Micronutrient Cheat Sheet

Antioxidant Vitamins and Minerals

Vitamin E

Signs and Symptoms of Deficiency

• Vitamin E deficiency is best understood from malabsorption disorders impacting all fat-soluble vitamins and from a rare genetic disorder known as alpha-tocopherol transfer protein deficiency that causes a specific disruption of vitamin E supply to all tissues except the liver.
• These result in ataxia (loss of full control over body movements), peripheral neuropathy (weakness, numbness, pain, or tingling in the hands and feet), retinopathy (damage to the eye’s retina). The ataxia of vitamin E is often mistaken for Friedrich’s ataxia, a genetic disorder in iron metabolism.

Risk Factors for Deficiency

Vitamin E’s only well-established role is to protect polyunsaturated fatty acids (PUFAs) from a process known as lipid peroxidation, which is a form of oxidative damage.

Moderate deficits of vitamin E are most likely to occur on diets that cause tissue concentrations of PUFA to increase without a proportionate increase in vitamin E. Most high-PUFA oils are rich in vitamin E. However, years of consuming them can cause tissue concentrations of PUFA to remain elevated for up to four years after one stop consuming them. By contrast, vitamin E levels drop very soon after discontinuing these oils. This may cause an extended period where dietary vitamin E is inadequate to protect tissue concentrations. As an example, someone who eats sunflower oil for years and then switches to coconut oil may spend up to four years in a moderate vitamin E deficit because coconut oil does not provide enough vitamin E to protect the fatty acids that came from the sunflower oil.

Excess Vitamin E

Excess vitamin E is broken down and excreted in the urine, so there is no toxicity syndrome associated with it. However, vitamins E and K share the same catabolic pathway, and excess vitamin E may cause a vitamin K deficiency and thin the blood.

Testing for Vitamin E

Plasma vitamin E is the best marker of vitamin E status. It is low in deficiency.

Testing Caveats

Since vitamin E is carried in lipoproteins, hypolipoproteinemias may cause vitamin E status to appear lower than it is and hyperlipoproteinemias may have the opposite effect.

Correcting Vitamin E Deficiency

Vitamin E deficiency only occurs with malabsorption disorders or defects in alpha-tocopherol transfer protein, and these must be managed with appropriate medical treatment.

Vitamin C

Summary

Vitamin C is an antioxidant that many animals produce, especially during stress. Humans have lost that ability to synthesize vitamin C and thus we need to get it from the diet. Vitamin C has been shown to increase glutathione levels. It also recycles oxidized vitamin E, providing cellular membranes protection against lipid peroxidation. It is also essential for collagen synthesis and collagen is what most organs, including the lungs and the endothelium, are made of.

There’s some evidence showing that the need for vitamin C increases only in diets of glucose-based metabolism. In fact, ascorbic acid and glucose compete for cellular transport. High levels of blood glucose inhibit the uptake of vitamin C because both of them use the same membrane transport chain and because glucose is a much more prioritized nutrient.

• A systematic review of 23 clinical studies, encompassing 6,000 children, found that supplementing with 1-2 grams of vitamin C per day decreased the duration and/or severity of the common cold by 13-26%. In adults, 1-4.1 grams of vitamin C/day reduced the duration and/or severity of the common cold by 6.9-20%. Among military recruits, 1-2 grams of vitamin C/day reduced the duration of cold symptoms by up to 69%.
• In elderly patients with acute respiratory infections, 200 mg of vitamin C/day has been shown to speed recovery and lower mortality. Many doctors also use intravenous vitamin C as a potential treatment for COVID-19, however, it is not yet a standard care. In organ failure and sepsis, intravenous vitamin C has not improved organ dysfunction or markers of inflammation, but it has lowered mortality rates.
• Athletes who take vitamin C regularly are half as likely to catch a cold as athletes who do not. Supplementing 600 mg of vitamin C a day after an ultramarathon reduced the incidence of upper respiratory infections by over 50%.
• A recent 2020 meta-analysis published in the Journal of Intensive Care showed that 1–6 grams of intravenous vitamin C per day shortened the ventilation time of patients needing intensive care by 25 %. 
• Vitamin C may help with autoimmunity by controlling histamine levels and destroying excess histamine. Histamine is an organic compound involved in immune responses, especially inflammation, allergies and itching. In excess, it can cause autoimmunity and hypersensitivity. It has been found that 2 grams of vitamin C can decrease histamine levels by 38%.

Signs and Symptoms of Deficiency

• Scurvy, defects in collagen synthesis that cause bleeding at or underneath the surface of the skin and oral cavity. The skin may appear to bruise without requiring any physical trauma. Hairs may become kinkier and appear in a “corkscrew” shape. Fatigue and shortness of breath on exertion also occur. Plausible signs of more moderate deficits include decreased immunity, faster aging skin, low bone mineral density and an increased risk of osteopenia and osteoporosis.
• Vitamin C recycles vitamin E, and its deficiency lowers vitamin E status. It is also possible that moderate deficits might cause low noradrenaline production resulting in lethargy and trouble focusing, and low oxytocin, compromising the sense of affection and bonding in response to physical intimacy.
• Lack of vitamin C may have a contributing role in insulin resistance. Supplemental antioxidants in type-2 diabetes could improve the condition and attenuate diabetic pathogenesis. An imbalance between the declining endogenous antioxidants and increasing production of reactive oxygen species can lead to a state of chronic systemic inflammation that onsets many pathologies. Taking 500 mg of vitamin C twice a day has potential to reduce proinflammatory markers like CRP and IL-6 in obese/diabetic patients. Oral vitamin C increases polymorphonuclear phagocytosis in diabetics and improves glucose tolerance in older subjects with diabetes. A daily dose of 1000 mg of vitamin C (500 mg twice daily) may be beneficial in lowering blood sugar and lipids in type-2 diabetics. Ascorbic acid supplementation improves skeletal muscle insulin sensitivity in type-2 diabetes.

Risk Factors for Deficiency

A diet low in fresh foods, especially fruits and vegetables, that does not contain vitamin C supplements or vitamin C-containing multivitamins is most likely to produce scurvy. Diets poor enough to cause scurvy can sometimes be found among chronic alcoholics.

There are opposed claims that carbohydrates increase and decrease the vitamin C requirement but at the present time neither high nor low carbohydrate intake should be considered a direct cause of vitamin C deficiency. High levels of physical activity, illness, and exposure to toxins including ethanol and cigarette smoke especially increase the need for vitamin C.

Vitamin C Excess

• Vitamin C is not toxic, but when consumed above the rate of intestinal absorption it may cause diarrhea. Bowel tolerance occasionally occurs as low as 4 grams per day but often takes more than 10 grams per day.
• Excess vitamin C may cause some problems in vulnerable individuals: it increases iron absorption and possibly iron-induced oxidative damage in individuals with hemochromatosis; it increases the risk of oxalate stones in individuals with kidney disease; it increases the risk of hemolysis in newborns with glucose 6-phosphate dehydrogenase deficiency, a genetic disorder.

Testing for Vitamin C

Fasting plasma ascorbate is the best marker of vitamin C status.

Correcting Vitamin C Deficiency

• All citrus fruits, including orange, grapefruit, lime, and lemon are excellent sources of vitamin C. Papaya, strawberries, pineapples, kiwis, cantaloupes, and raspberries too. Even Swiss chard and cruciferous vegetables such as broccoli and cauliflower are also excellent sources, as is parsley, which provides over half of the recommended daily amount.
• Athletes, smokers who cannot quit, and individuals with frequent illness or who otherwise appear to have a high need may raise this dose to two grams. 
• Ascorbic acid is a synthetic form of vitamin C that is typically made from GMO corn, and lacks the beneficial bioflavonoids present in whole-food form of vitamin C. Look for an all-organic food-based supplement or a USP-grade vitamin C, produced in a GMP-certified facility. Whole Foods Market Food-Sourced Vitamin C, American Nutraceuticals Vitality C, and OrthoMolecular Buffered C Capsules. Take no more than 500mg at a time. At 100mg all the tissues are saturated, at 200mg the blood plasma is saturated, but at 500mg dose the absorption appears complete and rate of absorption will decrease.

Manganese

Summary

Manganese (Mn) is an essential mineral involved in the function of many enzymes, the immune system, blood clotting, bone formation and metabolism. In nature, it is found in combination with iron. Deficiencies in manganese impair growth, lead to skeletal defects, reduce fertility and alter glucose tolerance. Manganese metalloenzymes include arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase and MnSOD, all of which have an important role in antioxidant defense and metabolic reactions. Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect, which may promote cancer and metastasis.

Manganese deficiency reduces bone mineral density, whereas supplementation improves bone health. Women with osteoporosis have been observed to have lower serum manganese levels than those without osteoporosis.

One of primary functions of manganese is that it makes up Mn superoxide dismutase (MnSOD), which scavenges free radicals and reactive oxygen species (ROS) in the mitochondria, endothelium and even in atherosclerotic plaque.

