Zinc suggest an improvement to this article

Background

Zinc is an essential nutrient that participates in numerous biological processes and modulates the activity of more than 300 enzymes and 2,000 transcription factors.[1] First identified for its influence on growth and development, zinc is now understood to play critical roles in immune function, protein synthesis, wound healing, DNA synthesis, and cell division.

History

The importance of zinc in the human diet first became apparent in the early 1960s, after a patient with a rare syndrome presented to Dr. Ananda Prasad, a physician working at a hospital in Shiraz, Iran. The patient, a 21-year-old male farmer who was pale, stunted, and physically and sexually underdeveloped, resembled a 10-year-old boy. The farmer also exhibited signs of severe anemia, his nails were spoon-shaped, and his liver and spleen were grossly enlarged. Over a period of three months, ten other patients with similar symptoms presented at the same hospital.[2] Prasad eventually identified zinc deficiency as the causative factor, and now, nearly 60 years later, Prasad is widely recognized as the world's leading expert in zinc metabolism.[3]

Dietary sources

Zinc is found primarily in animal products such as beef, poultry, and shellfish. Oysters contain the highest amount of zinc in foods, providing 39 milligrams per 100-gram serving (roughly six oysters).(Source: USDA) Most Americans obtain zinc through the intake of beef and poultry, which provide around 3 to 7 milligrams per 100-gram serving. To a lesser extent, zinc is also found in nuts, beans, and grain products; however, these foods contain phytates – natural substances in plants that inhibit the absorption of zinc and other minerals, thereby decreasing the minerals’ bioavailability.(Source: NIH) Estimates indicate that adults living in the United States obtain approximately 12 milligrams of zinc per day from foods, including naturally occurring zinc and zinc added to food via fortification and enrichment.[4]

The recommended dietary allowances, or RDAs, for zinc vary according to age, sex, and life stage of healthy people. Total needs are lowest in infancy and steadily increase into adulthood. Pregnancy and breastfeeding increase a woman's zinc needs due to zinc's essential roles in growth, development, and immune response.[5] The clinical indicators used to estimate zinc requirements include excretion and absorption patterns. The physiological signs of growth deficiency such as growth defects, increased infection risk, diarrhea, impaired cognitive function, delayed wound healing, and alopecia (the absence of hair on parts of the body) are typically not used to estimate requirements because they are difficult to quantify.[6] The RDAs for zinc are shown in Table 1.

Table 1. Recommended dietary allowances for zinc (Adapted) Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2001.

To reduce the risk of copper deficiency, a tolerable upper intake level for zinc has been established at 40 milligrams per day in adults aged 19 years and older. Acute intakes of zinc at doses over 50 milligrams per day is associated with gastrointestinal distress, abdominal pain, diarrhea, nausea, and reduced high-density lipoprotein, or HDL, levels.[7][8]

Zinc deficiency

The classic manifestation of severe zinc deficiency is observed in people with the genetic disorder acrodermatitis enteropathica, which results in severe zinc deficiency due to impairments in intestinal zinc uptake. People with acrodermatitis enteropathica have serum zinc levels of approximately 25 micrograms per deciliter, with symptoms that include growth and cognitive defects, chronic diarrhea, skin rashes, immunodeficiencies, impaired wound healing, taste abnormalities, and weight loss, among others.[9][10] The spectrum of symptoms identified in people with severe zinc deficiency is used to characterize mild to moderate zinc deficiency based on their zinc intake.[11] An estimated 4 percent of children and 8 percent of adults living in the United States are at risk of zinc deficiency. Zinc deficiency is uncommon in developed nations, but an estimated 2 billion people worldwide have low intake.[12]

Serum zinc concentrations in population-based studies have guided the establishment of cutoffs for determining zinc deficiency in individuals. These cutoffs are shown in Table 2. However, significant challenges exist in identifying zinc deficiency and establishing its prevalence due to the broad range of clinical manifestations that occur in people who are zinc deficient.

Table 2. Serum zinc concentrations for determining zinc deficiency in individuals. Abbreviations: mcg, micrograms; dL, deciliter

Populations at risk for zinc deficiency

Generally, dietary zinc intake among people living in the United States is thought to be at or above the RDA for all age groups.[13] People who follow vegetarian or vegan diets, consume alcohol, or have been diagnosed with certain diseases such as sickle cell anemia or gastrointestinal diseases may require higher intake than healthy people or those who consume meat.[8]

Evidence suggests that vegetarians and vegans may be at a higher risk of developing zinc deficiency due to the avoidance of meat products, which are high in zinc. Furthermore, vegetarians typically eat higher amounts of phytate-rich foods such as grains and legumes, which bind zinc and reduce its absorption. Consequently, vegetarians may require more of the RDA for zinc compared to people who consume meat. However, needs may vary widely depending on overall dietary composition.

Alcohol consumption decreases absorption and increases urinary excretion of zinc.[14][15] Alcoholics (who commonly consume more than a third of their calories in the form of alcohol) often have inadequate dietary intake of zinc compared to healthy people, and some estimates indicate that 30 to 50 percent of alcoholics are zinc deficient.[16][14] Furthermore, people who have alcohol-related liver disease due to excessive alcohol consumption typically have low serum zinc levels compared to healthy people.[17]

Zinc deficiency is associated with chronic liver disease, chronic kidney disease, sickle cell disease, diabetes, cancer, and gastrointestinal diseases.[1][18] Retrospective studies indicate that between 15 and 40 percent of people with an inflammatory bowel disease have zinc deficiency, which is associated with poor clinical outcomes.[19][20] An analysis of nearly 1,000 patients with inflammatory bowel disease (either Crohn’s or ulcerative colitis) determined that zinc deficiency was present in the majority of the patients and increased their risk of poor clinical outcomes. Patients with Crohn's disease who were zinc deficient were 44 percent more likely to require hospitalization, 103 percent more likely to require surgery, and 50 percent more likely to experience complications related to their illness. Similarly, patients with ulcerative colitis who were zinc deficient were 114 percent more likely to require hospitalization, 64 percent more likely to require surgery, and 97 percent more likely to experience complications.[21]

Measurement of zinc status

Zinc status is difficult to measure due to diurnal fluctuations in serum zinc concentrations, nonspecific biomarkers linked to zinc deficiency, and tight regulation of homeostatic zinc levels with zinc intakes between 5 and 20 grams per day.[22][23] Typically, zinc status is determined by measuring plasma or serum zinc concentrations from blood samples using simple and readily available techniques.(Source: MayoClinic) Normal serum zinc concentrations range between 70 and 100 micrograms per deciliter.[24]

A meta-analysis of 48 studies assessed the usefulness of various biomarkers of zinc status to determine how best to access zinc in response to supplementation or depletion. The analyses identified 32 potential zinc biomarkers, including zinc concentrations in serum, hair, and red and white blood cells; urinary and fecal zinc excretion; and enzyme activities. The analysis determined that serum zinc, urinary zinc excretion, and hair zinc levels significantly responded to changes in zinc intake outside the normal range for extended periods of time, whereas the findings for the other zinc biomarkers were inconclusive.[25]

Although serum zinc concentrations are the standard measurement of zinc status, accurately assessing this biomarker could be problematic due to fluctuations in serum levels by as much as 20 percent over a 24-hour period and the redistribution of zinc to various tissues upon exposure to a pathogen.[26] [27] Fluctuations in daily zinc concentrations may be a result of hormonal regulators and protein turnover. Additionally, reviews have shown that doubling zinc intake from 7 milligrams per day to 14 milligrams per day changed serum levels by only 6 percent, which would fall in the margin of error when measuring serum zinc.[28] Therefore, serum zinc levels could be different depending on the time of the day and health status of an individual. Hair turnover is slow; thus, the zinc levels in hair specimens might be useful in determining long-term zinc status but do not reflect recent changes with respect to dietary zinc status. In addition, dietary zinc intake status. In addition, hair zinc concentrations can vary with age, sex, and hair growth rate. More studies are needed to establish cutoffs to identify zinc deficiency using hair.[29][30] Urinary zinc excretion is tightly linked to whole-body zinc status, making it a valuable measure of zinc, but excretion levels do not provide a sensitive analysis of zinc status.

