• Zinc is present in all organs, tissues, fluids and secretions. About 90% of total body zinc is found in skeletal muscle and bone, with much smaller amounts in the liver, gastrointestinal tract, skin, kidney, brain, lung, prostate and other organs.
• The adult human body contains approximately 1.5 to 2.5 grams of zinc.
• In general, about 20% of zinc consumed from a usual mixed diet is absorbed. Unlike other trace elements, zinc does not accumulate in the body to form permanent stores .
• Processing of certain foods may affect amount of zinc content that is available for absorption. Heat treatment may make foods resistant to hydrolysis, by complexing with zinc, making it unavailable for absorption.
• Zinc is primarily an intracellular ion and it functions in association with more than 300 different enzymes of various classes.[~20~]

• Zinc is needed for DNA synthesis, RNA transcription, mitosis, and cell activation.[~21~]
• Zinc-dependent enzymes are involved in metabolism of proteins, lipids and carbohydrates.
• Zinc plays as essential role in cell membrane integrity.
• Zinc helps manage insulin action and blood glucose concentration.
• Zinc has an essential role in development and maintenance of the body's immune system.
• Zinc is required for bone and teeth mineralization.
• Zinc is involved with normal taste and wound healing.
• Zinc is required for the synthesis of various biological markers of nutrition and of collagen.[~22~]
• Zinc is essential in regulating gene expression.
• Zinc has long been considered to have anti-inflammatory properties.[~21~]
• Zinc containing enzymes such as carbonic anhydrase and lactate dehydrogenase are involved in intermediary metabolism during exercise.[~17~]
• Zinc is particularly important for cells that are rapidly turning over such as those in the immune system; as well as in the maintenance of the central nervous system.[~16~]

• Zinc can be deficient even if plasma levels appear to be “normal.” A practical criterion is clinical response to zinc supplementation.[~37~]
• Traditional indicators of zinc status such as plasma levels and measuring activity of zinc metalloenzymes in blood are relatively resistant to changes in dietary zinc. A good way to measure zinc levels is by looking at granulocytes and lymphocytes because they reflect the body’s zinc status fairly accurately. A quantitative assay of alkaline phosphotase activity in the granulocytes is also very useful. [~23~]
• Numerous factors play a role in zinc deficiency. These include poor dietary zinc intake, excessive dietary phytate intake, chronic illness, malabsorption, or over-supplementation with iron or copper.[~27~] [~38~]
• Incidence of zinc deficiency in well-nourished humans is unknown due to difficulties in sufficiently diagnosing zinc deficiency and the diversity of its metabolic roles.
• Among the most sensitive enzymes to dietary zinc intake are deoxythymidine kinase (involved in skin collagen formation) and alkaline phosphotase (involved in the function of granulocytes).[~21~]
• Symptoms of zinc deficiency include poor growth and development, appetite loss, dermatitis, hypogonadism, alopecia, reduced taste acuity, delayed wound healing, impaired reproduction and poor immune function.
• Growth retardation and delayed sexual maturation have been some of the most characteristic features of zinc deficiency.[~21~]
• Clinical zinc deficiency in breastfed infants is accompanied by rashes, dermatitis, failure to thrive, decreased zinc levels in the serum and irritability.[~33~]
• Severe zinc deficiency is rare and caused by genetic or acquired conditions. Acrodermatitis enteropathica is an autosomal recessive inherited condition of severe zinc deficiency. Symptoms include eczematoid skin lesions, alopecia, diarrhea, bacterial and yeast infections, and eventually death if left untreated.[~40~]
• Moderate deficiency leads to rough skin, poor appetite, mental lethargy, abnormal neurosensory change.[~21~]
• Mild deficiency symptoms include low testosterone levels, oligospermia, decreased natural killer cell activity, decreased interleukin-2 activity and decreased activity of T helper cells. In addition it may lead to decreased thymulin activity, hyperammonemia, hypogeusia, decreased adaptation to darkness, and a decrease in lean body mass.[~21~]It’s also been suggested that immature B cells accumulate in the spleen in zinc deficiency and as a result lead to enlargement of this organ.
• Other conditions and populations associated with increase risk for zinc deficiency are:

  Alcoholism	Trauma	Elderly	Sicle cell anemia
  Stress	Surgery	Lacto vegetarians	Chronic renal disease	Anorexia Nervosa [~28~]
  Malabsorptive syndrome	Geophagia

• Acute zinc toxicity is rare but has been reported. Outbreaks of acute zinc toxicity have occurred as a result of food and beverage intake contaminated with zinc from galvanized containers, and industrial or accidental exposure. There is also a report regarding one patient suffering from schizophrenia who swallowed one kilogram of pennies, which were made out of zinc and covered with a thin copper layer, resulted in sideroblastic anemia and neutropenia. Ferric iron accumulated in the mitochondria and erythrocyte precursors. Intakes of 2 g or more of zinc sulfate can cause GI irritation. [~22~] Other acute toxicity symptoms include metallic taste, nausea, vomiting, lethargy, fatigue, diarrhea, muscle pain and fever.
• Chronic zinc toxicity (100-300 mg/d) is more common than acute toxicity and may retard immune function. This type of toxicity occurs from self-supplementation or prolonged use of oral zinc supplements for medicinal purposes.
• Excess zinc may also effect copper and iron status and lower plasma HDL concentrations.

• Adult women are more likely to consume inadequate amounts of zinc. Data reported from NHANES III and CSFII confirm a low dietary intake of zinc for adult women. Results from the Total Diet Study in 1991 indicated that the amounts of zinc provided by the typical diet are below the required daily allowance for children, adolescent females, and women during their reproductive years.[~34~] The side effects commonly exhibited may include amenorrhea, weight and appetite loss, and skin abnormalities.[~26~]
• During pregnancy, there are increasing zinc requirements to meet the needs of the mother as well as the developing fetus. Since nutrient stores are deposited during the last three months of pregnancy, a premature fetus is greatly compromised. Zinc is usually the first mineral to be immediately supplemented when it comes to the premature infant. Since zinc is deposited into the body's tissues, low birth weight or intra uterine growth retardation could limit zinc reserves and lead to quick zinc defiency once the child is born. [~32~]
• Both men and women are at risk for zinc deficiency especially between puberty and the age of 25 due to low dietary intake of zinc as well as increased urinary zinc loss secondary to estrogen and/or stress.[~26~]
• Zinc deficiency is commonly found in people with eating disorders, malabsorptive syndrome, alcoholic liver disease, chronic renal disease, sickle cell anemia, chronically debilitated individuals, and in those cases when patients present with geophagia. [~22~]
• Genetic disturbances in zinc metabolism occur in acrodermatitis enteropathica which result in severe zinc deficiency.[~39~] It's been noted that supplementation with zinc results in increased hedonic tone, motivation, alertness, responsivity, and a decrease in nervousness and restlessness in these patients.[~46~]
• Patients on TPN may also suffer from zinc deficiency if not adequately replaced since the body loses 6-12 mg of zinc per day. Zinc deficiency can be fatal if left untreated. Common signs of the zinc deficient TPN patient include pustular dermatitis, alopecia, diarrhea, immune dysfunction, weight loss, intercurrent infections due to cell mediated immune dysfunctions and hypogonadism in males. [~30~] [~22~]
• Because of Zinc's role in cellular growth it is of particular importance in early childhood as well as for patients needing tissue repair.¹⁴ There is also an increased risk of pneumonia in children with zinc deficiency. [~27~] Reduced rates of anorexia, cough, diarrhea, fever, and vomiting among zinc supplemented children with stunted growth have also been observed. Studies suggest that zinc may be a more important limiting factor to growth among children in the first two years of life when zinc requirements are higher than compared to older children. [~36~] Special attention also needs to be placed on children with potential zinc deficiency because, unlike adults, they tend to fail to adapt to the increased absorption of zinc that happens naturally in adult when there are decreased levels of zinc in the body. [~37~]
• Older adults often have marginal zinc status.
• Individuals totally dependent in IV feedings without added zinc can experience severe zinc deficiency ²

Therapeutic dosages usually between 5-10 mg of zinc have been used for the treatment of acute diarrhea in infants and children.[~19~] Therapeutic doses of zinc for the common cold usually range between 10-50 mg of zinc given every 6-8 hours throughout the day. Zinc is usually the preferred therapy to treat Wilson's disease and sickle cell anemia sinc it has proven to be an effective treatment and is relatively non toxic.