Atherosclerosis is a disease of chronic inflammation that damages the blood vessel wall and oxidizes LDL cholesterol. Superoxide dismutase protects against the oxidation of lipids. Manganese protects against heart mitochondria lipid peroxidation in rats through MnSOD. MnSOD can reduce oxLDL-induced cell death of macrophages, inhibit LDL oxidation and protect against endothelial dysfunction. There is an association between decreased MnSOD and atherogenesis.

Insulin resistance can be thought of as a cellular antioxidant defense mechanism against oxidative stress in the absence of other antioxidant defense systems, such as manganese superoxide dismutase or glutathione. In other words, a lack of manganese may be a direct cause of insulin resistance.

Manganese is required for creating oxaloacetate from pyruvate via pyruvate carboxylase. In mammals, oxaloacetate is needed for gluconeogenesis, the urea cycle, neurotransmitter synthesis, lipogenesis and insulin secretion.

Oxaloacetate also synthesizes aspartate, which then gets converted into other amino acids, asparagine, methionine, lysine and threonine. During gluconeogenesis, pyruvate is converted first into oxaloacetate by pyruvate carboxylase, which is then simultaneously decarboxylated and phosphorylated into phosphoenolpyruvate (PEP). This is the rate-limiting step in gluconeogenesis. Pyruvate carboxylase is expressed the most in gluconeogenic tissues, such as the liver, kidneys, pancreatic islets and lactating mammary glands.

Arginase is another manganese-containing enzyme and the final enzyme in the urea cycle, during which the body gets rid of ammonia. Arginase converts L-arginine into L-ornithine and urea. Manganese ions are required for stabilizing water and hydrolyzing L-arginine into L-ornithine and urea. Arginase is also involved with nitric oxide synthase. Disorders in arginase metabolism are implicated with neurological impairment, dementia and hyperammonemia. Excess ammonia is not acutely harmful to humans as it will either be converted into amino acids or excreted through urine. However, high ammonia is associated with upper gastrointestinal bleeding in cirrhosis and kidney damage. Urea cycle disorders cause delirium, lethargy and even strokes in adults.

Manganese is a co-factor for glutamine synthetase (GS), which is an enzyme that forms glutamine from ammonia and glutamate. Glutamine is used by activated immune cells. It supports lymphocyte proliferation and helps to produce cytokines by lymphocytes and macrophages. Additionally, glutamine may help people with food hypersensitivities by reducing inflammation on the gut surface. It can thus protect against and repair leaky gut, hence improving immunity. Getting enough glutamine from the diet or by using a supplement may help to protect intestinal epithelial cell tight junctions, which prevents intestinal permeability. Glutamine synthetase is most predominantly found in the brain, astrocytes, kidneys and liver. In the brain, glutamine synthetase regulates ammonia detoxification and glutamate – the excitatory neuro-transmitter. Manganese gets in the brain with the help of the iron-carrying protein transferrin, but manganese doesn’t seem to compete with iron absorption.

Manganese-Dependent Enzymes, Functions and Consequences of Deficient Manganese Intake

Manganese-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Superoxide Dismutase: Removes superoxide anions: Increased tissue and mitochondrial damage and oxidative stress
• Arginase: Participates in the urea cycle to remove harmful ammonia: Ammonia accumulation, kidney damage
• Pyruvate Carboxylase: Converts glucose into oxaloacetate, gluconeogenesis, lipogenesis, neurotransmitter biosynthesis, insulin secretion: Impaired insulin production, low-carb intolerance, ammonia accumulation
• Glutamine Synthetase: Glutamine formation, nitrogen metabolism, ammonia detoxification: Weaker immunity, intestinal permeability, ammonia accumulation, neurotoxicity
• Divalent Metal Transporter 1 (DMT1): Transports ferrous iron, regulates iron homeostasis, absorption and transportation of manganese, binds to divalent metals: Poor iron homeostasis, manganese deficiency
• Transferrin Receptor (TfR): Imports iron into the cell, manganese influx and efflux: Poor iron homeostasis, manganese overload or deficiency

Requirements

There is no established RDA for manganese. The estimated safe and adequate daily intake for manganese has been set at 2-5 mg/d. Adequate intakes for adult males are 2.3 mg/d and 1.8 mg/d for females. Men on experimentally manganese-deficient diets (< 0.74 mg/d) have been shown to develop erythematous rashes. Women consuming < 1 mg of manganese per day experience altered mood and increased pain during their premenstrual phase of the estrous cycle. During pregnancy or lactation, the demand for manganese increases to 2.0-2.6 mg/d. Children that are 1-3 years old should get 1.2 mg/d, 4-8 years old 1.5 mg/d and boys 9-13 years old should get 1.9 mg/d and girls 1.6 mg/d. Newborns that are 6 months old or younger should get 0.003 mg/d and 7– 12-month-olds should obtain 0.6 mg/d. The tolerable upper intake levels for manganese have been set at 9-11 mg for adults and 2-9 mg for children 12 months of age or older.

Manganese absorption and influx is mostly mediated by the divalent metal transporter 1 (DMT1) and transferrin receptor (TfR) on the cell surface that also transport other divalent cations, such as iron and calcium. Iron deficiency can increase the risk of manganese poisoning because manganese absorption will increase under low iron states.

• About 75% of the manganese in human milk is bound to lactoferrin. Excess ferric lactoferrin could inhibit the absorption of this manganese complex. The addition of calcium to human milk significantly decreases manganese absorption, while addition of phytates, phosphate and ascorbic acid to infant formulas, as well as iron and magnesium to wheat bread has no significant effect. High manganese intake leads to adaptive changes that include reduced gastrointestinal absorption of manganese, enhanced liver metabolism and increased manganese excretion.
• In adults, 3-5% of manganese is absorbed through the gastrointestinal (GI) tract with women absorbing slightly more than men, possibly due to poorer iron status. After GI absorption, manganese enters the bloodstream and is distributed throughout different tissues. Intravenous administration of manganese bypasses GI regulation and results in 100% of absorption. Aging decreases manganese absorption and retention. Thus, we need more manganese as we get older.
• The primary manganese excretion pathway is biliary secretion. More than 95% of manganese is excreted through bile so the threshold for dietary manganese toxicity is quite high.

Food Sources

Manganese is found in many foods, including grains, clams, oysters, legumes, vegetables, tea and spices. One of the most commonly consumed sources of dietary manganese are rice, nuts and tea. Dietary and non-experimental manganese deficiency is quite rare, and toxicity occurs mostly due to environmental exposure. Some supplements are also fortified with manganese, ranging from 5 to 20 mg. The amount of manganese in human breast milk ranges from 3-10 mcg/L. Cow’s milk-based infant formulas contain 30-100 mcg/L. Soy-based formulas have the highest concentration of manganese (200-300 mcg/L), which might lead to manganese accumulation. The absorption of manganese from human milk is the highest (8.2%) compared to soy formulas (0.7%) and cow’s milk formula (3.1%).

Signs and Symptoms of Manganese Deficiency

Miliaria crystallina, a form of dermatitis resulting from blocked sweat glands that appear as tiny clear bubbles on the skin. This can also result from excessive sweating, sunburn, or fever. It may also cause bone irregularities, low bone mineral density, low cholesterol, slow hair and nail growth, and reddening of beard hair. Moderate deficits of manganese may accelerate atherosclerosis.

Risk Factors for Deficiency

Manganese is particularly rich in whole grains, legumes, nuts, seeds, coffee, tea, spices, and mussels. Diets low in plant products are likely to be considerably lower in manganese than diets rich in plant products.

Manganese Toxicity

• Acute manganese toxicity causes manganism, characterized by neurological symptoms, mood swings, compulsive behavior and decreased response speed. Manganese overexposure can also impair cardiovascular function and heartbeat. Chronic exposure leads to a more permanent dysfunction that resembles Parkinson’s disease. Unlike Parkinson’s, manganism does not appear to cause a loss of sense of smell and patients do not respond to LDOPA treatment. The neurotoxic effects appear to be caused by disturbed iron and aluminum metabolism and iron overload that cause oxidative stress. Oxidative stress is one of the main factors of manganese-induced neurotoxicity. It is important to note that a lack of copper in the body leads to iron overload, which can lead to manganese overload in tissues. Thus, a lack of one mineral, such as copper, can lead to the harmful accumulation and dysregulation of other minerals in the body.
• Manganese accumulation in the mitochondria can also cause mitochondrial dysfunction by inhibiting complex I and II. The highest accumulation rate is observed in the mitochondria of astrocytes and neurons compared to other organelles after chronic manganese exposure. Excessive manganese gets excreted out of the mitochondrial lumen through sodium-independent mechanisms, but it gets imported mainly by the calcium uniporter. Manganese inhibits calcium efflux, which increases the probability of mitochondrial permeability transition associated with brain injury and stroke.
• Manganese poisoning can occur due to drinking contaminated water or when exposed to the fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) and the pesticide manganese ethylene-bisdithiocarbamate (Maneb). Permanganate (Mn 7+) is much more toxic than Mn 2+ with potassium permanganate having a lethal dose of 10 grams. Mining and processing manganese causes air and water pollution, which threatens the health of workers and local residence, especially in South Africa, China and Australia where most of the world’s manganese is mined from.
• The olfactory tract is the most direct pathway for manganese to get into the brain. By using two zinc transporters ZIP8 and ZIP14, it can bypass the blood-brain barrier. Infants have an immature blood-brain barrier, making them more vulnerable to manganese toxicity. MRI studies show that manganese accumulates predominantly in the globus pallidus located in the basal ganglia. Dopamine oxidation by manganese causes oxidative stress. Chronic manganese exposure has been seen to reduce choline levels in the hypothalamus and thalamus.
• Intravenous absorption of manganese is close to 100%, which can cause manganese toxicity. Infants have a much higher absorption and retention of manganese than adults, making them more susceptible to manganism. They also have a higher total amount of manganese in the body than older children and adults. The amount of manganese in the hair of newborn babies increases from 0.19 mcg/g at birth to 0.965 mcg/g at 6 weeks of age and 0.685 mcg/g at 4 months when they’re fed infant formulas. Normal children at age 8 have a hair manganese concentration of 0.268 mcg/g and those with learning disability (hyperactive) have 0.434 mcg/g.
• Liver damage impairs manganese excretion, causing high levels of manganese in the blood. Patients with portosystemic shunts (also known as liver shunts) and biliary atresia (narrowed or blocked bile ducts) exhibit hypermanganesemia, even without increasing dietary manganese intake.