Identification of new biomarkers is needed to reliably and efficiently determine zinc status of individuals. Current research regarding zinc transporting and binding proteins such as metallothionein (described below) or zinc-dependent enzymatic activity may become better methods for assessing zinc status.[31][32] For example, the enzymes involved in the metabolism of omega-6 fatty acids seem to be particularly sensitive to the zinc status of the individual.

Zinc transport and absorption

Zinc is primarily absorbed in the jejunum, the second portion of the small intestine.[33] It is taken up into the enterocytes (cells that line the intestine) and passes into the general circulation. The absorbed zinc is primarily bound to albumin and transferred from the intestine to the liver via the portal system. However, zinc exists as a divalent cation (a positively charged ion) and cannot enter cells without a transporter. Uptake of zinc requires an ionophore, which is a molecule that can transport ions across a lipid membrane. Two major protein families facilitate zinc uptake and excretion: the ZnT (SLC30) family and the ZIP (SLC39) family.[34] In general, the ZnT transporters move zinc out of cells while the ZIP transporters import zinc into cells.[35] The metal-response element-binding transcription factor, or MTF-1, is considered the master cellular zinc sensor. MTF-1 responds to intracellular zinc levels and regulates the transcription of almost 200 genes, including zinc transporters and binding proteins.[36] Cellular distribution of zinc is as follows: 50 percent in the cytoplasm, bound to proteins or sequestered within vesicles; 30 to 40 percent in the nucleus; and 10 percent within the cell membrane.[35] Metallothioneins, a class of metal-binding proteins, control the storage and release of zinc within the cell.[37][36]

The average zinc absorption from a mixed diet of fruits, vegetables, and meat is thought to be around 33 percent; however, absorption may be as low as 20 percent depending on the particular foods consumed.[6][38] The body contains approximately 2 to 3 grams of zinc, with the highest levels found in skeletal muscle (60 percent) and bone (30 percent), and the remainder distributed throughout the body’s various tissues. Serum zinc is thought to comprise only 0.1 percent – roughly 2 to 3 milligrams – of the total zinc pool.[36] Approximately 75 to 85 percent of the serum zinc is bound to the protein albumin while the remaining is bound to alpha-2-macroglobulin and individual amino acids.[39]

Zinc homeostasis and bioavailability

Evidence suggests that there is an inverse relationship between dietary zinc intake and the percentage of intestinal zinc absorption. The use of stable isotopes has shown a direct relationship between increasing dietary zinc intake and fecal excretion. Similarly, decreases in dietary zinc intake are also directly related to decreases in urinary and fecal excretion, the body’s response to maintain zinc homeostasis.[40][41][42] This phenomenon was demonstrated in a 75-day metabolic study in which six young men ate a diet containing either 16.5 or 5.5 milligrams of zinc per day. With an intake of 16.5 milligrams of zinc per day, the absorption of zinc was approximately 25 percent. However, when the intake of zinc was 5.5 milligrams per day, absorption increased by 53 percent after 13 days, but only increased by 49 percent after 42 days.[43] In other words, whether ingesting an insufficient or excessive amount of zinc, the body will adjust the percentage of zinc absorption to maintain its exact needs.

Zinc and nutrient interactions

Zinc bioavailability can be affected by the co-ingestion of other dietary components. Phytates and iron can inhibit zinc absorption, while protein can increase zinc absorption.[44]

Phytate – a natural substance primarily found in seeds, nuts, legumes, and grains – is the primary dietary inhibitor of zinc bioavailability.[38] Typically, the germ and bran components of grain have the highest phytate levels, with up to 9 grams of phytate per 100 grams of grain.[45] A higher ratio of phytate to zinc, such as 50 milligrams of phytate to 3 milligrams of zinc found primarily with plant-based diets, can reduce zinc absorption by roughly half.(Source: WHO) (Source: ILSI)[46][47]

Although phytate inhibits total zinc absorption, the addition of animal protein to plant protein-based diets increases zinc bioavailability.[48][49] Further, evidence indicates that the percentage of zinc absorption from animal proteins is as much as 46 percent greater than from a plant protein source like soybeans, likely due to the higher phytate levels found in plant products.[50] Consequently, vegetarians or vegans who consume higher quantities of grains and legumes are likely to absorb less zinc compared to those consuming a mixed diet.

Food processing techniques such as fermentation, sprouting, and steeping can activate endogenous phytases – enzymes that break down phytate – and increase the bioavailability of zinc from plant products.[51][52][53] Furthermore, in vitro studies suggest that quercetin, a plant-based dietary compound, facilitates the transport of zinc into cells.[54] Foods that naturally contain quercetin include onions, green tea, apples, berries, Ginkgo biloba, St. John's wort, American elderberry, and buckwheat tea.

Evidence demonstrates that supplemental iron inhibits zinc absorption.[55] Studies in both young healthy women and pregnant women who took supplemental iron doses greater than 35 milligrams per day have reported decreased serum zinc concentrations among the women.[56][57][58][59] A single-meal study demonstrated that iron given as an aqueous solution of doses up to 5.585 milligrams per deciliter reduced zinc absorption in a dose-dependent manner. When iron was supplemented with the amino acid histidine or added to solid food, zinc absorption was minimally affected.[60] While supplemental iron may increase one's risk of zinc deficiency, intake of iron with a meal or with a zinc ligand such as histidine might negate iron’s inhibitory effect on zinc absorption.

Zinc and DNA damage

Zinc is a cofactor and structural component of numerous proteins involved in gene regulation, DNA repair, signal transduction, and antioxidant defense.[61] It is an essential component of the antioxidant enzyme copper-zinc superoxide dismutase and can induce the expression of other antioxidant enzymes such as metallothioneins.[62][63] The DNA binding protein p53, which guides a variety of DNA damage response mechanisms, requires zinc for proper function.[64][65] Thus, zinc deficiency is thought to promote oxidative stress and DNA damage. Clinical studies have found that inadequate zinc intake leads to an increase in DNA damage, but the damage can be reversed with zinc repletion.

