Achieving the recommended dietary intake amount of zinc through diet and, if necessary, supplementation is critical for maintaining health and well being.

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inc is an essential mineral found in all body cells and necessary for most of the processes in cellular metabolism.^1-4 It acts as a cofactor in more than 100 enzymes and, as a result, regulates many biochemical processes in the body. Zinc is needed for DNA synthesis, cellular growth and differentiation, wound healing, antioxidant defense, and maintaining cardiorespiratory function, and it plays an important role in gene expression.^2-4 Zinc is also necessary to support a healthy immune system as well as maintain a sense of taste and smell. Zinc is critical in all stages of life for its influence on growth and development during pregnancy, childhood, and adolescence as well as maintaining the normal physiological functioning of mature individuals.

Dietary Sources of Zinc

       Zinc is found in a wide variety of protein-rich foods (see Table 1).⁵

Table 1

Red meat and poultry are the main sources of zinc in the American diet. Other good dietary sources of zinc include beans, nuts, seafood, whole grains, fortified breakfast cereals, and dairy products. Zinc absorption is, however, typically greater from a diet high in animal protein than a diet rich in plant proteins because of phytates (a compound found in plants that bind minerals, decreasing their bioavailability).
       The Continuing Survey of Food Intake by Individuals (CSFII) shows that older men consume 12 mg of zinc daily, on average, while the women consume approximately 9 mg.⁶ Major contributors of dietary zinc intake in the CSFII study were beef, pork, fish, legumes, poultry, ready-to-eat and hot cereals, hot dogs and sausages, pasta, yogurt and fast-food milkshakes, cheese products, and eggs. Yogurt and fast-food milkshakes as well as ready-to-eat and hot cereals were consumed most frequently by these individuals.

Zinc Homeostasis

       The gastrointestinal (GI) tract is the major site of zinc homeostasis through adjustments in the rate of zinc absorption and excretion into feces.^2,7 In order to limit zinc entering the body, the efficiency of zinc absorption decreases as the amount of zinc in the diet increases. Under the condition of zinc deficiency, there is an increase in the efficiency of zinc absorption. Renal losses of zinc tend to be low and remain constant over a wide range of intakes as opposed to losses from the GI tract, which varies widely. In addition to being expelled through the feces, zinc is lost daily through sweat, seminal fluids, menstrual losses, and hair and nail growth. In an effort to maintain adequate zinc status, however, endogenous losses can decrease by 50% during periods of low zinc intake.

Dietary Intake Recommendations for Zinc

       The dietary reference intakes (DRI) recommendations for dietary zinc consumption are specific to an individual’s age

Table 2

and gender (see Table 2).⁴ The zinc DRI for infants (0–6 months) is called the adequate intake (AI). The AI is defined as the recommended average daily nutrient intake, based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people, which is assumed to be adequate. The AI is set when insufficient data exist to determine the estimated average requirement (EAR) for a nutrient, and thus no recommended daily allowance (RDA) can be determined. It is important to note that the AI may not always have a consistent relationship with the EAR or RDA because the AI is set without being able to estimate the requirement.
       For infants 7–12 months of age, children, and adults, the RDAs have been defined (see Table 2). The RDA is the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97–98%) healthy individuals within that age and gender group. The tolerable upper limit (UL) does not apply to individuals who are receiving zinc for medical treatment, but it is important for these individuals to be monitored for potentially adverse health effects. Zinc toxicity has been reported in both acute and chronic forms.⁴ Signs of acute zinc toxicity include abdominal pain, diarrhea, nausea, and vomiting. A single dose (225 mg) of supplemental zinc usually induces vomiting, and milder GI distress occurs at doses of 50–150 mg/day. Long-term consumption of excessive zinc results in 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.⁴

