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).
1 Raulin J. Chemical studies on vegetation. Annales Des Sci Naturelles 1869; 11:293–299.
2 Todd WR, Elvejheim CA, Hart EB. Zinc in the nutrition of the rat. Am J Physiol 1934; 107:146–156.
3 Drinker K. The significance of zinc in the living organism. J Indust Hygiene 1926; 8:257–269.
4 Wuehler SE, Peerson JM, Brown KH. Use of national food balance data to estimate the adequacy of zinc in national food supplies: methodology and regional estimates. Public Health Nutr 2005; 8:812–819.
5 Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961; 31:532–546.
6 Prasad AS, Miale A, Farid Z, et al
. Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypognadism. J Lab Clin Med 1963; 61:537–549.
7 Cavdar AO, Arcasoy A, Cin S, et al
. Geophagia in turkey: iron and zinc deficiency, iron and zinc absorption studies and response to treatment with zinc in geophagia cases. Prog Clin Biol Res 1983; 129:71–97.
8 Pilch SM, Senti FR. Analysis of zinc data from the second national health and nutrition examination survey (NHANES II). J Nutr 1985; 115:1393–1397.
9 Wakimoto P, Block G. Dietary intake, dietary patterns, and changes with age: an epidemiological perspective. J Gerontol A Biol Sci Med Sci 2001; 56 (Spec No. 2):65–80.
10 Russell R, Beard JL, Cousins RJ, et al.
Zinc. In: Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, zinc. Washington, DC: The National Academies Press; 2002. pp. 442–501.
11 Cousins RJ. Metal elements and gene expression. Annu Rev Nutr 1994; 14:449–469.
12 Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993; 73:79–118.
13 Maret W. Cellular zinc and redox states converge in the metallothionein/thionein pair. J Nutr 2003; 133(5 Suppl 1):1460S–1462S.
14 Theocharis SE, Margeli AP, Koutselinis A. Metallothionein: a multifunctional protein from toxicity to cancer. Int J Biol Markers 2003; 18:162–169.
15 Theocharis SE, Margeli AP, Klijanienko JT, Kouraklis GP. Metallothionein expression in human neoplasia. Histopathology 2004; 45:103–118.
16 Dalton TP, Bittel D, Andrews GK. Reversible activation of mouse metal response element-binding transcription factor 1 DNA binding involves zinc interaction with the zinc finger domain. Mol Cell Biol 1997; 17:2781–2789.
17 Günes C, Heuchel R, Georgiev O, et al
. Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J 1998; 17:2846–2854.
18 Liuzzi JP, Cousins RJ. Mammalian zinc transporters. Annu Rev Nutr 2004; 24:151–172.
19 Liuzzi JP, Blanchard RK, Cousins RJ. Differential regulation of zinc transporter 1, 2, and 4 mrna expression by dietary zinc in rats. J Nutr 2001; 131:46–52.
20 Huang L, Gitschier J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet 1997; 17:292–297.
21 Kelleher SL, Lönnerdal B. Zinc transporters in the rat mammary gland respond to marginal zinc and vitamin A intakes during lactation. J Nutr 2002; 132:3280–3285.
22 Liuzzi JP, Bobo JA, Lichten LA, et al
. Responsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis. Proc Natl Acad Sci U S A 2004; 101:14355–14360.
23 Wang F, Kim BE, Dufner-Beattie J, et al
. Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. Hum Mol Genet 2004; 13:563–571.
24 Dufner-Beattie J, Wang F, Kuo YM, et al
. The acrodermatitis enteropathica gene ZIP4 encodes a tissue-specific, zinc-regulated zinc transporter in mice. J Biol Chem 2003; 278:33474–33481.
25 Dufner-Beattie J, Kuo YM, Gitschier J, Andrews GK. The adaptive response to dietary zinc in mice involves the differential cellular localization and zinc regulation of the zinc transporters ZIP4 and ZIP5. J Biol Chem 2004; 279:49082–49090.
26 Kim BE, Wang F, Dufner-Beattie J, et al
. Zn2+-stimulated endocytosis of the mzip4 zinc transporter regulates its location at the plasma membrane. J Biol Chem 2004; 279:4523–4530.
27 Wang K, Zhou B, Kuo YM, et al
. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 2002; 71:66–73.
