencies. While poor overall nutrition is a major contributor to micronutrient inadequacies in the US, micronutrient needs may be increased during different life stages or disease states. Certain dietary and lifestyle choices, as well as use of pharmaceuticals, can also place individuals at risk for select micronutrient inadequacies. Some of these factors are discussed below.

Individuals with Dark-colored Skin

Sunlight exposure is the primary source of vitamin D for most people. Solar ultraviolet-B radiation (UVB; wavelengths of 290 to 315 nanometers) stimulates the production of vitamin D3 from 7-dehydrocholesterol (7-DHC) in the epidermis of the skin (1). People with dark-colored skin synthesize markedly less vitamin D on exposure to sunlight than those with lighter complexion (2); melanin, the dark brown pigment found in skin, is thought to block absorption of UV light (3).

In an analysis of data from NHANES 2001-2010, including more than 32,000 individuals, mean 25-hydroxyvitamin D serum concentrations of those 6 years and older was 29 ng/mL for Non-Hispanic whites, 22 ng/mL for Mexican-Americans, and 17 ng/mL for Non-Hispanic blacks (4). Only 17% of Non-Hispanic whites had serum concentrations below 20 ng/mL, while 41% of Mexican-Americans and 68% of Non-Hispanic blacks had concentrations below 20 ng/mL (4). Serum concentrations below this cutoff point is indicative of vitamin D deficiency according to the US Endocrine Society (5). Using serum 25-hydroxyvitamin D concentrations that correspond to intakes at the level of the EAR (i.e., 16 ng/mL or 40 nmol/L) (6) and data from NHANES 2003-2006, the estimated prevalence of inadequacy was found to be 51.6% among Non-Hispanic blacks, 24.4% among Mexican Americans, and 9.4% among Non-Hispanic whites (7).

Exclusively Breast-fed Infants

Infants who are exclusively breast-fed and do not receive vitamin D supplementation are at high risk for vitamin D deficiency, particularly if they have dark skin and/or receive little sun exposure (8). Human milk generally provides 10 to 80 IU/L of vitamin D, which corresponds to vitamin D intakes of 0.2 to 1.5 µg/day (8 to 60 IU/day) when using an average daily milk intake of 0.75 L (25 oz) (9). The American Academy of Pediatrics recommends that all breast-fed and partially breast-fed infants be given an oral vitamin D supplement of 400 IU/day (8). Maternal vitamin D supplementation during breast-feeding may contribute to improved vitamin D status of the breast-fed infant, especially in populations with a high prevalence of vitamin D deficiency (10). Older infants and toddlers exclusively fed milk substitutes (e.g., soy-based formulas) and weaning foods that are not vitamin D fortified also are at risk for severe vitamin D deficiency associated with rickets (11).

Adolescents

Adolescence, the transitional stage of development between childhood and adulthood, is associated with marked physical growth, reproductive maturation, and cognitive transformations. Good nutrition, including adequate intake of vitamins and essential minerals, is needed to support the growth and developmental changes of adolescence — micronutrient requirements are increased during this life stage compared to childhood. However, overall adherence to the US Dietary Guidelines is especially poor among adolescents (12), and consequently, there is a high prevalence of micronutrient inadequacy among US adolescents. Gender differences exist, with female adolescents having a higher prevalence of micronutrient inadequacy compared to male adolescents (see Table 1). While fortified foods are an important source of micronutrients for adolescents (13), when accounting for intake from these foods, many adolescents still have insufficient intakes for vitamins A, C, D, and E; calcium, magnesium, phosphorus (females only), and zinc (females only; Table 1) (13). For the nutrients in which there is no estimated average requirement (EAR), average intakes of males and females ages 12-19 years are well below the AI for potassium and choline (14). It is important to note, however, that assessments of dietary intake in children and adolescents appear to be more prone to measurement error than assessments in adults, especially with respect to underreporting of intake (15).

While the prevalence of micronutrient inadequacies is higher for other micronutrients, iron deficiency is the only micronutrient deficiency that is commonly described among adolescents, especially among females (16). For more information on iron needs during adolescence, see the separate article on Micronutrient Requirements of Adolescents.

The EAR is used to assess dietary intake of an individual or a population, and the recommended dietary allowance (RDA) should be used in the planning of diets for individuals (17). For a list of gender-specific RDAs for adolescents and in-depth discussion of specific micronutrients, see Table 1 in the separate article on adolescence.

Table 1. Percentage of US Adolescents (Ages 14-18 Years) with Dietary Intakes below the EAR, NHANES 2003-2006 (13)
Micronutrient Males, % < EAR Females, % < EAR
 Folate 4.0
19.0
 Niacin 0.2 4.1
 Riboflavin 1.2 4.7
 Thiamin 1.5
10.2
 Vitamin A 56.4
57.2
 Vitamin B6 2.9
17.8
 Vitamin B12 0.3 6.5
 Vitamin C 38.7 44.8
 Vitamin D 88.2 97.6
 Vitamin E 94.6 98.7
 Calcium 47.4 81.4
 Copper 1.9 15.6
 Iron 0.5 11.5
 Magnesium 75.6 89.7
 Phosphorus 9.9 48.1
 Selenium 0.1
2.1
 Zinc 4.5
23.5

Premenopausal Women

Iron

Iron is the most common nutritional deficiency worldwide (18). Women of childbearing age are at increased risk for iron deficiency mainly due to insufficient dietary intake and menstrual blood loss. While menstrual blood loss varies among women, the Food and Nutrition Board of the Institute of Medicine used an average daily iron loss of 0.51 mg to establish the dietary requirement for iron, in addition to basal iron losses (median, 0.896 mg/day) and assuming an 18% bioavailability of dietary iron (19). The EAR and RDA for adult, premenopausal women were set at 8.1 mg/day and 18 mg/day, respectively (19).

Average dietary intake of iron among premenopausal women in the US is between 12-13 mg/day, which is above the EAR but below the RDA (NHANES 2013-2014) (20). In addition to assessing dietary intake from 24-hour food recalls, NHANES has included several nutritional biomarkers of iron status. Based on data from NHANES 2003-2006, the percentage of nonpregnant US women with markers of iron status below the cutoff value for deficiency was 6.9% for hemoglobin concentration, 10.9% for ferritin concentration, and 29.7% for percent transferrin saturation (21). The prevalence of having two of these values below the cutoffs for iron deficiency was 9.8% among nonpregnant women (21).

On average, the use of oral contraceptives decreases menstrual blood loss and is thus associated with improved iron status among women (21, 22). While the mechanisms for this are not fully understood, estrogen has been shown to inhibit the iron regulatory protein, hepcidin (23), allowing for increased iron absorption and cellular uptake of iron.

Moreover, breast-feeding is associated with a lower dietary requirement of iron due its low excretion in breast milk and because of lactational amenorrhea (EAR, 6.5 mg/day; RDA, 9 mg/day), allowing for repletion of iron stores depleted during pregnancy and delivery. However, iron repletion may be incomplete in high-parity women, who are at increased risk for iron deficiency (21).

Folic acid

Routine supplementation with folic acid (the synthetic form of folate) is universally recommended for all women capable of becoming pregnant to reduce the risk of neural tube defects (NTDs), devastating birth defects caused by abnormal development of the neural tube (24-26). Specifically, the US Preventive Services Task Force recommends a daily supplement of 400 to 800 μg/day of folic acid for all women planning or capable of pregnancy (26). Women with a previously NTD-affected pregnancy are advised to take 4,000 μg (4 mg) of folic acid daily when they are planning a pregnancy (27, 28). Recommendations were made to all women of childbearing age because adequate folate must be available very early in pregnancy, and because many pregnancies in the US are unplanned.

Folic acid found in fortified food and supplements is more bioavailable than folate in food (see the article on Folate). Together, intake from fortified food and high-dose supplements (e.g., prenatal supplements that often contain 800 μg of folic acid) can easily exceed the tolerable upper intake level (UL) of 1,000 μg/day of folic acid. The UL was established based on masking the diagnosis of a vitamin B12 deficiency; however, consumption of folic acid at or above the UL is considered to be safe in women of childbearing age because vitamin B12 deficiency is quite rare in this population (24).

Calcium and vitamin D

Both calcium and vitamin D are underconsumed in the US population and were labeled as "nutrients of public health concern" in the 2015-2020 Dietary Guidelines because of their importance in bone health (24). Adequate amounts of these nutrients are necessary to preserve skeletal integrity and health and to limit bone resorption and the loss of bone mineral density.

When intake of calcium is low, calcium is leeched from bone to maintain normal calcium concentrations in the blood. Thus, premenopausal women should strive to reach the RDA of 1,000 mg/day. Calcium intake is especially low among adolescent females (81% prevalence of inadequacy), and the RDA in this age group is even higher at 1,300 mg/day.

Adequate vitamin D status is important for maintenance of bone density throughout adulthood; vitamin D regulates blood concentrations of calcium and phosphorus and has a number of non-skeletal effects. The Linus Pauling Institute recommends aiming for a serum 25-hydroxyvitamin D concentration of at least 30 ng/mL (75 nmol/L) — supplementation may be needed to reach this recommendation (see the article on Vitamin D).

Pregnant Women

Pregnancy is associated with increased nutritional needs due to physiologic changes of the woman and the metabolic demands of the embryo/fetus. This increased need is met by a combination of physiological adaptations by the woman’s body and increased nutrient intake from food and supplements. For some micronutrients, such as folate, iron, iodine, and zinc, the requirement is substantially increased, and for other micronutrients, the requirement is slightly increased (magnesium, vitamin C) or unchanged (calcium, vitamin D, vitamin E). It is critical for women to meet recommended intake levels to help ensure a healthy pregnancy (see Pregnancy In Brief). In the United States, several of these micronutrients are underconsumed and considered 'shortfall nutrients' (29).

Deficiencies in certain micronutrients during the periconceptual period and during pregnancy have been linked with a range of adverse pregnancy outcomes, including miscarriage, congenital anomalies, intrauterine growth restriction and low birth weight, gestational diabetes, gestational hypertension, preeclampsia, eclampsia, and preterm birth. For example, maternal iodine deficiency and hypothyroidism can result in fetal loss, placental abruption, preeclampsia, preterm delivery, and in its most severe form, congenital hypothyroidism called cretinism (30). As mentioned above, folate deficiency can cause neural tube defects in offspring.