The increasing number of reports that daily supplementation with zinc affects the activities of selective metalloenzymes along with specific cellular and organ processes, further point out the need to differentiate between meeting the requirements for this nutrient and optimal nutrition.

• Excess zinc can interfere with copper absorption and cause a copper deficiency, which indirectly affects iron status and leads to anemia. Zinc blocks dietary copper but also endogenous copper as well as that in salivary, gastric, and gastrointestinal juices, and so it tends to produce a chronic negative balance. However these characteristics make it an excellent treatment for Wilson’s disease in which excessive copper accumulations occur. In the treatment of Wilson’s disease the dose given is usually 50 mg of elemental zinc (as acetate) 3 times a day given in a fasting or post-absorptive state. It is relatively non-toxic and only about 10% of patients on this therapy complain of stomach upset which is relieved by taking zinc only in the post-absorptive state instead of the fasting state.[~31~]
• In the treatment of patients with sickle cell anemia, zinc supplements have been found to induce hypocupraemia and associated neutropenia and microcytosis. This condition can be corrected by administration of copper. [~22~]
• Excess copper intake, calcium, dietary fiber, or iron supplements can decrease absorption of zinc. Intake of iron supplements should be separated from zinc-containing supplements.
• Zinc interferes with folate absorption.
• Many minerals, including zinc, may interfere with absorption of fluoroquinolone antibiotics, such as lomefloxacin [Maxaquinâ], and tetracyclines, such as doxycycline [Doxycinâ]. To prevent this interaction problem, take mineral supplements far apart from antibiotic intake.
• Angiotensin-converting enzyme (ACE) inhibitors may cause zinc depletion.
• Zidovudine [AZTâ], an antiviral agent used to treat HIV infection, may deplete plasma concentrations of many minerals, including zinc.
• Orlistat or any medication which can result in steatorrhea or malabsorption can lead to poor absorption of zinc and possibly deficiency. [~42~]
• The use of some chelating agents, such as penacillamine is used in the treatment Wilson’s disease and other various chronic debilitating illnesses may also lead to zinc deficiency. [~30~]
• More research is needed to assess the bioavailability of different zinc compounds used in supplements. However, looking at a meta-analysis of 25 clinical trials including compounds such as zinc sulfate, zinc acetate, zinc gluconate, zinc methionine, zinc carbonate and zinc oxide it is reasonable to conclude that zinc acetate and zinc sulfate are fairly similar in terms of bioavailability, and that zinc oxide and zinc carbonate are usually poorly absorbed. However this meta-analysis is limited by the amount of data available. Most data available involves either zinc sulfate or zinc acetate. In addition, when investigating how the source of zinc was decided for each trial scientists stated that they were limited to only using compounds which the subjects found palatable. Apparently zinc sulfate has an acceptable taste in doses of 15-50 mg if mixed with citric foods such as orange juice. [~16~]

An increasing number of studies indicate that linear and ponderal growth and incidence of infections among children are responsive to zinc supplementation.[~18~] One study in particular concluded that zinc treatment (10 mg zinc as acetate 2x/day for 5 days) significantly reduced duration of fever and very ill status in boys with severe Acute lower respiratory infection (ALRI)[~24~]. [~25~] Reduced rates of anorexia, cough, diarrhea, fever, and vomiting among zinc supplemented stunted children were also observed and it’s been suggested that these factors contribute to the improved growth response seen in such cases[~35~]. ^{2 10 11}

Immunity: Zinc is a potent mediator of host resistance to infection. This is due to its many roles in basic cellular functions such as DNA replication, RNA transcription, cell division and activation. Numerous animal and human studies indicate that zinc deficiency lowers resistance to infectious diseases. In humans, several studies demonstrated the benefits of zinc supplementation on infectious diseases. Zinc supplementation has been shown to benefit acute and chronic diarrhea and related sickness, acute lower respiratory infections and malaria. Zinc supplementation restored those immunologic indexes associated with sickle cell anemia to near normal. Zinc supplementation normalized certain immune functions and increased resistance to infection in patients with Down's Syndrome. It is suggested that immunodeficiency in the elderly is due in part to zinc deficiency.²

