Nutrition: Micronutrient Intake, Imbalances, and Interventions

Issues of Concern

Micronutrients are crucial for normal metabolism and tissue function. Both deficient and excess intake may result in adverse health outcomes.[3] Micronutrient requirements should be met through a healthy, varied diet; supplementation should be reserved for those with clinical indications such as demonstrated deficiency or at-risk populations. It is also essential to identify nutrient inadequacies (where the consumption falls below intake recommendations while staying above the deficiency level) to prevent the development of clinical nutrient deficiencies that impair the body's ability to perform everyday functions.[3]

Fat-Soluble Vitamins

Vitamin A (retinol): Vitamin A deficiency continues to be a public health concern, especially in developing countries and populations where the diet consists of rice, cassava, or white potato, with a low content of meat and colored vegetables.[8] While rare in developed countries, it can be seen in patients with malabsorptive syndromes.[10] Vitamin A deficiency can cause xerophthalmia, which first manifests as night blindness and, if untreated, may progress to keratinization of the conjunctival epithelium (bitot spots), xerosis, and blindness.[9] Additionally, both subclinical and clinical deficiency have been associated with recurrent infections and increased all-cause mortality.[9][10]

While significantly less frequent, excess intake of vitamin A can lead to hypervitaminosis, which can manifest with hypercalcemia, congenital disabilities (teratogenicity), bone/joint pain, cheilitis, stomatitis, conjunctivitis, desquamation, alopecia, headache, diarrhea, nausea, vomiting, fever, and liver dysfunction.[8]

Vitamin D (cholecalciferol): Vitamin D deficiency is a public health issue worldwide. Approximately 50% of the population has vitamin D insufficiency (suboptimal levels), and about 1 billion people have vitamin D deficiency.[12] Vitamin D deficiency is defined as a 25-hydroxyvitamin D below 20 ng/mL, and vitamin D insufficiency as a 25-hydroxyvitamin D of 21 to 29 ng/ml.[13] Screening is recommended in individuals at risk of deficiency.[13]

Insufficient vitamin D levels have been associated with osteoporosis, risk of falls, and fragility fractures, as well as cancer, cardiovascular disease, diabetes, depression, and autoimmune conditions.[12] Vitamin D deficiency may result in hypocalcemia and hyperparathyroidism, which can cause muscle weakness, bone pain, fatigue, rickets in children, and osteomalacia in adults.[11][12]

Vitamin D toxicity is rare but can occur when 25-hydroxyvitamin D levels exceed 100 to 150 ng/mL and present with hypercalcemia, constipation, polydipsia, polyuria, and confusion.[14]

Vitamin E (tocopherol): Vitamin E deficiency is rare and tends to occur from fat absorption and metabolism disorders, such as cystic fibrosis, Crohn disease, and abetalipoproteinemia.[16] Vitamin E deficiency manifests with neuromuscular symptoms, including peripheral neuropathy, gait abnormalities, loss of proprioceptive and vibratory sense, and hemolysis.[15]

As with deficiency, vitamin E toxicity is rare but may occur with very high doses of vitamin E supplements. Hypervitaminosis E is considered less toxic than hypervitaminosis from other fat-soluble vitamins and has been associated with an increase in all-cause mortality and a reduction in the absorption of other fat-soluble vitamins.[15]

Vitamin K (phylloquinone): Clinical vitamin deficiency is uncommon in healthy adults but can be seen in patients with malabsorption syndromes and those treated with medications that interfere with the metabolism of vitamin K.[18] Vitamin K deficiency bleeding is common in newborns due to vitamin K not being efficiently transported across the placenta. Vitamin K deficiency bleeding tends to present with intracranial, intrathoracic, and intraabdominal bleeding.[19] For this reason, prophylaxis with 1 mg of vitamin K1 via intramuscular injection is recommended at birth for all newborns.

No known toxicity is associated with high doses of vitamin K1 or K2.[18] However, caution should be taken in neonates, patients with vitamin k–dependent anticoagulation, or hypersensitivity to vitamin K.[18]

Water-Soluble Vitamins

Vitamin B1 (thiamine): Vitamin B1 deficiency is relatively uncommon in the healthy population and commonly presents in patients with alcohol use disorder, acquired immunodeficiency syndrome (AIDS), and malnutrition. It can also be seen in patients with older age, diabetes, hyperthyroidism, and postbariatric surgery.[21] Thiamine deficiency leads to adenosine triphosphate (ATP) depletion, compromising tissues dependent on aerobic metabolism, with the brain, nerves, and heart being particularly susceptible.[7] When thiamine deficiency compromises cardiac function (wet beriberi), it manifests with high-output heart failure, dyspnea on exertion, and edema.