A study in nine healthy men between the ages of 19 and 50 years determined that a zinc-deficient diet caused an increase in DNA strand breaks, but the DNA damage was mitigated with a zinc adequate diet. The men in the study ate a zinc adequate diet providing 11 milligrams of zinc per day for two weeks. Then they ate a zinc depletion liquid diet providing 0.6 milligrams of zinc per day for seven days and a low-zinc diet containing 4 milligrams of zinc per day for an additional four weeks. Zinc depletion was significantly associated with increased DNA strand breaks in the men’s blood cells compared to the zinc adequate diet. When the men resumed the zinc adequate diet along with 20 milligrams of supplemental zinc, the increase in DNA damage observed from zinc depletion was ameliorated.[66]

A separate randomized controlled trial in 40 women between the ages of 18 and 50 years analyzed the effects of zinc supplementation on intracellular DNA damage. The women had average serum zinc concentrations of 73.2 micrograms per deciliter and received a placebo or 20 milligrams of zinc per day for 17 days. The researchers found a significant decrease in DNA strand breaks in blood cells of zinc-supplemented women.[67]

Another study found that a modest increase of 4 milligrams of zinc can mitigate DNA single-strand breaks in leukocytes, a type of white blood cell. The study involved 18 healthy men between the ages of 19 and 45 years with normal serum zinc levels who consumed a moderate zinc diet containing 6 milligrams of zinc per day for six weeks. DNA single-strand breaks within leukocytes increased over this period but decreased after the men resumed a moderate diet containing 10 milligrams of zinc per day for four weeks. This modest increase of 4 milligrams of zinc per day also induced a global increase in serum proteins involved in DNA repair, antioxidant defense, and anti-inflammatory activity. These effects occurred without a change in serum, erythrocyte, or leukocyte zinc concentrations, indicating that modest changes in zinc intake can affect DNA integrity.[68]

Zinc and immune function

Zinc modulates numerous aspects of the immune system and is essential for proper immune function. Studies suggest that mild nutritional zinc deficiency (generally with serum zinc less than 70 micrograms per deciliter) impairs immune function due to decreased activity and regulation of the immune system.[69]

Clinical and mechanistic studies have shown that zinc deficiency can cause T cell dysregulation and decrease total T cell numbers.[70][71][72] T cells are immune cells that play important roles in both destroying pathogens and regulating the immune response. The functions of T cells are in part regulated by the zinc-dependent hormone thymulin.[73] Thymulin drives the differentiation of T cells and downregulates proinflammatory signals while upregulating the release of anti-inflammatory signals.[74] In mouse models of chronic inflammation, thymulin treatment decreased the pro-inflammatory response.[75][76] In a clinical study, zinc deficiency due to zinc restriction to just 3 milligrams per day corresponded with lower levels and decreased activity of thymulin. Thymulin activity was corrected with supplementation of 50 milligrams of zinc per day.[70]

Zinc is effective at fighting certain types of bacteria such as streptococcus pneumoniae, which can lead to the development of pneumonia, meningitis, and other serious infectious diseases. These bacteria require manganese to function properly and an in vitro study showed that zinc blocked the protein transporter in the bacteria that is responsible for importing manganese.[77] On the other hand, macrophages – a type of immune cell that engulfs foreign substances for degradation – were found to expose captured bacteria such as streptococcus pneumoniae to toxic levels of zinc.[78]

Multiple in vitro studies identified zinc and other compounds that stimulate cellular zinc import as inhibitors of RNA viruses.[79][80][81][82] One study in particular identified zinc as an inhibitor of RNA-dependent RNA polymerase – an enzyme that drives the replication of RNA from an RNA template – in the virus SARS-CoV-1. Zinc is a positively charged ion and cannot enter cells without a transporter. As described above, zinc requires an ionophore, a molecule that can transport ions across a lipid membrane. The zinc-ionophore (pyrithione) in combination with supplemental zinc inhibited RNA polymerase activity and blocked viral replication of SARS-CoV-1.[83] In addition, in vitro studies have identified quercetin as having antiviral properties against SARS-CoV-1 as well as other respiratory viruses such as rhinovirus, adenovirus, and other coronaviruses.[84][85] A recent bioinformatics analysis screened for drugs that could be repurposed for treatment of SARS-CoV-2 (the virus that causes COVID-19) and identified quercetin as one of the thirty potential drug candidates.[86]

Zinc also helps control infections by preventing excess inflammatory signals mediated by the innate immune system. Inflammation is a natural response of the immune system. However, excess inflammation can cause unwanted damage to cells. Researchers discovered that human monocytes – a type of immune cell – increased their import of zinc after recognition of a pathogen. The increase in cellular zinc was found to regulate the immune response by inhibiting proinflammatory signals such as lambda interferons.[87] A study in mice showed that an endotoxin-induced inflammatory response in zinc-deficient mice resulted in an increase in proinflammatory cytokines compared to controls.[88] This study demonstrated that zinc plays a role in regulating the immune system by preventing excess inflammation.

Zinc deficiency can lead to immune system dysregulation, a common feature in older adults.[89] Some researchers have estimated that people older than 65 have an intake of zinc less than half the recommended amounts.[90] Therefore, zinc supplementation may reduce aged-associated inflammation and immune dysfunction.

A study in 50 healthy older adults between the ages of 55 and 87 years provided participants a placebo or 15 milligrams of elemental zinc every day for 12 months. During the supplementation period, the average incidence of infections among those who took zinc was 0.29 infections per person, compared to the placebo group who had an average of 1.4 infections per person. In addition, the participants who took the supplemental zinc exhibited lower levels of serum markers of oxidative stress (malondialdehyde, 4-hydroxyalkenals, and 8-hydroxydeoxyguanine) after just six months of zinc supplementation.[91]

A separate randomized controlled trial in 118 people over the age of 65 years assessed the effects of zinc and vitamin A supplementation on the immune response. The participants received 800 micrograms of vitamin A, 25 milligrams of zinc sulfate (alone or in combination with vitamin A), or a placebo daily for three months. Those who received zinc alone had significant increases in a subset of T cell populations (CD4+ T cells and cytotoxic T cells). Those who supplemented with vitamin A had reductions in some of the measured immune cells (CD3+ and CD4+ T-cells.)[92] More studies are needed to determine what aspects of the immune system may be improved with zinc supplementation.

Zinc and pneumonia

Pneumonia is an inflammatory lung infection that impairs respiratory function. Pneumonia tends to be more severe among children under the age of 5 years and adults over the age of 65 years.(Source: NIH). Supplemental zinc may be effective at reducing the duration and severity of pneumonia in children and older adults.

Researchers have hypothesized that zinc deficiency in older adults is associated with decreased immune function and increased susceptibility to illnesses such as pneumonia.[93][94] A randomized placebo-controlled trial involved more than 600 participants over the age of 65 years who supplemented with or without 200 IUs of vitamin E per day along with a daily capsule containing 50 percent of the RDA for essential micronutrients, including zinc, for one year. At the end of the trial the participants were categorized into two groups: low serum zinc (less than 70 micrograms per deciliter) or normal serum zinc (greater than or equal to 70 micrograms per deciliter). The participants with normal serum zinc levels had a 48 percent lower incidence of pneumonia compared to those with low serum zinc levels. In addition, the duration of pneumonia among the participants decreased by nearly four days, and antibiotic use decreased by nearly three in those with serum zinc concentrations in the normal range compared to those with low concentrations.[95]

A separate randomized placebo-controlled trial in 270 children less than 2 years of age determined that in conjunction with standard antibiotic treatment, zinc reduced the recovery time and overall hospital stay of children with severe pneumonia. The children who received 20 milligrams of zinc per day experienced a shorter duration of severe symptoms by 30 percent compared to a placebo.[96] A meta-analysis of six randomized controlled studies that involved more than 5,000 children analyzed the effectiveness of zinc supplementation in the prevention of pneumonia in children between the ages of 2 and 59 months. The analysis determined that children who supplemented with zinc were 13 percent less likely to develop pneumonia.[97]

Zinc and the common cold

The average American has between two and three episodes of the common cold each year.[98] The economic burden of the common cold is approximately $25 billion due to loss of productivity and medical costs.[99] Evidence suggests that zinc in the form of zinc lozenges may be beneficial in reducing the duration of the common cold.