Considering that many women of childbearing age do not meet the recommended levels of intake for many micronutrients to begin with, special effort should be made to meet micronutrient needs during the periconceptual period and throughout pregnancy. This includes making healthful dietary choices and possibly taking micronutrient supplements under the supervision of a qualified healthcare provider. For detailed information on these and other micronutrients during pregnancy, see Pregnancy In Brief or the in-depth article on Micronutrient Needs during Pregnancy and Lactation.

Folic acid

As mentioned above, routine supplementation with folic acid (a synthetic form of folate) is universally recommended for all women capable of becoming pregnant to reduce the risk of neural tube defects (24-26). The developing embryo/fetus requires folate to form new cells, tissues, and organs, and folate is needed for the closure of the neural tube (the precursor to the brain and spinal cord). Closure of the neural tube occurs very early in pregnancy, by the sixth week of gestation, a time when many women do not realize they are pregnant. Thus, supplementation with folic acid must be done during the periconceptual period (about one month before and at least one month after conception). The US Preventive Services Task Force recommends a daily supplement of 400 to 800 μg/day of folic acid for all women planning or capable of pregnancy (26). Women who have had a previous NTD-affected pregnancy are advised to take 4,000 μg/day (4 mg/day) of folic acid when they are planning to become pregnant. This dosage should be prescribed and monitored by a healthcare provider (see the CDC recommendations).

Iron

Adequate iron status of the woman at the time of conception is important for a healthy pregnancy to meet the increased needs for fetal growth and development, to avoid anemia during pregnancy and postpartum, and to provide the breast-fed infant with sufficient iron stores until six months of age when complementary feeding is recommended. The developing fetus needs iron for growth and development of all tissues and organs, and the pregnant woman requires iron to meet the increased production of red blood cells that transport oxygen to the developing fetus — inadequate iron intake can lead to iron deficiency and iron-deficiency anemia.

The EAR for iron during pregnancy is 22 mg/day (RDA = 27 mg/day), yet dietary surveys indicate that average intake among pregnant women in the US is only 15 mg/day (19). Analysis of data from NHANES 1999-2006 found an 18% prevalence of iron deficiency among pregnant women (n=1,171) measured by assessing total body iron using serum ferritin and soluble transferrin receptor concentrations (31). Not surprisingly, the prevalence of iron deficiency increased with each trimester of pregnancy — nearly 30% of women in the third trimester of pregnancy were iron deficient (31). An analysis of data from NHANES 2003-2006 found that 25% of pregnant women in the US had iron deficiency, measured by two out of three markers of iron status (i.e., hemoglobin, ferritin, and % transferrin saturation) below cutoff values indicative of deficiency (21). Multiple pregnancies may deplete a woman’s iron stores if the interval between pregnancies is short: some studies have shown that iron status declines with increasing parity (reviewed in 21).

While supplemental iron during pregnancy is recommended in areas of the world with high rates of malnutrition and anemia, the need for iron supplementation in women living in the US and other developed nations is generally evaluated by a healthcare professional on an individual basis. However, most women will require iron supplements to meet the increased requirement during pregnancy, usually beginning at 12 weeks’ gestation (32). Iron supplementation improves maternal iron status and decreases the risk of anemia at term.

HIGHLIGHT: TWO FORMS OF DIETARY IRON
  • Heme iron: red meat, poultry, fish
  • Nonheme iron: beans, lentils, vegetables (e.g. spinach), fortified food
HIGHLIGHT: IRON SUPPLEMENTS DURING PREGNANCY
  • Most women will require iron supplements to meet the increased requirement during pregnancy.
  • Reversible, gastrointestinal side effects (nausea, constipation, vomiting, and diarrhea) are associated with the use of high-dose (≥60 mg/day) iron supplements.
  • In general, iron supplements are better absorbed on an empty stomach and with vitamin C, either from food or supplements.
  • Take iron supplements separately (several hours apart) from single-dose calcium and zinc supplements.
  • Do not take iron supplements with coffee, tea, bran, or milk.

Iodine

Iodine is another mineral where the requirement is substantially increased during pregnancy; the RDA for iodine is increased from 150 to 220 μg/day during pregnancy. Iodine is required for maternal thyroid hormone production, which is needed for myelination of the central nervous system and normal brain development of the fetus. While severe iodine deficiency during pregnancy can result in hypothyroidism and brain damage in the offspring, milder forms of maternal deficiency may have adverse effects on intellectual development and mental abilities of the offspring. A median urinary iodine concentration less than 150 μg/L in pregnant women is indicative of insufficient iodine intake (33). Pooled data from NHANES 2005-2010 reported that US pregnant women had a median urinary iodine concentration of 129 µg/L, and the lowest median concentration (109 µg/L) was observed during the first trimester of gestation, when the embryo/fetus relies exclusively on maternal thyroid hormones (34).

To meet the increased iodine requirement, the American Thyroid Association recommends that all pregnant women in North America take 150 μg/day of iodine from oral supplements and have a minimum total daily intake of 250 μg/day of iodine (30). Dairy foods account for about 50% of iodine intake among US adults (35); other dietary sources include iodized salt, seafood, eggs, poultry, and grains (see the article on Iodine). Although used worldwide to prevent iodine deficiency disorders, universal salt iodization has not been adopted in the United States — only about 70% of table salt marketed in the US contains iodine (36). Processed foods can contribute to iodine intake if iodized salt or food additives, such as calcium iodate and potassium iodate, are added during production. Yet, in the US, virtually no iodized salt is used in the manufacturing of processed food and fast food products, and the food industry is not required to list the iodine content on food packaging (37).

Zinc

Zinc is crucial for the formation, growth, and development of the cells and tissues of the developing fetus. While the requirement for zinc is increased during pregnancy, it is generally advised that women should focus on improving overall nutritional status versus taking single-nutrient zinc supplements. Shellfish, beef, and other red meats are rich sources of zinc; nuts and legumes are relatively good plant sources of zinc. Zinc is usually included in multivitamin/mineral supplements marketed to pregnant women.

Older Adults

Aging is associated with a number of physiologic and metabolic changes that can modify nutritional needs and place older adults at risk for nutritional deficiencies. Older adults generally have less lean body mass (fat-free mass) and lower levels of physical activity than younger adults; thus, total energy expenditure is reduced with advanced age (38). Other age-related changes, such as menopause, immunosenescence, and medical conditions like atrophic gastritis, can affect individual micronutrient requirements (38). Moreover, declines in oral health and sensory alterations in smell and taste, as well as social variables like living alone, can decrease food intake in older adults and place them at risk for undernutrition (38). Undernutrition is especially prevalent among those who are institutionalized, with an estimated prevalence of 40%-85% in nursing home residents and greater than 50% in hospitalized older adults (reviewed in 39). Further, many older adults have chronic diseases that affect nutrient metabolism (39), and older adults are particularly vulnerable to drug-nutrient interactions (see the section below: Those Taking Drugs Known to Interact with Nutrients). This is especially concerning because polypharmacy is quite common among older adults: 39% of US adults ≥65 years simultaneously use at least five different prescription drugs (40).

Because energy intakes of older adults are lower than younger adults, it is especially important for older adults to consume a diet rich in micronutrients, healthy fats, dairy, whole grains, legumes, and nuts (see Healthy Eating in a separate article). Dietary intake requirements (i.e., the EAR) are specific to life stage, set for adults 50-70 years and those greater than 70 years, to reflect micronutrient needs associated with the physiologic and metabolic changes associated with aging. Some micronutrient requirements are increased with aging (e.g., calcium, vitamin D), while some requirements are decreased (e.g., iron, sodium). Using the EAR to assess adequacy of intake in the US population, data from NHANES What We Eat in America (2013-2014) show that older adults have inadequate intakes of some micronutrients but adequate intakes of others. In general, average dietary intakes (from food and beverages) of older adults meet or exceed the EAR for thiamin; riboflavin; folate; vitamins A, B6, B12, C, and K; copper; iron; and zinc (41). Average intakes of magnesium are near the EAR for those ages 50-60 years but lower than the EAR for older age groups, especially those 70 years and older. Moreover, dietary intake assessments show that older adults generally have inadequate intakes of vitamin D, vitamin E, and calcium; average dietary intakes of choline are also below the AI (41). In addition to examining average micronutrient intakes of older adults, a recent analysis that compiled data from NHANES 2009-2012 reported the prevalence of micronutrient inadequacy (i.e., percent of the populations with dietary intakes below the EAR) by age group: 51-70 years and ≥71 years (42). A high prevalence of inadequacy was found for several micronutrients, including vitamins A, C, D, and E; calcium; and magnesium — and more than half of older adults had intakes less than the AI for vitamin K (Table 2).

Nutritional screening and counseling in the geriatric population should be the standard of care (38); the discussion below highlights some micronutrients of concern — underconsumed nutrients as well as potential effects of excessive intake — for older adults.

Table 2. Prevalence of Micronutrient Inadequacies Among Older Adults in the US when Accounting for Intake from Food Only (n=4,905), NHANES 2009-2012 (42)
Micronutrient Ages 51-70 Years, % < EAR Ages ≥71 Years, % < EAR
 Folate 10.6
17.0
 Niacin 1.3 4.0
 Riboflavin 2.6 3.4
 Thiamin 6.0
8.9
 Vitamin A 39.2 37.2
 Vitamin B6 15.6 22.4
 Vitamin B12 5.2 4.9
 Vitamin C 42.1 44.2
 Vitamin D 94.6 95.5
 Vitamin E 85.0 91.7
 Vitamin K* 48.7 62.9
 Calcium 51.4 72.9
 Copper 4.1 9.6
 Iron <1 <1
 Magnesium 51.3 68.6
 Phosphorus <1 2.1
 Selenium <1
2.4
 Zinc 17.9
26.1
 *% ≤ AI

Vitamin B12

Atrophic gastritis is thought to affect 9%-30% of people over 60 years of age (43). The condition results in decreased stomach acid production and reduced secretion of the digestive enzyme pepsin, causing an inability to liberate vitamin B12 from protein in food and thus food-bound vitamin B12 malabsorption. Atrophic gastritis is frequently associated with the presence of autoantibodies directed against stomach parietal cells or intrinsic factor (a protein secreted by stomach cells and needed for intestinal vitamin B12 absorption), as well as with infection by the bacteria, Helicobacter pylori (H. pylori) (44). Diminished gastric function in individuals with atrophic gastritis can result in bacterial overgrowth in the small intestine, further causing food-bound vitamin B12 malabsorption. The ability to absorb crystalline vitamin B12 from fortified food or dietary supplements is not affected by atrophic gastritis. Thus, affected individuals do not have an increased requirement for vitamin B12, they simply need it in the crystalline form.