Physiological Functions of Zinc

       Zinc is essential for growth and development.^1-4 It is important for enzyme activity as well as transcription and replication factors. The human body contains approximately 2 g of zinc, but in the plasma, zinc is present only at concentrations of 12–16 µmol/L. Plasma zinc represents less than 0.1% of the total zinc, which translates to approximately 3.5 mg. Approximately 85% of whole-body zinc is localized in muscle and bone, 11% in skin and liver, and 2-3% in all other tissues.⁷ Bone contains one-third of whole-body zinc and is a significant source of endogenous zinc, which may be liberated for use when the dietary zinc supply is low. Therefore, bone provides a passive reserve of zinc that can be released, but not replaced, during periods of zinc deficiency.
       Plasma zinc pool is highly mobile and important immunologically. In serum, zinc is predominantly bound to proteins like albumin. Because albumin is a major transport protein of zinc, hypoalbuminemia has the potential to impair zinc transport and availability.
       Zinc is needed for maintaining the structural integrity of cells and catalytic action of more than 200 enzymes, including pyruvate carboxylase, alkaline phosphatase, alcohol dehydrogenase, and carboxypeptidase. Zinc is important for maintaining epithelial and tissue integrity by promoting cell growth and suppressing apoptosis through the antioxidant system. As a result, zinc has the effect of protecting cells against free-radical damage during inflammatory responses. Cytosolic superoxide dismutase, an enzyme containing both copper and zinc, is found in almost all oxygen-utilizing cells and is essential for catalyzing the reactions that remove the highly reactive superoxide anion.⁶
       Several gonadal and anabolic hormones, such as growth hormone, are zinc-dependent. Deficiencies in zinc have been associated with poor growth performance that was eventually correlated back to low growth hormone; on the other hand, zinc supplementation has been shown to promote serum concentrations of insulin-like growth factor (IGF-1), the cellular effector of growth hormone’s anabolic action.⁸ Zinc is also required for activity of insulin, glucagon, and gonadal hormones. However, zinc functions as more than just a component of anabolic hormones. Immune cells also require zinc for function, as thymulin (a thymic hormone necessary for the differentiation and maturation of thymus-derived T-lymphocytes) requires zinc.
       Improvements in brain development and neuropsychological performance have been attributed to improved zinc status. Poor maternal zinc status can adversely affect fetal brain function as well as prenatal and postnatal development. In the central nervous system, zinc exists in 1 of 2 pools that include protein-bound zinc (metalloenzymes and metalloproteins) and a small portion (approximately 10%) as free zinc. The free zinc is present along with the neurotransmitter glutamate and modulates postsynaptic glutamate receptors. Patients who are immobilized following traumatic brain injury are at risk of developing moderate to severe zinc deficiency due to increased loss of free zinc from metalloproteins and mitochondrial zinc pools.⁹ Central nervous system damage has been reported to increase the concentration of free zinc, which may cause neuronal damage and death.⁹ However, Young et al¹⁰ observed that administration of zinc to brain-injured patients (12 mg/day intravenously and 22 mg/day orally) resulted in increases in serum prealbumin and retinal-binding protein. The increased prealbumin and retinal-binding protein have been associated with improved visceral protein synthesis and increased Glasgow Coma Scale Scores, suggesting improved recovery scores.¹⁰

Zinc Deficiency

       It is estimated that approximately 20% of men 19–50 years of age have inadequate zinc intakes and that this increases to 40% in women of the same ages.⁴ Surveys of physically active individuals have indicated that low dietary zinc is common, especially among those who participate in aerobic activities.³ Low zinc status influences physiological functions required for optimal physical performance and function.³ Rapid onset of clinical symptoms of zinc deficiency occurs with severe depletion, indicating that there are no stores for zinc.¹¹ In children, a marked reduction in dietary zinc is followed quickly by growth failure. Adjustments in GI zinc absorption and intestinal endogenous zinc excretion are the main means by which the body maintains constant tissue levels of zinc with varying intakes.⁷
       Signs and symptoms of zinc deficiency include anorexia, growth retardation, delayed sexual maturation, hypogonadism and hypospermia, alopecia, impaired immunocompetency, dermatitis, night blindness, blunted taste acuity (hypogeusia), and impaired wound healing.¹¹
       A meta-analysis of zinc supplementation studies showed that the incidence of pneumonia was reduced by 41% and diarrhea 18%.^1,11 Furthermore, the duration of diarrhea was reduced by 24% and cases of malaria 38%. Like all supplements, however, zinc doses must be not be excessive. Elevated zinc intake, via excessive supplementation, can impair immunologic function, interfere with the metabolism of other essential minerals, and alter lipid indices. Ingesting doses of 200–800 mg zinc/day can cause vomiting and diarrhea. Lower doses ranging from 100–150 mg may interfere with copper metabolism and cause hypocupremia, red blood cell microcytosis, and neutropenia.^4,11
       Certain groups, such as older individuals, vegetarians, and patients with renal insufficiency, are more susceptible to zinc deficiency.⁴ Zinc deficiency most commonly occurs when zinc intake is inadequate or dietary zinc poorly absorbed, when there are increased losses of zinc from the body, and when the body’s requirements of zinc increases.
       Organ and functional systems affected clinically by severe zinc deficiency include the epidermis, GI tract, central nervous system, immune organs, skeletal muscle, and reproductive system.^1,11 Zinc deficiency is a major factor in the etiology of adolescent nutritional dwarfism syndrome and the inherited autosomal recessive disorder acrodermatitis enteropathica (AE). Zinc-dependent metabolic functions are impaired in all tissues during zinc deficiency. In animal models, central nervous system injury concomitant with moderate zinc deficiency increased cell death, while severe zinc deficiency resulted in anorexia along with an increased number of apoptotic cells at the site of injury.⁹ Therefore, systemic zinc deficiency after a central nervous system injury should be avoided; whether brain-injured patients should be provided supplemental zinc remains to be determined.