Testing Manganese Status

Lymphocyte manganese is thought to be better than whole blood manganese for measuring manganese deficiency.

Most of blood manganese gets distributed in soft tissue (~60%), with the remainder being in the liver (30%), kidney (5%), pancreas (5%), colon (1%), bone (0.5.%), urinary system (0.2.%), brain (0.1.%) and erythrocytes (0.0.2%). Divalent Mn 2+ is the predominant form of blood manganese and it is complexed with different molecules, such as albumin (84% of total Mn 2+), hexahydrated ion (6%), bicarbonate (6%), citrate (2%), and transferrin (Tf) (1%), whereas almost all trivalent Mn 3+ is bound to transferrin. Mn 3+ is more reactive and gets reduced to Mn 2+ and Mn 2+ can be oxidized to Mn 3+ by ceruloplasmin the active form of copper. Mn 3+, typically coming in the form of manganese (III) fluoride, manganese (III) oxide and manganese (III) acetate, is more effective at inhibiting the mitochondrial complex I. The reduction of Mn 3+ to Mn2 + is mediated by ferrireductase, which helps to avoid oxidative stress.

Tissues with a high energy demand like the brain and liver as well as high pigment regions such as the retina and skin have the highest concentrations of manganese. Approximately 40% of total body manganese is stored in the bones (1 mg/kg). It has been found that the hand bone manganese levels of welders exposed to high manganese environments are significantly higher compared to non-occupationally exposed individuals.

Testing Caveats

The syringe used to draw the blood can contaminate the blood with manganese and the first draw should be discarded so the second draw can be used for the measurement. If heparin is used as an anticoagulant in the blood tube rather than EDTA, the heparin can provide manganese contamination. The water used for dilutions in the laboratory analysis must be properly purified because it also can be contaminated. Red blood cell or whole blood measurements are ideal because red blood cells contain 25 times as much manganese as plasma or serum. This brings the concentration far away from the limit of detection and makes the possibility of contamination less threatening to interpretation. It also eliminates the possibility that hemolysis could release manganese to contaminate the serum or plasma.

Correcting Manganese Deficiency

Increasing the amount and diversity of plant foods is the most likely thing to improve manganese status. Supplements often contain 8 milligrams or higher. Then reducing to 3-5 milligrams when levels stabilize. 

Zinc

Summary

Zinc is another important nutrient needed for optimal immune cell functioning. It plays a key role in over 300 enzymatic reactions and cellular communications. A deficiency in zinc promotes proinflammatory cytokines and weaker immunity. Many studies since the 1970s have noted zinc deficiency is related to different autoimmune diseases such as type-1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus, autoimmune hepatitis, celiac disease and Hashimoto’s thyroiditis.

Zinc also plays an important role as a structural agent of proteins and cell membranes preventing oxidative stress. Zinc is important for hormone production and immunity. Low zinc status can cause gastrointestinal problems and increase the risk of pneumonia. However, high zinc supplementation can lead to toxicity and stomach pain.

Zinc acetate and zinc gluconate lozenges have been shown to inhibit cold viruses from latching onto cells and shorten flu duration. Lozenges are beneficial only in the early stages of infection. The optimal dose in adults according to clinical studies is around 80-200 mg/day divided into multiple doses taken 2–3 hours apart. Best results are achieved when starting within 24 hours of first symptoms. According to studies in children, regular use of zinc can prevent the flu. It has been shown to inhibit the replication of viruses like SARS and arterivirus. Do not exceed 200 mg of zinc per day for any longer than one to two weeks and copper should always be taken in conjunction with it. Avoid nasal sprays as they might cause a lingering loss of smell perception.

Zinc/copper – Typical ratios for general population is 15-20 mg/1 mg zinc/copper or (30-40 mg/2 mg copper), in elderly populations usually 40-80 mg of zinc with 1-2 mg of copper is used, respectively. In AREDs, 40 mg/1mg zinc/copper twice daily lowered mortality by 27%, which was driven by a reduction from deaths from respiratory causes. Copper is needed as a cofactor for lysyl oxidase which crosslinks collagen and elastin giving it tensile strength. Copper is important for elastin/collagen synthesis and both are important for healthy lung function.

Zinc helps to catalyze the calcification of bone. Zinc deficiency causes skeletal abnormalities by reducing parameters of calcium metabolism in the bone. Zinc is also needed for collagen synthesis and zinc deficiency can increase damage to the body’s soft tissue. Supplementation with arginine, glutamine, vitamin C and zinc has been shown to increase collagen synthesis during the first 2 days after inguinal hernia repair. Zinc also helps those with bed sores.

Zinc speeds up wound healing. Wounds do not heal as fast with zinc deficiency. Oral zinc sulfate improves foot and leg ulcers. Zinc deficiency exacerbates ulcers by increasing oxidative stress in the skin. Zinc sulfide nanoparticles improve skin regeneration. Healing of the aorta requires zinc. Think of zinc as a healing mineral. Zinc can be thought of as our adamantium and the source of our healing power.

Atherosclerosis Protection

• Zinc, especially when taken with appropriate amounts of copper, prevents the oxidation of LDL cholesterol, which is one of the main mechanisms for atherosclerosis. Excess iron promotes LDL oxidation, whereas zinc protects against this. Zinc supplementation at doses over 50 mg/day can reduce HDL cholesterol, however, if copper status is maintained, this will likely not occur. Atherosclerosis develops in parallel with the decrease of zinc absorption, greater prevalence of zinc deficiency and increased inflammation that happens during aging.
• The preventative effect of zinc on cardiomyopathy is mediated by metallothionine, the main protein zinc is bound to. Metallothionine has an antioxidant effect, including in the heart. It controls the amount of zinc in tissues. Zinc deficiency causes a deficiency in metallothionine, which results in increased reactive oxygen species in the cell, enhanced oxidative stress, inhibition of cytochrome c oxidase activity, impaired mitochondrial function and eventually cellular death, especially in the liver, kidney and connective/collagenous tissues. Metallothionine expression protects against the toxicity of cancer treatment drugs like doxorubicin. In other words, if you are zinc deficient you will likely experience worse chemotherapy side effects. Zinc has also been shown to protect metallothionine-deficient mice from alcohol-induced myocardial fibrosis. Selenium promotes the release of zinc from metallothionine and their combination improves immunity in the elderly after influenza vaccination. Inflammation also makes metallothionine use zinc, which explains why zinc levels are low in inflammatory conditions such as atherosclerosis. High homocysteine also impairs metallothionine and disrupts redox homeostasis.
• Zinc supplementation may help heal unstable plaque by promoting calcification, which is less likely to rupture. Statins work by reducing inflammation and promote the calcification of unstable plaques. Statin drugs, however, also reduce zinc levels by 8%. Thus, their benefits are limited and are they are not without side effects. Elevated serum copper, with low zinc and magnesium, is associated with an increased risk of cardiovascular disease mortality. A low urinary zinc, which is indicative of zinc deficiency, is associated with atherosclerosis severity. In atherosclerosis, there is a significant decrease in plasma, aorta, liver, myocardium and pancreas zinc levels. Patients with myocardial infarctions have low plasma zinc levels, averaging just 67 mcg/dL, instead of the 75-125 mcg/dL that is considered normal.

Brain Development

Zinc is important for brain development, learning and plasticity. Zinc deficiencies are implicated in brain disorders. Zinc supplementation in malnourished schoolboys has been shown to increase cortical thickness significantly more than in those who have received all the essential amino acids, vitamins and minerals without zinc.

• Zinc is needed for synthesizing many neurotransmitters, such as serotonin and melatonin. Taking zinc has been shown to improve sleep in humans.
• Zinc homeostasis regulates the central nervous system. Dysregulated zinc homeostasis and excess synaptic zinc concentrations, typically induced by inflammation, can cause neurotoxicity and mitochondrial damage. Zinc also regulates the activity of the adrenal glands and cortisol levels.