When the nervous system is affected by vitamin B1 deficiency (dry beriberi), it presents with polyneuritis and muscle wasting.[7] Additionally, thiamine deficiency may damage the brain's mammillary bodies and the thalamus's medial dorsal nucleus, causing Wernicke encephalopathy, which classically manifests with confusion, ophthalmoplegia, and ataxia. If symptoms accompany memory loss and personality changes, Wernicke-Korsakoff syndrome is treated with thiamine followed by intravenous glucose.

Thiamin supplementation is considered safe, but supplementation can cause nausea, urticaria, ataxia, and impaired gut motility in some patients.[21]

Vitamin B2 (riboflavin): Vitamin B2 deficiency is widespread in children in developing countries, where milk and meat intake is low, and in adolescent girls, who have increased metabolic demands. Riboflavin deficiency can also be seen in older individuals and patients with cancer, eating disorders, or malabsorption syndromes.[22] Manifestations of vitamin B2 deficiency include cheilitis, seborrheic dermatitis, conjunctivitis, sore throat, and fatigue.

Riboflavin is considered safe, and toxicity is rare, but caution is recommended in pregnant women. Vitamin B2 supplementation may also cause benign changes in urine color (yellow-orange discoloration).[7][22]

Vitamin B3 (niacin): Niacin deficiency is rare in developed countries but can be seen in patients with eating disorders, corn-based diets, chronic alcoholism, and malabsorptive syndromes.[23] Clinical vitamin B3 deficiency is known as pellagra and classically presents with the "4 D's", which are diarrhea, dermatitis, dementia, and death (if untreated).[23] Niacin is considered safe, but supplementation may cause skin flushing and itching, affecting patient adherence to supplementation regimens.[23]

Vitamin B5 (pantothenic acid): Pantothenic acid deficiency is rare but can sometimes be seen in patients with severe malnutrition. Specific manifestations of deficiency can be hard to characterize, as vitamin B5 deficiency is commonly seen with concurrent deficiencies in other micronutrients.[24] Reported consequences of vitamin B5 deficiency include dermatitis, enteritis, alopecia, fatigue, headache, muscle cramps, paresthesia, and impaired muscle coordination.[7][24] Vitamin B5 is considered safe, and toxicity has not been reported.[24]

Vitamin B6 (pyridoxine): Pyridoxine deficiency rarely results from inadequate intake and tends to be seen in patients with compromised renal function, autoimmune diseases, alcohol abuse, and with the use of certain medications such as valproic acid, phenytoin, carbamazepine, hydralazine, and theophylline. Vitamin B6 deficiency presents with seborrheic dermatitis, sideroblastic anemia, glossitis, convulsions, peripheral neuropathy, confusion, and impaired immune function.[7][25]

Pyridoxine hypervitaminosis may occur in cases of excess supplementation, particularly when intake exceeds 1 g/d, and may result in sensory neuropathy, testicular atrophy, and reduced sperm motility. Consequences of excess intake usually resolve after supplementation cessation.[25]

Vitamin B7 (biotin): Biotin deficiency is rare in individuals with a regular diet. It is usually reported in patients with inborn errors of metabolism, in association with certain medications (isotretinoin, as well as some antiepileptics and antibiotics), or with large intakes of raw egg whites, where intact avidin binds biotin and reduces its absorption.[27]

Vitamin B7 deficiency can manifest with alopecia, periorificial dermatitis, muscle pain, anemia, depression, and neurological symptoms such as hypotonia, seizures, paresthesia, and developmental delay.[7][27] Biotin can be excreted in the urine, making toxicity rare; however, a biotin overdose may cause insomnia, excessive thirst, and increased urination.[26]

Vitamin B9 (folate): Folate deficiency is common in people with a history of chronic alcoholism, malabsorption disorders, hemolytic anemia, or pregnancy.[7][28] Isolated folate deficiency can result in macrocytic megaloblastic anemia, which can be differentiated from a vitamin B12 deficiency by normal methylmalonic acid levels (versus elevated levels in vitamin B12 deficiency) and the absence of neurological symptoms.[7][28]