Vitamin B12 deficiency impairs DNA synthesis and results in megalogblastic anemia, characteristic of large, immature red blood cells. If not corrected, vitamin B12 deficiency can cause neurologic complications, which are manifest in 75%-90% of those diagnosed with vitamin B12 deficiency (43). In fact, neurologic symptoms can occur without hematological abnormalities and be irreversible (43).

US dietary surveys show that 39% of men and 43% of women 60 years or older take vitamin B12-containing supplements, which greatly contributes to total daily intake of the vitamin (NHANES 2013-2014) (14). Nutritional status of vitamin B12, however, is more accurately assessed using various biomarkers. Serum methylmalonic acid and holotranscobalamin II are useful clinical indicators of vitamin B12 deficiency in older adults. Although blood vitamin B12 concentration is often measured, it is not helpful on its own as it poorly reflects vitamin B12 nutritional status (43).

It is important to note that a number of medications can reduce absorption of vitamin B12 from food, including proton-pump inhibitors, histamine2 (H2)-receptor antagonists (e.g., cimetidine, famotidine, and ranitidine), cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol and neomycin (antibiotics), and colchicine (medicine for gout treatment). Metformin, a medication for individuals with type 2 diabetes mellitus, was found to decrease vitamin B12 absorption by tying up free calcium required for absorption of the intrinsic factor-B12 complex (45); however, the clinical significance of this is unclear (46). Moreover, nitrous oxide, a commonly used anesthetic, oxidizes and inactivates vitamin B12, thus inhibiting both of the vitamin B12-dependent enzymes, and can produce many of the clinical features of vitamin B12 deficiency, such as megaloblastic anemia or neuropathy. Since nitrous oxide is commonly used for surgery in the elderly, some experts feel vitamin B12 deficiency should be ruled out prior to its use (43). For more information, see the section on Those Taking Drugs Known to Interact with Nutrients.

Because of the increased risk of food-bound vitamin B12 malabsorption in older adults, the Institute of Medicine’s Food and Nutrition Board recommended that adults over 50 years of age get most of the RDA (2.4 μg/day) from fortified food or vitamin B12-containing supplements (47). The Linus Pauling Institute recommends that adults older than 50 years take 100 to 400 μg/day of supplemental vitamin B12. For more information, see the article on Vitamin B12.

Vitamin D

Older adults have a reduced capacity to synthesize vitamin D in skin when exposed to ultraviolet-B radiation, and they are also more likely to stay indoors or use sunscreen, which prevents vitamin D synthesis. Institutionalized adults who are not supplemented with vitamin D are at extremely high risk for vitamin D deficiency (48). Moreover, chronic kidney disease is more common with advanced age, and kidney disease patients are at a heightened risk of vitamin D deficiency due to reduced renal synthesis of 1α,25-dihydroxyvitamin D and increased urinary loss of 25-hydroxyvitamin D (49).

Dietary intakes of vitamin D are low for all age groups in the United States, including older adults. In the US, average vitamin D intakes from food and beverages range from 5.1-5.7 μg/day for older men and 4.1-4.4 μg/day for older women (ages ≥50 years; NHANES 2013-2014) (41) — well below the EAR of 10 μg/day. Among vitamin D supplement users 60 years or older — 45% of the men and 58% of the women surveyed — average total vitamin D intakes (diet + supplements) were 43 μg/day in men and 50 μg/day in women. Supplement nonusers in this study had much lower total vitamin D intakes: 5.2 μg/day and 3.9 μg/day in older men and women, respectively (NHANES 2013-14) (14).

The RDA is increased to 800 IU (20 μg)/day for adults older than 70 years (6), but the optimal levels of recommended intakes and serum 25-hydroxyvitamin D to maximize health throughout the lifespan remain controversial (5). The Linus Pauling Institute recommends that older adults take 2,000 IU (50 μg) of supplemental vitamin D daily. Most multivitamins contain 400 IU (10 μg) of vitamin D, and single-ingredient vitamin D supplements are available for additional supplementation. Sun exposure, diet, skin color, and body mass index (BMI) have variable, substantial impact on body vitamin D concentrations. To adjust for individual differences and ensure adequate body vitamin D status, the Linus Pauling Institute recommends aiming for a serum 25-hydroxyvitamin D concentration of at least 30 ng/mL (75 nmol/L).

Since vitamin D inadequacy is linked to osteoporosis, muscle weakness, falls, fractures, and frailty with advanced age, it is critical to ensure adequate vitamin D status among older adults.

Calcium

Adequate intake of calcium is needed to limit the progressive demineralization of bones with aging, which leads to osteoporosis, bone fragility, and an increased risk of bone fracture. Dietary surveys show that many US residents fall short of the dietary recommendations for calcium, including many older adults. In NHANES 2013-2014, those 60 years or older who took a calcium-containing supplement — 46% of men and 53% of women surveyed — had average total calcium intakes of 1,412 mg/day in men and 1,568 mg/day in women; these intakes are above the RDA of 1,000 mg/day-1,200 mg/day, which is set to cover the nutrient needs of 97.5% of the population (14). However, supplement nonusers of this age group — 54% of men and 47% of women surveyed — had significantly lower average intakes of calcium from food alone compared to supplement users (928 vs. 1,034 mg/day in men and 739 vs. 888 mg/day in women) (14). Thus, calcium supplements are helping some older adults meet intake recommendations, but those who most need the supplements are not the ones taking them.

Although energy intakes decline with age, older adults should make sure that their diet contains enough calcium to cover their needs.

Vitamin B6

Older adults are at higher risk of vitamin B6 deficiency compared to younger individuals. When accounting for intake from food sources only, 15.6% of adults ages 51-71 years and 22.4% of adults ≥71 years had intakes less than the EAR compared to 4% of adults ages 19-50 years (42). Biomarker data, which are a better indicator of body vitamin B6 status, confirm that older adults are at a heightened risk of deficiency. NHANES 2005-2006 found that 16% of adults 60 years and older had serum pyridoxal-5’-phosphate concentrations (PLP) <20 nmol/L (7), which is indicative of vitamin B6 deficiency (concentrations >30 nmol/L are considered adequate) (50).

Vitamin A

Some, but not all, studies have found that high intakes of retinol (preformed vitamin A) are associated with reduced bone mineral density and increased risk of osteoporotic fractures in older adults. A meta-analysis of four prospective cohort studies, including nearly 183,000 older adults, found that high dietary intakes of retinol and high retinol blood concentrations were associated with increased risk of hip fracture but not total fractures (51). This analysis also found an increased risk with low concentrations of blood retinol (51). Only excessive intakes of retinol, not β-carotene (provitamin A), have been associated with adverse effects on bone health. For more information, see the article on Vitamin A.

Iron

Moderately elevated iron stores may be much more common than iron deficiency in older individuals (52). Dietary iron requirements decrease in women following menopause due to the cessation of menstrual blood loss and iron being efficiently recycled by the body. Moreover, hereditary hemochromatosis is not uncommon in the US population, and the effects of long-term dietary iron excess on chronic disease risk are not yet clear. For these reasons, it is generally recommended that older adults should not take dietary supplements containing iron unless they have been diagnosed with iron deficiency. A number of multivitamin/mineral supplements formulated specifically for older adults do not contain iron.

Sodium

As with other age groups in the US, the concern for sodium is excessive intake in older adults. A report of NHANES 2007-2010 found that more than 99% of older adults (≥51 years) had intakes of ≥1,500 mg/day of sodium (the AI is 1,300 mg/day for ages 51-70 and 1,200 mg/day for ≥71 years), and more than 85% consumed more than the tolerable upper intake level (UL) of sodium (2,300 mg/day) (53). Because the sensitivity to the blood pressure-raising effect of salt increases with age, sodium reduction in the context of a healthful dietary pattern is especially important for older adults, who are at increased risk of high blood pressure, cardiovascular disease, and kidney disease. The 2015-2020 Dietary Guidelines for Americans and the 2013 American Heart Association/American College of Cardiology Guidelines recommend that individuals who would benefit from blood pressure lowering, particularly prehypertensive and hypertensive adults, should follow the DASH eating pattern to lower sodium intakes (29). Recommendations include sodium intakes of no more than 2,400 mg/day, further sodium intake reduction to 1,500 mg/day for an even greater blood pressure-lowering effect, or a reduction in sodium intake of at least 1,000 mg/day if those levels cannot be achieved (29, 54). Among older adults, table salt and salt added during cooking account for only 22% of total sodium intake — the majority of sodium intake comes from processed food (55). More information on the adverse health effects of excessive sodium intake can be found in the article on Sodium.

Potassium

Similar to other age groups, older adults in the US are not meeting daily intake recommendations for potassium: only 1.3% of adults ages 51 to 70 years and 0.5% of those 71 years or older consume the recommended 4,700 mg/day of potassium (NHANES 2003-2008) (56). The richest sources of potassium are fruit and vegetables — older men and women fall short of reaching the recommended intakes of both fruit and vegetables (29). High-potassium diets have been associated with a lower risk of stroke, hypertension, osteoporosis, and kidney stones (for more information, see the article on Potassium). Several foods are listed in Table 3, along with their potassium content in milligrams.