Thyroid Hormone Production

Zinc and other trace minerals like copper and selenium are needed for the production of thyroid hormones. On the flip side, you need adequate amounts of thyroid hormones to absorb zinc, which is why hypothyroidism can cause an acquired zinc deficiency. Hypothyroidism reduces zinc absorption in the intestine. Zinc is required to activate the T3 receptor, hence zinc deficiency impairs T3 receptor action. Zinc deficiency is associated with hypothyroidism and severe alopecia, i.e., hair loss. Supplementing with zinc in those who are deficient improves thyroid function. Thus, it’s a vicious cycle of zinc deficiency impairing thyroid hormone function, which drives more zinc deficiency.

• The overconsumption of sugar, especially in conjunction with copper deficiency, also drives zinc deficiency through the promotion of fatty liver disease. Indeed, since the liver produces the active thyroid hormone T3, and active thyroid hormones are required for the absorption of zinc, damage to the liver will reduce zinc status. Considering that millions of people have hypothyroidism, a zinc deficit may be more rampant than originally thought.

Blood Sugar Regulation

Zinc is important for glucose metabolism and insulin production. Zinc helps with the uptake of glucose into the cell and with insulin synthesis. A 2012 systematic meta-analysis that included 22 studies concluded that zinc supplementation has a beneficial effect on glycemic control and lipids in patients with type-2 diabetes. In type-1 diabetes, a combination of zinc and vitamin A (10 mg zinc a day and 25,000 IU vitamin A every other day) can improve apolipoprotein-B/A1 ratios (essentially LDL+VLDL/HDL ratios).

• Zinc is required for pancreatic carboxypeptidase, which may be needed for insulin maturation and secretion. Furthermore, zinc supplementation has been shown to improve insulin resistance and metabolic syndrome in obese children.
• Zinc deficiency may also lead to metabolic acidosis by reducing carbonic anhydrase activity. Carbonic anhydrases are a family of enzymes that catalyze the conversion of carbon dioxide and water to bicarbonate and protons. Most carbonic anhydrases contain a zinc ion at their active site and are thus classified as metalloenzymes. Without carbonic anhydrases, tissue oxygenation decreases, and lactic acidosis increases. Zinc losses increase in urine and sweat during exercise. Additionally, zinc needs increase during exercise to help working muscle, as well as after exercise to repair and build muscle. Thus, many athletes are at risk of zinc deficiency, which can impair performance and decrease the lactate threshold (i.e., when lactate accumulates faster than it can be removed). In zinc-deficient rats, lactic acid buffering agents like lactic dehydrogenase (LDH), malic dehydrogenase (MDH), alcohol dehydrogenase (ADH) and NADH diaphorase are lower.

Zinc and the Immune System

Even a modest zinc deficiency can impair the functions of macrophages, neutrophils, natural killer cells and the complement system, reducing their cytotoxicity. Zinc is needed for the production of T cells. People with zinc deficiency show reduced natural killer cell cytotoxicity, which can be fixed with zinc supplementation.

Zinc is an essential cofactor for thymulin, which is a thymic hormone. Without zinc, thymulin can’t bind to zinc and this impairs immunity. With the help of zinc, thymulin helps to differentiate immature T cells, preserving the balance between killer T cells and helper T cells. Autoimmune diseases with a T cell imbalance, such as rheumatoid arthritis, are associated with zinc deficiency. Thymulin also modulates the release of cytokines.

Zinc is needed for the interaction between the natural killer cell inhibitory receptor p58 and major histocompatibility complex (MHC) class I molecules. A deficiency in zinc impairs natural killer cell activity, phagocytosis of macrophages, cytotoxicity of neutrophils and generation of the oxidative burst needed to kill pathogens. Zinc ions have been shown to stimulate the production of lymphocytes, which attack invading pathogens. The addition of zinc releases interleukin-1, interleukin-6, tumor necrosis factor-α and interferon gamma in human peripheral blood mononuclear cells, which help us fight infections.

Low zinc status has been associated with an increased risk of pneumonia, respiratory tract infections, diarrhea and other infectious diseases.

Zinc administration helps patients with hepatitis C virus-induced chronic liver disease. It is also noted that zinc deficiency is related to different autoimmune diseases such as type-1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus, autoimmune hepatitis, celiac disease and Hashimoto’s thyroiditis. A significant number of COVID-19 patients are zinc deficient, which is associated with worse COVID-19 outcomes. Zinc has been shown to inhibit the replication of viruses like SARS and arterivirus.

Zinc enables the calcium-binding protein calprotectin to inhibit the reproduction of bacteria through neutrophil degradation. Prophylactic zinc intake before LPS treatment in a porcine sepsis model has been shown to reduce the inflammatory response. Thus, doses of zinc before an LPS infection may be protective.

Extremely large doses of zinc (up to 400 mg/day) have been shown to impair immune function. In vitro, doses 7-8 times the physiological level inhibit T cell function and reduce interferon-alpha production.

Typical ratios for the general population are 15-20 mg/1 mg zinc/copper or (30-40 mg/2 mg copper), in elderly populations usually 40 of zinc with 1 mg of copper is used once to twice daily. In the AREDs study, 40 mg/1mg of zinc/copper twice daily significantly lowered mortality by 27%, which was seemingly driven by a reduction from deaths from respiratory causes.

Requirements

The human body contains about 2-4 grams of zinc, out of which about 0.1% gets depleted every day. Only 1/1000 of the total zinc pool gets renewed on a daily basis. Zinc’s biological half-life is 280 days. Up to 57% of zinc in the body is located in muscle and 29% in bone. There is no separate storage site for zinc in the body, which is why it needs to be obtained from dietary sources on a regular basis.

Supplementing 400 mcg of folic acid every other day for 4 weeks has been shown to reduce zinc excretion by 50%. However, polyphenols, such as resveratrol and quercetin, may enhance the uptake of zinc into certain cells via metallothionine.

Bioavailability

Phytate, phosphate and other phytonutrients are able to chelate zinc, including other minerals. Phytate is a mineral chelator that affects zinc bioavailability. In Korean adults, lower zinc bioavailability because of phytates is related to a higher risk of atherosclerosis. Foods high in phytates like grains bind to zinc, iron and calcium and reduce their absorption, which is why diets high in phytates can cause zinc and iron deficiency.

Another inhibitor of zinc absorption is calcium, which enhances phytate’s ability to reduce zinc absorption. The ratios between phytate-zinc and phytate-zinc-calcium can predict the risk of zinc deficiency.

A high intake of other minerals like copper, magnesium, calcium, iron and nickel also reduces the absorption of zinc.

Ferrous iron (Fe 2+) supplements can reduce zinc absorption and lower plasma zinc levels. That is why experts recommend taking iron supplements away from food. However, when zinc and iron are consumed together in a meal, this effect does not seem to happen.

Certain antibiotics can inhibit the absorption of zinc. Taking these either 2 hours before, or 4-6 hours after zinc intake, can minimize this effect. Zinc reduces the absorption of penicillamine, which is used to treat rheumatoid arthritis. Diuretics like chlorthalidone and hydrochlorothiazide increase zinc excretion by as much as 60%. ACE inhibitors, like lisinopril and other blood pressure lowering medications in this class that end in “pril” deplete zinc. Omeprazole, a common antacid/heartburn medication, has been found to lower serum zinc levels. This is because proton pump inhibitors reduce zinc absorption from food due to a reduction in stomach acid.

Inflammation and certain disease states also promote zinc excretion. Picolinate complexes are more easily absorbed by the body. Zinc picolinate has been seen to improve zinc status in children with a genetic mutation that prevents them from absorbing zinc from cow’s milk.

Food Sources

Since zinc is a copper antagonist, too much dietary zinc can lead to copper deficiency. Accordingly, too much zinc in relation to copper is associated with hypercholesterolemia and increased coronary heart disease mortality. At the same time, excess iron supplementation inhibits zinc and copper absorption, which can weaken the immune system and cause copper-deficient anemia. Thus, it is necessary to balance these three minerals – iron, zinc and copper.

• Consume copper-laden organ meats, such as liver, into your diet (0.5-1 oz. per day or 1-3 oz. two to three times per week). Oysters and mollusks are the highest sources of zinc and can be consumed perhaps 1-2 times per week. Other high copper foods include shellfish (lobster and crab), dark chocolate, certain seaweeds, nuts, lentils and beans.
• Daily zinc and iron requirements can be met with appropriate intakes of red meat based on your body’s protein and iron/zinc requirements. The RDA for protein is 0.36 g/lb. of bodyweight or 0.8 g/kg, however, many experts consider this to be inadequate. In fact, a higher protein intake has been found to be superior in terms of weight loss, satiety, body composition, wound healing and bone density. Thus, a more appropriate intake for most people is at least 0.6-0.7 g of protein/lb. of body weight or 1.2-1.4 g/kg. The optimal daily protein intake for muscle growth and hypertrophy appears to be 0.8-1.0 g/lb or 1.6-2.2 g/kg of body weight.
• If you are eating a vegetarian diet, a diet high in phytates, and/or are using zinc inhibitors such as certain medications and antacids, then your zinc demand increases. Thus, you may need up to 50- 100% more zinc every day.