Zinc lozenges are typically sold as over the counter treatments for the common cold. Both acetate and gluconate are types of water-soluble salts typically used in formulations of zinc lozenges.[100] A meta-analysis of three trials involving nearly 200 patients between the ages of 20 to 50 years who were diagnosed with the common cold assessed the efficacy of zinc acetate lozenges on reducing the duration of a common cold. The analysis found that patients who supplemented with zinc at a dose between 80 and 92 milligrams per day recovered approximately three times faster compared to those who did not take zinc, based on typical cold symptoms. On the fifth day of supplementation, 70 percent of the patients who supplemented with zinc acetate lozenges had recovered, based on typical cold symptoms, compared to 27 percent of the placebo patients.[101]

A separate meta-analysis of seven randomized trials involving 575 participants assessed the efficacy of zinc acetate lozenges and zinc gluconate lozenges in common cold treatment. In the studies selected for the analysis, the zinc dose ranged from 80 to 207 milligrams per day, with three trials using zinc acetate and four using zinc gluconate. The pooled analysis of the seven trials indicated that zinc supplementation significantly reduced cold duration by 33 percent. The three studies that used zinc acetate reduced the duration of the common cold an average of 40 percent, but the four trials that used zinc gluconate reduced duration an average 28 percent. The difference between the two types of lozenges was 12 percentage points, but this difference was not statistically significant. The analysis further determined whether there was a dose-dependency between supplementation and the effect of zinc lozenges. Five trials used zinc doses between 80 and 92 milligrams per day while two trials used doses between 192 and 207 milligrams per day. The average reduction in common cold duration was 33 percent with the lower dose range and 35 percent with the higher dose range.[102]

Studies that have used doses less than 75 milligrams have been unsuccessful at decreasing the duration of the common cold. A meta-analysis of 13 placebo-controlled trials separated the trials by dose. Five of the trials used a total daily zinc dose of less than 75 milligrams while 10 trials used zinc in daily doses of over 75 milligrams. The five trials that used less than 75 milligrams of zinc found no effect while the 10 trials that used over 75 milligrams of zinc reduced the duration of colds by an average of 20 percent. Three of the 10 trials that supplemented with a dose over 75 milligrams used zinc acetate specifically, and the pooled result indicated a 42 percent reduction in the duration of colds.[103]

Taken together these analyses conclude that both zinc acetate and zinc gluconate are effective at reducing the duration of the common cold with zinc acetate being potentially more effective. Furthermore, zinc supplementation of at least 75 milligrams per day is needed to decrease the duration of the common cold.

Zinc and sepsis

Sepsis, a life-threatening inflammatory condition that can arise due to the body's response to a bacterial or viral infection, can cause severe injury to multiple tissues or organs.(Source: CDC) Many studies have observed that patients diagnosed with sepsis have significantly lower serum zinc concentrations compared to healthy people. These observations have led researchers to investigate zinc homeostasis and the effects of zinc supplementation in sepsis.

Patients diagnosed with sepsis commonly have low serum levels of zinc, an indicator of the severity of outcomes.[104][105] A study evaluated 44 patients, 22 admitted to the intensive care unit with sepsis and 22 critically ill patients without sepsis, along with 12 healthy donors for serum zinc concentrations in relation to disease severity. The healthy people had average zinc concentrations of 89.6 micrograms per deciliter of blood, which was in the normal range (70 to 100 µg/dL).[24] Upon admission to the intensive care unit, serum zinc concentrations among the patients without sepsis decreased approximately 36 percent, whereas among the patients with sepsis, concentrations decreased approximately 44 percent.[106]

A separate study in 44 patients diagnosed with surgically-induced sepsis found that persistent low serum zinc concentrations were associated with an additional septic episode along with higher in-hospital death, compared to 18 surgical patients without sepsis and 20 healthy people. The healthy people had serum zinc concentrations of approximately 72.5 micrograms per deciliter of blood. Serum zinc concentrations decreased 36 percent among the surgical patients without sepsis and decreased 64 percent among the patients diagnosed with sepsis. It is noteworthy that eight of the 44 patients diagnosed with sepsis died, and of these, their serum zinc concentrations had dropped nearly 60 percent 28 days after admission.[107]

Zinc and nutritional immunity

The decrease in serum levels of zinc observed in people with sepsis may be a result of nutritional immunity – a biological phenomenon wherein a host organism sequesters minerals such as zinc or iron in an effort to reduce a pathogen's virulence. During an infection, circulating levels of these minerals decrease rapidly and dramatically, starving the invading pathogens of essential nutrients and limiting disease progression and severity.[108]

To investigate zinc redistribution, researchers administered endotoxin twice a day to 12 healthy participants in order to induce an inflammatory response. Six hours after endotoxin administration, serum zinc concentrations decreased approximately 46 percent compared to baseline levels. The researchers concluded that zinc was redistributed throughout the body based on their observations that levels of serum zinc-binding proteins and levels of urinary excretion were unchanged.[109]1

Studies in mice suggest that zinc is primarily redistributed to the liver during infection. Mouse models of induced inflammation showed increased zinc concentrations and upregulated levels of the zinc transporter ZIP14 and the zinc intracellular binding protein metallothionein in the liver.[110][111] The increased levels of zinc in the liver may offer protection against infection, as evidenced by mouse studies demonstrating that zinc played a protective role against infection-induced lipid peroxidation (the degradation of lipids that leads to cell damage) in the liver.[112] Furthermore, some researchers have proposed that zinc redistribution during sepsis reprograms the immune system toward a fast innate immune reaction to boost the host’s immediate defense against a pathogen.[113]

Other researchers have suggested that zinc supplementation during sepsis could render a potentially harmless dose of zinc into a toxic one due to a decrease in albumin (a zinc-binding protein) during septic episodes. For example, concentrations of albumin decrease during sepsis and, in turn, reduce zinc binding capacity in the blood.[39] A study in pigs with endotoxin-induced sepsis demonstrated that the pigs’ serum zinc levels decreased linearly over a four hour period after induction. After four hours, albumin levels significantly declined, leading to reduced zinc binding capacity. When the pigs were supplemented with 16.5 micrograms per deciliter of zinc, their serum-free zinc concentrations increased.[114] Consequently, zinc supplementation during sepsis may counteract nutritional immunity and provide pathogens access to zinc.

Zinc supplementation for the treatment of sepsis

The drastic changes in serum zinc levels observed during sepsis have led investigators to study the effects of zinc supplementation on sepsis severity and outcomes. To date, zinc supplementation has only been effective in treating neonatal sepsis.

Multiple studies have demonstrated that zinc supplementation in neonatal sepsis can decrease disease severity and death.[115][116][117] A meta-analysis of four randomized controlled trials involving 986 newborns diagnosed with sepsis concluded that zinc supplementation reduced death rates by 52 percent compared to newborns not treated with zinc.[118] One of the trials in 614 neonates diagnosed with sepsis concluded that zinc supplementation does not have any influence on death rates.[119] However, the dose of zinc given to the newborns was 1 milligram per kilogram of body weight per day while the studies with positive outcomes used approximately 3 milligrams per kilogram of body weight, given one to two times per day. Therefore, the difference in dose may have contributed to the conflicting outcomes.

