Zinc

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Zinc Zinc is an essential trace element for all forms of life. The significance of zinc in human nutrition and public health was recognized relatively recently. Clinical zinc deficiency in humans was first described in 1961, when the consumption of diets with low zinc bioavailability due to high phytic acid content (see Food sources) was associated with "adolescent nutritional dwarfism" in the Middle East (1). Since then, zinc insufficiency has been recognized by a number of experts as an important public health issue, especially in developing countries (2). Function Numerous aspects of cellular metabolism are zinc-dependent. Zinc plays important roles in growth and development, the immune response, neurological function, and reproduction. On the cellular level, the function of zinc can be divided into three categories: 1) catalytic, 2) structural, and 3) regulatory (3). Catalytic role Nearly 100 different enzymes depend on zinc for their ability to catalyze vital chemical reactions. Zinc-dependent enzymes can be found in all known classes of enzymes (4). Structural role Zinc plays an important role in the structure of proteins and cell membranes. A finger-like structure, known as a zinc finger motif, stabilizes the structure of a number of proteins. For example, copper provides the catalytic activity for the antioxidant enzyme copper-zinc superoxide dismutase (CuZnSOD), while zinc plays a critical structural role (4, 5). The structure

and function of cell membranes are also affected by zinc. Loss of zinc from biological membranes increases their susceptibility to oxidative damage and impairs their function (6). Regulatory role Zinc finger proteins have been found to regulate gene expression by acting as transcription factors (binding to DNA and influencing the transcription of specific genes). Zinc also plays a role in cell

signaling and has been found to influence hormone release and nerve impulse transmission. Recently, zinc has been found to play a role in apoptosis (gene-directed cell death), a critical cellular regulatory process with implications for growth and development, as well as a number of chronic diseases (7). Nutrient Interactions Copper Taking large quantities of zinc (50 mg/day or more) over a period of weeks can interfere with copper bioavailability. High

intake of zinc induces the intestinal synthesis of a copper-binding protein called metallothionein. Metallothionein traps copper within intestinal cells and prevents its systemic absorption (see Copper). More typical intakes of zinc do not affect copper absorption and high copper intakes do not affect zinc absorption (5). Iron Supplemental (38-65 mg/day of elemental iron) but not dietary levels of iron may decrease zinc absorption (8). This interaction is of concern in the management of iron supplementation during pregnancy and lactation and has led some experts to recommend

zinc supplementation for pregnant and lactating women taking more than 60 mg/day of elemental iron (9, 10). Calcium High levels of dietary calcium impair zinc absorption in animals, but it is uncertain whether this occurs in humans. One study showed that increasing the calcium intake of postmenopausal women by 890 mg/day in the form of milk or calcium phosphate (total calcium intake, 1,360 mg/day) reduced zinc absorption and zinc balance in postmenopausal women (11), but increasing the calcium intake of adolescent girls by 1,000 mg/day in the form of calcium citrate malate (total calcium intake, 1,667 mg/day) did not affect zinc absorption or balance (12). Calcium in combination with phytic acid reduces zinc absorption. This effect is particularly relevant to individuals who very frequently consume tortillas made with lime (i.e., calcium oxide). For more information on phytic acid, see Food sources. Folic acid The bioavailability of dietary folate is increased by the action of a zinc-dependent enzyme, suggesting a possible interaction between zinc and folic acid. In the past, some studies found low zinc intake decreased folate absorption, while

other studies found folic acid supplementation impaired zinc utilization in individuals with marginal zinc status (4, 5). However, a more recent study reported that supplementation with a relatively high dose of folic acid (800 mcg/day) for 25 days did not alter zinc status in a group of students being fed low-zinc diets (3.5 mg/day); level of zinc intake did not impair folate utilization in this study (13). Vitamin AZinc and vitamin A interact in several ways. Zinc is a component of retinol-binding protein, a protein necessary for transporting vitamin A in the blood. Zinc is also required for the enzyme that