In pregnant women, folate deficiency can result in neural tube defects.[7] For this reason, supplementation with 400 to 800 mcg/d of folate is recommended in all women of reproductive age, with higher doses recommended in women with a history of neural tube defects in previous pregnancies or women who take certain medications, such as antiepileptics. For best results, supplementation should begin 5 to 6 months before pregnancy.[28] As with other water-soluble vitamins, toxicity is uncommon due to the lack of significant storage in the body.[28]

Vitamin B12 (cobalamin): Unlike other water-soluble vitamins, excess vitamin B12 can be stored in the liver, decreasing the risk of deficiency. However, if hepatic stores are depleted, a deficiency will develop.[29] Cobalamin deficiency can result from impaired absorption, which can be the result of autoimmune conditions, such as pernicious anemia or other malabsorptive states such as postbariatric surgery, infection with Diphyllobothrium latum, or inflammation from celiac disease. Additionally, deficiency can result from insufficient intake, as seen in some elderly patients and those with strict vegan diets.[29][31]

Vitamin B12 deficiency presents macrocytic, megaloblastic anemia, similar to folate deficiency. However, isolated vitamin B12 deficiency can be distinguished by elevated serum methylmalonic acid levels (standard in the setting of folate deficiency) and neurologic symptoms, which do not occur in isolated folate deficiency.[7]

Preventing or treating cobalamin deficiency requires special considerations regarding individual risk factors. In those where oral vitamin B12 cannot be absorbed, eg, patients with pernicious anemia or postbariatric surgery, parenteral B12 should be administered.[29]

While hepatic cobalamin stores can last months or years, vitamin B12 supplementation is recommended in those who do not consume foods of animal origin, eg, strict vegans or vegetarians with limited egg or dairy intake). In this setting, oral supplementation is considered adequate.[29][30][31]

Vitamin C (ascorbic acid): Vitamin C deficiency is rare in individuals with a healthy diet. Still, it can be seen in people at risk of inadequate intake, such as older patients, those with alcohol use disorder, anorexia, food allergies, tobacco use, kidney disease, or who take certain medications, eg, aspirin, indomethacin, contraceptives, tetracyclines, and corticosteroids.[32]

When vitamin C deficiency occurs, it impairs collagen formation in the skin, mucous membranes, blood vessels, and bone.[32] Scurvy is the most classical form of vitamin C deficiency, developing 1 to 3 months after a deficient vitamin C intake.[32] Scurvy manifests with fatigue, weight loss, arthralgias, diarrhea, swollen or bleeding gums, loss of teeth, easy bleeding, and poor wound healing.[7][32]

Vitamin C is safe and is not thought to cause toxicity at high intakes; however, supplementation may cause headaches, flushing, nausea, or vomiting. Additionally, high doses of vitamin C can acidify the urine and increase the risk of kidney stones.[32]

Minerals

Calcium: Inadequate calcium intake is common worldwide and linked to loss of bone mass, pregnancy complications, cancers, and cardiovascular disease; however, there is no consensus on what constitutes calcium deficiency.[38]

Toxicity from dietary calcium is rare, but high intakes (from supplementation) have been linked to a higher risk of kidney stones and myocardial infarction; however, this remains controversial. The upper limit for calcium intake is 2500 mg/d for people aged 19 to 50 years and 2000 mg/d for people 50 years and older.[39]

Phosphorus: Acute reductions in phosphorus intake can result in bone demineralization. Chronic phosphorus deprivation may result in muscle atrophy and weakness. Severe hypophosphatemia manifests with nervous system dysfunction, weakness, and tremors.[40]

Phosphorus toxicity from dietary intake is rare; chronic excess intake has been linked to endothelial dysfunction, calcification, and cardiovascular disease.[40]

Potassium: Potassium deficiency is rare but also considered a shortfall nutrient because most people have a suboptimal intake. Suboptimal potassium intake has been associated with higher blood pressure and cardiovascular disease.[34][41]

Sodium: Chronic, inappropriately high, and low sodium intakes have been shown to have a strong association with adverse health outcomes.[42] However, sodium balance is well-regulated, and acute changes in dietary intake are unlikely to impact serum sodium levels and result in clinical excess or deficiency in healthy people. Chronic low intakes can result in hyponatremia, especially in older patients, due to medications and age-related changes in osmolality and sodium regulation.[43]