28 Cousins RJ. Theoretical and practical aspects of zinc uptake and absorption. Adv Exp Med Biol 1989; 249:3–12.
29 Lee HH, Prasad AS, Brewer GJ, Owyang C. Zinc absorption in human small intestine. Am J Physiol 1989; 256(1 Pt 1):G87–91.
30 Lonnerdal B. Intestinal absorption of zinc. In: Mills CF, editor. Zinc in human biology. New York: Springer-Verlag; 1989. pp. 33–55.
31 Baer MT, King JC. Tissue zinc levels and zinc excretion during experimental zinc depletion in young men. Am J Clin Nutr 1984; 39:556–570.
32 Jackson MJ, Jones DA, Edwards RH, et al
. Zinc homeostasis in man: studies using a new stable isotope-dilution technique. Br J Nutr 1984; 51:199–208.
33 Steel L, Cousins RJ. Kinetics of zinc absorption by luminally and vascularly perfused rat intestine. Am J Physiol 1985; 248(1 Pt 1):G46–G53.
34 Taylor CM, Bacon JR, Aggett PJ, Bremner I. Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men. Am J Clin Nutr 1991; 53:755–763.
35 King JC, Shames DM, Woodhouse LR. Zinc homeostasis in humans. J Nutr 2000; 130(Suppl 5S):1360S–1366S.
36 Sandstrom B, Lonnerdal B. Promoters and antagonists of zinc absorption. In: Mills CF, editor. Zinc in human biology. New York: Springer-Verlag; 1989. pp. 57–78.
37 Roth HP, Kirchgessner M. Utilization of zinc from picolinic or citric acid complexes in relation to dietary protein source in rats. J Nutr 1985; 115:1641–1649.
38 King JC, Keen CL. Zinc. In: Shils ME, Olson JA, Shike M, Ross AC, editors. Modern nutrition in health and disease. Baltimore: Williams & Wilkins; 1999. pp. 223–239.
39 Fischer Walker CL, Ezzati M, Black RE. Global and regional child mortality and burden of disease attributable to zinc deficiency. Eur J Clin Nutr 2008. http://dx.doi.org/10.1038/ejcn.2008.9
[Epub ahead of print].
40 Prasad AS, Meftah S, Abdallah J, et al
. Serum thymulin in human zinc deficiency. J Clin Invest 1988; 82:1202–1210.
41 Beck FW, Prasad AS, Kaplan J, et al
. Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol 1997; 272(6 Pt 1):E1002–E1007.
42 Beck FW, Kaplan J, Fine N, et al
. Decreased expression of CD73 (ecto-5'-nucleotidase) in the CD8+ subset is associated with zinc deficiency in human patients. J Lab Clin Med 1997; 130:147–156.
43• Prasad AS. Zinc: mechanisms of host defense. J Nutr 2007; 137:1345–1349. This article is a review of the molecular mechanisms of the immune system in which zinc plays a role.
44• Rink L, Haase H. Zinc homeostasis and immunity. Trends Immunol 2007; 28:1–4. This article reviews zinc homeostasis and the molecular mechanisms of zinc function in immune cells.
45 Fraker PJ, King LE. Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr 2004; 24:277–298.
46•• Overbeck S, Rink L, Haase H. Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. Arch Immunol Ther Exp (Warsz) 2008; 56:15–30. This is a good review of the influence of zinc in infectious and autoimmune disease and the effect of supplementation.
47 Ibs KH, Rink L. Zinc-altered immune function. J Nutr 2003; 133(5 Suppl 1):1452S–1456S.
48 Rink L, Gabriel P. Extracellular and immunological actions of zinc. Biometals 2001; 14:367–383.
49 Metz CH, Schröder AK, Overbeck S, et al
. T-helper type 1 cytokine release is enhanced by in vitro zinc supplementation due to increased natural killer cells. Nutrition 2007; 23:157–163.
50 Long KZ, Rosado JL, Montoya Y, et al
. Effect of vitamin A and zinc supplementation on gastrointestinal parasitic infections among mexican children. Pediatrics 2007; 120:e846–e855.
51•• Prasad AS, Beck FW, Bao B, et al
. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr 2007; 85:837–844. This article shows significant reduction in infections in elderly patients with zinc supplementation.