Table 3. Some Foods Rich in Potassium
Food Serving Potassium (mg)
 Beet greens, cooked ½ cup
654
 Russet potato, baked with skin 1 medium 620
 Sweet potato, baked, without skin  1 medium 542
 Yogurt, plain, low-fat  1 cup 531
 Avocado  ½ fruit 487
 Swiss chard, cooked  ½ cup 480
 Lima beans, cooked  ½ cup 478
 Acorn squash, baked  ½ cup 448
 Banana 1 medium 422
 Spinach, cooked ½ cup  419
 Tomato juice 6 fluid ounces 396
 Dried apricots ¼ cup  378
 Salmon, sockeye, cooked  3 ounces 371
 Tomato sauce, canned ½ cup  364
 Prunes (dried plums) ¼ cup  319
 Raisins, seedless  ¼ cup 309
 Molasses  1 tablespoon 308
 Black beans, cooked ½ cup  305
 Tomato 1 medium 292
 Raisin bran cereal  1 cup 290
 Beets, cooked ½ cup 259
 Sunflower seeds 1 ounce 241
 Almond butter 2 tablespoons 239
 Orange 1 medium 232
 Peanuts 1 ounce 200
 Watermelon 1 cup 170

Those with Restrictive Diets

Any diet that eliminates entire food groups has the potential for being inadequate in several micronutrients.

Vegan and vegetarian diets

Those who adhere to a vegan diet, which excludes all foods of animal origin, are at increased risk for select micronutrient deficiencies and inadequacies, especially vitamin B12, but also vitamin D, calcium, and potentially iodine, iron, and zinc. Vegetarians who consume dairy and eggs may also be at a heightened risk of certain micronutrient inadequacies, particularly iron and zinc. For these micronutrients, intake from fortified food and/or supplements may therefore be needed.

Because vitamin B12 is found only in foods of animal origin, a vegan diet will result in vitamin B12 deficiency — and devastating neurologic consequences — unless there is intake from fortified food or supplements. Few plant-source foods, including certain fermented beans and vegetables and edible algae and mushrooms, may contain substantial amounts of vitamin B12 (57). Together with B-vitamin fortified food and supplements, these foods may contribute, although modestly, to prevent vitamin B12 deficiency in individuals consuming vegetarian or vegan diets.

Data from a large prospective cohort study in the UK, the EPIC-Oxford study, indicate that vegans (n=2,596) had substantially lower average intakes of retinol (preformed vitamin A), vitamin B12, vitamin D, calcium, and zinc compared to other dietary patterns: vegetarians who consumed animal products (e.g., eggs, milk), fish-eaters, or meat-eaters (58). Another large cohort in the US and Canada, the Adventist Health Study 2, assessed nutrient intake among more than 71,000 participants of which 5,694 were vegans (59). This study found an average daily intake of 6.3 μg of vitamin D among vegans, considerably lower than the requirement and significantly lower than non-vegetarians; mean intakes of other micronutrients were above daily requirements (59). Fish and dairy products are the main dietary sources of vitamin D; thus, vitamin D is a nutrient of concern for vegans, as well as vegetarians who don’t consume dairy. Adequate status of vitamin D is needed for optimal bone health.

Other studies have found that intake of calcium — another nutrient essential for bone health — is a concern for vegans (60, 61). Calcium inadequacy is less of a concern for vegetarians who consume dairy, but it is still a ‘shortfall nutrient' that is underconsumed by the US population (29). While dairy is an important source of calcium, some plant foods are good sources of bioavailable calcium. The calcium in foods of the kale family (broccoli, bok choy, cabbage, mustard, and turnip greens) is as bioavailable as that found in milk. However, other plant-based foods contain components that inhibit the absorption of calcium. Oxalic acid (oxalate) is the most potent inhibitor of calcium absorption and is found at high concentrations in spinach and rhubarb and at lower concentrations in sweet potatoes and dried beans. Phytic acid (phytate) — found in whole grains, legumes, and cereal (62) — can also inhibit calcium absorption but to a lesser extent than oxalic acid (see the article on Calcium).

Fortified food can contribute substantially to total daily calcium and vitamin D intake, although the availability of fortified food varies by country. Nutrient intake assessments also differ among studies and can account for variation. Of note, a vegan-specific food frequency questionnaire has recently been developed (63).

Limited data also suggest that vegans may be at risk of inadequate iodine intake: A small US cross-sectional study in 63 vegans reported a median urinary iodine concentration of 78.5 µg/L (urinary iodine concentrations), suggesting inadequate iodine intakes among vegans (the cutoff for sufficiency is 100 μg/L) (64). The US population is currently considered to be iodine-sufficient, but vegans and other subpopulations, e.g., women of childbearing age and pregnant women (34), may be at increased risk of marginal iodine deficiency.

While vegans and vegetarians may have similar iron and zinc intake compared to omnivores, the bioavailability of these two minerals is lower from plant versus animal sources. Iron from plants, i.e., nonheme iron, is less efficiently absorbed than that from animal sources (heme iron), and the RDA of iron for individuals strictly consuming a  vegetarian or vegan diet may be 1.8 times higher than the RDA for non-vegetarians (19). Yet, a diet that excludes meat 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 (65). Absorption of nonheme iron is influenced by various dietary factors (see HIGHLIGHT; for references and more information, see the article on Iron).

HIGHLIGHT: NONHEME IRON

Sources:
  • Plants, dairy products, meat, iron salts used in food enrichment/fortification and supplements

Enhancers of absorption:

  • Vitamin C (ascorbic acid): reduces dietary ferric iron (Fe3+) to ferrous iron (Fe2+) to form an absorbable, iron-ascorbic acid complex
  • Other organic acids: Citric, malic, tartaric, and lactic acids

Inhibitors of absorption:

  • Phytic acid (phytate) in legumes, whole grains, nuts, and seeds
  • Polyphenolic compounds in coffee, black tea, and herbal tea; this inhibitory effect may be reduced by the presence of vitamin C
  • Soy protein, e.g., tofu, soymilk, soybeans, edamame
  • Calcium, from food or supplements

In a 2013 systematic review and meta-analysis of 26 studies, vegetarians had lower dietary intakes and serum zinc concentrations compared to non-vegetarians; a secondary analysis found this association was stronger among vegans (66). However, it is important to note that measuring circulating zinc levels has some limitations (e.g., lack of sensitivity to detect marginal deficiency, reduced in inflammation, diurnal variation) and may not be a good measure of body zinc status (67).

Compared to animal sources, zinc bioavailability from plant sources (e.g., nuts, legumes, and whole grains) is low due to their relatively high content of phytic acid (phytate), a compound that inhibits zinc absorption (68). According to the US Institute of Medicine, the dietary requirement for zinc may be 50% higher for vegans who consume a diet rich in grains and legumes and have a dietary phytate:zinc ratio of greater than 15:1 (69). The enzymatic action of yeast reduces the level of phytic acid in food (69), and leavened whole-grain bread therefore has more bioavailable zinc than unleavened whole-grain bread. High levels of dietary calcium impair zinc absorption in animals, but it is uncertain whether this occurs in humans (for more information, see the article on Zinc).

Gluten-free diets

Gluten-free grain products are often subject to a milling process that removes the bran and the germ layers of the grain; this refining process strips out fiber and other nutrients. Moreover, these products may not be enriched or fortified with micronutrients like is typically done with refined wheat products. Gluten-free diets may therefore not supply sufficient amounts of certain vitamins and essential minerals, especially thiamin, riboflavin, niacin, folate, and iron (70, 71). Several micronutrient inadequacies, including folate, vitamin B12, vitamin D, calcium, magnesium, iron, and zinc, have been reported in patients treated for Celiac disease, an autoimmune condition that requires avoidance of dietary gluten (72). However, these inadequacies may in part be due to the underlying pathological condition rather than nutritional quality of the diet. Celiac disease patients are known to display a number of micronutrient deficiencies at the time of diagnosis (73, 74).

Other restrictive diets

Diets that exclude iodized salt, fish, and seaweed have been found to contain very little iodine (75). Two cases of goiter and/or hypothyroidism have also been recently reported in children following restrictive diets to control esophageal inflammation (eosinophilic esophagitis) (76) or allergies (77).

Additionally, certain energy-restricted diets used for weight loss, especially if followed long term, may place individuals at increased risk of micronutrient deficiencies. One study found that adherence to various weight-loss diets for just eight weeks resulted in a higher prevalence of inadequate micronutrient intakes at eight weeks compared to baseline (78). In particular, micronutrient intake significantly decreased in those who followed the Atkins (thiamin, folate, vitamin C, iron, magnesium), LEARN (Lifestyle, Exercise, Attitudes, Relationships, Nutrition; thiamin, vitamin E, calcium, magnesium), or Ornish (vitamin B12, vitamin E, zinc) diets (78).

Alcoholics

Alcoholics are at increased risk for deficiency of several micronutrients, especially vitamin A and the B vitamins. Chronic alcohol consumption results in depletion of liver stores of vitamin A and may contribute to alcohol-induced liver damage (cirrhosis) (79, 80). Moreover, the liver toxicity of preformed vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics (81).

It is well established that alcoholics are at a heightened risk for inadequate status of many B vitamins, including thiamin, riboflavin, niacin, vitamin B6, folate, and vitamin B12. B vitamins are important in various aspects of energy metabolism in various tissues, including the brain (see the article on Cognitive Function); thus, deficiencies in several B vitamins can cause cognitive disorders.

Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric disorder resulting from thiamin deficiency, is common among those who chronically abuse alcohol. Symptoms of WKS include learning deficits, amnesia, eye-movement and gait disorders, disorientation, and confabulation. Moreover, WKS is one of the more common causes of dementia (82). In alcoholics, general malnutrition, decreased intestinal absorption, impaired phosphorylation of thiamin, and increased urinary excretion may all contribute to thiamin deficiency (82, 83). Administration of intravenous thiamin to WKS patients generally results in prompt improvement of the eye symptoms, but improvements in motor coordination and memory may be less, depending on how long the symptoms have been present and the WKS stage at the time of intervention. Evidence of increased immune cell activation and increased free radical production in the areas of the brain that are selectively damaged suggests that oxidative stress plays an important role in the neurologic pathology of thiamin deficiency (84). Taken together, alcoholics have an increased requirement for thiamin.

Moreover, alcoholics are at increased risk for riboflavin deficiency due to decreased intake, decreased absorption, and impaired utilization of riboflavin. In rats chronically fed alcohol, the inhibition of riboflavin transporters caused impairment in intestinal absorption and renal re-uptake of the vitamin (85). A combination of low dietary intakes and impaired vitamin metabolism appear to place alcoholics at a higher risk for deficiencies in niacin (86), vitamin B6 (86), folate (87), vitamin B12 (88), and zinc (69). Although not as well established, alcoholics are also at increased risk of having inadequate status of magnesium (89) and phosphorus (90), due to general malnutrition, decreased intestinal mineral absorption, and/or increased mineral excretion.