Zinc supplementation was also investigated in adults diagnosed with catheter sepsis or pancreatitis who were on total parenteral nutrition, a method of feeding fluids through a vein to provide adequate nutrition. The patients, who were in their 40s, were randomized to receive 30 milligrams of zinc or a placebo daily for three days. The patients who received zinc had a measured body temperature of 37.8℃ (100.4℉) while the patients without zinc had a temperature of 37.4℃ (99.32℉). The researchers concluded that zinc supplementation caused a significant increase in body temperature – an indication of an exaggerated inflammatory response.[120] Given that body temperature can fluctuate as much as 0.6℃ (1℉) during the day, at best zinc supplementation had no effect on the outcomes.(Source: University of Michigan)

Studies of induced sepsis in pigs have shown conflicting results with zinc supplementation.[121][122][123][124][124] The studies that observed positive outcomes provided prophylactic zinc supplementation while the studies showing adverse effects provided zinc supplementation during the septic episode only. Therefore, some researchers suggest that zinc supplementation during sepsis should be used with caution. However, data indicate that zinc supplementation is beneficial for treating neonatal sepsis, but more studies are needed to determine whether zinc supplementation in adults with sepsis can reduce disease severity and improve outcomes.

Zinc and HIV

Human immunodeficiency virus, or HIV, promotes systemic inflammation and immune dysfunction.[125] Reports suggest that 30 to 51 percent of people living with HIV are zinc deficient compared to healthy people.[126][127][128][129]

Zinc deficiency is associated with dysregulation of the immune system, along with increases in C-reactive protein, a pro-inflammatory marker.[130] Among people who are infected with HIV, C-reactive protein is an independent indicator of survival and is associated with disease progression.[131][132] A study in 311 HIV-positive people between the ages of 18 and 60 determined that increases in C-reactive protein concentrations were significantly associated with decreased serum zinc concentrations. Those with the highest serum zinc levels (greater than 80 micrograms per deciliter) had 44.2 percent lower C-reactive protein levels compared to those with zinc concentrations of less than 69 micrograms per deciliter.[133]

Zinc supplementation may also be beneficial in increasing CD4+ cell levels in people with HIV. CD4+ cells are white blood cells that fight infection and are used as a biomarker for HIV disease progression.(Source: NCBI) A study assigned 231 HIV-positive adults with less than 75 micrograms per deciliter of serum zinc to receive either zinc supplementation (12 milligrams of elemental zinc for women and 15 milligrams for men) or a placebo for 18 months. The study measured immunological failure measured by CD4+ levels dropping below 200 cells per cubic millimeter of blood. The study participants who took the zinc supplement were four times less likely to experience immunological failure compared to those who took the placebo. After 12 months, the rate of diarrhea among the participants who took the zinc supplement dropped by more than half compared to those who took the placebo, and the effect was maintained for the study duration.[134]

A meta-analysis of six randomized controlled trials involving HIV-positive children, adults, or pregnant women analyzed the efficacy and safety of zinc supplementation. The dose of zinc supplementation in the studies ranged between 10 to 100 milligrams per day over two weeks to 18 months. The authors of the analysis determined that CD4+ cell counts in adults and children increased with zinc supplementation but fell with the placebo or no treatment, regardless of the dose and duration, indicating that zinc may prevent immunological failure. Zinc supplementation elicited no benefit over the placebo on other outcomes such as viral load, death rates, mother-to-child transmission of HIV, and fetal outcomes such as miscarriage, stillbirth, fetal death and neonatal death.[135]

Zinc stabilized body weight in patients diagnosed with stage 3 and stage 4 AIDS and reduced the number of opportunistic infections that commonly occur due to a weakened immune system. A study involving 35 stage 3 patients and 22 stage 4 patients administered 200 milligrams of zinc sulfate (46 milligrams of elemental zinc) or a placebo co-administered with azidothymidine (a treatment used against HIV and AIDS) for 30 days. At 120 days post supplementation, zinc significantly increased stage 3 patients’ body weight and maintained stage 4 patients’ body weight. The patients who took a placebo lost approximately 2 kilograms of body weight, regardless of stage. The stage 3 patients’ CD4+ cell counts increased by 15 percent, and the stage 4 patients’ counts increased by 34 percent, compared to levels before supplementation. In contrast, CD4+ cell counts among those who took a placebo decreased by 32 percent in stage 3 patients and decreased by 40 percent in stage 4 patients compared to baseline levels. In the 24 months following entry into the study, the frequency of opportunistic infectious was markedly lower among those who took the zinc supplements. Stage 4 patients had 11 infections (compared to 25 infections among those who took a placebo), and stage 3 patients had only one infection (compared to 13 infections among those who took a placebo.[136]

Zinc and the treatment of acne

Acne is a chronic inflammatory skin condition that occurs when dead skin cells and oil from the skin clog hair follicles.[137] Zinc’s broad functions in immune and inflammatory regulation may affect acne prognosis and treatment.[138]

In teenagers with grade 3 moderately severe acne – characterized by numerous papules and pustules – serum zinc levels were lower than those observed in teens without acne.[139][140] One review analyzed data from 12 studies that tested zinc alone for the treatment of acne. Eight of the studies concluded that zinc was effective in treating acne while four of the studies concluded it was not. The oral doses of acne ranged from 30 to 150 milligrams per day for six weeks to 12 months. It is unclear why there is a discrepancy between results, but more studies are needed to determine which grade of acne zinc might benefit, along with the proper dose. An additional three studies utilized topical 1.2 percent zinc acetate with topical 4 percent erythromycin (an antibiotic) and found the combination to significantly improve acne compared to the placebo treatments. The combination of oral zinc complexed with additional antioxidants and natural compounds such as azelaic acid, copper, folic acid, vitamin C, and nicotinamide demonstrated significant improvement compared to placebo treatments.[138]

Zinc and its role in childhood development, disease, and death

The consequences of zinc deficiency in children include growth defects and increased rates of morbidity.[141] An estimated 4 percent of the global disease and death burden of young children in developing countries may be due to zinc deficiency, largely related to inadequate intake or absorption of zinc from the diet.[142] Zinc supplementation could eliminate zinc deficiency in children.

A meta-analysis of five studies evaluated the effects of zinc supplementation on growth outcomes in children less than 6 months of age. Four of the studies compared zinc with a placebo, and one compared zinc plus riboflavin (a B vitamin) versus riboflavin alone. All studies supplemented with 10 milligrams or less of zinc for a period of at least six months. Zinc supplementation positively affected multiple parameters of growth outcomes, including weight-for-age and weight-for-length compared to the placebo.[143]

A comprehensive review of 80 studies including more than 205,000 children between the ages of six months to 12 years analyzed the effect of zinc supplementation for preventing disease, growth failure, and death. The analysis observed that in 13 studies that reported death rates, there was a slight decrease in the relative risk of death with zinc supplementation, although the results were statistically insignificant. In 26 of the studies involving more than 15,000 children, zinc supplementation reduced the risk of all-cause diarrhea by 13 percent. When the studies were subdivided by dose (less than 5 milligrams, 5 to 10 milligrams, 10 to 15 milligrams, 15 to 20 milligrams, and 20 milligrams or more per day) there was no coherent pattern of increasing or decreasing effect on the incidence of diarrhea nor was there any effect when analyzed by study duration. In 13 studies including more than 8,500 participants, the prevalence of all-cause diarrhea decreased 12 percent, with potentially larger effects observed at doses above 15 milligrams per day. Vomiting was a reported side effect due to zinc supplementation.[144]

Diarrhea causes approximately 10 percent of deaths in children younger than five years, according to estimates from the World Health Organization.(Source: WHO) Diarrhea has also been a reported side effect of severe zinc deficiencies, particularly in the genetic disorder acrodermatitis enteropathica.[145] Evidence suggests that the mechanistic function for zinc in treating diarrhea is due in part to its capacity to maintain the integrity of gastrointestinal membranes, support the absorption of water and electrolytes, and enhance aspects of the immune system.[146][147]

