Common Name(s): Zinc, Zinc acetate, Zinc gluconate, Zinc sulfate, Zn
Zinc is an essential trace element necessary for normal human functioning. It serves as an enzyme cofactor and protects cell membranes from lysis caused by complement activation and toxin release. Zinc is not stored in the body; therefore, dietary intake is required. Meat and seafood are rich in zinc.1, 2 The role of zinc in human health and functioning has primarily focused on dietary supplementation for the promotion of health and disease prevention. Aside from dietary zinc supplementation, zinc has been studied for therapeutic use in the common cold, atopic eczema, psoriasis, acne vulgaris, degenerative retinal lesions, age-related macular degeneration, inflammatory bowel disease, and various other disorders.3, 4, 5, 6, 7, 8
Zinc is a metallic element available in various salt forms, including zinc gluconate, zinc gluconate-glycine, zinc acetate, zinc ascorbate, zinc orotate, zinc citrate, zinc chloride, and zinc sulfate. Zinc gluconate, zinc gluconate-glycine, and zinc acetate have been studied most often in the lozenge form for the treatment of the common cold.
Uses and Pharmacology
Trials evaluating the efficacy of zinc versus placebo or a comparator drug are likely to have methodological issues related to blinding, as the taste of the zinc preparation is difficult to mask. Therefore, subjective outcomes are likely to be affected by bias.9, 10, 11
Age-related macular degeneration
Cochrane systematic reviews have been conducted for both the prevention of age-related macular degeneration and slowing the progression of this disease.12, 13 No evidence exists to support the role of zinc in the prevention of macular degeneration or to delay its onset.12 Zinc supplementation slows the progression of the disease, but this beneficial effect should be weighed against the evidence of harm of long-term use of zinc, such as genitourinary problems.13
Zinc is found in high concentration in brain tissue and is important in neurotransmission across glutamatergic synapses.14 Zinc ions have been associated with the formation of beta-amyloid plaques that are characteristic of Alzheimer disease, but direct causality has not been established.11, 14, 15 Specific zinc-binding sites on the amyloid plaques have been demonstrated16 and acceleration of aggregation of amyloid peptides by zinc has been suggested.1 Other authors describe a protective role for zinc, noting that zinc deficiency is a common observation in elderly patients, and suggest that loss of zinc homeostasis may be important in Alzheimer disease.1, 11, 16, 17 Clinical trials are limited but focus on the chelation of free metal ions, which may prevent binding to beta-amyloid plaques.11, 18, 19
Attention-deficit hyperactivity disorder
Evidence from a systematic review of herbals and minerals for managing attention-deficit hyperactivity disorder (ADHD) found mainly positive support for zinc in the 3 studies enrolling a total of 496 children and adolescents. High-dose zinc (150 mg/day) produced significant improvements in hyperactivity and impulsivity but not inattention compared with placebo, while 55 mg/day added to methylphenidate resulted in greater improvements in symptoms versus psychostimulant alone. A third study found no significant difference with zinc 15 or 30 mg/day versus placebo or psychostimulant. It was noted by the authors that beneficial effects may have resulted from addressing zinc deficiencies.83
A Cochrane review of high-quality trials evaluating the value of zinc in the prevention of type 2 diabetes found no evidence to support the use of zinc supplementation.9 Zinc is thought to stimulate insulin action and insulin receptor activity. Trials evaluating the effect of zinc supplementation in the management of type 2 diabetes have found conflicting results, including no difference in serum zinc levels,20 no effect on glucose,21 reductions in total cholesterol and triglycerides,21 and improved antioxidant status.22, 23
Diarrhea (in children)
A Cochrane systematic review of clinical trials found evidence to support the use of zinc in the management of acute and persistent diarrhea in children older than 6 months of age.24 A decrease in the duration of diarrhea has been shown. Insufficient data are available from these trials on mortality outcomes, and vomiting was found to be more common among zinc-treated children than placebo-treated children. In contrast, a double-blind, randomized placebo-controlled trial in 134 children in India 5 to 12 years of age with acute dehydrating diarrhea (range, 6 to 27 diarrheal stools/day prior to admission) found no significant difference in resolution of diarrhea, rehydration, or hospitalization with zinc 40 mg for 14 days compared to placebo.92
Several trials have evaluated the relationship between zinc deficiency and male fertility, but direct causality is not established.25 Subfertility is seen in men with Crohn disease. Decreased serum zinc levels have been found in these patients.26 Other investigators suggest that seminal zinc levels are more important than blood zinc content. The ratio of copper/zinc has been found to be higher in men with sperm of abnormal motility.27 Among healthy volunteers, dietary intake of zinc did not appear to be associated with semen quality.28
