Zinc is an essential trace element critical to a large number of structural proteins, enzymatic processes, and transcription factors. Zinc deficiency can result in a spectrum of clinical manifestations.
The importance of the role of zinc in the development of an organism was first reported in 1869, when it was shown to be a requirement for growth of Aspergillus niger. It was not until the mid 20th century, however, that its importance in the growth and development of mammals was recognized [2,3]. Since that time, zinc deficiency has been recognized as a cause for significant clinical problems.
The prevalence of zinc deficiency worldwide is estimated at more than 20% . It may affect over two billion people in the developing world [5–7]. A study of 14 770 individuals aged 3–74 years estimated the prevalence of zinc deficiency in the USA at 1–3% . Ten percent of the US population consumes less than half the recommended level for zinc and is at risk for zinc deficiency .
Roles and functions of zinc
The functions of zinc can be broadly divided into three categories: catalytic, structural, and regulatory [10,11]. Zinc is a critical component of the catalytic site of hundreds of metalloenzymes, including pancreatic carboxypeptidases, carbonic anhydrase, alkaline phosphatase, RNA polymerases, and alcohol dehydrogenase [10,12].
In its structural role, zinc coordinates with certain protein domains, facilitating protein folding and producing structures such as ‘zinc fingers’. In this manner, zinc is crucial to the production of biologically active molecules. Zinc is also involved in the structure and stabilization of some enzymes, such as the antioxidant superoxide dismutase.
Zinc is essential to the regulation of a number of biologic processes, including gene regulation. For example, zinc regulates the expression of metallothionein. Metallothionein has multiple different functions, including intracellular zinc compartmentalization  and antioxidant function [14,15]. The binding of zinc to the metal response element transcription factor 1 (MTF1) activates the transcription of metallothionein as well as many other genes [11,16]. The importance of MTF1 in biologic pathways is illustrated by the lethality of a null mutation of MTF1 in mice .
Zinc transport in the intestine
Zinc homeostasis is highly regulated via the gastrointestinal tract. This tight regulation requires multiple transporters to work in coordination. All zinc transporters have transmembrane domains and are encoded by two solute-linked carrier (SLC) gene families: ZnT (SLC30) and Zip (SLC39) .
There are nine ZnT and 15 Zip transporters in humans. These transporters have opposing roles in cellular zinc homeostasis. ZnT transporters decrease intracellular zinc concentrations by promoting either zinc efflux from cells or zinc movement into intracellular vesicles. Zip transporters, however, increase intracellular zinc concentration by promoting zinc influx into cells or intracellular vesicular release of zinc.
ZnT1, the first zinc transporter discovered, is located in the small intestine, renal tubular epithelium, and placenta . It acts to transfer zinc from enterocytes to the circulation. Its expression is regulated by dietary zinc, with increased zinc intake resulting in the upregulation of ZnT1 mRNA. ZnT4 is highly expressed in the mammary gland. Mutation of this gene in mice results in the death of their pups from zinc deficiency prior to weaning, supporting the role of ZnT4 in zinc transport in milk [18,20]. Zinc depletion results in an increase in ZnT4 expression .
The role of the Zip protein, Zip4, in zinc homeostasis has been well studied [22–26]. Its expression is limited to the small intestine and kidney , and its expression in the small intestine is upregulated by zinc deficiency.
Absorption and metabolism of zinc
The majority of zinc is absorbed in the small intestine, primarily in the jejunum, via a transcellular process [28–30]. The kinetics of absorption are likely saturable, as there is an increase in transport velocity with depletion of zinc . In addition, transporter expression in the small intestine is responsive to dietary zinc intake in that intestinal zinc absorption increases with low dietary intake of zinc resulting in decreased intestinal loss of zinc [18,22,31–34].
The majority of total body zinc is stored in the skeletal muscle and bone. Another 11% is found in the liver and skin . Plasma zinc represents only 0.1% of total zinc stores, but its concentration is tightly regulated with a range of approximately 10–15 μmol/l. This concentration is often maintained despite fluctuations in zinc intake, unless the changes in zinc intake are severe or prolonged or both . Albumin-bound zinc accounts for 80% of the plasma zinc concentration.