A meta-analysis of 33 trials that included more than 10,800 children between the ages of one month and 5 years evaluated the effects of zinc supplementation on acute or persistent diarrhea. The doses used in the studies ranged from 5 to 45 milligrams per day. The analysis reported that zinc supplementation shortened the average duration of diarrhea by half a day but only in children over six months of age. The effect appeared greater in children with signs of malnutrition, with an average reduction of approximately one day. Across all age groups, zinc supplementation increased the relative risk of vomiting by more than 50 percent. The authors concluded that zinc supplementation may be beneficial in shortening the duration of diarrhea in children over the age of six months who are at risk of zinc deficiency.[148]

A randomized placebo-controlled trial in more than 42,000 children between the ages of one to 36 months accessed the effects of zinc supplementation on overall death rates. For approximately one year, the children received a placebo or 10 milligrams of zinc per day if older than one year of age and 5 milligrams of zinc per day if younger than one year. Additionally, all children aged 12 months or older were given 200,000 IUs of vitamin A every 6 months; children between the ages of six to 11 months were given 100,000 IUs. Overall, there was a 7 percent reduction in the relative risk of all-cause mortality with zinc supplementation, but the results were statistically insignificant. However, when the results were sub-analyzed by age, zinc supplementation in children 12 months and older reduced deaths among children by 18 percent.[149]

Taken together the studies of zinc supplementation in children suggest that supplementation may be effective in improving growth outcomes, decreasing the incidence of diarrhea, and reducing death rates in children older than 12 months.

Zinc and the brain

Zinc exerts a diverse range of effects in the brain throughout a person’s lifespan. During development, zinc is required for the function of numerous enzymes and proteins that are necessary for neurogenesis.[150] Zinc also plays a role in regulating communication between neurons.[151][152] Some researchers have suggested that zinc dysregulation during aging may contribute to neurodegeneration.[153] Zinc dysregulation is a common feature in people who have a traumatic brain injury or have been diagnosed with depression.

Zinc and Alzheimer’s disease

Currently, there is no consensus as to whether zinc concentrations in the brain are altered during Alzheimer’s disease progression. Some studies have demonstrated that zinc concentrations increase with Alzheimer's disease, while others demonstrate the converse.[154] Lower serum zinc concentrations among people with Alzheimer’s disease may be related to dietary inadequacies due to altered eating patterns and behaviors that can manifest with the disease. Alternatively, some researchers have observed abnormal expression of zinc transporters in the brains of Alzheimer’s disease patients, indicating that zinc redistribution in the brain may promote disease progression.[155][156][157] Additionally, amyloid plaques (aggregates of misfolded proteins that are characteristic of Alzheimer’s disease) sequester zinc and copper.[158] and in vitro studies have indicated that zinc can promote amyloid-beta aggregation.[159][160][161] The role of zinc in Alzheimer’s disease has divided researchers into two camps: those who believe zinc redistribution causes zinc deficiency or those who believe it causes toxicity. This divide has led to clinical trials testing zinc supplementation or zinc chelation (binding metal ions with small molecules) for the treatment of Alzheimer’s disease.[162]

A study in which six Alzheimer’s disease patients between the ages of 63 and 72 years took 15 milligrams of zinc methionine - a complex of elemental zinc and the amino acid methionine - twice a day for one year found that the patients performed better on cognitive tests compared to their baseline measurements, but over the remainder of the year, they followed the expected trajectory of decline.[163] A placebo-controlled trial gave 60 Alzheimer’s disease patients 150 milligrams of supplemental zinc or a placebo for six months. The patients who were given zinc showed minor but insignificant improvements in three neuropsychological tests. A subset analysis in the oldest patients (older than 70 years) revealed significant improvements in clinical dementia and Alzheimer's disease assessments.[164]

Some evidence suggests that metal chelators may be beneficial for the treatment of Alzheimer’s disease. Metal chelators are small molecules that can bind to metal ions. The metal protein attenuating compounds clioquinol (PTB-1) and the second generation compound PTB-2, which bind and sequester copper and zinc, have been tested in separate phase 2 clinical trials for Alzheimer’s disease. The trials indicated that the two compounds reduced serum amyloid-beta protein levels and had nominally significant effects on verbal fluency and working memory.[165][166] Follow-up studies have been halted due to manufacturing difficulties with PTB-1 and likely insufficient positive data for PTB-2.[167](Source: Alzforum)

A better understanding of zinc homeostasis derived from future research in patients with Alzheimer’s disease could help direct the recommendations of zinc supplementation and the development of new therapeutics.

Zinc and brain injury

Traumatic brain injury alters many aspects of metabolism and may increase the risk for zinc deficiency. A clinical study in 26 patients with head trauma found that all of the patients had increased urinary zinc losses, and these losses were particularly high among patients with a more severe head injury. The average peak urinary zinc losses increased approximately 1300 percent compared to normal excretion for someone consuming the recommended dietary allowance.[168]

A randomized controlled trial in 68 patients with severe closed head injury evaluated whether supplemental zinc could improve neurological recovery. Within 72 hours of injury, the patients were assigned to two groups receiving either an intravenous standard 2.5 milligrams of zinc or intravenous supplemental 12 milligrams of zinc every day for 15 days. For the following three months the patients received a placebo or 22 milligrams of oral zinc. The patients’ Glasgow Coma Scale scores, which are used to assess the level of consciousness in a person with traumatic brain injury, improved markedly by day 15 in the supplemental zinc group compared to the standard zinc group. One month after injury, 26 percent of the patients in the standard zinc group died, but only 12 percent of the patients in the zinc-supplemented group died. Several of the patients in the standard zinc group had to undergo brain surgery, however, which could have influenced the number of deaths.[169]

The available clinical evidence suggests that zinc supplementation may be beneficial as adjunctive therapy to those with traumatic brain injury, but more research is needed to determine the best practices for zinc supplementation.

Zinc and depression

The etiology of depression remains unknown but is widely believed to be multifactorial, stemming from a confluence of psychological, physiological, and environmental aspects. Selective serotonin reuptake inhibitors, or SSRIs, in conjunction with cognitive behavioral therapy, are typically the first line of treatment for people who have depression. The response to treatment with SSRIs is moderate and variable, however, ranging from 40 to 60 percent, with remission rates ranging from 30 to 45 percent.[170] The pathophysiology of depression has been linked to alterations in the activity of glutamate, a type of amino acid. In addition, a growing body of evidence suggests that the N-methyl-D-aspartate, or NMDA, a type of glutamate receptor, plays an important role in the neurobiology and treatment of depression.[171] Zinc is an NMDA antagonist and has been evaluated for its effectiveness as an antidepressant therapy.

A placebo-controlled study in 14 patients diagnosed with major unipolar depression tested the effects of standard antidepressant therapy with or without supplemental zinc. Fourteen patients were treated with standard antidepressant therapy (tricyclic antidepressants and/or SSRIs) and 25 milligrams of zinc or a placebo daily for 12 weeks. Zinc supplementation significantly reduced the participants’ depressive symptoms at six and 12 weeks of supplementation compared to the placebo.[172]

A larger placebo-controlled trial investigated the effects of standard antidepressant therapy with or without supplemental zinc in 60 treatment-resistant patients between the ages of 18 and 55 years who were diagnosed with depression. The patients received the antidepressant imipramine and 25 milligrams of zinc or a placebo per day for 12 weeks. The study concluded that the participants who took imipramine and zinc had significantly reduced depression scores, compared to patients who were given imipramine and a placebo.[173] These studies suggest that the effects of antidepressants can be enhanced with zinc supplementation.