Factors that Increase Zinc Demand

• Intestinal malabsorption conditions and gut issues, like inflammatory bowel disease, Crohn’s, sickle cell anemia, cystic fibrosis as well as diabetes, can cause secondary zinc deficiency.
• Chronic diarrhea can lead to an excessive loss of zinc, whereas supplementation can help to offset these effects.
• Infections, like hookworms, can result in zinc deficiency, leading to physical and mental developmental problems in children. Hookworms can also promote iron deficiency.
• Kidney diseases and liver diseases such as liver cirrhosis and non-alcoholic liver disease, alcoholism and chronic inflammation can increase the urinary excretion of zinc. Liver cirrhosis patients show abnormally high levels of zinc in the urine.
• Mercury exposure and heavy metal toxicity can cause zinc deficiency
• Zinc demand increases during pregnancy, nursing and growth periods. Pregnancy is hallmarked by an increased zinc retention and a lack of nutrition can lead to harm to the fetus that may have long lasting consequences.
• Bariatric surgery causes impaired zinc absorption and promotes zinc deficiency
• Obesity can increase zinc excretion due to kidney damage. In obese subjects, plasma zinc concentrations are significantly lower. Low serum zinc levels in obese patients have been correlated with higher urinary zinc excretion.
• Athletes also have a lower serum zinc level than nonathletes due to increased zinc demands and losses during exercise

Supplemental doses of 80-150 mg/day of zinc can be immunosuppressive if not taken with copper. The lowest median effective dose of supplementary zinc is deemed to be 24 mg/day. Using zinc-containing nasal gels or sprays has been associated with a loss in the sense of smell.

Men taking over 100 mg/day of zinc experience a 2.9-fold increase in the risk for metastatic prostate cancer, which is likely due to copper deficiency.

Frequency of Deficiency

Red meat avoidance is thought to contribute to iron and zinc deficiency, especially in young premenopausal women. Vegetarian diets, as well as a preference of poultry, fish and dairy over red meat has been shown to increase the risk of zinc deficiency. The requirement of zinc for vegetarians is at least 50% higher than omnivores because zinc is not particularly bioavailable in plant-based foods. Thus, adult vegetarian males might need up to 16-20 mg/day and vegetarian females 12-14 mg/day of zinc.

Children in certain U.S. middle- and upper-income families, have been seen to have impaired taste acuity, low hair concentrations of zinc and poor growth. This is due to “picky eating”, but technically, it is due to not eating zinc-rich animal foods like red meat. When giving these children zinc at 2 mg/kg of body weight, their ability to taste, appetite and growth rate improves.

The demonization of all grains, especially in those who consume large amounts of muscle meat but not organ meats, may be a leading contributor of copper deficiency. On the flip side, a high intake of grains and low intake of animal protein can lead to dwarfism, as observed in Middle Eastern countries such as Turkey, Morocco, Tunisia, Iran and Egypt. The high phytate content of bread in some regions like Iran, where the diet is primarily made up of grains, contributes to zinc deficiency.

• Phosphates in clay bind to zinc, which is why geophagia (clay eating) is known to cause Iranian dwarfism. Zinc deficiency has been observed in regions like Egypt and Iran, who typically consume adequate amounts of zinc in their diet, but this is on top of excessive amounts of phytate and fiber.

It has been observed that the rising CO2 levels in the atmosphere can reduce the amount of zinc and iron in common crops, such as rice, wheat, peas and soybeans, with projections that a 10% drop in these minerals will occur by the end of the century. These puts developing countries, which are particularly dependent on these crops, in greater danger of zinc/iron deficiencies.

The low level of HCl in the stomach is also a predisposing factor.

Zinc-Dependent Enzymes, Functions and Consequences of a Deficit

Zinc-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Metallothionine: Protection against oxidative stress: Increased oxidative stress and tissue damage
• Zinc, Copper Superoxide Dismutase: Protect against oxidative stress: Increased oxidative stress and tissue damage
• p53: DNA damage repair: DNA damage and DNA mutations
• Poly (ADP-ribose) Polymerase: DNA damage repair: DNA damage and DNA mutations
• Glutathione Synthesis: Protect against oxidative stress: Increased oxidative stress and weaker immunity
• Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
• Nitric Oxide Synthase: Cardiovascular function, antiviral effects: Oxidative stress, atherosclerosis, and hypertension
• Thyroid Hormones: Regulate metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
• Luteinizing Hormone: Precursor to testosterone Hypogonadism and low sex hormones
• Growth Hormone: Physical repair, fat burning: Frailty, aging and muscle loss
• Insulin Secretion: Shuttle nutrients into the cells: Insulin resistance and metabolic syndrome
• Serotonin: Promotes melatonin production and relaxation: Chronic stress, insomnia and altered mood
• Melatonin: Promotes sleep onset and antioxidant activity: Sleeping problems, poor metabolic health, increased oxidative stress and neurodegeneration
• Dopamine Transporter: Feeling of reward and motivation: Depression and apathy
• Glycolysis Oxidation of glucose and lactate: Lactic acidosis and glucose intolerance
• Beta-Oxidation: Oxidation of lipids and triglycerides: Dyslipidemia and obesity
• Autophagy: Removes cellular waste material and dysfunctional organelles: Mitochondrial dysfunction, excess inflammation and impaired immunity
• Lysosomes: Engulf debris and mediates autophagy: Waste material accumulation
• Carboxypeptidase: Digestive enzyme and digestion of protein: Digestion problems and nutrient deficiencies
• Carbonic Anhydrase: Conversion of carbon dioxide and water to bicarbonate and protons: Anemia and reduced tissue oxygenation
• Alkaline phosphatase: Helps to break down proteins: Liver dysfunction

Signs and Symptoms of Zinc Deficiency

• The earliest sign of zinc deficiency is usually patches of dry skin, eczema, dermatitis, and psoriasis. These often progress to acne, blisters, or pustules. Infection risk increases, resulting in sore throat or diarrhea. Poor glucose tolerance, impaired wound healing, low or dysregulated sex hormones, and hair loss (alopecia) also may occur. Lower appetite and increased caloric needs often result in weight loss, especially of lean mass.
• In children, zinc deficiency delays puberty.
• Zinc deficiency may cause resistance to vitamin A, vitamin D, thyroid hormone, sex hormones, cortisol, and pharmaceutical glucocorticoids. Zinc is involved in virtually every aspect of vitamin A metabolism, and an apparent vitamin A deficiency that cannot be corrected with vitamin A should be seen as a major indicator of zinc deficiency. Zinc deficiency may also impair acid-base balance and increase the vulnerability to heavy metal toxicity.
• A deficiency in zinc creates an imbalance between Th1 and Th2, regulatory and killer T cells and reduced NK cell function. 
• Zinc deficiency promotes oxidative stress, DNA damage and undermines antioxidant defenses in rats. In humans, zinc deficiency causes DNA damage. Zinc is involved in hundreds of proteins, including DNA-binding proteins, copper/zinc superoxide dismutase (CuZnSOD), and DNA damage repair proteins like p53. Zinc is also needed for activating poly (ADP-ribose) polymerase that are involved in DNA repair at DNA damage sites.
• Loss of taste and smell
• Night blindness and vision impairment
• Frequent diarrhea and enteropathy
• Loss of cognition and impaired learning
• Behavioral abnormalities, ADHD and depression
• Schizophrenia and psychiatric disorders

Risk Factors for Zinc Deficiency

• Zinc is most abundant in oysters, red meat, and cheese, and the principal inhibitor of absorption is phytate. Phytate is found in whole grains, nuts, seeds, and legumes, and is especially high if these foods have not been prepared through soaking, sprouting, or fermentation. The overwhelming risk factor for zinc deficiency is a diet low in animal products and high in phytate.
• Chronic diarrhea, persistent vomiting of bile (giving the vomit a green color), malabsorption disorders, impaired methylation, and rare genetics in zinc transporters can all cause zinc deficiency as well.
• A collection of disorders in the production of heme, known as porphyrias, can cause zinc deficiency. If this is the cause of zinc deficiency, zinc protoporphyrin should be elevated.

Zinc Excess and Toxicity

Acutely, zinc toxicity can cause gastric distress, such as nausea and vomiting, and dizziness. A high-dose zinc supplement of 50 mg or more on an empty stomach can cause mild nausea, but dangerous levels of toxicity are rare. One death has been attributed to an accidental intravenous infusion of seven grams of zinc over a 60-hour period. Chronically, excess zinc can impair immune function and lead to copper deficiency, and perhaps deficiencies of other poorly studied minerals like molybdenum and chromium. To prevent this, zinc supplements should not be used at doses higher than 45 milligrams per day unless there is strong justification to do so, and the ratio to copper should be kept between 2:1 and 15:1, preferably toward the middle of that range.