Supplemental Zinc Requirements

       Currently, there is no single laboratory test that accurately measures the nutritional zinc status of individuals. This is because plasma zinc concentrations are well conserved at the expense of other tissues, even during a condition of zinc-deficiency, and thus may not accurately reflect zinc status.^1,2,4,7,11 Risk factors, such as inadequate caloric intake, alcoholism, digestive diseases, impaired growth in infants and children, and protein-energy malnutrition, are predictors of potential zinc deficiency and may be suggestive indicators of the need for supplemental zinc. Meta-analysis has shown zinc to have a positive impact on increasing height and weight velocity when administered to children.^1,11 Zinc supplementation in children has resulted in significant reduction in prevalence of pneumonia and malaria. Vegetarians may be at increased risk for zinc deficiency and may need as much as 50% more zinc than non-vegetarians because of lower bioavailability of dietary zinc from plant sources. Low zinc (and other trace mineral) status has been observed in 30–50% of alcoholics. Alcohol both decreases the absorption of zinc and increases loss of zinc in urine. Additionally, most alcoholics have poor dietary intake, resulting in inadequate dietary zinc consumption and exacerbating zinc deficiency. Gastrointestinal disorders like diarrhea may result in a loss of zinc. Diarrhea generally entails poor absorption of nutrients as a result of rapid transit through the gut, deterioration of the absorptive mucosa, and loss of specific transporters. In addition, diarrhea may produce a secretory state in the small intestine, preventing or reducing net absorption.¹² Individuals experiencing chronic diarrhea should include sources of zinc in their diet because adding zinc to conventional therapy has been observed to be effective in reducing the duration of acute and persistent diarrhea while reducing the severity of the illness. Individuals undergoing GI surgery or who have digestive disorders that result in malabsorption, such as Crohn’s disease or short bowel syndrome, are at greater risk of zinc deficiency.

Zinc and Infections

       Based on observations of suppressed immune function during mild zinc deficiency, zinc is necessary for the normal immune system.¹³ The innate immune system, which is the first line of defense against infections and responds to different antigens in a similar manner (ie, not a specific response), is altered by changes in zinc status. Natural killer cell activity, phagocytosis of macrophages and neutrophils, and generation of oxidative bursts are impaired by decreased zinc concentrations. The immune system is adversely affected by moderate degrees of zinc deficiency, but severe zinc deficiency depresses the immune function dramatically. Zinc is required for the development and activation of T-lymphocytes (T cells) to help fight infection. Zinc deficiency affects the immune system by reducing the number of B-lymphocytes (B cells) and T cells through cellular apoptosis and reduced functional capacity. Zinc supplementation given to individuals who had low zinc levels resulted in increasing the number of circulating T cells and improved their ability to fight infection. Malnourished children have been observed to experience shorter durations of infectious diarrhea after taking zinc supplements. The amount of zinc in the form of zinc acteate, zinc gluconate, and zinc sulfate ranged from 4 mg/day up to 40 mg/day.
       A specific immune system’s B and T cells have a great variety of specific receptors and can produce memory cells that respond quickly and powerfully to the antigens to which they have been primed. These cells are reduced in number with zinc deficiency, affecting the body’s ability to produce antibodies in response to specific antigens. Zinc deficiency causes apotosis of B cells, decreases normal functions, and increases the autoreactivity and alloreactivity of T cells. Zinc influences natural killer cell-mediated killing and affects the activity of cytolytic T cells. Zinc deficiency is responsible for thymic atrophy, affecting development of T cells.
       Zinc deficiency also influences the production and potency of several cytokines, which in turn can influence the immune system. As stated earlier, zinc is an essential cofactor for thymulin in that it not only regulates the differentiation of T cells in the periphery but also modulates cytokine release by peripheral blood mononuclear cells, induces proliferation of CD8+ T cells in combination with interleukin-2 (IL-2), and ensures expression of the high-affinity receptor for IL-2 on mature T cells. T-helper cells (CD4+) are affected by zinc deficiency, which may promote an imbalance between TH1 and TH2 function.
       Optimal intake of zinc, via zinc supplementation or a normal balanced diet, can restore impaired immune response and decrease infection incidence in vivo. Zinc supplementation can reverse the zinc deficiency-induced changes in thymus and peripheral cells. The optimal therapeutic dosage required to reverse symptoms of zinc deficiency is unclear, but plasma zinc levels should not exceed 30 µmol/L. T-cell functions are inhibited at high zinc dosages, and suppression of immune function is observed when oral zinc intake is 100 mg/day. Zinc supplementation may be beneficial for individuals (eg, the elderly, who often exhibit high rates of infections) who suffer from zinc deficiency. Zinc administration should be adjusted to the individual’s actual requirements, because high dosages can have negative effects on the immune system.

