Zinc & Human Health

Zinc is an essential element required for the activity of over 300 enzymes in the body, covering all six classes of enzymes. Zinc forms the catalytic centre in numerous enzymes and has an important structural role in a wide range of proteins, and is often a cofactor with vitamin B6. Vitamin B6 is also one of the most central molecules in the cells of living organisms. Together they are crucial to cellular metabolism such as amino acid biosynthesis, protein folding, cell division and growth as well as neurotransmitter activity.

Zinc deficiency is common in developing countries and affects over two billion people worldwide. Zinc insufficiency is widespread globally and is associated with inadequate protein intake. Zinc food sources are mainly muscle meats, squid and seeds (pumpkin and sunflower seeds are good sources for vegetarians). Globally, vegetarian populations and those eating less protein, such as the elderly, fall short in the mineral. In athletes, amino acid turnover increases the zinc demand.

Zinc deficiency symptoms

Zinc deficiency results in symptoms including poor prenatal development, impaired growth and mental retardation, impaired nerve conduction and nerve damage, reproductive failure, low testosterone and sperm counts, hypogonadism, low T3 hormone, hair loss, dermatitis, delayed wound healing, macular degeneration, loss of appetite from hypochlorhydria, loss of taste and smell, and immune dysfunction with susceptibility to infections such as pneumonia, low lymphocyte counts and thymic involution.

[1]

A common symptom of zinc deficiency is taste disorders and loss of appetite. Zinc administration improves taste in 50–82% of patients suffering from taste disorders.[2]

Zinc deficiency is known often to accompany Wilsons Disease, diarrhoea, type 2 diabetes mellitus, chronic kidney disease, cardiac insufficiency, short stature, and is also more common in the elderly, weightlifters and professional athletes.
Apart from the zinc deficient diet, other causes of zinc deficiency resulting from interference with zinc absorption such as chronic diarrhoea, liver diseases, cirrhosis, inflammatory bowel diseases, excess intake of phytic acid from some whole-grains, and other causes.[3]

Zinc has now been used to treat and prevent diarrhoea in infants and children throughout the world resulting in saving millions of lives.[4]

Zinc is needed in phosphatases (e.g. ALP), kinases, caspases, and phosphodiesterases (PDEs) – all critical to life. Zinc is also crucial for the detoxification function via the zinc metalloprotein, necessary for the removal of cadmium, lead and mercury. Without adequate zinc metalloprotein, Cd2+, Hg2+, Pb2+ and arsenite interfere with the refolding of proteins and cause oxidative damage.[5]

The prevalence of zinc insufficiency in Asian areas such as Japan and Hong Kong:

Percentage of people with zinc intake less than the RDA in Japan.  Blue bars for males and red bars for females.[6]

Note that Hong Kong’s average intake of 7.9 mg/day for women and 11 mg/day for men is essentially the same as from the Japanese diet. According to WHO standards used by the FEHD in Hong Kong, this is sufficient.[7]

The above Japanese data uses the USDA standards i.e. 3mg/day for children, 9mg/day for women (11mg/day if pregnant), and 11mg for men. Hong Kong women average 7.9 mg/day, therefore approximately half fall below this intake i.e. figures similar to the Japanese diet represented above. While Hong Kong men on average do consume the USDA recommended 11mg/day of zinc in their diet, statistically approximately half must consume less than the average. It is advised to include zinc blood testing if in doubt, especially if a low protein diet is consumed.

How to test for zinc insufficiency and deficiency
The Japanese Society of Clinical Nutrition issued Japan’s Practical Guideline for Zinc Deficiency 2018 setting forth the following criteria for diagnosing zinc deficiency:
(a) one or more symptoms of zinc deficiency or low serum alkaline phosphatase (ALP)
(b) ruling out other diseases
(c) low serum zinc, <60 μg/dL or 60–80 μg/dL respectively indicate zinc deficiency and marginal deficiency and
(d) alleviation of symptoms upon zinc administration.

When taking a blood sample for zinc serum testing is the most easily obtained, and is best taken from the fasting blood sample, since postprandial serum zinc levels rise.

Seek fasting serum zinc levels between 80 – 120 µg/dL, following the Japanese Society of Clinical Nutrition guidelines. Note that most labs tests report normal as over 60 µg/dL.