converts retinol (vitamin A) to retinal. This latter form of vitamin A is necessary for the synthesis of rhodopsin, a protein in the eye that absorbs light and thus is involved in dark adaptation. Zinc deficiency is associated with decreased release of vitamin A from the liver, which may contribute to symptoms of night blindness that are seen with zinc deficiency (14, 15). Deficiency Severe zinc deficiency Much of what is known about severe zinc deficiency was derived from the study of individuals born with acrodermatitis enteropathica, a genetic disorder resulting from the impaired uptake and transport of zinc. The symptoms of severe zinc deficiency include the slowing or cessation of growth and development, delayed sexual maturation,

characteristic skin rashes, chronic and severe diarrhea, immune system deficiencies, impaired wound healing, diminished appetite, impaired taste sensation, night blindness, swelling and clouding of the corneas, and behavioral disturbances. Before the cause of acrodermatitis enteropathica was known, patients typically died in infancy. Oral zinc therapy results in the complete remission of symptoms, though it must be maintained indefinitely in individuals with the genetic disorder (5, 16). Although dietary zinc deficiency is unlikely to cause severe zinc deficiency in individuals without a genetic disorder, zinc malabsorption or conditions of increased

zinc loss, such as severe burns or prolonged diarrhea, may also result in severe zinc deficiency. Mild zinc deficiency It has recently become apparent that milder zinc deficiency contributes to a number of health problems, especially common in children who live in developing countries. The lack of a sensitive indicator of mild zinc deficiency hinders the scientific study of its health implications. However, controlled trials of moderate zinc supplementation have demonstrated that mild zinc deficiency contributes to impaired physical and neuropsychological development and increased susceptibility to life-threatening infections in young children (16). For a more detailed discussion of the relationship of zinc deficiency to health problems, see Disease Prevention. Individuals at risk of zinc deficiency (5): Infants and children Pregnant and lactating (breast-feeding) women, especially teenagers Patients receiving total parenteral nutrition (intravenous feedings) Malnourished individuals, including those with protein-energy malnutrition and anorexia nervosa Individuals with severe or persistent diarrhea Individuals with malabsorption syndromes, including celiac disease and short bowel syndrome Individuals with inflammatory bowel disease, including Crohn's disease and ulcerative colitis Individuals with alcoholic liver disease who have increased urinary zinc excretion and low liver zinc levels Individuals with sickle cell anemia Older adults (65 years and older) Strict vegetarians: The requirement for dietary zinc may be as much as 50% greater for

strict vegetarians whose major food staples are grains and legumes, because high levels of phytic acid in these foods reduce zinc absorption (4) (see Food sources). The Recommended Dietary Allowance (RDA) The U.S. recommended dietary allowance (RDA) for zinc is listed by gender and age group in the table below. Infants, children, and pregnant and lactating women are at increased risk of zinc deficiency. Since a sensitive indicator of zinc nutritional status is not readily available, the RDA for zinc is based on a number of different indicators of zinc nutritional status and represents the

daily intake likely to prevent deficiency in nearly all individuals in a specific age and gender group (4). The Recommended Dietary Allowance (RDA) for Zinc Life Stage Age Males (mg/day) Females (mg/day) Infants 0-6 months 2 (AI) 2 (AI) Infants 7-12 months 3 3 Children 1-3 years 3 3 Children 4-8 years 5 5 Children 9-13 years 8 8 Adolescents 14-18 years 11 9 Adults 19 years and older 11 8 Pregnancy 18 years and younger - 12 Pregnancy 19 years and older - 11 Breast-feeding 18 years and younger - 13 Breast-feeding 19 years and older - 12 Prevention of Diseases or Conditions Related to Zinc Deficiency Impaired growth and development Growth retardation Significant delays in linear growth and weight gain, known as growth retardation or failure to thrive, are common features of mild zinc deficiency in children. In the 1970s and 1980s, several randomized, placebo-controlled studies of zinc supplementation in young children with significant growth delays were conducted in Denver, Colorado. Modest zinc supplementation (5.7 mg/day) resulted in increased growth rates compared to placebo (17). More recently, a number of larger studies in developing countries observed similar