Smokers

Exposure to toxins in cigarette smoke causes oxidative damage to indispensable molecules in the body, i.e., protein, lipids (fats), carbohydrates, and nucleic acids (DNA and RNA). Along with other cellular antioxidants, vitamins C and E play important roles to protect against the oxidative damage caused by exposure to smoke. Smokers generally have lower vitamin C status than nonsmokers due to increased metabolic turnover and thus require more from their diets (91). The Institute of Medicine’s RDA is 35 mg/day higher for smokers compared to nonsmokers: 125 mg/day for male smokers and 110 mg/day for female smokers. However, vitamin C pharmacokinetic studies have not been done in smokers; the LPI recommendation for all adults is to consume at least 400 mg/day of vitamin C (see the article on Vitamin C).

Vitamin C is capable of regenerating the antioxidant capacity of α-tocopherol, the form of vitamin E with the greatest nutritional significance (see Figure 1) (92). The main function of α-tocopherol is to function as a fat-soluble antioxidant, protecting cell membranes from lipid peroxidation. Oxidative stress caused by smoking is thought to increase the utilization of α-tocopherol such that smokers might be at increased risk of deficiency compared with nonsmokers (93). In a double-blind, placebo-controlled trial in 11 smokers and 13 nonsmokers given α-tocopherol and γ-tocopherol that was labeled with deuterium (hence traceable), supplementation with vitamin C reduced the rate of vitamin E loss in plasma, likely by regenerating tocopheryl radicals back to nonoxidized forms (94). Additionally, a 19-year follow-up analysis of the Alpha-Tocopherol, Beta-Carotene cancer (ATBC) trial in older, male smokers indicated that participants in the highest versus lowest quintile of serum α-tocopherol concentrations (>31 μmol/L vs. <23 μmol/L) at baseline had reduced risks of total and cause-specific mortality (95). Thus, smokers should ensure adequate intake of both vitamins C and E.

Those Experiencing Food Insecurity

Food insecurity (i.e., the lack of access to nutritionally adequate food obtained in socially acceptable ways) has been associated with poor dietary quality (96), suggesting that individuals in food insecure households may be at increased risk for micronutrient inadequacies. Some US cross-sectional studies have linked food insecurity with iron-deficiency anemia in young children (97, 98). Additionally, US national surveys (NHANES) have associated food insecurity with iron-deficiency anemia among adolescents (ages 12-15 years) (99) and with insufficient iron stores (low ferritin) among pregnant females (100).

"Food insufficiency" has been used as a measure of food insecurity assessing the quantity of food in the household (vs. nutritional quality) and thereby more resembling the concept of hunger (101). In a US national survey among 9,809 adults (NHANES III), a higher prevalence of low vitamin E and calcium intake was observed among young adults (ages, 20-59 years) of food-insufficient versus food-sufficient families, and a higher prevalence of low zinc intake was found among older adults (≥60 years) of food-insufficient families versus food-sufficient families (102). This survey also found lower serum concentrations of vitamin A (among both younger and older adults) and vitamin E (older adults only) in those of food-insufficient households compared to food-sufficient households; yet, the mean concentrations for these micronutrients were above the cutoffs typically associated with even marginal deficiency (102). In another analysis of data from NHANES III, old (ages 60-96 years) food-insufficient individuals had lower intakes of several micronutrients compared to those who were classified as food-sufficient (103). However, both groups had average micronutrient intakes above the EAR with the exception of magnesium, in which intakes were lower than the requirement in both groups (220.9 mg/day in food-insufficient and 241.0 mg/day in food-sufficient) (103).

Lower socioeconomic status has been linked to lower intakes of micronutrients, including most of the 'shortfall' nutrients (NHANES 2011-2012) (104). Differences in micronutrient intakes between low and high socioeconomic status might be attributed to differences in food security, food diversity, and use of supplements (104). In addition, the Seattle Obesity Study (470 men and 825 women) found a direct link between the price of food and the level of micronutrient intake (105). In this study, intakes of vitamin C, vitamin E, β-carotene, potassium, and magnesium — nutrients abundant in fruit and vegetables (and their oils) — were directly associated with a higher socioeconomic status (105).

Those with Certain Medical Conditions

Obese individuals

A recent national survey of US adults, NHANES 2013-2014, found that the prevalence of obesity (defined by a BMI ≥30 kg/m2) was 35% and 40% among men and women, respectively (106). Moreover, the overall prevalence of obesity among children and adolescents (ages 2-19), defined by a BMI at or above the sex-specific 95th percentile for BMI by age (according to CDC growth charts), has been estimated at 17% (107). Obesity is associated with an increased risk of a number of chronic diseases, including high blood pressure, type 2 diabetes mellitus, liver and gallbladder disease, osteoarthritis, sleep apnea, and certain cancers.

Although multifactorial in etiology, obesity is linked with consumption of an energy-dense, nutrient-poor diet. Obese individuals generally consume excessive calories (i.e., state of overnutrition) but insufficient amounts of micronutrients. Past studies have found a high incidence of micronutrient inadequacies among obese individuals, especially those considered morbidly obese (sometimes called ‘severe’ or ‘extreme’ obesity; often defined as BMI ≥40 kg/m2 or BMI ≥35 kg/m2 with certain medical conditions) (108, 109). In particular, it is well established that obesity increases the risk of vitamin D deficiency. Once vitamin D is synthesized in the skin or ingested, it can be sequestered in body fat stores, making it less bioavailable to people with higher body fat mass (see the article on Vitamin D).

An analysis of data from NHANES 2001-2008 among 18,177 adults found that US adults who were obese (BMI ≥30 kg/m2) had lower intakes of vitamin D and several other micronutrients, including vitamins A, C, and E; calcium; magnesium, and potassium compared to normal-weight adults defined as a BMI <25 kg/m2) (110). Accordingly, the prevalence of inadequacy for vitamins A, C, D, and E; calcium; and magnesium was higher among obese individuals compared to those of normal weight, and additionally, the proportion of obese adults that met the AI for potassium was smaller compared to normal-weight adults (110).

Bariatric surgery patients

As mentioned above, morbidly obese individuals have preexisting micronutrient deficiencies before they undergo bariatric surgery. Bariatric (weight-loss) surgery to treat morbid obesity can further increase the risk of micronutrient deficiencies due to decreased food intake and surgical alteration of the gastrointestinal tract. Most micronutrients are absorbed in the upper small intestine, which is often removed or bypassed in certain types of bariatric surgeries, and gastric, biliary, and pancreatic secretions are important for nutrient absorption (111). While the recommendations for nutrient supplementation vary by the specific type of surgery (e.g., Roux-en-Y gastric bypass, gastric banding, etc.), it is generally recommended that all bariatric surgery patients will need lifelong supplementation with a multivitamin/mineral, as well as calcium and vitamin D to maintain bone health. Supplementation with other micronutrients, including thiamin; vitamins A, B12, C, and K; iron; zinc; and possibly others may be needed depending on the specific type of surgical procedure (111). Nutritional evaluation and counseling of the patient must be done prior to and following bariatric surgery, and supplemental micronutrient recommendations should be tailored to individual needs (112).

Inflammatory bowel disease

Malnutrition may be present in up to 85% of patients with inflammatory bowel disease (IBD), i.e., Crohn’s disease and ulcerative colitis, and deficiencies of several micronutrients are common (113). Most micronutrients are absorbed in the upper small intestine (duodenum and jejunum), although some nutrients (e.g., vitamin B12 and fat-soluble vitamins) are absorbed in the ileum (114). Thus, Crohn’s disease, which can affect any part of the gastrointestinal tract — both small and large intestines — is associated with more severe micronutrient deficiencies compared to ulcerative colitis, which affects only the large intestine (colon) and rectum.

The causes of malnutrition in IBD patients are multifactorial and include (1) reduced food intake and avoidance of certain foods or food groups; (2) impaired micronutrient absorption (e.g., due to inflammation and small intestine resection surgery) and metabolism; (3) increased intestinal loss of nutrients (due to diarrhea and fistulas); and (4) drug-nutrient interactions that interfere with micronutrient absorption (114). IBD patients have been reported to experience deficiencies in multiple micronutrients; the below discussion includes the more commonly reported deficiencies that have clinical relevance. Deficiencies or inadequacies in other micronutrients not discussed may also be present in IBD patients.

Iron

Iron deficiency has been reported among 36%-90% of patients with IBD (115), likely due to inadequate dietary intake, impaired intestinal absorption of iron, and/or blood loss from ulcerated mucosa (114, 116). However, the exact prevalence is difficult to estimate because the typically reliable measures of iron status, like serum ferritin (an iron-storage protein that is an acute-phase reactive protein), are affected by inflammation. While other measures of iron status (transferrin saturation, soluble transferrin receptor) are often assessed in IBD patients, the diagnosis of iron deficiency is made using serum ferritin in the absence or presence of inflammation. In IBD patients with normal concentrations of C-reactive protein (CRP), a general biomarker of inflammation, the cutoff for iron deficiency is <30 μg/L ferritin; in active disease states, the cutoff for iron deficiency is <100 μg/L ferritin (117).

The most severe level of iron deficiency is iron-deficiency anemia (see the article on Iron). Anemia is quite common among IBD patients (estimated 17% prevalence; reviewed in 115), especially in those with Crohn’s disease where the prevalence ranged from 6.2% to 73.7% in one review (118). IBD disease activity has also been positively associated with the degree of anemia. Thus, it is prudent that iron status be monitored in IBD patients and, when necessary, treated with iron supplementation (115). Iron may also be administered parenterally (reviewed in 113).