52 Cuevas LE, Koyanagi A. Zinc and infection: a review. Ann Trop Paediatr 2005; 25:149–160.
53 Sazawal S, Black RE, Jalla S, et al
. Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial. Pediatrics 1998; 102(1 Pt 1):1–5.
54 Brooks WA, Yunus M, Santosham M, et al
. Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial. Lancet 2004; 363:1683–1688.
55 Brooks WA, Santosham M, Naheed A, et al
. Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomised controlled trial. Lancet 2005; 366:999–1004.
56 Sandstead HH. Understanding zinc: recent observations and interpretations. J Lab Clin Med 1994; 124:322–327.
57 Prasad AS, Fitzgerald JT, Hess JW, et al
. Zinc deficiency in elderly patients. Nutrition 1993; 9:218–224.
58 Garfinkel D. Is aging inevitable? The intracellular zinc deficiency hypothesis of aging. Med Hypotheses 1986; 19:117–137.
59 Ozaki Y, Ohashi T, Kume S. Potentiation of neutrophil function by recombinant dna-produced interleukin 1a. J Leukoc Biol 1987; 42:621–627.
60 Berkow RL, Wang D, Larrick JW, et al
. Enhancement of neutrophil superoxide production by preincubation with recombinant human tumor necrosis factor. J Immunol 1987; 139:3783–3791.
61 Powell SR. The antioxidant properties of zinc. J Nutr 2000; 130(Suppl 5S):1447S–1454S.
62 DiSilvestro RA. Zinc in relation to diabetes and oxidative disease. J Nutr 2000; 130(Suppl 5S):1509S–1511S.
63 Parsons SE, DiSilvestro RA. Effects of mild zinc deficiency, plus or minus an acute-phase response, on galactosamine-induced hepatitis in rats. Br J Nutr 1994; 72:611–618.
64 Chvapil M, Elias SL, Ryan JN, Zukoski CF. Pathophysiology of zinc. In: International review of neurobiology. New York: Academy Press; 1972. pp. 105–124.
65 Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant. Free Radic Biol Med 1990; 8:281–291.
66 Prasad AS, Bao B, Beck FW, et al
. Antioxidant effect of zinc in humans. Free Radic Biol Med 2004; 37:1182–1190.
67 Stehbens WE. Oxidative stress, toxic hepatitis, and antioxidants with particular emphasis on zinc. Exp Mol Pathol 2003; 75:265–276.
68 Palmiter RD, Cole TB, Findley SD. Znt-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J 1996; 15:1784–1791.
69•• Stamoulis I, Kouraklis G, Theocharis S. Zinc and the liver: an active interaction. Dig Dis Sci 2007; 52:1595–1612. This is an extensive review of the role of the liver in zinc homeostasis and the role of zinc in liver disease.
70 Prasad AS, Kucuk O. Zinc in cancer prevention. Cancer Metastasis Rev 2002; 21:291–295.
71 Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M. Brain, aging and neurodegeneration: role of zinc ion availability. Prog Neurobiol 2005; 75:367–390.
72 Cakman I, Kirchner H, Rink L. Zinc supplementation reconstitutes the production of interferon-alpha by leukocytes from elderly persons. J Interferon Cytokine Res 1997; 17:469–472.
73 Prasad AS, editor. Biochemistry of zinc. New York: Plenum; 1993.
74 Krebs NE, Hambidge KM. Zinc metabolism and homeostasis: the application of tracer techniques to human zinc physiology. Biometals 2001; 14:397–412.
75 Grungreiff K. Zinc in liver disease. J Trace Elem Exp Med 2002; 15:67–78.
76 Fota-Markowska H, Przybyła A, Borowicz I, Modrzewska R. Serum zinc (zn) level dynamics in blood serum of patients with acute viral hepatitis B and early recovery period. Ann Univ Mariae Curie Sklodowska [Med] 2002; 57:201–209.
77 Kalkan A, Bulut V, Avci S, et al
. Trace elements in viral hepatitis. J Trace Elem Med Biol 2002; 16:227–230.
78 Bode JC, Hanisch P, Henning H, et al
. Hepatic zinc content in patients with various stages of alcoholic liver disease and in patients with chronic active and chronic persistent hepatitis. Hepatology 1988; 8:1605–1609.