In vitro studies in salmon sperm found negative effects of zinc on DNA at higher concentrations, despite previously demonstrated positive antioxidant effects.29 Similar positive results have been reported for the effect of zinc on sperm fragmentation, and negative findings on sperm head chromatin decondensation.30 In female rabbits, a zinc deficiency was correlated with abnormal estrous cycles, a disinterest in males, and an inability to conceive.29
Trials have been conducted to evaluate the effect of zinc in fertile and subfertile men, alone and in combination with folic acid.25, 31, 32 A difference in total healthy sperm count was found, but changes in serum zinc concentration could not be correlated to this effect.25 In large trials investigating the effect of antioxidants and vitamin/mineral supplements, an increased risk of some prostate cancers was associated with long-term administration of zinc greater than 100 mg/day.33 Case reports show that zinc supplementation in women results in improved fertility.29 A 2014 Cochrane systematic review and meta-analysis on antioxidants for use in male subfertility identified 4 trials (N=393) that investigated zinc alone or in combination with another antioxidant. Only 1 trial was identified that compared zinc to no treatment, which found an increase in live birth associated with zinc supplementation (P=0.05, N=100). A meta-analysis of the 2 trials (N=153; I2=0%) that compared zinc to placebo or no treatment on clinical pregnancy rates found a positive association with zinc (P=0.01). Sperm parameters were also shown to be improved with co-administration of zinc plus selenium (n=30) as well as zinc plus folic acid (n=103); the latter also improved varicocelectomy outcomes (n=160). Zinc was also one of 2 antioxidants associated with an increase in clinical pregnancy rate based on evidence from analyses of specific antioxidants.96
In an 18-month, double-blind, placebo-controlled, multicenter trial, 42 young patients with thalassemia major and low bone mass were randomized to receive placebo or zinc supplementation (25 mg elemental zinc daily). Approximately 25% of the participants had low plasma zinc concentrations upon enrollment. Of the 32 patients (mean age, 17.1 years) that completed the study, zinc supplementation resulted in significant increases in bone mass when compared with placebo, specifically for lateral spine and whole body bone content, and areal bone mineral density (aBMD). Adjusted spine and hip aBMD decreased by 0.3 standard deviations in the placebo group when compared with the zinc group over the 18-month period. It should be noted that the cohort sample was small with a large dropout rate (25%), 90.6% were Asian, and 80% were transfusion dependent.80
No significant change in bone alkaline phosphatase (BAP), a marker of osteoblastic activity, was observed in hemodialysis patients (n = 9) with normal-to-low bone turnover disease who received 18 months of daily zinc supplementation (34 mg elemental zinc) in a non-controlled study. However, the authors noted a significant trend of increase in BAP (P = 0.04).88
Respiratory tract infections
Zinc lozenges and zinc spray are designed to release zinc ions in the oropharyngeal cavity. The exact mechanism of action of zinc ions is still controversial but may involve a combination of actions. According to in vitro studies, zinc ions interfere with rhinoviral capsid proteins, thereby altering protease activity.34, 35, 36 However, zinc ions have not been shown to affect mature rhinoviruses. It has also been suggested that zinc may interfere with viral docking and the resulting inflammatory process.37 Another mechanism for zinc may involve the inhibition of histamine release from mast cells and basophils.38 Effects on immune function remain unclear and may be dependent on the dosage of zinc administered, with higher dosages being detrimental.33, 39, 40, 41, 42, 43
In a double-blind, randomized, placebo-controlled trial in 40 children with cystic fibrosis, daily zinc supplementation (30 mg/day) for 1 year was not found to have an effect on pulmonary exacerbations (upper or lower) or forced expiratory volume (FEV1) over the 12-month follow up period. Duration of antibiotic therapy, spirometry, and detection of Pseudomonas aeruginosa was similar between groups. Zinc was well tolerated.93
Upper respiratory tract infections/common cold
Methodological quality of the clinical trials is highly variable, making meta-analysis difficult. An earlier Cochrane systematic review (now withdrawn pending an update) was conservative in its recommendations regarding the role of zinc in the management of the common cold. Numbers needed to benefit ranged from 4 to 6, while numbers needed for harm (irritation of the oral mucosa and taste distortions) were almost equivalent (numbers needed to treat for one person to harm = 8).44