Zinc binds strongly to proteins at or near neutral pH. As a consequence, efficient zinc absorption is dependent on dietary protein intake, as changes in protein digestion may effect significant changes in the absorption of zinc . As protein is digested, zinc becomes available for transport through intestinal cells. For example, casein-rich cow's milk has three times the protein concentration of human milk. The higher protein content of cow's milk results in lower bioavailablity of zinc and subsequent decreased zinc absorption as compared with human milk . In addition, a diet high in animal proteins as compared with plant proteins such as soy will generally result in greater zinc absorption . Nutritional deficiency of zinc in developing countries results from inadequate dietary intake, lack of intake of animal foods, and reduced bioavailability of zinc due to high dietary intake of phytate . Diets rich in cereal protein contain large amounts of phytate, an organic phosphate compound that inhibits the absorption and utilization of zinc.
The loss of zinc occurs primarily in the intestine from pancreatic secretions and can vary from 27–90 μmol/day . Urinary losses are comparably lower, as the kidney reabsorbs filtered zinc with estimated losses of only 8–11 μmol/day. Zinc is also lost through shedding of epithelial cells, sweat, semen, hair, and menstruation. Current dietary recommendations for humans are based on calculations in which zinc intake must balance losses .
Clinical manifestations of zinc deficiency
Many organ systems are affected by severe zinc deficiency, including the integumentary, gastrointestinal, central nervous system, immune, skeletal, and reproductive systems. The symptoms attributable to zinc deficiency encompass a wide spectrum of disease, depending on the magnitude of the deficiency. The variety of clinical manifestations seen in zinc deficiency illustrates the numerous roles zinc plays in the body.
Severe zinc deficiency can be inherited or acquired. Acquired zinc deficiency has been seen in patients receiving total parenteral nutrition without supplementation of zinc, following excessive alcohol use, and as a consequence of penicillamine therapy. In addition, a rare autosomal dominantly inherited disease, acrodermatitis enteropathica, is a result of a mutation in the Zip4 transporter, which leads to severe zinc deficiency. Bullous pustular dermatitis, alopecia, diarrhea, psychological impairment, weight loss, infections secondary to cell-mediated immunity dysfunction, hypogonadism in men, neurosensory disorders, and problematic healing of ulcers can be seen. Severe zinc deficiency can be fatal if left untreated.
Moderate zinc deficiency results in growth retardation and hypogonadism in male adolescents, rough skin, poor appetite, mental lethargy, delayed wound healing, dysfunction in cell-mediated immunity, and abnormal neurosensory changes. Mild dietary deficiency of zinc results in impaired growth velocity in children, decreased serum testosterone level and oligospermia in men, immune system impairment, hyperammonemia, hypogeusia, decreased dark adaptation, and decreased lean body mass [10,40–42].
In addition to nutritional deficiency of zinc, a number of disease and nondisease states can result in zinc deficiency, including malabsorption syndrome, sickle cell disease, chronic liver and renal diseases, and excessive sweating in hot tropical climates. Zinc may also be depleted in the setting of trauma, burns, blood loss, severe ischemia, major surgery, and severe infection. Measurement of serum zinc as an indicator of zinc nutritional status is problematic in that only 0.1% of the body's zinc stores are contained in the circulation. In addition, serum zinc levels may be lowered by hypoalbuminemia, infection, acute stress, pregnancy, and use of oral contraceptive agents [8,10]. Serum zinc levels are also subject to diurnal variation and influenced by the fasting status of the individual .
Zinc deficiency and immunity
The functions of zinc in the immune system have been studied extensively and reviewed recently [43•,44•]. Zinc is essential in both cell-mediated and humoral immunity. Zinc deficiency results in a multitude of alterations in immune function, including impairment of cellular mediators of innate immunity such as phagocytosis by macrophages and neutrophils, natural killer (NK) cell activity, delayed-type hypersensitivity, generation of the oxidative burst, cytokine production, and complement activity [45,46••,47,48]. Among the various alterations in immunity associated with zinc deficiency, T lymphocytes are the most susceptible . Zinc deficiency results in decreased numbers of peripheral and thymic T cells, impaired proliferative response, and decreased function of T-helper and cytotoxic T cells [46••]. In addition, a T-helper lymphocyte population important in protecting against intracellular infections, T-helper1 (Th1), is downregulated by zinc deficiency [49,50], whereas the Th2 response is upregulated. The accumulation of these impairments in immunity results in increased susceptibility to infection [51••].