results with modest zinc supplementation. A meta-analysis of growth data from zinc intervention trials recently confirmed the widespread occurrence of growth-limiting zinc deficiency in young children, especially in developing countries (18). Although the exact mechanism for the growth-limiting effects of zinc deficiency are not known, recent research indicates that zinc availability affects cell-signaling systems that coordinate the response to the growth-regulating hormone, insulin-like growth factor-1 (IGF-1) (19). Delayed neurological and behavioral development in young children Low maternal zinc nutritional status has been associated with diminished attention in newborn infants and poorer motor function at six months of age. Zinc supplementation has been associated with improved motor development in very low-birth-weight infants, more vigorous activity in Indian infants and toddlers, and more functional activity in Guatemalan infants and toddlers (20). Additionally, zinc supplementation was associated with better neuropsychologic functioning (e.g., attention) in Chinese first grade students, but this was observed only when zinc was provided with other micronutrients (21). Two other studies failed to find an association between zinc supplementation and measures of attention in children diagnosed with growth retardation. Although initial studies suggest that zinc deficiency may depress cognitive development in young children, more controlled research is required to determine the nature of the effect and whether zinc supplementation is beneficial (22). Impaired immune system function Adequate zinc intake is essential in maintaining the integrity of the immune system (23), and zinc-deficient individuals are known to experience increased susceptibility to a variety of infectious agents (24). Increased susceptibility to infectious disease in children Diarrhea: It is estimated that diarrheal diseases result in the deaths of over 3 million children in developing countries each year. The adverse effects of zinc deficiency on immune system function are likely to increase the susceptibility of children to infectious diarrhea, and persistent diarrhea contributes to zinc deficiency and malnutrition. Recent research indicates that zinc deficiency may also potentiate the effects of toxins produced by diarrhea-causing bacteria like E. coli (25). Zinc supplementation in combination with oral rehydration therapy has been shown to significantly reduce the duration and severity of acute and persistent childhood diarrhea and to increase survival in a number of randomized controlled trials (26, 27). Recently, a meta-analysis of randomized controlled trials concluded that zinc supplementation reduces the frequency, severity, and duration of diarrheal episodes in children under five years of age (28). The World Health Organization and the United Nations Children's

Fund currently recommend zinc supplementation as part of the treatment for diarrheal diseases in young children (29). Pneumonia: Zinc supplementation may also reduce the incidence of lower respiratory infections, such as pneumonia. A pooled analysis of a number of studies in developing countries demonstrated a substantial reduction in the prevalence of pneumonia in children supplemented with zinc (30). A recent meta-analysis found that zinc supplementation reduced the incidence but not duration of pneumonia or

respiratory tract illnesses in children under five years of age (28). Malaria: Some studies have indicated that zinc supplementation may reduce the incidence of clinical attacks of malaria in children (31). A placebo-controlled trial in preschool-aged children in Papua New Guinea found that zinc supplementation reduced the frequency of health center attendance due to plasmodium falciparum malaria by 38% (32). Additionally, the number of malaria episodes accompanied by high blood levels of this malaria-causing parasite was reduced by 68%, suggesting that zinc supplementation may be of benefit in preventing more severe episodes of malaria. However, a 6-month trial in more than 700 West African children did not find the frequency or severity of malaria episodes caused by P. falciparum to be different in children supplemented with zinc compared to those given a placebo (33). Additionally, a randomized controlled trial reported that zinc supplementation did not benefit preschool-aged children with acute, uncomplicated P. falciparum malaria (34). Further, a randomized controlled trial in over 42,000 children aged one to 48

months found that zinc supplementation did not significantly reduce mortality associated with malaria and other infections (35). Due to conflicting reports, it is not yet clear whether zinc supplementation has utility in treating childhood malaria. Immune response in the elderly Age-related declines in immune function are similar to those associated with zinc deficiency, and the elderly are vulnerable to mild zinc deficiency. However, the results of zinc supplementation trials on immune function in the elderly have been mixed. Certain aspects of immune function in the elderly have been found to improve with zinc supplementation (36). For example, a randomized placebo-controlled study in men and women over 65 years of age found that a zinc supplement of 25 mg/day for three months increased levels of some circulating immune cells (i.e., CD4 T-cells and cytotoxic T-lymphocytes) compared to placebo (37). However, other studies have reported zinc supplementation does not improve parameters of immune function, indicating that more research is required before any recommendations can be made regarding zinc and immune system response in the elderly. Pregnancy complications It has been estimated that 82% of pregnant women worldwide are likely to have inadequate zinc intakes. Poor maternal zinc nutritional status has been associated