Chronic high intakes have been associated with high blood pressure, especially in people with higher sodium sensitivity or a low potassium intake. It is important to note that processed foods (rather than table salt) are the main contributor to high sodium intake in most people.[42]

Chloride: Chloride intake is closely associated with that of sodium, making dietary chloride deficiency rare; however, chloride deficiency has been reported in infants fed with chloride-deficient milk, presenting with hypokalemic metabolic alkalosis, gastrointestinal symptoms, growth failure, lethargy, irritability, anorexia, and weakness.[44] Chloride toxicity from excess intake is uncommon, and an upper tolerable intake has not been established.[44]

Magnesium: Magnesium deficiency is common, and it is estimated that half of the US population has a suboptimal magnesium intake. Magnesium inadequacy has been linked to cardiovascular, metabolic, respiratory, and psychiatric conditions. Symptoms of clinical magnesium deficiency are unspecific, eg, muscle spasms and arrhythmias, and can be easily confounded with other nutrient deficiencies.[45]

Magnesium toxicity is rare but can be caused by excess supplement intake, magnesium-containing medications, and renal disease. When present, hypermagnesemia presents with hypotension, bradycardia, and coma.[45]

Iron: Iron deficiency is the most common micronutrient deficiency around the world and significantly compromises oxygen delivery and impairs immune and endocrine function.[1] Iron deficiency usually results from insufficient intake, especially in people with increased needs, eg, infancy, menstruation, and pregnancy. The main manifestation of iron deficiency is microcytic hypochromic anemia.[1][33]

Iron toxicity from dietary intake is rare in healthy individuals but can occur in the setting of excess supplement intake. In the setting of iron deficiency, educating patients on common adverse effects of iron supplementation, primarily gastrointestinal discomfort such as heartburn, diarrhea, constipation, nausea, or vomiting, is essential.[46]

Zinc: Zinc deficiency is common, especially in developing countries, but also in older adults and the setting of chronic illness. Zinc deficiency can manifest with hypogonadism, impaired taste, eczematous rash, cheilitis, brittle hair, and impaired immune function.[47]

Toxicity is rare but can occur with excess supplementation. Additionally, excess Zinc supplementation can impair copper absorption and result in copper deficiency. Common adverse effects of zinc supplementation include nausea and vomiting.[47]

Copper: Copper deficiency and toxicity from dietary intake are rare in the general population but can be seen in individuals treated with bariatric surgery or certain genetic diseases.[33][48] Copper deficiency in infancy can impair bone, cardiovascular, immune, and neurologic development. In adulthood, copper deficiency has been associated with impaired cholesterol metabolism.[48]

Copper toxicity is unlikely to result from dietary excess; however, high serum levels of copper have been known to increase oxidative damage and cell death and have been linked to cardiovascular disease.[48]

Manganese: Manganese deficiency is extremely rare and has not been reported in nonexperimental settings. Additionally, toxicity from dietary exposure has not been reported.[36]

Selenium: Unlike most micronutrients, selenium has a narrow range of safety, and low and high levels have been associated with adverse health outcomes.[49] Selenium deficiency has been associated with impaired immune function, cognitive decline, infertility, impaired fetal development, thyroid dysfunction, and increased mortality. Selenium deficiency is more commonly seen in the population than at the individual level.[50]

Selenium toxicity is strongly influenced by the chemical form of selenium, with inorganic forms showing higher toxicity and vice versa. Acute selenium poisoning can present with hypotension, tachycardia, tremor, and muscle spasms.[49] On the other hand, chronic toxicity can cause hair loss, fingernail fragility, skin rash, joint pain, increased risk of type 2 diabetes, and a characteristic garlic-breath odor due to the concentration of dimethyl selenide in exhaled breath.[49]

Molybdenum: Molybdenum deficiency due to dietary intake has not been reported, and its potential for toxicity is considered low. However, extremely high molybdenum intakes have been reported in places with unusually high soil concentrations, resulting in joint pain, gout-like symptoms, and hyperuricosuria.[37]

Iodine: Extremes of iodine intake have important consequences for thyroid function. Iodine deficiency continues to be common worldwide and is an important cause of goiter, impaired neurocognitive development, hypothyroidism, and congenital abnormalities.[1][51]