Pregnancy: Taking a multiple vitamin and mineral supplement with zinc during gestation is one way to ensure a healthy baby . Adverse fetal outcomes associated with maternal zinc status include congenital anomalies, reduced birth weight for gestational age, neural tube defects, and fetal brain function. Maternal complications such as preeclampsia, prolonged labor, and pre-term delivery have also been associated with zinc status. A study conducted in California showed the risk of neural tube defects was associated with increased maternal preconceptional zinc intake.¹²Women who have altered zinc utilization may be advised to take ~25 mg zinc during pregnancy to reduce the risk of complications.¹³ However, a study reported that gestational plasma zinc concentrations may not accurately predict pregnancy outcomes. In addition, more recent studies have shown that a mild zinc deficiency increases maternal morbidity, may result in inefficient labor, and lead to increased bleeding which pose increased risks to the fetus as well[~31~].

Vision: Zinc is known to interact with vitamin A in the retina and control the light-rhodopsin reaction within the photoreceptor. Zinc deficiency appears to play a role in developing some degenerative eye diseases. Zinc has also been studied in relation to blindness and age related degeneration. The study involved one group of patients on an antioxidant plus zinc, a second group on zinc only, and a third on vitamins only, no zinc. The group which received the antioxidant plus zinc had about a 25% decrease in risk of AMD and a 19% decrease in risk of vision loss. The group which received only zinc showed a 21% decrease in risk for developing AMD and an 11% decrease in risk for vision loss. The group which received only the antioxidant vitamins without zinc had a 17% decrease in the risk for AMD and a 10% decrease in the risk for vision loss. None of the groups experienced any side effects[~52~].

Diabetes: The evidence for increased zinc excretion in both types of diabetes is uniform. Studies continue to show that serum and plasma zinc concentrations are lower in diabetes groups vs. control groups. ¹⁵

Prostate cancer: In patients with malignant prostate cancer, high zinc levels which are normally found in normal glandular epithelial tissue, are all greatly reduced by 70-80%. There is no known case where malignant tissue has retained the high zinc or citrate levels which are normally characteristic of healthy prostate tissue. Epidemiological studies have produced contradictory results which have led to the conclusion that the effect of dietary zinc on prostate cancer is complex and possibly confounded by many factors[~47~] [~48~].

Anorexia nervosa: Randomized, double blind, controlled clinical trials indicate that zinc therapy enhances the rate of recovery in these patients by increasing weight gain and by improving levels of anxiety and depression[~25~]. The mechanism for these results has not been identified. .

Osteoporosis: Some studies indicate that urinary zinc reflects bone resorption because there is a significant correlation between zinc and hydroxyproline. One interpretation is that there is increased zinc mobilization as a result of increased bone resorption in osteoporosis as compensatory mechanism. The same situation is observed in cases of disuse, osteopeonia, and paraplegic patients[~49~] [~50~]. An increase in excretion of urinary zinc is also seen in patients with hyperparathyroidism as well as hyperthyroidism due to increased bone remodeling[~28~].

Sexual dysfunction: A study suggested that supplemental zinc can reverse sexual dysfunction in uremic patients[~41~].

Colon cancer: zinc intake has been associated with decreased risk of distal colon cancer as well as proximal colon cancer. Zinc has been shown to retard the oxidative process possibly by inducing the synthesis of metallothionein a sulfhydryl rich protein that protects against free radicals [~43~] [~44~].

Gastric disease: Recent clinical and experimental findings have reinforced the link among zinc deficiency, malabsorption, and diarrheal disease. It is believed that zinc deficiency makes an organism more susceptible to toxin production by bacteria or enteroviral pathogens that activate guanylate and adenylate cyclases, stimulate chloride secretion, produce diarrhea, and decrease absorption of nutrients further exacerbating an already compromised mineral status. Studies have concluded that zinc deficiency may further decrease the absorption of water and electrolytes and that the gastrointestinal tract is therefore one of the first targets[~51~]. Zinc has been studied in regards to patients with IBS but results have been contradictory. Zinc is decreased in patients with inflammatory diseases but as of now, experts state that the benefit from supplemental treatment is limited until more studies are completed [~21~].

Athletes: Accumulating evidence supports the hypothesis that magnesium and zinc play significant roles in promoting strength and cardio respiratory function in healthy persons and athletes[~45~].