with a number of adverse outcomes of pregnancy, including low birth weight, premature delivery, labor and delivery complications, and congential anomalies (38). However, the results of maternal zinc supplementation trials in the U.S. and developing countries have been mixed (20). Although some studies have found maternal zinc supplementation increases birth weight and decreases the likelihood of premature delivery, two placebo-controlled studies in Peruvian and Bangladeshi women found that zinc supplementation did not affect the incidence of low birth weight or premature delivery (39, 40). Supplementation studies designed to examine the effect of zinc supplementation on labor and delivery complications have also generated mixed results, though few have been conducted in zinc-deficient populations (20). A recent systematic review of 17 randomized controlled trials found that zinc supplementation during pregnancy was associated with a 14% reduction in premature deliveries; the lower incidence of preterm births was observed mainly in low-income women (41). This analysis, however, did not find zinc supplementation to benefit other indicators of maternal or infant health (41). Disease Treatment Common cold Zinc lozenges The use of zinc lozenges within 24 hours of the onset of cold symptoms, and continued every 2-3 hours while awake until symptoms resolve, has been advocated for reducing the duration of the common cold. At least ten controlled trials of zinc gluconate lozenges for the treatment of common colds in adults have been published. Five studies found that zinc lozenges reduced the duration of cold symptoms, whereas five studies found no difference between zinc lozenges and placebo lozenges with respect to the duration or severity of cold symptoms. A recent meta-analysis of published randomized controlled trials on the use of zinc gluconate lozenges in colds found that evidence for their effectiveness in reducing the duration of common colds was still lacking (42). Two clinical trials examined the effect of zinc acetate lozenges on cold symptoms. While one of the trials found that zinc acetate lozenges (12.8 mg of zinc per lozenge) taken every 2-3 hours while awake reduced the duration of overall cold symptoms (4.5 vs. 8.1 days) compared to placebo (43), the other study found that zinc acetate lozenges were no different from placebo in reducing the duration or

severity of cold symptoms (44). Despite numerous well-controlled trials, the efficacy of zinc lozenges in treating common cold symptoms remains questionable. The physiological basis for a beneficial effect of high-dose zinc supplementation on cold symptoms is not known. Taking zinc lozenges every 2-3 hours while awake often results in daily zinc intakes well above the tolerable upper level of intake (UL) of 40 mg/day (see Safety). Short-term use of zinc lozenges (e.g., less than five days) has not resulted in serious side effects, though some individuals experienced gastrointestinal disturbances and mouth irritation. Use of zinc lozenges for prolonged periods (e.g., 6-8 weeks) is likely to result in copper deficiency. For this reason, some experts have recommended that a person who does not show clear evidence of improvement of cold symptoms after 3-5 days of zinc lozenge treatment seek medical evaluation (43). Intranasal zinc (zinc nasal gels and nasal sprays) Intranasal zinc preparations, designed to be applied directly to the nasal epithelium (cells lining the nasal passages), are also marketed as over-the-counter cold remedies. While two placebo-controlled trials found that intranasal zinc gluconate modestly shortened the duration of cold symptoms (45, 46), three other placebo-controlled studies found intranasal zinc to be of no benefit (47-49). In the most rigorously controlled of these studies, intranasal zinc gluconate did not affect the severity or duration of cold symptoms in volunteers inoculated with rhinovirus, a common cause of colds (47). Of serious concern are several case reports of individuals experiencing loss of the sense of smell (anosmia) after using intranasal zinc as a cold remedy (50, 51). Since zinc-associated anosmia may be irreversible, intranasal zinc preparations should be avoided. Age-related macular degeneration A leading cause of blindness in people over the age of 65 in the U.S. is a degenerative disease of the macula, known as age-related macular degeneration (AMD). The macula is the portion of the retina in the back of the eye involved with central vision. Zinc is hypothesized to play a role in the development of AMD for several reasons: (1) zinc is found at high concentrations in the part of the retina affected by AMD (2) retinal zinc content has been shown to decline with age, and (3) the activities of some zinc-dependent retinal enzymes have been shown to decline with age. However, scientific evidence that zinc intake is associated with the development or progression of AMD is limited. Observational studies have not demonstrated clear associations between dietary zinc intake and the incidence of AMD (52-54). A randomized controlled trial provoked interest when it found that 200 mg/day of zinc sulfate (81 mg/day of elemental zinc) over two years reduced the loss of vision in patients with AMD (55). However, a later trial using the same dose and duration found no beneficial effect in patients with a more advanced form of AMD in one eye (56). A large randomized controlled trial of daily supplementation with antioxidants (500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta carotene) and high-dose zinc (80 mg of zinc and 2 mg of copper) found that the antioxidant combination plus high-dose zinc, and high-dose zinc alone, both significantly reduced the risk of advanced macular degeneration compared to placebo in individuals with signs of moderate to severe macular degeneration in at least one eye (57). Data from smaller trials have generally not observed a protective effect of vitamin and mineral supplementation on AMD (58). At present, there is little evidence that zinc