79 Kiilerich S, Dietrichson O, Loud FB, et al
. Zinc depletion in alcoholic liver diseases. Scand J Gastroenterol 1980; 15:363–367.
80 Polavarapu R, Spitz DR, Sim JE, et al
. Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil. Hepatology 1998; 27:1317–1323.
81 Zhou Z, Sun X, Lambert JC, et al
. Metallothionein-independent zinc protection from alcoholic liver injury. Am J Pathol 2002; 160:2267–2274.
82 Chetri K, Choudhuri G. Role of trace elements in hepatic encephalopathy: zinc and manganese. Indian J Gastroenterol 2003; 22(Suppl 2):S28–S30.
83 Loomba V, Pawar G, Dhar KL, Setia MS. Serum zinc levels in hepatic encephalopathy. Indian J Gastroenterol 1995; 14:51–53.
84 DiSilvestro RA, Carlson GP. Effects of mild zinc deficiency, plus or minus acute phase response, on ccl4 hepatotoxicity. Free Radic Biol Med 1994; 16:57–61.
85 Cagen SZ, Klaassen CD. Protection of carbon tetrachloride-induced hepatotoxicity by zinc: role of metallothionein. Toxicol Appl Pharmacol 1979; 51:107–116.
86 Cagen SZ, Klaasen CD. Carbon tetrachloride-induced hepatotoxicity: studies in developing rats and protection by zinc. Fed Proc 1980; 39:3124–3128.
87 Ademuyiwa O, Onitilo O, Dosumu O, et al
. Zinc in ccl4 toxicity. Biomed Environ Sci 2002; 15:187–195.
88 Itoh N, Kimura T, Nakanishi H, et al
. Metallothionein-independent hepatoprotection by zinc and sakuraso-saponin. Toxicol Lett 1997; 93:135–140.
89 Davis SR, Samuelson DA, Cousins RJ. Metallothionein expression protects against carbon tetrachloride-induced hepatotoxicity, but overexpression and dietary zinc supplementation provide no further protection in metallothionein transgenic and knockout mice. J Nutr 2001; 131:215–222.
90 Srinivasan S, Balwani JH. Effect of zinc sulphate on carbon tetrachloride hepatotoxicity. Acta Pharmacol Toxicol (Copenh) 1969; 27:424–428.
91 Poo JL, Rosas-Romero R, Rodríguez F, et al
. Serum zinc concentrations in two cohorts of 153 healthy subjects and 100 cirrhotic patients from Mexico City. Dig Dis 1995; 13:136–142.
92 Pramoolsinsap C, Promvanit N, Komindr S, et al
. Serum trace metals in chronic viral hepatitis and hepatocellular carcinoma in Thailand. J Gastroenterol 1994; 29:610–615.
93 Prasad AS. Clinical and biochemical manifestation zinc deficiency in human subjects. J Pharmacol 1985; 16:344–352.
94 Barry M, Keeling PW, Feely J. Tissue zinc status and drug elimination in patients with chronic liver disease. Clin Sci (Lond) 1990; 78:547–549.
95 Cabré M, Camps J, Paternáin JL, et al
. Time-course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis. Clin Exp Pharmacol Physiol 2000; 27:694–699.
96 Madden AM, Bradbury W, Morgan MY. Taste perception in cirrhosis: its relationship to circulating micronutrients and food preferences. Hepatology 1997; 26:40–48.
97 Solis-Herruzo J, De Cuenca B, Muñoz-Rivero MC. Intestinal zinc absorption in cirrhotic patients. Z Gastroenterol 1989; 27:335–338.
98 Sartori M, Calgaro M, Campanini M, et al
. Determination of zinc and copper in patients with liver cirrhosis of diverse clinical severity. Minerva Med 1988; 79:891–895.
99 Göksu N, Ozsoylu S. Hepatic and serum levels of zinc, copper, and magnesium in childhood cirrhosis. J Pediatr Gastroenterol Nutr 1986; 5:459–462.
100 Gaveau D, Piette F, Cortot A, et al
. Cutaneous manifestations of zinc deficiency in ethylic cirrhosis. Ann Dermatol Venereol 1987; 114:39–53.