Other meta-analyses determined that zinc as a lozenge was not superior to placebo with regard to symptom duration or severity but noted wide variations in methodologies, including formulation issues related to blinding.10, 45, 46, 47, 48 As a nasal spray, zinc decreased symptom duration in one trial but was not different from placebo in another.49, 50 Pooling the effects of 3 double-blind, randomized controlled trials (n = 199) demonstrated that, in the absence of substantial heterogeneity, the use of zinc acetate lozenges significantly shortened the duration of the cold, nasal discharge, nasal congestion, scratchy throat, hoarseness, and muscle ache from 33% to 54% relative to the total duration for the placebo group (range, 5.1 to 8.1 days). No association was found between the effect of the zinc lozenge and symptoms originating from the pharynx versus non-pharynx regions. The zinc dose ranged from 80 to 92 mg/day.90 Because the presence of mannitol and sorbitol in the formulation of zinc lozenges has been demonstrated to chelate zinc ions in saliva and prevent their release, a meta-analysis of 7 trials (N=575) sought to minimize heterogeneity and re-evaluate the effects of only the acetate and gluconate formulations of zinc lozenges on duration of the common cold. Pooled data indicated an overall reduction in cold duration by 33% for zinc doses ranging from 80 to 207 mg/day; individual reductions were 40% for zinc acetate and 28% for zinc gluconate. The 12% difference between the 2 salt forms was not significant, which was further reduced to only 2% with the exclusion of 1 outlier trial. Additionally, no significant difference was found between the use of low-dose zinc (80 to 92 mg/day; 5 trials) and high-dose (192 and 207 mg/day; 2 trials); mean reduction in cold duration of 33% and 35%, respectively.97
Lower respiratory tract infections/pneumonia
Trials among residents of nursing homes for elderly patients have found a decrease in incidences of infections and oxidative stress markers and increases in plasma zinc levels with moderate zinc supplementation (15 to 45 mg/day).39, 40 In a large, multicenter study of 33 nursing homes, supplemental zinc was associated with a decrease in the incidence and duration of pneumonia and a decrease in antibiotic use.51
A clinical trial showed a decreased duration of pneumonia and reduced length of hospital stay in children treated with supplemental zinc 20 mg/day.52 Outcome measures such as chest indrawing, respiratory rate, and hypoxia were also improved. Baseline serum zinc was not measured. Other authors suggest a more conservative approach, as mixed results have been found, and suggest zinc may even be harmful in children with bacterial pneumonia.53, 54 A Cochrane review determined zinc supplementation to be associated with a reduction in the incidence (by 13%) and prevalence (by 41%) of pneumonia in children 2 to 59 months of age based on low-quality evidence. The reduction in incidence was most significant (reduced by 21%) when pneumonia was defined by specific and stringent clinical criteria, such as radiological examination. Overall, 6 studies conducted in Bangladesh, India, Peru, and South Africa involving 5,193 participants were included; daily doses were generally 10 or 20 mg of elemental zinc given for up to 20 months.94
Nutritional zinc deficiency has been associated with decreased wound healing by damaging epidermal cells and altering polymorphonuclear cell function, natural killer cell function, and complement activity.41, 42, 43 Delayed healing after burns because of micronutrient deficiency has been reported.55 Supplementation with selenium, copper, and zinc has been associated with increased circulating plasma and skin tissue ions, enhanced antioxidant status, and improved clinical outcomes in a small trial (n = 21) among burn patients.56 A Cochrane systematic review found no evidence to support the role of oral zinc sulfate in healing chronic venous ulcers.57, 58
In another randomized, placebo-controlled, double-blind trial conducted in Iranian high school females (n = 150) with primary dysmenorrhea and a pain score higher than 4 on the visual analog scale, reduction in pain was significant in the ginger (250 mg 3 times daily) and zinc sulfate (220 mg 3 times daily) groups compared with placebo (P < 0.001). Interventions were taken for 4 days; the day before menstruation and for the next 3 days. Adverse effects were not significantly different among groups.87 A Cochrane systematic review and meta-analysis of dietary supplements for dysmenorrhea identified only low or very low quality studies with very small sample sizes. Very limited evidence of effectiveness was found for the treatment of primary dysmenorrhea with zinc sulfate (50 mg daily × 3 months) compared to placebo or no treatment (1 randomized clinical trial, n = 99), and no difference in efficacy was identified between zinc sulfate 220 mg and ginger powder 250 mg 3 times a day for 4 days starting the day before menstruation to day 3 of menstrual bleeding × 2 cycles (1 randomized clinical trial, n = 150).91
A 2012 Cochrane review identified 2 randomized clinical trials evaluating zinc for atopic eczema/dermatitis that met criteria for analysis. Zinc supplementation (equivalent to zinc 67.5 mg/day) for 4 weeks did not result in significant changes in extent or severity of disease in 50 children 1 to 16 years of age. However, a significant reduction in mean itch scores was seen at 8 weeks.81
Use of zinc sulfate may provide benefit to patients with uremic pruritus based on 2 studies assessed in the 2016 updated Cochrane systematic review of pharmacological interventions for pruritus in adult palliative care. Each of the double-blind, randomized, placebo-controlled trials enrolled 40 patients suffering from uremic pruritus. Zinc sulfate 220 mg was administered twice daily for 8 weeks in one study and once daily for 4 weeks in the second. Although a statistically significant change from baseline was found in the 440 mg/day group (P=0.018), no statistically or clinically significant effects were found between treatment and placebo groups in either study.95