On the other hand, acute iodine toxicity can cause abdominal pain, nausea, vomiting, diarrhea, and cardiovascular symptoms. Chronic toxicity has been associated with increased thyroiditis, hypothyroidism, and hyperthyroidism.[51]

Food Quality and Nutrient Sources

Ensuring the intake of essential nutrients is crucial at all stages of life. Nevertheless, it's vital to obtain these nutrients primarily from whole foods. Research has repeatedly demonstrated that the benefits of foods extend beyond just the sum of individual nutrients.[52]

This may be due to the food matrix, which captures the interactions between a food's nutrient and non-nutrient components. While the exact mechanisms behind these health benefits are still under investigation, they are thought to be linked to the bioactive compounds and phytochemicals inherent in such food matrices.[52]

Clinical Significance

Maintaining a healthy, varied dietary pattern rich in whole, nutrient-dense foods in adequate quantities is imperative for maintaining health and preventing disease throughout the lifespan. The body needs micronutrients in small amounts to support biochemical processes and cellular function. To achieve the best outcomes, micronutrient needs should be primarily met through various whole foods, recurring to supplementation only when clinically necessary.[3]

Both deficient and excessive micronutrient consumption can have adverse health consequences and should be avoided. Vitamin A, folate, iodine, iron, and zinc are the most common micronutrient deficiencies worldwide and contribute to perinatal complications, poor growth, cognitive impairment, and increased morbidity and mortality.[1] It must be noted that single micronutrient deficiencies are rare, and patients with malnutrition commonly present with multiple micronutrient deficiencies.[1]

Supplementation is warranted in the setting of established deficiency as well as prevention in individuals at risk; however, fortification (adding vitamins and minerals to common foods) is also an effective strategy for prevention that has been shown to decrease the burden of micronutrient deficiencies at the population level.[1]

Biofortification is often utilized to enhance the nutritional content of plant-based foods. This technique can combat widespread critical micronutrient shortages, such as zinc, iodine, iron, selenium, and carotenoids. Biofortification can be achieved through traditional plant breeding, genetic modifications, or certain farming practices.[53]

Various methods are classified under biofortification. One popular method is mineral fertilization, where mineral-rich fertilizers are used to improve the nutrient content of the soil, benefiting the plants growing in it.[54] Another is foliar fertilization, which involves applying fertilizers directly to the plant's leaves.[55] Research has shown that this method led to higher amounts of micronutrients like iron, zinc, and selenium in the grains when used on pulse crops.[56]

If the required nutrient variation does not exist naturally in a plant's gene pool, or if certain nutrients cannot be introduced through traditional breeding, then genetic engineering comes into play. This method has successfully enhanced the nutritional value of many crops.[57] A notable example is the creation of 'golden rice.' This genetically altered rice has been engineered to contain higher iron levels by producing an iron-storage protein known as ferritin.[58] Additionally, it has been modified to produce β-carotene (a precursor to vitamin A) to help combat vitamin A deficiencies.[59]

Nursing, Allied Health, and Interprofessional Team Interventions

An adequate intake of micronutrients is essential for optimal health at all life stages. While micronutrient deficiencies are preventable, they continue to be frequent worldwide. Interprofessional collaboration among physicians, nurses, dietitians, and other healthcare professionals must identify patients at risk of deficiency and act early to improve health outcomes. Healthcare teams must also remain vigilant against the dangers of excess micronutrient intake from inappropriate or unnecessary supplementation.

Physicians and nurses can identify patients at risk of micronutrient imbalances, manage the consequences of inappropriate micronutrient intake, and provide timely referrals to dietitians for a deeper nutritional assessment and tailored guidance to ensure a more holistic approach.

Furthermore, recognizing the pivotal impact of micronutrient intake on overall health, healthcare professionals must continually access and advocate for evidence-based nutrition guidelines. This approach ensures the promotion of sustainable dietary patterns tailored to individual preferences and requirements. Patients should be provided with education emphasizing the significance of fulfilling their micronutrient requirements primarily through a diverse diet, with caution against unnecessary supplementation unless clinically warranted.

An interprofessional team-based approach involving doctors, advanced practice practitioners, nurses, dietitians, and pharmacists is essential for improving patient outcomes and addressing micronutrient imbalances. This approach reduces the long-term burden of micronutrient imbalances on patients and the healthcare system, enhancing overall health and well-being through teamwork and patient-centered care.