supplementation would be beneficial to people with early signs of macular degeneration, but further randomized controlled trials are warranted (59). Diabetes mellitus Moderate zinc deficiency may be relatively common in individuals with diabetes mellitus. Increased loss of zinc by frequent urination appears to contribute to the marginal zinc nutritional status that has been observed in diabetics (60). Although zinc supplementation reportedly improves immune function in diabetics, zinc supplementation of 50 mg/day adversely affected control of blood glucose in insulin-dependent (type 1)

diabetics in one study (61). In a more recent study, supplementation of type 2 diabetics with 30 mg/day of zinc for six months reduced a non-specific measure of oxidative stress (plasma TBARS) without significantly affecting blood glucose control (62). Presently, the influence of zinc on glucose metabolism requires further study before high-dose zinc supplementation can be advocated for diabetics (5). HIV/AIDS Sufficient zinc is essential in maintaining immune system function and HIV-infected individuals are particularly susceptible to zinc deficiency. In HIV-infected patients, low serum levels of zinc have been associated with a more advanced stage of the disease and also with increased mortality (63, 64). In one of the few zinc supplementation studies conducted in AIDS patients, 45 mg/day of zinc for one month resulted in a decreased incidence in opportunistic infections compared to placebo (65). However, the HIV virus also requires zinc, and excessive zinc intake may stimulate the progression of HIV infection. In an observational study of HIV-infected men, increased zinc intake was associated with more

rapid disease progression, and any intake of zinc supplements was associated with poorer survival (66). These results indicate that further research is necessary to determine optimal zinc intakes for HIV-infected individuals (23, 67). Sources Food sources Shellfish, beef, and other red meats are rich sources of zinc. Nuts and legumes are relatively good plant sources of zinc. Zinc bioavailability (the fraction of zinc retained and used by the body) is relatively high in meat, eggs, and seafood because of the relative absence of compounds

that inhibit zinc absorption and the presence of certain amino acids (cysteine and methionine) that improve zinc absorption. The zinc in whole grain products and plant proteins is less bioavailable due to their relatively high content of phytic acid, a compound that inhibits zinc absorption (5). The enzymatic action of yeast reduces the level of phytic acid in foods. Therefore, leavened whole grain breads have more bioavailable zinc than unleavened whole grain breads. Recently, national dietary surveys in the U.S. estimated that the average dietary zinc intake was 9 mg/day for adult women and 13 mg/day for adult men (4). The zinc content of some relatively zinc-rich foods is listed in milligrams (mg) in the table below. For more information on the nutrient content of specific foods, search the USDA food composition database. Food Serving Zinc (mg) Oysters 6 medium (cooked) 76.3 Crab, Dungeness 3 ounces (cooked) 4.7 Beef 3 ounces* (cooked) 6.0 Pork 3 ounces (cooked) 2.2 Chicken (dark meat) 3 ounces (cooked) 1.8 Turkey (dark meat) 3 ounces (cooked) 3.8 Yogurt, fruit 1 cup (8 ounces) 1.8 Cheese, cheddar 1 ounce 0.9 Milk 1 cup (8 ounces) 1.8 Cashews 1 ounce 1.6 Almonds 1 ounce 1.0 Peanuts 1 ounce 0.9 Beans, baked 1/2 cup 1.8 Chickpeas (garbanzo beans) 1/2 cup 1.3 *A three-ounce serving of meat is about the size of a deck of cards. Supplements A number of zinc supplements are available, including zinc acetate, zinc gluconate, zinc picolinate, and zinc sulfate. Zinc picolinate has been promoted as a more absorbable form of zinc, but there are few data to support this idea in humans. Limited work in animals suggests that increased intestinal absorption of zinc picolinate may be offset by increased elimination (4). Safety Toxicity Acute toxicity Isolated outbreaks of acute zinc toxicity have occurred as a result of the consumption of food or beverages contaminated with zinc released from galvanized containers. Signs of acute zinc toxicity are abdominal pain, diarrhea, nausea, and vomiting. Single doses of 225 to 450 mg of zinc usually induce vomiting. Milder gastrointestinal distress has been reported at doses of 50 to 150 mg/day of supplemental zinc. Metal fume fever has been reported after the inhalation of zinc oxide fumes. Specifically, profuse sweating, weakness, and rapid breathing may develop within eight hours