A double-blind, placebo-controlled randomized trial assessed the effect of zinc supplementation on depression and neurological signs in 50 multiple sclerosis patients with moderate to severe depression. Zinc sulphate 220 mg (elemental zinc 50 mg) was provided for 12 weeks. Mean depression scores were significantly lower after zinc supplementation with a significant association between response and changes in nystagmus and right hemiparesis. No changes were observed in neurological signs.89
The role of zinc remains controversial. Intracerebral zinc injections have been used experimentally to induce seizures. Animal studies suggest that lower zinc levels might modulate synaptic activity and be protective.18 A study of serum zinc levels in pediatric febrile seizures found a difference in children with low serum zinc levels and seizures when compared with age-matched controls.61
A double-blind, randomized, placebo-controlled community-based trial involving 200 infants (age, 6 to 24 months) from 4 countries in Central and West Africa, evaluated the effect of zinc added to vitamin A treatment in the incidence of clinical malaria. When given in combination with vitamin A, zinc gluconate 10 mg daily for 6 months significantly reduced the incidence of clinical malaria by 27% (P = 0.03) compared with children who received only vitamin A.82
A meta-analysis of 8 trials (N = 87,854) that reported mortality data in preschool children administered zinc supplementation revealed no effect of zinc (5, 10, or 12.5 mg/day) on overall mortality or mortality related to diarrhea, pneumonia, malaria, or other causes. A subgroup analysis did find an association with zinc and total mortality in boys older than 12 years of age when followed for less than 1 year.84
A Cochrane systematic review found only one well-controlled trial that met inclusion criteria evaluating the effect of zinc supplementation on cancer-related mucositis.64 The small trial (n = 27) found a difference in severe mucositis versus placebo. A further trial using zinc 75 mg/day found a difference in the time to develop mucositis and a reduction in the development of more severe grades.65
Taste disorders were common in elderly patients and correlated with low serum zinc levels; taste disorders were resolved in up to 70% of cases, with zinc administered daily (elemental zinc 34 mg) in one trial66 but not in another.67
The American Association of Otolaryngology – Head and Neck Surgery clinical practice guidelines for tinnitus (2014) recommend against the use of zinc or other dietary supplements for treating patients with persistent, bothersome tinnitus (moderate-quality aggregate evidence).85
Zinc salts (150 to 200 mg/day) are used in this rare autosomal recessive disease, in which copper accumulates in the liver, brain, and kidneys, and manifests as liver disease and neuropsychiatric symptoms.68
Zinc has been studied in clinical trials for a variety of diseases. Typical daily doses include 12 to 150 mg daily as free zinc, or up to 220 mg as zinc sulfate.11, 24, 40, 51, 64 Doses of 220 mg 3 times a day for 4 days starting the day before menstruation to day 3 of menstrual bleeding × 2 cycles were used in low quality studies in primary dysmenorrhea.91 Reviews of the role of zinc supplementation suggest a conservative approach that recognizes a differential effect, with lower doses having positive effect and higher dosages being potentially harmful, as well as the potential for displacement of other metal ions.69
Bioavailability of zinc is variable, with absorption generally better than aqueous solutions.70
Pregnancy / Lactation
Zinc supplementation in pregnancy has been studied. A Cochrane review found a slight reduction in incidence of preterm births, but no effect on low birth weight.71 No differences were found for maternal or other neonatal outcomes. The reviewers favor addressing overall nutritional status rather than focusing only on maternal zinc status.
Ingestion of zinc salts has been associated with a decrease in the absorption of orally administered tetracyclines72, 73, 74 and quinolone antibiotics (eg, ciprofloxacin, norfloxacin)75, 76 possibly decreasing the anti-infective response.
Interference with absorption and metabolism of iron, copper, and vitamin A has been described and is relevant considering the coexistence of other micronutrient deficiencies common in zinc deficiency.69
The most common adverse reactions reported in clinical trials for zinc lozenges were nausea, bad taste, diarrhea, vomiting, mouth irritations, and mouth sores. For zinc spray, nasal irritation and throat irritation were reported most often.
There are case reports of high-dose, chronic zinc supplementation resulting in severe copper deficiencies, and manifesting as sideroblastic anemia, neutropenia, and irreversible neurological symptoms.60, 77, 86 Immune dysfunction and myelopolyneuropathies consequent to zinc overload have been described.33, 78 An increase in genitourinary symptoms and some prostate cancers has been found in large trials evaluating the role of zinc in age-related eye disease.33
Information is lacking.79
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