101 Rocchi E, Borella P, Borghi A, et al
. Zinc and magnesium in liver cirrhosis. Eur J Clin Invest 1994; 24:149–155.
102 Gür G, Bayraktar Y, Ozer D, et al
. Determination of hepatic zinc content in chronic liver disease due to hepatitis B virus. Hepatogastroenterology 1998; 45:472–476.
103 Goode HF, Kelleher J, Walker BE. Relation between zinc status and hepatic functional reserve in patients with liver disease. Gut 1990; 31:694–697.
104 Gil Extremera B, Maldonado Martin A, Ruiz Martinez M, et al
. Zinc and liver cirrhosis. Acta Gastroenterol Belg 1990; 53:292–298.
105 Ijuin H. Evaluation of pancreatic exocrine function and zinc absorption in alcoholism. Kurume Med J 1998; 45:1–5.
106 Schlienger JL, Willemin B, Lang JM, et al
. Evaluation of malnutrition and immunity in alcoholic liver diseases. Presse Med 1986; 15:1023–1027.
107 Bro S, Stokholm M, Jørgensen PJ. Zinc in mononuclear leucocytes in alcoholics with liver cirrhosis or chronic pancreatitis and in patients with Crohn's disease before and after zinc supplementation. J Trace Elem Electrolytes Health Dis 1989; 3:243–248.
108 Aaseth J, Smith-Kielland A, Thomassen Y. Selenium, alcohol and liver diseases. Ann Clin Res 1986; 18:43–47.
109 Vallee BL, Wacker WE, Bartholomay AF, Hoch FL. Zinc metabolism in hepatic dysfunction. II. Correlation of metabolic patterns with biochemical findings. N Engl J Med 1957; 257:1055–1065.
110 Chapman KM, Prabhudesai M, Erdman JW. Vitamin A status of alcoholics upon admission and after two weeks of hospitalization. J Am Coll Nutr 1993; 12:77–83.
111 Grüngreiff K, Abicht K, Kluge M, et al
. Clinical studies on zinc in chronic liver diseases. Z Gastroenterol 1988; 26:409–415.
112 Yang SS, Lai YC, Chiang TR, et al
. Role of zinc in subclinical hepatic encephalopathy: comparison with somatosensory-evoked potentials. J Gastroenterol Hepatol 2004; 19:375–379.
113 Romero-Gómez M, Boza F, García-Valdecasas MS, et al
. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001; 96:2718–2723.
114 Reding P, Duchateau J, Bataille C. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet 1984; 2:493–495.
115 Riggio O, Ariosto F, Merli M, et al
. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy. Results of a double-blind crossover trial. Dig Dis Sci 1991; 36:1204–1208.
116 Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Eur J Med 1993; 2:414–416.
117 Blei AT, Córdoba J, Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. Am J Gastroenterol 2001; 96:1968–1976.
118 Quero Guillén JC, Carmona Soria I, García Montes JM, et al
. Hepatic encephalopathy: nomenclature, pathogenesis and treatment. Rev Esp Enferm Dig 2003; 95:135–142, 127–134.
119 Karayalcin S, Arcasoy A, Uzunalimoglu O. Zinc plasma levels after oral zinc tolerance test in nonalcoholic cirrhosis. Dig Dis Sci 1988; 33:1096–1102.
120 Milman N, Hvid-Jacobsen K, Hegnhøj J, Sørensen SS. Zinc absorption in patients with compensated alcoholic cirrhosis. Scand J Gastroenterol 1983; 18:871–875.
121 Yoshida Y, Higashi T, Nouso K, et al
. Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama 2001; 55:349–355.
122 Atukorala TM, Herath CA, Ramachandran S. Zinc and vitamin A status of alcoholics in a medical unit in Sri Lanka. Alcohol Alcohol 1986; 21:269–275.
123 Kahn AM, Ozeran MD. Liver and serum zinc abnormalities in rats with cirrhosis. Gastroenterology 1967; 53:193–197.
124 Pöschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol 2004; 39:155–165.
125 Black RE, Morris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003; 361:2226–2234.
126 Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 2003; 81:197–204.
127 Roy SL, Scallan E, Beach MJ. The rate of acute gastrointestinal illness in developed countries. J Water Health 2006; 4(Suppl 2):31–69.