Zinc deficiency and low Alkaline Phosphatase (ALP)
ALP activity levels measured as a part of a liver function test (LFT) can indicate low zinc levels. Zinc (Zn) and Magnesium (Mg) are important causes of low ALP activity, that is levels < 45U/L. One 2017 study investigated Zn and Mg deficiencies as causes of decreased ALP levels and then to initiate supplementation of these minerals to examine the effects in humans. The study covered 42 persons having low ALP activity and 45 healthy controls. 52.38% of cases were found to be Mg deficient and 47.62% were Zn deficient. In the healthy controls with normal ALP, just 6.67% were Zn deficient and 13% had low Mg. Average zinc was 73.4±8.6 (µg/dl) in controls and 59.2 ±17.1 in the low ALP cases (p value <0.001). A significant decrease in Zn and Mg was observed in low ALP cases when compared with control (p<0.001, p<0.05). This human clinical study showed a positive correlation between the two minerals and ALP. Serum Zn and Mg are essential for the human body and by screening their deficiency, and supplementation of the appropriate mineral/s can normalize ALP, with benefits for liver, intestinal and bone health.[8]

Zinc and detoxification
The heavy metals, particularly cadmium, tend to displace zinc reserves, reducing heavy metal detoxification and allowing an increase in their toxic oxidative damage and related pro-inflammatory effects. For example, zinc restored the activity of GPx and SOD in the testes and attenuated DNA oxidation in the gonads of male rats exposed to cadmium.[9]

As zinc has similar chemical and physical properties to cadmium (Cd) and lead (Pb), it competes for the binding sites of metal absorptive and enzymatic proteins. Intake of zinc also induces the synthesis of metallothionein (MT) - a low molecular weight protein that has a high affinity for Cd and causes detoxification by binding Cd. Moreover, zinc intake has been reported to alleviate the oxidative stress caused by Cd and Pb exposure, which may be due to zinc’s functionality as a cofactor of the antioxidant enzyme copper zinc-superoxide dismutase (Cu/Zn SOD) as well as MT. Zinc is one of the most well studied essential metals for the alleviation of heavy metal toxicity.[10] 

Zinc and immunity

With advanced ageing the zinc pool undergoes progressive reduction both in humans and in rodents. It has been suggested that such zinc deficiency may be involved in immunosenescence and thymic failure. In particular, zinc is required to confer activity to the best-known thymic peptide, thymulin, responsible for cell-mediated immunity. Thymic involution common with age and the subsequent amplified release of auto-reactive T cells increase the susceptibility toward developing autoimmunity and inflammaging. Thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype with increased TNF-α, and elevated IL-6.[17]

Marginally zinc deficient old mice had significant increases in Lipopolysaccharide (LPS) and enhanced intestinal inflammation via macrophage activation of IL-1B, with increased IL-6 compared to zinc adequate old mice. Zinc supplemented old mice had significantly reduced plasma monocyte chemoattractant protein 1 (MCP1) levels, reduced T cell activated IFNγ, as well as more naïve CD4+ T-cells compared to zinc adequate old mice. This experimental data suggest that zinc deficiency is an important contributing factor in immune aging, and that improving zinc status can in part reverse immune dysfunction and reduce chronic inflammation associated with aging.[18]

Correction of zinc deficiency via supplementation in a study conducted in 2015 showed that after 3 months of adequate zinc supplementation, it not only improved serum concentrations, but produced a valuable effect on T-cell counts, which increased in both the number and activity in the treatment group compared to the control group.[19]

Zinc supplementation trials in the elderly reduced the incidence of infections by approximately 66%. Zinc supplementation also decreased oxidative stress biomarkers and decreased inflammatory cytokines in the elderly. In an experimental model of zinc deficiency in humans, zinc deficiency per se increased the generation of IL-1β following LPS stimulation. Zinc supplementation inhibited the activation of NF-κB, resulting in decreased generation of inflammatory cytokines. Zinc is very effective in decreasing reactive oxygen species (ROS) and increased SOD, an important intercellular antioxidant. Oxidative stress and chronic inflammation are important contributing factors for several chronic diseases attributed to aging, such as atherosclerosis, cancer, neurodegeneration, immunologic disorders and the aging process itself.[20]

The studies of age-related eye diseases study group in macular degeneration subjects has shown that during 10 years of follow-up, the mortality due to cardiovascular events in the elderly was significantly decreased in the zinc group.[21]

One study showed that zinc supplementation increased plasma antioxidant power, decreased plasma inflammatory cytokines, and oxidative stress biomarkers in the elderly subjects. Zinc decreased NF-κB activation and its target genes such as TNF-α, IL-1β, and VCAM and increased the gene expression of A20 and PPAR-α. Zinc decreased the expression of these cytokines and molecules by inhibition of NF-κB activation via A20 and PPAR-α pathways, as indicated by the diagram:

