Zinc

Zinc is an essential trace element that participates in over 300 enzymatic reactions as well as in metabolic functions, regulation of gene expression, apoptosis and immune modulation. ^[1] At the proteome level, zinc functions in more than 3000 human proteins, collectively described as the zinc proteome. ^[2] Zinc cannot be stored in significant amounts, so regular dietary intake is essential, and meat, seafood, dairy products, nuts, legumes and whole grains contain relatively high concentrations. ^{[3] [4]} According to the World Health Organization, the dietary reference value is 6.7 to 15 mg per day. ^[1] As an intervention, zinc is given as oral supplements such as zinc gluconate, zinc sulphate or zinc chloride, and common-cold trials have also used lozenges, syrups, tablets and intranasal preparations. ^{[3] [5]} Zinc deficiency remains a global public health issue, affecting close to half of all children in the few low-income and middle-income countries with data. ^[6]

Dietary zinc is transported from the duodenum into the enterocyte by ZIP4 and/or ZnT5B and from the enterocyte into the circulation by ZnT1, with amino acids and citrate promoting absorption and phytates, casein and calcium reducing bioavailability. ^[3] In circulation, 70% of zinc is bound to albumin, while most of the body's zinc is found in skeletal muscle and bone, and excretion is predominantly faecal. ^[3] Cellular zinc homeostasis is controlled by zinc importers (ZIP), exporters (ZnT) and zinc-binding proteins, and zinc ions regulate intracellular signaling pathways in innate and adaptive immune cells. ^[7] Zinc deficiency impairs innate immune mediators such as phagocytosis, natural killer cell activity and the oxidative burst, and causes dysfunction of both humoral and cell-mediated immunity with increased susceptibility to infection. ^{[8] [9]} Zinc deficiency is associated with the development of a pro-inflammatory phenotype, and although anti-inflammatory properties of zinc have long been documented, the underlying mechanisms are still not entirely clear. ^[7] Zinc ions are redox-inactive, so zinc is not itself an antioxidant, but it can have indirect pro-oxidant or antioxidant effects depending on how cellular zinc is buffered, notably through binding to cysteine sulfur.

Correcting deficiency is the established indication: patients with zinc deficiency should receive oral supplementation, and the inherited deficiency acrodermatitis enteropathica is treated with zinc gluconate, sulphate or chloride. ^{[11] [3]} A WHO-commissioned systematic review that included 38 RCTs in children younger than 10 years found that zinc shortened acute diarrhoea by a mean of 13.27 hours versus placebo (moderate certainty) but increased vomiting (RR 1.46), and the authors concluded the dose should be reduced. ^[12] For prevention of the common cold, a Cochrane review of 34 placebo-controlled trials (8526 participants) found zinc may produce little or no reduction in the risk of developing a cold (RR 0.93, 95% CI 0.85 to 1.01; low-certainty evidence). ^[5] When zinc is used to treat an ongoing cold, the same review found it may reduce mean cold duration (MD -2.37 days, 95% CI -4.21 to -0.53; 8 studies; low-certainty evidence with high heterogeneity), with a probable increase in non-serious adverse events (RR 1.34). ^[5] A separate systematic review in healthy adults likewise found that single-nutrient zinc supplementation may reduce cold duration by 2.25 days (95% CI -3.39 to -1.12), while micronutrients other than vitamin C may not prevent cold incidence.

Blood zinc is an incomplete measure of status: a recent perspective argues that deficiency in blood as the only measure of inadequate zinc status should be extended to cellular dyshomeostasis, and that additional biomarkers of cell-specific zinc status are needed. ^[2] Acquired deficiency usually presents later in life alongside risk factors such as malabsorption syndromes, and medications such as diuretics and angiotensin-receptor blockers can also cause it. ^[3] In a meta-analysis of inflammatory bowel disease, the pooled prevalence of zinc deficiency was 50% (54% in Crohn's disease, 41% in ulcerative colitis), and the authors advise listing zinc among trace elements monitored in serum. ^[14] Zinc deficiency can also occur as an isolated micronutrient deficiency in liver disease, and zinc status may be a concern in vegans because of limited bioavailability from plant foods. ^{[15] [16]} The European Food Safety Authority sets the tolerable upper intake level at 25 mg per day and the FDA allows 40 mg per day, and intake beyond recommendations may cause anemia, neutropenia and zinc-induced copper deficiency. ^[1]