128 Bahl R, Bhandari N, Hambidge KM, Bhan MK. Plasma zinc as a predictor of diarrheal and respiratory morbidity in children in an urban slum setting. Am J Clin Nutr 1998; 68(Suppl 2):414S–417S.
129 Koo SI, Turk DE. Effect of zinc deficiency on the ultrastructure of the pancreatic acinar cell and intestinal epithelium in the rat. J Nutr 1977; 107:896–908.
130 Roy SK, Tomkins AM. Impact of experimental zinc deficiency on growth, morbidity and ultrastructural development of intestinal tissue. Bangladesh J Nutr 1989; 2:1–7.
131 Bhatnagar S, Bahl R, Sharma PK, et al
. Zinc with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children: a randomized controlled trial. J Pediatr Gastroenterol Nutr 2004; 38:34–40.
132 Bhatnagar S, Sharma P, Bahl R, et al
. Zinc supplementation as an adjunct to ORT in children with non cholera diarrhea. Proceedings of the 9th Asian conference on diarrheal diseases and nutrition; 28–30 September 2001; New Delhi, India; 2001. p. 30.
133 Dutta P, Mitra U, Datta A, et al
. Impact of zinc supplementation in malnourished children with acute watery diarrhoea. J Trop Pediatr 2000; 46:259–263.
134 Bhan MK. Current concepts in management of acute diarrhea. Indian Pediatr 2003; 40:463–476.
135•• Lukacik M, Thomas RL, Aranda JV. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Pediatrics 2008; 121:326–336. This is a meta-analysis showing that zinc significantly reduces the duration and severity of acute and persistent diarrhea in children.
136 Bettger WJ, O'Dell BL. A critical physiological role of zinc in the structure and function of biomembranes. Life Sci 1981; 28:1425–1438.
137 Gebhard RL, Karouani R, Prigge WF, McClain CJ. The effect of severe zinc deficiency on activity of intestinal disaccharidases and 3-hydroxy-3-methylglutaryl coenzyme A reductase in the rat. J Nutr 1983; 113:855–859.
138 Fenwick PK, Aggett PJ, Macdonald DC, et al
. Zinc deprivation and zinc repletion: effect on the response of rats to infection with strongyloides ratti. Am J Clin Nutr 1990; 52:173–177.
139 Walker CF, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr 2004; 24:255–275.
140 Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990; 51:225–227.
141 Prasad AS, Brewer GJ, Schoomaker EB, Rabbani P. Hypocupremia induced by zinc therapy in adults. JAMA 1978; 240:2166–2168.
142 Porter KG, McMaster D, Elmes ME, Love AH. Anaemia and low serum-copper during zinc therapy. Lancet 1977; 2:774.
143•• Maverakis E, Fung MA, Lynch PJ, et al
. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol 2007; 56:116–124. This article reviews zinc metabolism and the clinical presentation of severe zinc deficiency. It also reviews laboratory indicators of zinc levels and provides recommendations for zinc replacement.
144•• Scrimgeour AG, Lukaski HC. Zinc and diarrheal disease: current status and future perspectives. Curr Opin Clin Nutr Metab Care 2008; 11:711–717. This article reviews the importance of zinc in protecting against and reducing severity of infectious diarrheal disease. It also provides recommendations for supplemental doses.
145•• Heyland DK, Jones N, Cvijanovich NZ, Wong H. Zinc supplementation in critically ill patients: a key pharmaconutrient? JPEN J Parenter Enteral Nutr 2008; 32:509–519. This article reviews the role of zinc supplementation in critically ill patients. It also provides recommendations for supplemental doses.
146 Matarese LE, Steiger E, Seidner DL. Review of a potential role for zinc supplementation in oral rehydration solutions. Nutr Clin Pract 2003; 18:240–246.
147 Sundaram A, Koutkia P, Apovian CM. Nutritional management of short bowel syndrome in adults. J Clin Gastroenterol 2002; 34:207–220.
148• Murakami M, Hirano T. Intracellular zinc homeostasis and zinc signaling. Cancer Sci 2008; 99:1515–1522. This article is a good review of the mechanisms of zinc homeostasis and the role of zinc signaling in immune cells.
149•• Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med 2008; 14:353–357. This article reviews the numerous and diverse roles zinc plays in the immune system.