Zinc supplementation has been shown to significantly reduce the morbidity and mortality from acute infectious diseases and shorten the recovery time in apparently well nourished children . In addition, supplementation with zinc reduces the incidence of acute lower respiratory infections in infants and preschool children . Zinc supplementation as prophylaxis has proven to be effective in reducing diarrhea, pneumonia, and mortality [54,55]. In elderly patients, zinc supplementation corrected impairments in wound healing and resistance to infection [56–58].
Oxidative stress as a result of production of reactive oxygen species (O2−, H2O2, and •OH) is an important factor contributing to several chronic diseases, such as atherosclerosis and cancer, and results in cellular damage. Inflammatory cytokines such as TNFα and IL-1β generate higher amounts of reactive oxygen species [59,60]. Zinc deficiency induces oxidative stress  and contributes to conditions related to oxidative stress, such as loss of acute-phase response protection against hepatitis and lipid oxidation [62,63].
Zinc has been shown to act as an antioxidant, protecting cells from the damaging effects of oxygen radicals produced as a byproduct of immune activation [64–67]. It is also involved in the regulation of metallothionein, which has antioxidant activity  and has a number of other antioxidant functions [69••].
Zinc supplementation is protective against oxidative tissue injury. In healthy individuals, zinc supplementation lowers levels of oxidative stress-related lipid peroxidation products and inhibits induction of TNFα and IL-1β mRNA . Zinc supplementation is believed to play a role in preventing cancer induction by decreasing oxidative stress and improving immune system function .
Elderly patients represent a special population. Elderly people often have multiple nutrient deficiencies due to several factors, including physiologic, social, and economic circumstances. Age-related changes in the elderly may be associated with dysfunctions influencing the intracellular availability of zinc ion . In addition, dietary intake of zinc declines with advancing age in both developed and developing countries [72,73]. Gastric acidity enhances zinc absorption, which presents a problem for elderly patients who are at risk for achlorhydria. Zinc deficiency and increased susceptibility to infections due to impairments in cell-mediated immunity have been reported [72,73]. Zinc supplementation has been shown to reduce the incidence of infection as well as lower the generation of TNFα and oxidative stress markers in elderly patients [51••].
Zinc deficiency and liver disease
The liver plays an important role in zinc homeostasis as a rapidly exchanging repository for zinc storage . As such, liver diseases impact zinc levels and, in turn, are influenced by zinc deficiency. Decreased zinc levels in the liver are associated with impaired liver function and regeneration .
Zinc deficiency has been correlated with acute viral hepatitis. In comparison with healthy individuals, patients with acute viral hepatitis were found to have significantly reduced serum zinc levels [76,77]. Viral infections produce severe oxidative stress, resulting in cellular damage. Low serum zinc levels contribute to this oxidative stress. Therefore, high-dose zinc repletion is recommended in the treatment of acute viral hepatitis .
Alcoholic hepatitis is associated with reduced hepatic zinc levels [78,79]. Animal studies have demonstrated that zinc supplementation may prevent both acute and chronic ethanol-induced liver injury [80,81]. Zinc supplementation was shown to reduce ethanol-induced hepatic zinc depletion and increase alcohol dehydrogenase, an enzyme known to suppress ethanol-induced oxidative stress.
Reduced zinc levels have also been found in patients with subacute and fulminant hepatic failure [82,83]. Both bilirubin and prothrombin measurements, used as biochemical parameters to ascertain the degree of liver dysfunction, were found to be inversely related to serum zinc levels in patients with fulminant liver failure and hepatic encephalopathy . In animal studies of acute liver injury induced by the hepatotoxic agent, carbon tetrachloride (CCl4), zinc deficiency was found to increase the degree of injury induced and decrease the level of the acute-phase response . Supplementation of zinc prior to the administration of CCl4, however, inhibited liver injury [85–88]. However, other animal studies have not shown a benefit of zinc supplementation in acute liver injury induced by alcohol or CCl4[89–91].
Zinc deficiency has been associated with chronic liver disease, chronic viral hepatitis, and cirrhosis [91–100]. In several studies, reduced zinc levels showed an inverse correlation with the degree of liver damage [91,101,102], liver fibrosis , and markers of liver dysfunction such as bilirubin, albumin, and cholesterol [92,103,104]. Serum zinc levels have also been noted in patients with alcoholic cirrhosis [105–110]. In fact, they have been noted to be lower in comparison with those found in nonalcoholic patients with cirrhosis .