Testing Zinc Status

• It is very important to measure it in plasma rather than serum, and if the order says “serum or plasma” explicit instructions should be put in the order to use plasma and not serum.
• Most ranges are too broad, with the lower end at 50-60 micrograms per deciliter. Measured in micrograms per deciliter, plasma zinc should be at least 70 in females and 74 in males, and the sweet spot is likely between 100-120. Measured in parts per billion, as on the ION panel, zinc should be above 700 in females and 740 in females, with the sweet spot likely to be between 1000 and 1200.
• Plasma and serum zinc levels are most commonly used to assess zinc deficiency, but they do not reflect cellular zinc status. Clinical symptoms of zinc deficiency can be seen even in the absence of low zinc indicators. What’s more, plasma and serum zinc values fluctuate diurnally and drop after meals and exercise.
• The best way to measure zinc deficiency is neutrophil zinc levels.
• Zinc concentrations in leukocytes or lymphocytes can be much more reflective of zinc status because they are associated with growth development and immunity. The ratio between CD4+ and CD8+ T cells has also been proposed as a test for zinc deficiency.
• The levels of zinc in hair can reflect dietary intake of zinc, at least in animals. There is also a correlation between zinc concentrations in plasma and hair. The advantage of hair tests is that it can reflect intakes over several months, giving a more accurate measurement of the body’s zinc status.
• Zinc-dependent enzyme activities such as superoxide dismutase, metallothionine and others in organs can be another way to measure zinc deficiency. In zinc-deficient animals, zinc-metalloenzymes and zinc itself are reduced.
• The most accurate measurement of zinc deficiency is neutrophil zinc levels and possibly hair mineral analysis. Neutrophil zinc levels in healthy individuals tend to average around 108 ug of zinc/10 10 cells, whereas those who are deficient in zinc average 82 ug of zinc/10 10 cells. Normal zinc values range from 150-240 mcg/g of hair, whereas less than 70 mcg/g may indicate zinc deficiency. Zinc concentration in hair depends on the rate of hair growth and the delivery of zinc to the root, and hence, it is not 100% accurate. Environmental contamination can also affect copper and zinc levels in hair. Thus, hair mineral analysis, in addition to neutrophil or perhaps lymphocyte or red blood cell zinc levels, and leukocyte copper levels, should be implemented for assessing suspected zinc and copper deficiency more accurately.

Testing Caveats

• Inflammation lowers plasma zinc, but this might simply reflect increased needs during inflammation.
• Plasma zinc modestly declines during pregnancy, but this also might indicate increased needs during pregnancy.
• Hemolysis can release zinc from red blood cells and cause falsely high zinc levels. Hemolysis can occur inside your body if you have certain medical disorders, but it can also occur during blood collection due to poor positioning of the needle or other technical difficulties.
• Plasma zinc in significant excess of 130 micrograms per liter or 1300 parts per billion is implausible in the absence of outright zinc poisoning and the measurement should be repeated.

Correcting Zinc Deficiency

• If the cause is a dietary pattern with a low zinc-to-phytate ratio, the ideal strategy is to alter the dietary pattern to one with a higher zinc-to-phytate ratio. If the cause is malabsorption, the malabsorption should be addressed as the root cause. 
• Zinc supplementation is not needed when you are getting enough of it from diet. Zinc supplementation is mostly beneficial for fixing deficiencies quickly or trying to help with an acute infection. Chronic intakes of zinc over 80-100 mg/day can promote copper depletion, especially if dietary copper intake is not concomitantly increased. The idea is to try and obtain anywhere from 20-80 mg of zinc, 8-18 mg of iron and 3 mg of copper each day. This will of course depend on the person.
• Zinc acetate, gluconate, sulfate, citrate, or methionine should be used, and not zinc oxide or zinc picolinate. Ideally, the zinc should be taken on an empty stomach, but if this causes nausea it should be taken with some food and should at least be taken far away from phytate-rich meals. The zinc should be spread out as much as possible to ensure better absorption. For example, 15 milligrams three times per day five hours apart is much better than taking 45 milligrams once per day.
• The goal should be correction of the plasma zinc and any signs and symptoms of deficiency. It is important to realize, however, that normalizing the plasma zinc means the deficiency is being fixed, not that it has been fixed. A zinc deficiency that has been sustained over months may take months to correct. Resolution of signs and symptoms is an important benchmark, and being able to cut down the dose of the supplement without plasma zinc falling back into the deficient range is the other key benchmark to reach before considering the deficiency fixed.
• Zinc modulates cell-mediated immunity, has antioxidant, and anti-inflammatory properties that can provide a potent cure for the common cold. Zinc lozenges are best for staving off a cold. It begins to release ionic zinc, which is the key to its antiviral activity. Dissolving a lozenge slowly in the mouth provides a steady release of free ions into the pharyngeal region in the nasal cavity, which can have a greater effect on reducing respiratory and nasal symptoms associated with sickness. Make sure it doesn’t have any additives or citric acid, as this commonly added compound can bind tightly to zinc ions, preventing them from being released. Zinc acetate. Avoid effervescent lozenges, which can reduce the production of ionic zinc.

Correcting Zinc Excess

• In acute zinc poisoning, medical treatment is required.
• Cases of zinc-induced copper deficiency should be corrected by removing the supplemental zinc and following the instructions for correcting a copper deficiency in that section.
• Screening for other mineral deficiencies is highly advised in this context because the ability of zinc to induce deficiencies in other positively charged minerals is very plausible and has not been well studied.

Copper

Copper Deficiency Anemia

Anemia is defined as a decrease in the oxygen carrying capacity of the blood. Anemia is suggested when levels are slightly below a normal hemoglobin level of around 13.8-17.2 g/dL in adult men and 12.1-15.1 g/dL in adult women.

As a result, you can experience chronic fatigue, shortness of breath, weakness, pale skin, lightheadedness and other problems. Both too much, as well as too little iron, can make people more susceptible to infections. Some amounts of iron are needed for fighting harmful bacteria; however, excess iron also promotes the growth of these pathogens.

Copper improves the ability of red blood cells to transport oxygen and nutrients, creating a ‘hypernutritive state’. Clinicians nowadays acknowledge that copper sulfate can increase the number of red blood cells. Copper can also protect against the oxidation of red blood cells, making them more resilient.

Copper stimulates the release of stored iron in tissues during the creation of red blood cells. Thus, copper mobilizes iron, helping to shift iron storage into hemoglobin.

Iron and copper are absorbed in the upper small intestine and hepcidin controls the absorption of iron, by inhibiting iron export in the intestine. Hepcidin expression is decreased on a copper deficient diet, potentially leading to iron deficiency. In other words, a low copper diet can lead to low iron absorption and iron deficiency anemia.

Hephaestin and its homologue ceruloplasmin, the latter being the major copper-carrying protein in blood, are required for efficient iron transformation into transferrin. Their synthesis and activity are positively correlated with copper levels in the cell. Thus, a copper deficiency can lead to a reduction in hepcidin, hephaestin and ceruloplasmin, jeopardizing iron metabolism and restricting its movement out of the gut and liver to areas where it may be needed in the body. Additionally, copper is also needed for the synthesis of heme, which is a constituent of hemoglobin. Thus, in order to get iron where it needs to go in the body, it must be placed onto transferrin, which requires copper.

• To sum it up, the absorption, export and transport of iron requires copper. All things regarding iron require adequate amounts of copper and many issues that are thought to be caused by “iron deficiency” may actually be caused by copper deficiency.

A copper deficiency can decrease iron levels and cause iron deficiency anemia in some tissues while resulting in iron overload in other tissues, such as the liver and intestine. An absence or dysfunction of ceruloplasmin leads to the accumulation of iron in the brain, liver, intestine, pancreas and retina. Tissue iron overload and very high serum ferritin levels have been seen in those with familial ceruloplasmin deficiency. Deficiencies in ceruloplasmin also cause iron to accumulate in the spleen, which leads to microcytic, hypochromic anemia, dementia, cerebellar ataxia and diabetes.

Cardiovascular Disease

Copper deficiencies are seen in animals and humans with a wide range of heart disease outcomes, such as aortic rupture, fissures, cardiac enlargement, abnormal lipid metabolism, and ischemic heart disease. Copper deficiency is one of the few nutrient shortages that elevates cholesterol, blood pressure, homocysteine, adversely affects the arteries, impairs glucose tolerance, and promotes thrombosis. People with hypertension tend to have lower copper than those with normal blood pressure. In men, copper deficiency can cause irregular heartbeat.