Signaling pathway for zinc prevention of atherosclerosis in monocytes/macrophages and vascular endothelial cells: a proposed hypothesis.
Reactive oxygen species (ROS) induced by many stimuli modifies LDL into oxidized LDL (ox-LDL) in macrophages and vascular endothelial cells. ox-LDL or ROS can activate the apoptotic pathway via activation of proapoptotic enzymes and the nuclear transcription factor κB (NF-κB) pathway via NF-κB inducible kinase (NIK) activation, which eventually results in the development and progression of atherosclerosis.

Zinc might have an atheroprotective function by the following mechanisms: (1) inhibition of ROS generation via metallothionein (MT), superoxide dismutase (SOD), and NADPH, and (2) down-regulation of atherosclerotic cytokines/molecules such as inflammatory cytokines, adhesion molecules, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), fibrinogen, and tissue factor (TF) through inhibition of NF-κB activation by A20-mediating tumor necrosis factor (TNF)-receptor associated factor (TRAF) signaling and peroxisome proliferator-activated receptor a (PPAR-a)-mediating crosstalk signaling.

The black arrows indicate up-regulation; arrows with a broken line indicate down-regulation or the inhibitory pathway. IKK, I-κB kinase; IL, interleukin; MCP-1, macrophage chemoattractant protein 1; CRP, C-reactive protein; ICAM-1, intercell adhesion molecule 1; VCAM-1, vascular cell adhesion molecule.[22]

It is worthwhile noting that high dose zinc for more than three months is potentially immune suppressive. A study of healthy 55- to 70-year-old individuals examined the relationship between zinc status and markers of immunity, following the effect of supplementation with 15 mg or 30 mg Zn/day for 6 months on immune status. At baseline, serum zinc concentration was positively associated with lymphocyte subpopulation counts and T-lymphocyte activation. Lower doses of Zn (15 mg Zn/d) significantly increased the ratio of CD4+:CD8+ T lymphocytes at month 6. However, Zinc supplementation of 30 mg/d significantly lowered B-lymphocyte count at the 6 months, beginning after three months.[23] There are other studies indicating excess zinc may negatively affect cognitive function.

High doses can effectively be given for two months in chronic viral scenarios such as viral warts. In a placebo-controlled clinical trial, eighty patients with more than 15 viral warts each (common, plantar and plane warts), were resistant to all forms of treatment, and had low serum level of zinc. Forty patients were treated by oral zinc sulphate at a dose of 10 mg/kg daily (i.e. 2.5mg/kg elemental zinc) up to 600 mg ZnSO4 (providing 150mg zinc) per day and followed-up for resolution of their warts and for any evidence of recurrence for 2-6 months. Another 40 patients were given a placebo oral treatment, and followed-up for the same period. In the zinc-treated group, the overall response was complete clearance of warts in 86.9% of those returning after 2 months of treatment. Fourteen patients (60.9%) showed complete disappearance of their warts after 1 month.[24]

Zinc is also essential for brain derived neurotrophic factor (BDNF) needed for brain neuron maintenance. Owing to this capacity, zinc is anti-depressive and is an essential CNS nutrient. [25] This again is especially worth to keep in mind in the elderly, in whom zinc optimization improves a multitude of senescence related symptoms. However excessive zinc may again be detrimental.

Recommended zinc supplement dosage
For adults, zinc can be given at doses of 30mg for insufficiency (60–80 μg/dL) and very high doses of 30mg bid for deficiency (<60 μg/dL). Continue for approximately 2 months. Once the optimal blood levels are achieved (at 2-3 months), then just 15mg daily is advised, and this is safe long-term. Long term (>3months) of 30mg may become immune suppressive, at least to the B lymphocytes.

Relatively high serum levels may be of value in managing high TNF-a, IL-6 related conditions, that is to manage inflammation. Zinc is unusual in that it can both stimulate immunity, but also down-regulate inflammation. This is a property shared with Vitamin D3.

Serum zinc testing will determine adequacy, seeking 80-120 µg/dL (10.7 - 22.9µmol/L). More anti-inflammatory effects will be gained in the higher end of the normal range. Normal zinc metabolism, such as ALP and immune function is gained at 80 µg/dL.

Many clinicians find that zinc levels seem to rise better when the supplement is taken with dinner. Zinc taken on an empty stomach may induce nausea.

The best supplemented forms of Zinc