of zinc oxide inhalation and persist 12-24 hours after exposure is terminated (4, 5). Adverse effects The major consequence of long-term consumption of excessive zinc is copper deficiency. Total zinc intakes of 60 mg/day (50 mg supplemental and 10 mg dietary zinc) have been found to result in signs of copper deficiency. In order to prevent copper deficiency, the U.S. Food and Nutrition Board set the tolerable upper level of intake (UL) for adults at 40 mg/day, including dietary and supplemental zinc (4). Tolerable Upper Intake Level (UL) for

Zinc Age Group UL (mg/day) Infants 0-6 months 4 Infants 7-12 months 5 Children 1-3 years 7 Children 4-8 years 12 Children 9-13 years 23 Adolescents 14-18 years 34 Adults 19 years and older 40 Intranasal zinc Intranasal zinc is

known to cause a loss of the sense of smell (anosmia) in laboratory animals (68), and there have been several case reports of individuals who developed anosmia after using intranasal zinc gluconate (50, 51). Since zinc-associated anosmia may be irreversible, zinc nasal gels and sprays should be avoided. Drug Interactions Concomitant administration of zinc supplements and certain antibiotics, specifically tetracyclines and quinolones, may decrease absorption of the antibiotic and potentially reduce its efficacy. Taking zinc supplements and these antibiotics at least two hours apart should prevent this interaction (69). Additionally, the therapeutic use of metal chelating (binding) agents like penicillamine (used to treat copper overload in 's disease) and diethylenetriamine pentaacetate or DTPA (used to treat iron overload) has resulted in severe zinc deficiency. Anticonvulsant drugs, especially sodium valproate, may also precipitate zinc deficiency. Prolonged use of diuretics may increase urinary zinc excretion, resulting in increased loss of zinc. Further, the tuberculosis medication, ethambutol, has metal chelating properties and has been shown to increase zinc loss in rats (5). Linus ing Institute Recommendation The RDA for zinc (8 mg/day for adult women and 11 mg/day for adult men) appears sufficient to prevent deficiency in most individuals, but the lack of sensitive indicators of zinc nutritional status in humans makes it difficult to determine the level of zinc intake most likely to promote optimum health. Following the Linus ing Institute recommendation to take a multivitamin/multimineral supplement containing 100% of the daily values (DV) of most nutrients will generally provide 15 mg/day of zinc. Adults over the age of 65 Although the requirement for zinc is not known to be higher for older adults, their average zinc intake tends to be considerably less than the RDA. A reduced capacity to absorb zinc, increased likelihood of disease states that alter zinc utilization, and increased use of drugs that increase zinc excretion may all contribute to an increased risk of mild zinc deficiency in older adults. Because the consequences of mild zinc deficiency, such as impaired immune system function, are particularly relevant to the health of older adults, they should pay particular attention to maintaining adequate zinc intake. References Written in December 2003 by:Jane Higdon, Ph.D.Linus ing InstituteOregon State University Updated in February 2008 by: J. Drake, Ph.D.Linus ing InstituteOregon State University Reviewed in February 2008 by: Ho,

Ph.D.Assistant Professor of Nutrition and Exercise SciencesPrincipal Investigator, Linus ing InstituteOregon State University Copyright 2001-2008 Linus ing Institute http://lpi.oregonstate.edu/infocenter/minerals/zinc/

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