• According to a 1965 autopsy study, people who died from a myocardial infarction, had lower amounts of copper in their myocardium. 
• Atherosclerotic arteries have been shown to have lower copper and reduced cytochrome c oxidase activity than those without atherosclerosis. Cytochrome c oxidase is a copper-dependent enzyme. A shutdown of the copper-dependent cytochrome c oxidase is how cyanide leads to death, by inhibiting the production of ATP. Decreased cytochrome c oxidase in heart muscle has been noted after myocardial infarction. There is an increase of copper levels in patients with myocardial infarction, which may lead to copper depletion due to an increase in copper need.
• A decline in the copper content of the aorta has been seen alongside increased atherosclerosis. Among Nigerians, in both older men and women, significant reductions of arterial copper are observed. Similar observations have been made in African Americans and Minnesota Caucasians, although their copper levels are higher.
• Copper deficiency and low ceruloplasmin raises iron levels and can cause iron overload. High iron is a risk factor for heart disease and is associated with cardiovascular events. Elevated iron raises the demand for copper by inducing a mild copper deficiency. 
• Copper is needed to strengthen collagen, and hence, a lack of copper may reduce the health of the arteries and the heart. Copper is needed as a cofactor for lysyl oxidase which cross-links collagen and elastin giving it tensile strength. High homocysteine increases homocysteine thiolactone, which inhibits lysyl oxidase. As a result, your arteries can get damaged and become more susceptible to atherosclerosis. Aneurysms and blood vessels are more likely to rupture/tear with high blood pressure on a diet deficient in copper due to decreased collagen/elastin strength. Low lysyl oxidase, a marker of reduced copper status, is associated with ischemic heart disease. Homocysteine alone is a risk factor for cardiovascular disease, stroke, and ischemic heart disease. Homocysteine can bind copper and induce copper deficiency.
• Copper is important for neovascularization or angiogenesis (the process of growing new blood vessels). Thus, copper is also important in wound healing, whether that be ulcers, cuts, bruises or organ damage. The repair of collaterals, which are new blood vessels that supply the heart when larger arteries become blocked due to atherosclerosis, may not occur if the diet is low in copper. Copper ions also activate endothelial nitric oxide synthase (eNOS), which explains its importance in vasodilation and better endothelial function.

Inflammatory Conditions

Elevated copper levels in the blood can indicate inflammation, which itself is a cardiovascular disease risk factor. That’s why it is more accurate to look at enzyme activity or leukocyte copper levels than just blood copper levels.

• Diabetics have a reduction in liver copper content. In fact, diabetes itself can cause an imbalance of copper and a loss in copper utilization in the heart. That can contribute to the pathogenesis of diabetic arteriopathy. Inflammation is also raised during hyperglycemia, hyperinsulinemia, glucose intolerance and diabetes. Patients with peripheral arterial disease show higher blood pressure, high triglycerides, lipids and elevated serum copper because inflammation raises copper. Thus, diabetes can cause copper dysregulation and lead to cardiovascular disease development.
• Other inflammatory conditions like rheumatoid arthritis or infections exhibit elevated copper levels. It is also known that diets low in copper can cause osteoporosis. Copper deficiency reduces bone integrity, leading to brittle bones and fractures by decreasing lysyl oxidase. Low serum copper, iron and zinc are risk factors for osteoporosis. Excessive intake of milk, high in calcium and low in copper, may exacerbate this problem instead of mitigating it.
• There is an epidemiologic association between osteoporosis, ischemic heart disease and a diet low in copper. Osteoblast activity, osteoblasts are the cells that build our bone, decreased in copper deficiency and human osteoporosis. A supplementation trial with trace minerals that included copper, zinc, manganese and calcium improved bone density compared to either calcium only or trace minerals only. Decreased copper has been found in people with bone spurs, ischemic necrosis of the arteries, fractures and decreased lumbar bone density.

Oxidative Stress

Copper inhibits oxidative stress and reactive oxygen species (ROS) via superoxide dismutase (SOD). Superoxide anions cause lipid peroxidation in addition to other problems, which can be neutralized primarily by copper-zinc superoxide dismutase (Cu,Zn SOD). Excessive oxidative stress is a key contributor to the pathogenesis of many diseases, primarily by raising inflammation.

• Endothelial dysfunction, which is when the lining of the arteries is damaged and there is decreased arterial relaxation, precedes cardiovascular disease and is caused by reduced nitric oxide availability. A low copper intake can be a major contributor to reduced nitric oxide status. This is because copper is a cofactor for the function of superoxide dismutase, which inhibits the free radical superoxide anion, which sequesters nitric oxide to form the toxic peroxynitrite. Thus, a copper deficiency can result in a “nitric oxide steal”, transforming it into a damaging and inflammatory molecule. Polyphenol-rich blackcurrant powder/juice may improve nitric-oxide mediated relaxation of coronary arteries via a copper- and iron-dependent antioxidant effect.
• Low dietary copper intake increases free radical production in healthy men, which may increase the risk of colon cancer. Elevated reactive oxygen species cause death of endothelial cells, which also leads to cardiovascular disease. Reperfusion injury, which occurs after a blocked artery is re-opened, is also driven by ROS. Maintaining adequate copper intake helps to reduce the amount of ROS by regulating extracellular SOD.
• Copper seems to increase the activity of glutathione peroxidase, which is needed for handling hydrogen peroxide. In fact, copper deficiency has been shown to decrease glutathione peroxidase. Through an overall reduction in oxidative stress, ensuring adequate levels of copper can boost glutathione levels, which is the main antioxidant in the body that protects against oxidative stress. Thus, copper acts as an antioxidant mineral. In fact, a lack of glutathione may reduce the ability of the body to store copper as a complex with metallothionein. Hence, a low copper status can increase oxidative stress, resulting in a reduction in glutathione, which leads to further loss of copper and dysfunctional copper utilization. In other words, a low intake of copper can lead to an increased loss of copper.

Mitochondrial Function 

Copper is a co-factor for respiratory complex IV in the mitochondria. A copper deficiency impairs immature red blood cell bioenergetics, which alters the metabolic pathways, turning off the mitochondria and switching over to more glycolysis (sugar burning). As a result, there is a reduction in energy production and excessive lactate production from glycolysis. Lactic acidosis or the buildup of lactic acid is associated with several cancers and inflammatory diseases. During oxygen shortage, which can accompany copper deficiency anemia, lactic acid can begin to accumulate.

• Copper also plays a role in burning fat. Obese patients require more copper than the RDA (typically exceeding 1.23 mg/day). Norepinephrine, the hormone that promotes fat burning and alertness, requires copper for its synthesis. The transcription factor in the hypothalamus called HIF-1 alpha, is also copper-dependent, and it has a role in preventing obesity.

Metabolic Syndrome

Copper deficiency has a detrimental role in your metabolic health and condition. Metabolic syndrome is a condition in which at least three or more of the five are present: high blood pressure, central obesity, high fasting triglycerides, high blood sugar and low serum HDL cholesterol. It is associated with cardiovascular disease and type 2 diabetes by causing inflammation. Metabolic syndrome doubles the risk of cardiovascular disease and increases all-cause mortality by 1.5-fold.

• Copper deficiency, induced by high fructose intakes, impairs insulin binding and reduces insulin sensitivity. Diabetes can disrupt copper metabolism and copper deficiency can alter glucose metabolism. Accumulation of iron ions in the pancreas, due to copper deficiency and a lack of ferroxidase activity, is thought to cause diabetes.
• Low copper intake also raises cholesterol and triglycerides and copper supplementation can lower their levels in the blood. Copper deficiency increases the activity of hydroxymethylglutaryl-coenzyme A reductase (HMGA-CoA reductase), which is the rate-controlling enzyme for cholesterol synthesis, and hence increases cholesterol levels. 
• Copper deficiency also impairs thyroid hormone production. The thyroid is central to regulating metabolic rate and energy balance. There is a positive correlation between serum copper and thyroid hormones in children with congenital hypothyroidism. The ratio of copper and selenium influences thyroid functioning in patients with hypothyroidism. In thyroid disease, the metabolism of zinc, copper, manganese and selenium is abnormal. Low copper status also reduces the conversion of T4 into T3. Serum copper is also regulated by thyroid hormones, which stimulates the synthesis and the export of ceruloplasmin. Less thyroid hormones (hypothyroidism) = decreased ceruloplasmin = copper deficit. In fact, thyroid hormones are known to be needed for kidney sodium reabsorption. Ironically, sodium is needed to bring iodine into the thyroid gland (as well as other tissues such as lactating breast, salivary glands, stomach and intestines) to make thyroid hormones. Indeed, two sodium ions are needed to transport one iodide molecule into these tissues. Thus, thyroid hormone production and sodium status are interdependent on one another.

Kidney Health

Ceruloplasmin protects the kidneys as it acts as an antioxidant. The development of kidney dysfunction may occur in part due to a lack of copper, with kidney function improving upon copper supplementation. One group of authors concluded, “Copper deficiency can worsen nephrotic syndrome by decreasing the ceruloplasmin activity, which protects the glomeruli.” Additionally, kidney damage can increase the loss of copper in the urine. Patients with kidney damage tend to develop moderate copper deficiency. An easy indication of copper loss is spillage of albumin into the urine. This is because most copper in the blood is bound to the protein ceruloplasmin. The urinary losses of copper can be 8-32 times higher than normal in those with kidney damage.

Reproductive Health

Both copper transport as well as ceruloplasmin’s ferroxidase activity are exhibited in the testicles, primarily helping in the processes of spermatogenesis. Thus, copper is important for male reproductive systems. Additionally, the copper-dependent cytochrome c oxidase has an integral role in energy metabolism in the testes, enabling the production of ATP needed for sperm motility. Essentially, if a man is deficient in copper, their sperm does not swim as well. On top of that, a copper deficiency can also make the sperm more vulnerable to oxidative stress and DNA damage. When couples are having difficulties getting pregnant, it might be due to inadequate copper status. Foods high in copper like liver, oysters and clams are also considered fertility-boosting foods.