Learn more about depression in our overview article.

Zinc is the most abundant mineral found in the human eye, where it concentrates in photoreceptors, a class of specialized cells in the retina that convert light into electrical signals.[174] Zinc participates in a wide range of activities in the eye, including aspects of cell metabolism, retinal development, and mediating the function of retinal-specific proteins essential for vision.[175] Some studies have associated aging with decreased levels of zinc in the eye, which may perturb zinc homeostasis and promote age-related neurodegenerative diseases.[176][177]

Age-related macular degeneration is one of the leading causes of vision loss, affecting more than 1.75 million people living in the United States and 196 million people worldwide.[178][179] A comprehensive review of 19 studies assessed the effects of vitamin and mineral supplements on age-related macular degeneration. Five of the studies compared zinc supplementation providing 30 to 50 milligrams of zinc to a placebo. The duration of zinc supplementation and follow-up measurements ranged from six months to seven years. People with age-related macular degeneration who supplemented with zinc were 17 percent less likely to progress to the late stage of macular degeneration, characterized as irreversible vision loss.[180] A separate review analyzed 10 studies and determined that due to inconsistent results, no conclusions could be made on the associations of zinc and the incidence of age-related macular degeneration. However, the authors of the review concluded that zinc treatment may significantly reduce the risk of progression to advanced age-related macular degeneration.[181] Zinc supplementation may be beneficial in preventing the progression of age-related macular degeneration to late stage.

Zinc and metabolic regulation

Zinc and diabetes mellitus

Zinc supplementation has been shown to improve glucose regulation in people with diabetes but may not be effective in healthy individuals without metabolic diseases. Type 1 and type 2 diabetes are generally characterized by the dysregulation of blood glucose levels. Type 1 diabetes is an autoimmune disorder in which the pancreas produces little to no insulin, while type 2 diabetes is an acquired disorder in which both insulin production and utilization are impaired. According to the Centers for Disease Control and Prevention, of the 34 million people living in the United States who have diabetes, approximately 90 to 95 percent of them have type 2. Similar rates have been observed worldwide.(Source: CDC)[182]

Zinc plays a major role in insulin biosynthesis. In the pancreas, insulin is stored as a hexamer (a structure composed of 6 individual subunits) containing two zinc ions. 1 Researchers showed that zinc prolonged insulin action when co-injected with insulin. Genetic variations in a zinc transporter expressed exclusively in insulin-producing beta cells confer type 2 diabetes risk.[50][50] Zinc supplementation may enhance blood glucose regulation in people who have diabetes.

A meta-analysis of 14 randomized controlled studies analyzed the effects of zinc supplementation on glycemic control. Of the 14 studies, four evaluated healthy people while the remaining 10 evaluated people classified as unhealthy due to obesity, diabetes, or metabolic syndrome. Zinc was used alone or in combination with other micronutrients at doses that ranged from 3 to 240 milligrams per day (median dose was 30 milligrams per day). None of the studies noted significant effects of zinc supplementation on HbA1c (a measure of long-term blood glucose control) or insulin levels. Fasting glucose concentrations among unhealthy patients who supplemented with zinc decreased by 8.8 milligrams per deciliter compared to controls. The studies with healthy people found no significant effect of zinc supplementation on fasting blood glucose.[183]

Another meta-analysis of 25 studies evaluated the effects of zinc supplementation on glucose and insulin regulation. The analysis included three studies on type 1 diabetes and 22 studies on type 2 diabetes. The duration of supplementation ranged from three weeks to five years with a maximum dose of 150 milligrams of elemental zinc per day. Sixteen studies supplemented with zinc alone and nine studies supplemented with zinc along with other vitamins and minerals. Twelve of the studies that compared the effects of zinc supplementation on fasting blood glucose in patients with type 2 diabetes found that zinc significantly reduced fasting blood glucose by an average of 18.13 milligrams per deciliter compared to placebo groups. Eight studies measured HbA1C and determined that zinc supplementation decreased HbA1c by 0.54 percent, a clinically significant reduction, compared to controls.[184]

Zinc and lipoprotein metabolism

The effects of zinc supplementation on serum HDL and low-density lipoprotein, or LDL, levels vary. A meta-analysis of 24 clinical trials that included zinc supplementation, either alone or in combination with other micronutrients, analyzed the effects on serum lipids. The duration of zinc supplementation ranged from one month to 6.5 months with the exception of one long-term study in which zinc was supplemented for 7.5 years. The dose of zinc supplementation ranged from 15 to 240 milligrams per day with an average dose of 39.3 milligrams per day. Of the 24 studies, seven involved participants with no preexisting conditions while the remaining involved participants with varying conditions including obesity, type 2 diabetes, heart disease, renal failure, and cancer. The analysis determined that HDL levels significantly increased by 6.15 milligrams per deciliter compared to a placebo, but only in the studies that included participants with preexisting conditions. In the studies with healthy participants, zinc supplementation significantly decreased HDL levels by 3 milligrams per deciliter. Furthermore, LDL decreased by 11.25 milligrams per deciliter among the participants with preexisting conditions who supplemented with zinc. Interestingly, zinc supplementation in healthy participants elicited a slight, but statistically and clinically insignificant, increase in LDL.[185]

Similar results were observed in a separate meta-analysis of 20 randomized controlled studies. The dose of zinc supplementation ranged from 15 to 150 milligrams per day with an average dose of 58 milligrams per day; the duration of zinc supplementation ranged from five weeks to seven years. When the studies were analyzed based on the health status of the participants, zinc supplementation lowered HDL levels by 3.86 milligrams per deciliter in healthy people, raised HDL levels by 13.9 milligrams per deciliter in those with type 2 diabetes, and raised HDL levels by 8.11 milligrams per deciliter in those undergoing dialysis. The analysis subdivided the studies according to zinc dosage and trial duration, but found no effect on HDL levels. In a single trial with dialysis patients, LDL levels decreased by 42.47 milligrams per deciliter, and in the studies in patients with type 2 diabetes, zinc supplementation decreased LDL, but the decrease was statistically insignificant.[186]

Taken together, zinc supplementation may be effective in decreasing the risk of cardiovascular disease in unhealthy people by decreasing LDL and increasing HDL levels. In healthy people, zinc supplementation at doses over 100 milligrams may result in reductions in HDL levels. Lower HDL levels are a risk factor for cardiovascular disease, so people supplementing with pharmacologic doses of zinc should exercise caution.