The pathogenesis of hepatic encephalopathy derived from liver failure is related to zinc deficiency [112,113]. Accordingly, zinc supplementation has resulted in some improvement in psychometric performances in encephalopathic patients with cirrhosis . However, other studies have shown no benefit of zinc supplementation compared with placebo  or standard therapy . Despite these mixed results, zinc supplementation is recommended for patients with hepatic encephalopathy that does not respond to standard therapy [117,118].
Cirrhosis has been implicated as a cause of zinc deficiency as a result of multiple factors. Decreased intestinal absorption of zinc may result from damage to intestinal mucosa  or insufficient pancreatic exocrine function and decreased ligand synthesis in the liver . Increased urinary loss of zinc occurs through increased use of diuretics in patients with cirrhosis [120,121], reduced circulating albumin levels, and reduced binding of zinc to albumin [122,123]. Malnutrition in cirrhotic patients is also likely to contribute to zinc deficiency, especially in alcoholic patients .
Zinc deficiency and diarrheal disease
Diarrheal disease represents a major public health problem, with approximately 1.5 billion episodes per year. It accounts for an estimated 2 million deaths each year among children younger than 5 years of age [125,126]. The estimated incidence of acute gastrointestinal illness in the USA is 0.65 episodes per person-year .
Zinc deficiency has been associated with increased diarrheal disease morbidity . In experimental studies, zinc deficiency has direct effects on the gastrointestinal tract, including villus atrophy, decreased brush border disaccharidase activity, and impaired intestinal transport [129,130]. Additionally, zinc deficiency results in impairments in immune function, such as lymphoid tissue atrophy, reduction in lymphocyte and T-helper cell proportion, cytotoxic activity of lymphocytes, and NK cell activity, resulting in enhanced secretory response to cholera toxin . However, the exact pathophysiologic mechanism that links diarrhea with zinc deficiency is yet to be elucidated. Nonetheless, the incidence of persistent diarrhea has been reduced by zinc supplementation, and the supplementation of oral rehydration solutions with zinc has substantially reduced the duration and severity of diarrhea in children with both acute and persistent diarrhea .
Zinc is effective in both prophylaxis and treatment of acute diarrhea. Supplementation of oral rehydration solutions with zinc has been shown to reduce stool output and diarrheal duration in children with acute and persistent diarrhea [131–133]. A pooled analysis of nine randomized trials demonstrated that zinc supplementation decreases the incidence of diarrhea by 18% . A recent meta-analysis has shown efficacy of zinc supplementation in reducing the duration and severity of acute and persistent diarrhea [135••]. Although the mechanism by which zinc supplementation reduces diarrhea is unknown, zinc treatment in patients with diarrhea has demonstrated improved water and electrolyte absorption by the intestine, quicker regeneration of gut epithelium , increased levels of brush border enzymes , and enhanced immune response resulting in increased clearance of pathogens from the intestine .
The benefits of zinc supplementation in the immune dysfunction secondary to zinc deficiency, diarrheal disease, and liver disease have been discussed above. Zinc supplementation is also beneficial in the treatment and prevention of acute lower respiratory infection and accelerates recovery from severe pneumonia [53,54,139]. In these studies, zinc has been administered easily and safely, has been well tolerated, and is inexpensive. Given the multitude of effects of zinc deficiency, it is reasonable to consider zinc supplementation as an adjunctive treatment of many diseases. Special consideration is, however, warranted in certain populations. Overbeck et al.[46••] recommends avoidance of zinc supplementation in patients with AIDS and diabetes mellitus type 1, as it may increase morbidity or deteriorate glucose metabolism, respectively. In addition, very high zinc intakes may result in copper or iron deficiency, anemia, and growth retardation [140–142]. Several articles review zinc dosing guidelines on supplementation as treatment for a variety of diseases [46••,143••–145••,146,147,148•,149••]. As with any nutritional supplement, one must exercise caution in taking excessive doses of zinc for a prolonged period of time.
The variety of clinical manifestations of zinc deficiency and numerous disease states associated with zinc deficiency illustrate the broad and essential roles that zinc plays in biochemical pathways. Zinc supplementation may be useful as adjunctive treatment in many diseases. More research is needed to further elucidate the many roles zinc plays in both normal and disease states.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 170).
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