Zinc and Wound Healing

       Zinc deficiency has been shown to increase wound closure time and decrease wound strength.^14,15 Zinc has been used as a topical agent to treat diaper rash and as a nutritional supplement in patients with bedsores, ulcers, and incisional wounds. Wound healing involves complex interactions of various cell types, structural proteins, cytokines, and reactive oxygen species. The 3 major stages of wound healing include inflammation, proliferation, and remodeling. Inflammation is the most critical stage of the healing process because it establishes the environment necessary for healing to occur. During the inflammation stage, neutrophils invade the wound site to prevent infections. Zinc deficiency can negatively influence the wound healing process. Lim et al¹⁴ observed that dietary zinc deficiency reduced the rate of wound closure and attenuated infiltration of neutrophils at the cutaneous wound site in mice, among other effects. A similar response was observed in mice supplemented with high doses of zinc (1 mg Zn/g diet). Thus adequate and appropriate zinc supplementation is necessary for beneficial effects on the inflammatory responses to enhance cutaneous wound healing.
       Zinc plays a role as an antioxidant in protecting sulfhydryl groups, essential in protein stability and activation, from oxidation and prevents superoxide and hydroxyl radical production by pro-oxidant metals, such as copper and iron. Therefore, zinc deficiency may increase oxidative stress-induced tissue damage by decreasing antioxidant functions—contributing to delayed wound healing.
       None of the potential mechanisms by which zinc affects healing processes is clear. Zinc supplements can increase the rate of wound healing but only in individuals with a low zinc status. Supplementation appears to have no effect on wound healing rates when a patient’s zinc status is normal.

Zinc and The Common Cold

       The effect of zinc supplementation on the severity and duration of cold symptoms is controversial.¹⁴ Several studies have suggested that zinc lozenges may potentially decrease the duration of colds, but the severity of the cold symptoms does not appear to be influenced by supplementation. Existing research suggests that the effect of zinc may be influenced by the ability of the specific supplement formula to deliver zinc ions to the oral mucus. However, additional research is needed to determine whether zinc compounds have any effect on common cold.

Zinc and Iron Absorption

       Iron deficiency anemia is considered a serious public health problem worldwide and this issue has been addressed with iron supplementation. Fortification of foods with iron can, however, have a negative impact on zinc absorption.^2,4 High concentrations (ie, greater than 25 mg) of iron in dietary supplements may decrease zinc absorption. Taking iron supplements between meals will help decrease its effect on zinc absorption by reducing direct competition between iron and zinc for absorption via the divalent metal transport protein.

Health Risks of Excessive Zinc

       Zinc toxicity has been observed in both acute and chronic forms.^2,4,7 Intakes of 150–450 mg of zinc per day have been associated with low copper status, altered iron function, reduced immune function, and reduced levels of high-density lipoprotein (HDL) cholesterol. Signs of acute zinc toxicity include abdominal pain, diarrhea, nausea, and vomiting. A single zinc dose of 225 mg usually induces vomiting, and mild GI distress occurs at doses of 50–150 mg/day of supplemental zinc.
       Long-term consumption of excess zinc results in copper deficiency, neutropenia, and anemia due to interference with copper absorption. Total zinc intakes of 60 mg/day (50 mg supplemental and 10 mg dietary) have been found to result in signs of copper deficiency. Zinc intake at concentrations 20-fold greater (300 mg/day) than the current RDA (15 mg/day) has been observed to decrease indices of immune function, including chemotactic response and phagocytic activity of neutrophils.¹⁶ High doses of zinc can also impair wound healing. As a result, supplemental doses of zinc more than double the RDA are not recommended.⁴

Conclusion

       Zinc is an essential trace element, influencing many key physiological functions. Maintaining adequate zinc nutritional status is critical for maintaining health and well being. It is important to achieve the RDIs of zinc through the diet and, if necessary, through supplementation if intake is inadequate. Excessive supplementation with zinc should, however, be avoided.