Vitamin B12

Vitamin B12, complexed to intrinsic factor, is absorbed by a receptor-mediated process in the ileum — the distal section of the small intestine. Thus, vitamin B12 deficiency and its associated neurological consequences are a concern for IBD patients who have had ileocecal resections that remove the terminal ileum, as well as those who have ileal or ileocolonic disease — up to 55% of Crohn’s disease patients (119). In general, studies have not found ileal resections of <20 cm in length to be associated with vitamin B12 deficiency (reviewed in 119). Vitamin B12 status in IBD patients should be monitored by assessing blood concentration of methylmalonic acid, the specific indicator of vitamin B12 deficiency; assessing blood concentration of homocysteine may also be useful in assessing vitamin B12 status in IBD patients (120)

Folate

Folate deficiency may be more common among IBD patients than in the general population due to inadequate intake, small intestine resection, and/or nutrient-drug interactions. However, many studies on the association have employed serum folate concentration, an indicator of only recent dietary folate intake, to assess body folate status. Red blood cell folate concentration better reflects tissue folate stores and body folate status (87). A Canadian study in 121 IBD patients found that all subjects had red blood cell folate concentrations in the normal range (>320 nmol/L) (121).

Use of certain medications may cause folate deficiency. In particular, patients taking the pharmaceuticals sulfasalazine (an inhibitor of the reduced folate carrier that mediates cellular uptake, which is used to treat rheumatoid arthritis and ulcerative colitis) or methotrexate (a tetrahydrofolate reductase inhibitor and folate antagonist used to treat cancer, rheumatoid arthritis, and psoriasis) are at increased risk of folate deficiency (122, 123) and should follow the advice of their physician or pharmacist regarding supplemental folic or folinic acid.

Calcium

IBD patients are at a heightened risk of low bone mineral density, osteoporosis, and osteopenia (124). Adequate intake of calcium is critical throughout life to maintain bone health; dietary calcium intake is low in the US population, and calcium is considered a nutrient of public health concern (29). Calcium supplementation may be needed in IBD patients, especially those who have taken glucocorticoids/corticosteroids (114). However, the efficacy of calcium supplementation to prevent bone loss in IBD patients has not been examined in long-term intervention trials.    

Vitamin D

Individuals with IBD are at increased risk of vitamin D deficiency, especially patients with Crohn’s disease who have had small bowel resections (125). Ecologic studies have found a higher prevalence of IBD in populations residing in temperate climates compared to those living near the equator (reviewed in 126), suggesting that IBD may be linked to vitamin D inadequacy. Higher vitamin D intakes and predicted circulating levels have been associated with a reduced incidence of both Crohn’s disease and ulcerative colitis in a large cohort of 72,719 women (127). Moreover, a meta-analysis of six observational studies found an inverse association between vitamin D status and severity of Crohn’s disease (128).

Three studies have investigated whether supplemental vitamin D3 could benefit patients with Crohn’s disease, possibly through reducing intestinal inflammation. In one multicenter, double-blind, placebo-controlled study, the relapse rate in Crohn’s disease patients in remission after one year of treatment was significantly lower in those supplemented daily with 1,200 IU of vitamin D3 and 1,200 mg of calcium compared to those who received calcium alone (13% vs. 29%) (129). In a second pilot study, incremental daily doses of vitamin D3, from 1,000 IU up to 5,000 IU, were administrated over a 24-week period to 18 Crohn’s disease patients in order to achieve circulating 25-hydroxyvitamin D concentrations >40 ng/mL. Although half of the patients failed to achieve 40 ng/mL, the mean 25-hydroxyvitamin D concentration was raised to 45 ng/mL (from a baseline mean of 16 ng/mL), and the overall improvement in vitamin D status was associated with a significant decrease in disease severity as assessed by Crohn’s Disease Activity (CDAI) scores (130). In a three-month, randomized, double-blind, placebo-controlled trial in 27 Crohn’s disease patients in remission, daily supplementation with vitamin D3 (2,000 IU) improved vitamin D status but had no significant effect on intestinal permeability ('leaky gut') or measures of inflammation and disease activity (131). Yet, the study suggested that achieving serum 25-hydroxyvitamin D concentrations ≥30 ng/mL might help reduce intestinal inflammation and improve patient quality of life.

While additional studies are needed to confirm the therapeutic efficacy of vitamin D in IBD, vitamin D supplementation is commonly recommended to decrease disease activity and relapse and improve bone mineral density in IBD patients (126).

Regarding drug interactions, the Endocrine Society recommends monitoring vitamin D status of patients treated with glucocorticoids because these medications increase the catabolism of 25-hydroxyvitamin D (5). Vitamin D supplementation is typically recommended in IBD patients treated with corticosteroids.

Fat-soluble vitamins (vitamins A, D, E, and K)

Because the fat-soluble vitamins are absorbed in the ileum part of the small intestine, IBD patients, especially Crohn’s disease patients with ileal disease or ileal resection, are at increased risk of deficiency (126). Yet, evidence is lacking to support supplementation with fat-soluble nutrients in Crohn’s disease (126).

Zinc

Those with Crohn’s disease or ulcerative colitis appear to be at increased risk of zinc deficiency. Serum or plasma concentration of zinc is typically used in studies to assess zinc status, but measuring blood concentration is not a sensitive indicator of marginal deficiency. Blood concentrations of zinc are also known to be depressed in inflammatory states (132); therefore, studies assessing circulating concentrations of zinc in IBD patients are difficult to interpret. Persistent diarrhea contributes to zinc deficiency, and zinc supplementation may be needed in patients with significant and chronic diarrhea (126).

Kidney dialysis patients

Micronutrient insufficiencies are common in dialysis patients for several reasons, including reduced appetite, restricted diets (e.g., low-protein diets are often low in vitamins), and intradialytic losses. Medications may also interfere with nutrient absorption, and the uremia may alter metabolism. Moreover, the increased oxidative stress and chronic inflammation experienced by dialysis patients may require increased intake of certain micronutrients, such as antioxidants (e.g., vitamin C) (133). However, high doses of vitamins and minerals should be avoided, and patients should follow the advice of their physician and/or dietitian regarding diet and supplements (133-135).

Multivitamin supplements that are specifically formulated for dialysis patients are available; these usually contain higher amounts of B vitamins (thiamin, vitamin B6, folic acid, vitamin B12) and vitamin C to compensate for losses of these micronutrients during the dialysis procedure. Such multivitamins do not contain vitamin A because vitamin A status is increased in dialysis patients, and supplementation with this vitamin may lead to toxicity in this patient population (133). Certain B vitamins are needed to decrease blood concentrations of homocysteine in dialysis patients; elevated levels of homocysteine are a risk factor for cardiovascular disease and possibly dementia. Additionally, vitamin C intake is generally low in dialysis patients as low-potassium diets are often low in vitamin C. Vitamin D is another micronutrient of concern: Vitamin D status is reportedly low in dialysis patients, and patients with kidney disease have been traditionally given the active form of vitamin D (1,25-dihydroxyvitamin D) or a vitamin D analog (134). Mineral intake and status of dialysis patients should also be closely monitored as patients are at risk of both deficiency and excess of certain minerals and trace elements (135).

It is important for dialysis patients to discuss the use of any and all dietary supplements with their physician and/or dietitian; personal needs for supplemental micronutrients in dialysis patients are based on whether micronutrient intake from the physician-prescribed diet meets intake recommendations for these patients.

Those Taking Drugs Known to Interact with Nutrients

Certain medications can affect micronutrient status by altering nutrient absorption or utilization, and conversely, some micronutrients — from food or supplements — can alter the pharmacokinetics or pharmacodynamics of certain drugs (136, 137). Older individuals are especially susceptible to drug-nutrient interactions due to impaired metabolism, increased risk of malnutrition, and prevalent use of prescription drugs (138). In fact, 39% of US adults ≥65 years simultaneously use at least five different prescription drugs — this practice of polypharmacy increases their risk for drug-nutrient interactions (40). Physicians, pharmacists, and dietitians need to consider potential drug-nutrient interactions and recommend ways to prevent adverse effects (139). For medications that reduce absorption of a micronutrient, or vice versa, drug-nutrient interactions can often be avoided by separating food/supplement intake from medication use by two to three hours. Some medications should be taken with a meal to maximize drug bioavailability, while others should be taken in a fasting state (140) — refer to the patient information leaflet accompanying the medication or consult a pharmacist for specific instructions.

Although drug-nutrient interactions have not been systematically studied, there are a number of known interactions reported in the scientific literature. The list below is not meant to be comprehensive but includes some of the more common clinically relevant drug-nutrient interactions, especially because they may result in micronutrient inadequacy. For more comprehensive lists, see the suggested references. It is important to note, however, that specific criteria to label interactions as "clinically significant" have not been established, although a threshold of ≥20% change in the kinetic and/or dynamic parameter of the drug or nutrient has been proposed (141). Long-term use of the drug is often needed to reach such a threshold and for clinical symptoms of the drug-nutrient interaction to manifest (141). For information regarding drug interactions with a particular micronutrient, see the "Drug interactions" section in the separate articles on the individual vitamins and minerals (links included in Table 6 below), as well as the suggested references.

Antacids and gastric acid suppressants (proton-pump inhibitors and histamine [H2] receptor antagonists)

Antacids are commonly used to neutralize stomach acid and thus to treat heartburn and indigestion; proton-pump inhibitors (e.g., omeprazole and lansoprazole) and histamine (H2) receptor antagonists (e.g., cimetidine, famotidine, and ranitidine) are drugs that suppress stomach acid and used to treat peptic ulcer disease and gastroesophageal reflux disease. Use of these medications may alter nutrient absorption such that intake may need to be separated from food or supplemental intake by two to three hours.

Folate

Although data are limited, use of antacids or gastric acid suppressants might slightly impair absorption of folate from supplemental folic acid (142). Separating folic acid supplementation by drug use by three hours would avoid any potential interaction.

Vitamin B12

Proton-pump inhibitors markedly decrease stomach acid secretion required for the release of vitamin B12 from food but not from supplements. Long-term use of proton-pump inhibitors has been found to decrease blood vitamin B12 concentrations. However, vitamin B12 deficiency does not generally develop until after at least three years of continuous therapy (143, 144). Use of histamine (H2)-receptor antagonists has also been found to decrease the absorption of vitamin B12 from food. It is not clear whether the long-term use of H2-receptor antagonists could cause overt vitamin B12 deficiency (145, 146). Individuals taking drugs that inhibit gastric acid secretion should consider taking vitamin B12 in the form of a supplement because gastric acid is not required for its absorption.

Calcium

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 such 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 147).

Fluoride

Aluminum-containing antacids can decrease the absorption of fluoride. It is best to take these products two hours before or after fluoride supplements (148).