Zinc safety

Zinc intake is associated with both acute and chronic toxicity. Doses between 50 and 150 milligrams can cause acute gastrointestinal discomfort, diarrhea, and nausea, while doses over 200 milligrams can cause acute vomiting.[8][187] Copper deficiency is a reported consequence of chronic zinc intake.[188] Intranasal zinc has been used as a treatment for the common cold; however, this method can cause the loss of sense of smell.[189][190] Placebo-controlled studies have identified impairments in iron status in children who supplemented with 5 to 10 milligrams of zinc per day and in adults who supplemented with 22 milligrams of zinc per day.[191][192][193]

Chronic zinc intake of 150 milligrams per day or more may be associated with reduced immune function. A study in 11 healthy men who were given 150 milligrams of zinc twice a day for 6 weeks found that zinc supplementation reduced lymphocyte activation after four weeks of supplementation compared to baseline levels.[194] A study in more than 46,000 men found that taking more than 100 milligrams of supplemental zinc daily was associated with an increase in the relative risk of prostate cancer by 129 percent. Taking supplemental zinc for 10 or more years was associated with a 137 percent increase in risk. The men who supplemented with zinc also consumed more multivitamins and fish, but had lower intakes of red meat.[195]

A case-control study compared 184 men diagnosed with benign prostatic hyperplasia (enlargement of the prostate gland) and 246 men without clinical evidence of prostate disease to determine whether nutrition played a role in their disease initiation and progression. The men completed food frequency questionnaires regarding their dietary intake for the year immediately preceding their diagnosis. Analysis of the questionnaires revealed that higher intake of dietary zinc from meat and seed sources was significantly correlated with an increase in the overall risk of benign prostatic hyperplasia.[196]

Separate studies have found that in patients with prostate cancer, tissue zinc levels are decreased compared to normal tissue.[197][198] A meta-analysis that investigated the relationship between serum zinc concentration and prostatic disease found that serum zinc decreased in patients with prostate cancer but increased in patients with benign prostatic hyperplasia.[199] These studies warrant further investigation of zinc regulation and toxicity in its potential role in prostate disease.

Zinc supplementation also increased hospital admissions due to genitourinary disorders or conditions. A study involving 3,640 patients who had been diagnosed with age-related macular degeneration and whose average age was 69 years gave patients either a placebo or one of three treatments: antioxidants (500 milligrams vitamin C, 400 IUs vitamin E, and 15 milligrams beta-carotene), 80 milligrams zinc, or antioxidants plus zinc. The patients who supplemented with zinc were 47 percent more likely to be admitted to the hospital compared to the patients who did not supplement with zinc. There was no increase in the frequency of hospitalizations among the patients who supplemented with antioxidants compared to the patients who did not take antioxidants. Among women who supplemented with zinc alone, the risk of developing a urinary tract infection was 2.3 percent higher, compared to 0.4 percent higher among women who took a placebo. Among men who supplemented with zinc, the risk of developing kidney stones was 2 percent higher, compared to 0.4 percent higher among men who took a placebo, but these findings were not statistically significant. Additional studies are needed in more patient populations to determine the effect of zinc supplementation on genitourinary complications.[200]

Zinc supplementation and copper deficiency

Copper deficiency can lead to a decrease in red and white blood cell number and can cause damage to the spinal cord and peripheral nerves.[201] To prevent copper deficiency, the tolerable upper intake level for adults in the United States is 40 milligrams of zinc per day.

A study in 18 women between the ages of 18 and 40 years who consumed a total of 60 milligrams of zinc per day for 10 weeks found that the participants’ erythrocyte copper-zinc dismutase, or ESOD, levels decreased 47 percent compared to pre-supplementation levels.[202] ESOD is a copper- and zinc-dependent enzyme that converts an oxygen radical to hydrogen peroxide and can be used to measure copper status.[203][204] Interestingly, a study in four people who used zinc-containing denture creams found that the use of two tubes of cream per week containing 17 to 34 milligrams of zinc per gram of cream caused copper deficiency.[205]

Furthermore, 47 healthy participants who took 50 milligrams of elemental zinc or a placebo three times a day for six weeks reported symptoms including headaches, abdominal cramps, nausea, loss of appetite, and vomiting, but none of the participants experienced reduced serum copper levels.[206] However, the study did not measure ESOD activity to assess copper status, which may be more clinically relevant than serum copper levels.

Zinc supplementation and drug interactions

Zinc supplementation can reduce the absorption of antibiotics such as cephalexin and tetracycline.[207] A study found that 50 milligrams of elemental zinc decreased the bioavailability of cephalexin, but the drug’s bioavailability was not notably altered if the zinc was administered three hours after cephalexin dosing.[208] Additionally, zinc co-administered with ciprofloxacin (an antibiotic) or atazanavir and ritonavir (antiviral drugs used in the treatment of HIV and AIDS) decreased the drugs’ bioavailability.[209][210] When ciprofloxacin and zinc administration was separated by at least two hours, the bioavailability of ciprofloxacin was not affected. Therapeutic metal-chelating agents such as diethylenetriamine pentaacetate, a drug used to expedite the elimination of plutonium, americium, or curium following acute radiation exposure, can cause zinc deficiency.(Source: REMM)

Zinc supplementation

Zinc supplements are typically sold as varying forms of water-soluble salts such as zinc gluconate, zinc sulfate, zinc acetate, zinc citrate, zinc oxide, and zinc picolinate. Each of these supplemental forms contains different percentages of elemental zinc: zinc gluconate (14 percent), zinc sulfate (23 percent), zinc acetate (30 percent), zinc citrate (31 percent), zinc oxide (80 percent), and zinc picolinate (21 percent).[100] In other words, 220 milligrams of zinc sulfate contains 50 milligrams of elemental zinc.

While there are limited published studies evaluating the bioavailability of each form of supplemental zinc, zinc gluconate and zinc sulfate appear to be absorbed better than zinc oxide.[211][212] A study using stable isotopes compared zinc absorption of zinc citrate, zinc gluconate, and zinc oxide in 15 healthy adults. Each form of supplemental zinc was administered without food at a dose of 10 milligrams of elemental zinc. After measuring zinc isotope enrichment in urine samples, the researchers concluded that the absorption of zinc from zinc citrate was 61.3 percent and from zinc gluconate was 60.9 percent. However, the absorption of zinc from zinc oxide was 49.9 percent, indicating that zinc oxide had lower bioavailability than zinc citrate and zinc gluconate.[100] In the context of treating the common cold, there appears to be no meaningful difference between zinc acetate and zinc gluconate at doses of 80 to 100 milligrams per day.[102]

A separate study in 15 healthy men compared the absorption of zinc after oral intake of three forms: zinc picolinate, zinc citrate, and zinc gluconate. Each supplemental form was taken over a period of four weeks at an equivalent dose of 50 milligrams of elemental zinc. Compared to baseline measurements, there was no difference in serum zinc levels for any of the supplemental forms. Zinc levels in hair increased 4.5 percent, and levels in erythrocytes increased 20 percent after zinc supplementation, compared to baseline measurements. However, zinc picolinate also caused a 78 percent increase in urinary zinc excretion, indicating a decrease in zinc retention.[213] More clinical studies are needed to determine how zinc picolinate affects zinc status and whether increasing hair and red blood cell zinc levels have clinical significance.

Supplemental zinc is most effective when taken without food due to the inhibitory effects of organic substances such as iron and phytates.(Source: Mayo Clinic) However, if zinc causes a person to have gastrointestinal upset, it should be taken with food.

Conclusion

Zinc modulates the activity of more than 300 enzymes and 2,000 transcription factors that are involved in numerous processes such as immune function, protein synthesis, wound healing, DNA synthesis, and cell division. Inadequate zinc intake can lead to an increase in DNA damage and immune dysregulation, which can affect how the body responds to bacterial and viral infections. Zinc dysregulation is a common feature in people who have a traumatic brain injury or have been diagnosed with depression. Although uncommon in developed countries, zinc deficiency can lead to growth defects and increased rates of disease in children. However, zinc supplementation is an effective method for boosting the immune system to fight illnesses such as the common cold, pneumonia, acne, and metabolic disorders. Zinc homeostasis is important for many facets of human health, and future research should determine better biomarkers to effectively measure zinc status.

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