Iron

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.

Magnesium

Symptoms of magnesium toxicity, including nausea, vomiting, respiratory problems, and heart block, have occurred in people with impaired kidney function taking magnesium-containing antacids (140).

Manganese

Magnesium-containing antacids may decrease the absorption of manganese if taken together with manganese-containing foods or supplements (149).

Phosphorus

Aluminum-containing antacids reduce the absorption of dietary phosphorus by forming aluminum phosphate, which cannot be absorbed by the body. When consumed in high doses, aluminum-containing antacids can lead to abnormally low blood phosphorus concentration (hypophosphatemia), as well as aggravate phosphorus deficiency due to other causes (150).

The reduction of stomach acidity by proton-pump inhibitors may also limit the efficacy of phosphate-binder therapy in patients with kidney failure (151).

Antibiotics

A number of antibiotics can affect micronutrient absorption, or conversely, certain micronutrients — from food or supplements — may affect absorption or efficacy of some antibiotics. Some antibiotics should be taken with food, while other antibiotics should be taken between meals (152); it is important to refer to the medication instructions and/or consult a pharmacist. Table 4 lists some of the known micronutrient-antibiotic interactions; however, this list is not comprehensive.

Table 4. Interactions between Antibiotics and Nutrients
Antibiotic Nutrient
Interaction Notes Reference
 Broad-spectrum antibiotics Biotin Prolonged use may decrease biotin synthesis by intestinal bacteria Contribution of bacterial synthesis to vitamin status is unclear 153
 Broad-spectrum antibiotics  Vitamin K Prolonged use may decrease vitamin K2 (menaquinone) synthesis by intestinal bacteria and lower vitamin K absorption   

Vitamin K1 (phylloquinone) is the major dietary form of vitamin K in most diets

 140
 Cephalosporins Vitamin K  May decrease vitamin K recycling by inhibiting vitamin K epoxide reductase in the liver  Observed only in vitamin K-deficient individuals   140
 Tetracycline, quinolone class antibiotics Calcium   Calcium from food or supplements may decrease absorption of the antibiotic Separate antibiotic dose from calcium-rich food or supplements by 2 hours before or 4-6 hours after calcium  153
 Penicillamine, tetracycline, quinolone class antibiotics Iron  Concomitant intake may decrease drug absorption  Separate iron supplements from antibiotics by at least 2 hours  149
 Nitrofurantoin, penicillamine, tetracycline, quinolone class antibiotics  Magnesium Concomitant intake may decrease both drug and mineral absorption  Separate antibiotic dose from magnesium-rich food or supplements by 2 hours or 4-6 hours after magnesium  149, 153, 154
 Tetracycline Manganese  Concomitant intake may decrease manganese absorption    149
 Penicillamine, tetracycline, quinolone class antibiotics Zinc   Concomitant intake may decrease both drug and mineral absorption Separate antibiotic dose from zinc supplements by at least 2 hours  149, 153

Anticoagulation drugs

Vitamin K

Some oral anticoagulants, such as warfarin (Coumadin, Jantoven), inhibit coagulation by antagonizing the action of vitamin K. Warfarin prevents recycling of vitamin K by blocking the enzyme, vitamin K oxidoreductase, thereby creating a functional vitamin K deficiency. Low dietary intakes of vitamin K can cause an unstable international normalized ratio (INR) (155). Additionally, very high dietary (>150 µg/day) (156) or supplemental intake of vitamin K may compromise the anticoagulant effect of warfarin. Daily phylloquinone (vitamin K1) supplements of up to 100 µg are considered safe for patients taking warfarin, but therapeutic anticoagulant stability may be undermined by daily doses of menaquinone-7 (a form of vitamin K2) as low as 10 to 20 µg (157).

It is generally recommended that individuals using warfarin try to consume the adequate intake for vitamin K (90 µg/day for women and 120 µg/day for men) and avoid large fluctuations in vitamin K intake that might interfere with the adjustment of their anticoagulant dose (155).

Vitamin E

Large supplemental doses of vitamin E may inhibit vitamin K-dependent carboxylase activity and interfere with the coagulation cascade (158). Thus, the use of vitamin E supplements may increase the risk of bleeding in individuals taking warfarin and other anticoagulant drugs, as well as antiplatelet drugs and non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen, and others.

Vitamin C

There is some evidence from case reports, though limited and controversial, that large oral doses of vitamin C may inhibit the action of warfarin (159, 160), requiring an increase in warfarin dose to maintain its effectiveness. It seems reasonable for individuals taking oral anticoagulants to limit their vitamin C intake to 1 gram/day and have their prothrombin time monitored by the clinician following their anticoagulant therapy.

Iodine

Pharmacologic doses of potassium iodide may decrease the anticoagulant effect of warfarin (161).

Other nutrients and dietary compounds

High intakes of other nutrients or phytochemicals may affect platelet aggregation and coagulation. See Table 5 for links to the "Drug interactions" section in articles on individual nutrients, phytochemicals, or foods; this list is not meant to be comprehensive. See the Natural Medicines database or the text, PDR for Nutritional Supplements (149), for more detailed information.

Table 5. Hyperlinks to Discussions of Nutrient/Dietary Compound Interactions with Anticoagulants
Nutrient or Dietary Factor
 Coenzyme Q10
 Curcumin
 Essential Fatty Acids
 Flavonoids
 Garlic
 Resveratrol
 Soy Protein
 Green Tea

Anticonvulsants

Biotin

Individuals on long-term anticonvulsant (anti-seizure) therapy, including primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Carbatrol, Tegretol), have been found to have reduced blood biotin concentrations, as well as an increased urinary excretion of organic acids (e.g., 3-hydroxyisovaleric acid) indicative of decreased carboxylase activity (162). Potential mechanisms for these effects may include inhibition of biotin intestinal absorption, decreased renal reabsorption, and increased biotin catabolism (162). Use of the anticonvulsant valproic acid in children has resulted in hair loss reversed by biotin supplementation (163).

Folate

The anticonvulsant, phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anticonvulsants, phenytoin, phenobarbital, and primidone (164). However, few studies controlled for differences in dietary folate intake between anticonvulsant users and nonusers.

Thiamin

Reduced blood concentrations of thiamin have been reported in individuals with seizure disorders (epilepsy) taking the anticonvulsant medication, phenytoin, for long periods of time (165).

Vitamin B6

High doses of vitamin B6 have been found to decrease the efficacy of two anticonvulsants, phenobarbital and phenytoin (166).

Vitamin D

The following anticonvulsant medications increase the metabolism of vitamin D and may decrease serum 25-hydroxyvitamin D concentrations: phenytoin, phenobarbital, carbamazepine, and primidone (167).

Vitamin E

Use of the anticonvulsant drugs, phenobarbital, phenytoin, or carbamazepine, may lower plasma concentrations of vitamin E (168).

Vitamin K

The prescription of anticonvulsants (phenytoin, phenobarbital) to pregnant or breast-feeding women may place the newborn at increased risk of vitamin K deficiency (169).

Selenium

Use of the anticonvulsant drug, valproic acid, may lower circulating selenium concentrations (170).

Bisphosphonates

Several micronutrients, including calcium, iron, magnesium, and zinc, can decrease absorption and thus efficacy of bisphosphonates (e.g., alendronate and etidronate), drugs used to treat osteoporosis (149). It may be best to take bisphosphonates at least two hours before or four to six hours after supplemental micronutrients or mineral-rich foods.

Diuretics

Thiamin

Through increasing urinary flow, diuretics may prevent reabsorption of thiamin by the kidneys and increase its excretion in the urine (171). Thus, the risk of thiamin deficiency is increased in diuretic-treated patients with marginal thiamin intake and in individuals receiving long-term, diuretic therapy.

Calcium

Use of thiazide diuretics (e.g., hydrochlorothiazide, chlorothiazide) increases the risk of developing hypercalcemia due to increased reabsorption of calcium in the kidneys (140).

Magnesium

Prolonged use of some diuretics may increase urinary magnesium excretion and result in magnesium depletion (140).

Phosphorus

Potassium-sparing diuretics (e.g., triamterene, amiloride, and spirononlactone) taken together with phosphorus supplements may result in hyperkalemia (high blood concentrations of potassium) (150).

Potassium

Loop and thiazide diuretics increase urinary excretion of potassium and may thus increase the risk of hypokalemia (low blood concentrations of potassium). Conversely, potassium-sparing diuretics (e.g., triamterene, amiloride, and spirononlactone) may cause hyperkalemia (high blood concentrations of potassium) (140), especially if combined with potassium supplementation (149).

Sodium

Use of loop or thiazide diuretics may increase the risk of hyponatremia (abnormally low blood concentrations of sodium) (172).

Zinc

Prolonged use of some diuretics may increase urinary zinc excretion and result in zinc depletion (140).

3-Hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins)

Nicotinic acid

Co-administration of nicotinic acid with a lipid-lowering HMG-CoA reductase inhibitor (i.e., a statin) may increase the risk of rhabdomyolysis (173), a condition in which muscle cells are broken down, releasing enzymes and electrolytes into the blood, and sometimes resulting in kidney failure (174). Rhabdomyolysis is relatively uncommon but increased in those who take HMG-CoA reductase inhibitors (174).

Furanocoumarins in citrus fruit like grapefruit

Some HMG-CoA reductase inhibitors, including atorvastatin, lovastatin, and simvastatin, are metabolized by cytochrome P450 (CYP) 3A4 enzymes. Consumption of grapefruit inhibits intestinal CYP3A4; the compounds responsible for this effect are thought to be furanocoumarins, particularly dihydroxybergamottin. Drugs with very low bioavailability like HMG-CoA reductase inhibitors are more likely to be toxic when CYP3A4 activity is inhibited; thus, for the HMG-CoA reductase inhibitors that utilize CYP3A4, consuming grapefruit increases the risk of rhabdomyolysis and other adverse effects of the drug. One grapefruit or as little as 200 mL (7 fluid ounces) of grapefruit juice have been found to irreversibly inhibit intestinal CYP3A4 (175). All forms of the fruit — freshly squeezed juice, frozen concentrate, or whole fruit — can potentially affect the activity of CYP3A4. Some varieties of other citrus fruit (Seville oranges, limes, and pomelos) contain furanocoumarins and can also interfere with CYP3A4 activity (see the article on Flavonoids).

Methotrexate

Methotrexate is a folate antagonist used to treat a number of diseases, including cancer, rheumatoid arthritis, and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and supplementation with folic or folinic acid (leucovorin) is used to reduce the antifolate toxicity (122, 123).

Nitrous oxide

Nitrous oxide, a commonly used anesthetic, oxidizes and inactivates vitamin B12, thus inhibiting both of the vitamin B12-dependent enzymes, and can produce many of the clinical features of vitamin B12 deficiency, such as megaloblastic anemia or neuropathy (43, 176). Some think that vitamin B12 deficiency should be ruled out before using nitrous oxide (43).

Multiple drugs interact with compounds in grapefruit

While not considered nutrients, furanocoumarins — either from food (e.g., citrus fruit) or supplements — an interfere with the metabolism of various medications, including drugs transported by the ATP-binding cassette (ABC) transporters, anticoagulant and antiplatelet drugs, and drugs metabolized by cytochrome P450 3A4 (i.e., approximately half of all drugs on the market) (177). For information on such interactions, see the article on Flavonoids.

Table 6. Hyperlinks to Articles on Individual Nutrients that Discuss Some Medication Interactions
Vitamins Minerals Other Nutrients
 Biotin Calcium
 Folate Chromium Essential Fatty Acids
 Niacin Copper Fiber
 Pantothenic Acid Fluoride  
 Riboflavin Iodine  
 Thiamin Iron  
 Vitamin A Magnesium  
 Vitamin B6 Manganese  
 Vitamin B12 Molybdenum  
 Vitamin C Phosphorus  
 Vitamin D Potassium  
 Vitamin E Selenium  
 Vitamin K Sodium (regarding deficiency and safety)  
HIGHLIGHT: FURTHER READING AND REFERENCES REGARDING DRUG-NUTRIENT INTERACTIONS:

  • Chan LN. Drug-nutrient interactions. JPEN J Parenter Enteral Nutr. 2013;37(4):450-459. (141)
  • Chan LN. Drug-nutrient interactions. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Philadelphia: Lippincott Williams & Wilkins; 2014:1440-1452. (137)
  • Conner KG. Drug-nutrient interactions. Encyclopedia of Human Nutrition. 2013;2:90-98. (136)
  • Hendler SS, Rorvik D. PDR for Nutritional Supplements. 2nd ed. Montvale: Physicians' Desk Reference Inc.; 2008. (149)
  • Utermohlen V. Diet, nutrition, and drug interactions. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 1999:1619-1641. (140)

Nutrient-Nutrient Interactions

Nutrients work together in the body to carry out its essential functions. However, a nutrient can interfere with the metabolism (i.e., intestinal absorption, utilization, excretion) of another nutrient — nutrient-nutrient interactions are more likely to occur at supplemental versus dietary intake levels (178). Table 7 lists some documented nutrient-nutrient interactions; more information on these interactions can be found in the individual nutrient articles (follow the hyperlinks in the table).

 

Table 7. Some Known Nutrient-Nutrient Interactions, with Hyperlinks to Articles with More In-depth Discussions and References
Nutrient Nutrient Interaction
 Biotin Pantothenic Acid
High doses of pantothenic acid may compete with biotin for absorption
 Folate Riboflavin Works synergistically with folate to lower blood concentrations of homocysteine
Vitamin B6 Along with other B vitamins, regulates blood concentrations of homocysteine
Vitamin B12 Works synergistically with folate to lower blood concentrations of homocysteine
Vitamin C Vitamin C may improve folate and folic acid bioavailability
 Pantothenic Acid Biotin High doses of pantothenic acid may compete with biotin for absorption
 Riboflavin B-complex vitamins Flavoproteins are involved in the metabolism of folate, vitamin B6, and niacin; thus, severe riboflavin deficiency may result in deficiency of other B vitamins. Riboflavin works synergistically with folate to lower blood concentrations of homocysteine.
Iron Vitamin A deficiency may exacerbate iron deficiency
 Vitamin A Vitamin K High doses of vitamin A may decrease vitamin K absorption
Iodine Vitamin A deficiency may exacerbate the effects of iodine deficiency
Iron Vitamin A deficiency may exacerbate iron deficiency 
Zinc Zinc deficiency may interfere with vitamin A metabolism
 Vitamin B6 Folate Along with other B vitamins, regulates blood concentrations of homocysteine
 Riboflavin Along with other B vitamins, may regulate blood concentrations of homocysteine
 Vitamin B12 Along with other B vitamins, regulates blood concentrations of homocysteine
 Vitamin B12  Folate Works synergistically with vitamin B12 to lower blood concentrations of homocysteine
Riboflavin  Works synergistically with vitamin B12 to lower blood concentrations of homocysteine
Vitamin B6  Works synergistically with vitamin B12 to lower blood concentrations of homocysteine
 Vitamin C  Folate Vitamin C may improve folate and folic acid bioavailability
Vitamin E Vitamin C can regenerate the antioxidant capacity of α-tocopherol
Chromium Concomitant intake may enhance the absorption of chromium
Copper High-dose vitamin C supplementation may impair ceruloplasmin oxidase activity
Iron Concomitant intake increases the absorption of nonheme iron
Selenium Selenium-dependent enzymes catalyze the regeneration of vitamin C and function synergistically in antioxidant defense
 Vitamin D
  
Calcium  Active form of vitamin D (calcitriol) increases intestinal calcium absorption and decreases urinary calcium excretion
Magnesium  Active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium
 Phosphorus Active form of vitamin D (calcitriol) increases intestinal absorption of phosphorus
 Vitamin E Vitamin C  Vitamin C can regenerate the antioxidant capacity of α-tocopherol
Vitamin K High doses of vitamin E may inhibit activity of vitamin K-dependent enzymes, interfere with coagulation, and result in functional vitamin K deficiency
Selenium Selenium-dependent enzymes function synergistically in antioxidant defense
 Vitamin K Vitamin A High doses of vitamin A may decrease vitamin K absorption
Vitamin E High doses of vitamin E may inhibit activity of vitamin K-dependent enzymes, interfere with coagulation, and result in functional vitamin K deficiency
 Calcium Vitamin D Active form of vitamin D (calcitriol) increases intestinal calcium absorption and decreases urinary calcium excretion
Fluoride Concomitant intake of calcium may decrease absorption of sodium fluoride
Iron Concomitant intake decreases heme and nonheme iron absorption; iron and calcium supplements should not be taken together
Manganese Concomitant intake may decrease manganese absorption
Phosphorus High intakes of phosphorus may increase urinary calcium excretion
Protein Increases urinary calcium excretion
Sodium Increases urinary calcium excretion
 Chromium Vitamin C Vitamin C may enhance chromium bioavailability
Carbohydrates Diets high in simple sugars (vs. complex carbohydrates) may increase chromium excretion
 Copper Vitamin C High-dose vitamin C supplementation may impair ceruloplasmin oxidase activity
Iron Copper deficiency may interfere with iron transport; high-iron formula may decrease infant copper absorption
Zinc High supplemental zinc intakes may cause copper deficiency by decreasing intestinal absorption
 Fluoride Calcium  Concomitant intake of calcium may decrease absorption of sodium fluoride
Magnesium Concomitant intake may decrease fluoride absorption
 Iodine Vitamin A Vitamin A deficiency may exacerbate the effects of iodine deficiency
Iron Severe iron-deficiency anemia may impair thyroid metabolism and exacerbate the effects of iodine deficiency
Selenium Selenium deficiency may exacerbate the effects of iodine deficiency
 Iron Riboflavin  Riboflavin deficiency may impair iron absorption or utilization
Vitamin A Vitamin A deficiency may exacerbate iron deficiency
Vitamin C Concomitant intake increases the absorption of nonheme iron
Calcium Concomitant intake decreases heme and nonheme iron absorption; iron and calcium supplements should not be taken together
Copper Copper deficiency may interfere with iron transport; high-iron formula may decrease infant copper absorption
Iodine Severe iron-deficiency anemia may impair thyroid metabolism and exacerbate the effects of iodine deficiency
Manganese Manganese absorption is increased in iron-deficient individuals; concomitant iron intake may decrease manganese absorption
Zinc Zinc deficiency may exacerbate the effects of iron deficiency; high supplemental doses of iron may decrease zinc absorption
 Magnesium Vitamin D Active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium
Fluoride Concomitant intake may decrease fluoride absorption
Manganese Supplemental magnesium may decrease manganese absorption
 Zinc High supplemental zinc intake may decrease magnesium absorption
 Manganese Calcium Concomitant intake may decrease manganese absorption
Iron Manganese absorption is increased in iron-deficient individuals; concomitant iron intake may decrease manganese absorption
Magnesium Supplemental magnesium may decrease manganese absorption
 Phosphorus Vitamin D Active form of vitamin D (calcitriol) increases intestinal absorption of phosphorus
Calcium High intakes of phosphorus may increase urinary calcium excretion
Potassium Taking potassium supplements together with phosphates may cause hyperkalemia
 Potassium Phosphorus Taking phosphates together with potassium supplements may cause hyperkalemia
 Selenium Vitamin C Selenium-dependent enzymes catalyze the regeneration of vitamin C and function synergistically in antioxidant defense
Vitamin E Selenium-dependent enzymes function synergistically in antioxidant defense
Iodine Selenium deficiency may exacerbate the effects of iodine deficiency
 Sodium Calcium Increases urinary calcium excretion
 Zinc Vitamin A Zinc deficiency may interfere with vitamin A metabolism
Copper High supplemental zinc intakes may cause copper deficiency by decreasing intestinal absorption
Iron Zinc deficiency may exacerbate the effects of iron deficiency; high supplemental doses of iron may decrease zinc absorption
Magnesium High supplemental zinc intake may decrease magnesium absorption

 


Authors and Reviewers

Written in January 2018 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2018 by:
Balz Frei, Ph.D.
Former Director, Linus Pauling Institute
Distinguished Professor Emeritus, Dept. of Biochemistry and Biophysics
Oregon State University

The writing of this article was supported by a grant from Pfizer Inc.

Copyright 2018  Linus Pauling Institute


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