Immune System

Micronutrients, including copper and iron, are needed for modulating immune function and reducing the severity of infections. A copper deficiency has been shown to cause thymus (one of the main organs that produces immune cells) atrophy, reducing the amount of circulating neutrophils and decreasing the ability of macrophages to kill pathogens. Repletion of copper appears to be able to reverse this. By causing iron deficiency, a copper deficiency can also reduce phagocytosis and lymphocyte proliferation. In fact, infants with copper deficiency have been documented to have recovery in their immune health with copper supplementation. Copper is also essential for the production of interleukin-2, which is a cytokine that helps us fight infections.

The Functions of Copper

1. Energy production (cytochrome c oxidase, composed of copper and iron)
2. Detoxification of superoxide anions (superoxide dismutase converts superoxide to oxygen and hydrogen peroxide)
3. Synthesis of collagen and elastin (copper makes up lysyl oxidase)
4. Production of hemoglobin (ceruloplasmin catalyzes the oxidation of iron, which is necessary for iron to bind to its transport protein, transferrin)
5. Melanin production (tyrosinase converts tyrosine to melanin and is a copper containing enzyme)
6. Myelin production (the synthesis of phospholipids in myelin sheaths in peripheral nerves are dependent on copper)
7. Fat burning and beta oxidation
8. Inhibition of inflammation through antioxidants
9. Synthesis of thyroid hormones (thyroxine)

“Copper metabolism is altered in inflammation, infection, and cancer. In contrast to iron levels, which decline in serum during infection and inflammation, copper and ceruloplasmin levels rise.” This is why so many doctors fear “copper overload” and don’t take copper deficiency seriously, i.e., because they rarely see low copper levels on a blood draw.

Requirements

Balance studies suggest that a daily intake of 0.8 mg leads to net copper loss whereas net gains are seen with 2.4 mg/day.

Men and women fed diets low in copper, around 1 mg/day, develop increases in blood pressure, cholesterol, glucose intolerance, and abnormal electrocardiograms.

There is around 50-120 mg of copper in the human body. Copper is mainly stored in the liver, but it is also found in the heart, brain, kidneys and muscle. About 1/3rd of the total body copper is in the liver. However, copper is present in almost every tissue of the body. The daily copper turnover is estimated to be around 1 mg through fecal loss. Thus, total body copper stores can be depleted in a few months if daily intake is not near this level of intake. More importantly, this does not take into account copper losses in sweat, which can be quite significant. Overweight people appear to require more copper than normal weight ones, generally needing more than 1.23 mg/day. In obese children, copper levels in the blood are lower, but slightly higher in the plasma, than in controls. They also have lower iron levels, which may be due to inflammation caused by excess body fat. It is inflammation that raises copper and lowers iron in the blood.

The upper safe threshold is deemed to be 10 mg/day for adults. Taking 10 mg/day of copper for 12 weeks has not been seen to cause liver damage, but one case reports that a long-term intake of 60 mg/day resulted in acute liver failure. Intakes of 7-7.8 mg/day for 4-5 months in healthy male volunteers between the ages of 27-48 may cause some negative side effects, such as decreased antioxidant defense, suppressed immunity and increased excretion of copper. However, it seems that the body’s own homeostatic regulation of copper absorption is being automatically regulated to minimize the amount of excess copper retention.

Copper and Iron in Food

The RDA for iron is 8 mg for adult men and 18 mg for adult women. During pregnancy, the RDA increases to 27 mg. Normal ranges for serum ferritin are 20-250 ng/ml for adult males and 10-120 ng/ml for women. A serum ferritin below 30 suggests iron deficiency. Numbers above the reference range may indicate oxidative stress or just iron overload. People, especially children, who take supplements may overdose on iron. You can get iron poisoning from doses as low as 10-20 mg/kg.

Our bodies have a hard time eliminating iron. Losses only occur, at least in a significant amount, during bleeding, blood donation, menstruation in women or through chelation. That is why females are more susceptible to anemia and iron deficiency, whereas men are more prone to iron overload. Common iron chelators include coffee, spirulina, chlorella, green tea, beans, whole grains and vegetables. That is why, although things like spinach and beans contain high amounts of iron, it is harder to reach iron overload eating them because a large proportion of the iron gets chelated and/or not absorbed.

Iron and zinc are copper antagonists. Foods are not fortified with copper, which contributes to this epidemic of copper deficiency. Unsaturated fats (omega-6 seed oils) are also lacking copper because transition metals are removed by chelation to increase shelf-life. At the same time, foods high in copper, such as liver, oysters, lobster and crab are eaten less frequently

Muscle meat is extremely low in copper but high in zinc and iron. Heme iron, as found in meat, is particularly well absorbed compared to non-heme iron. The highly bioavailable iron in cooked meat may also reduce the absorption of copper. Excess cystine and cysteine consumption enhances copper deficiency in rats. Foods high in cystine/cysteine are animal proteins like poultry, beef, pork, eggs, fish, etc., and in smaller amounts in lentils and oatmeal. These foods are also highest in iron. Zinc absorption is also greater when eating animal protein compared to plant foods, which inhibits copper absorption. This might be why vegetarians or vegans may need more zinc than omnivores but less copper.

• Total copper absorption is higher with a lacto-ovovegetarian (dairy, eggs, and vegetarian) diet (0.48 mg/day) compared to a non-vegetarian diet (0.40 mg/day) because of its higher copper content. Moreover, the “antinutrients” in plants (phytic acid and phytates) can increase copper absorption by antagonizing zinc.
• Increasing the intake of plants and reducing the intake of muscle meat can help to improve copper status; or simply eat other animal foods, such as liver and shellfish, which contain copper. Importantly, when you accumulate iron, your copper requirements increase.
• A higher copper intake may explain why some studies show that vegans live longer than those eating a Standard American Diet. Indeed, the daily copper intake is 27% higher in vegetarians compared to omnivorous adolescent females. These studies however are including people who do not frequently incorporate copper-rich organ meats like liver and rely mainly on high iron muscle meat, which is the issue. Despite the reduced bioavailability, the higher copper content of plant-based diets seems to at least provide an adequate amount of copper.
• Foods rich in fructo-oligosaccharides like chicory root, blue agave, artichoke, asparagus, Yacon root, garlic, and green bananas, have also been shown to enhance the absorption of copper, zinc and selenium. Soybean protein, however, seems to reduce copper absorption. A high fiber diet improves copper absorption because of fructo-oligosaccharides and inulin.

Zinc/Copper Ratio

Zinc is a copper antagonist, which is why ingesting large doses of zinc can lead to copper deficiency by inhibiting its absorption and increasing its secretion. A high concentration of zinc in the small intestine triggers the expression of metallothionines, which bind to copper.

The golden rule when supplementing with zinc, is that at a minimum, for every 40mg of zinc, 1 mg of copper should be employed.

High copper and phytate intake may be a protective factor against the Standard American Diet high in zinc and iron (phytate can also bind free iron). Phytic acid decreases the ratio of zinc to copper that gets absorbed in the intestinal tract. This is not to say that you need to eat fiber or phytic acid, but it’s important to balance the zinc/copper ratio, and that means sourcing more than just muscle meat and eggs.

Organ meats like liver have a much more appropriate iron-zinc to copper ratio than muscle meat. Per ounce of beef liver, you get 4.1 mg of copper or 4.5 times the RDA for copper of 0.9 mg. However, it is not recommended to consume more than 1 oz. of beef liver per day as total intakes of copper at or over 10 mg for several months could cause unwanted side-effects. Although the liver is high in cholesterol, it may be an antidote to the hypercholesterolemic effects of meat, which may actually be due to the low copper content of muscle meat. Liver, heart, kidney, suet, etc. have fat-soluble vitamins like K2, A, D as well as CoQ10. Per calorie, liver is one of the most nutrient dense foods in the world. It is also relatively low in calories compared to muscle meat (~130-150 vs ~150-200 calories/3.5 oz).

• You can cover nearly all your needs for most vitamins and minerals by eating a single ounce of liver. Unfortunately, most people find organ meats disgusting but a simple way around this is to eat a blend of ground muscle meat with liver/heart (75% muscle meat/25% liver and heart). Organ meats and offal have been completely neglected in the modern industrialized diet landscape, whereas they are relatively common in France and other Mediterranean countries.
• Oysters are another example of this as they’re high in copper, which seems more than sufficient to counteract the inhibitory effects of their high zinc content.

The zinc to copper ratio of cow’s milk is 38, whereas that of human milk is between 4 and 6, this might explain the health benefits of populations that breast feed for several years versus in the United States, where children are typically switched over to cow’s milk at 9-12 months of age. A zinc/copper ratio of 38 leads to copper deficit in infants and is clearly not healthy for infants or adult humans. Additionally, a higher zinc to copper ratio (as found in cow’s milk) positively correlates with mortality due to coronary heart disease in 47 cities in the United States.

Thus, an optimal intake of zinc in an adult can range anywhere from 20-80 mg/day, depending on the person and the situation. The optimal intake of copper, however, seems to sit at around 3 mg/day, providing an optimal Zn/Cu ratio of anywhere from 4-20:1.

Foods with a high Zinc:Copper Ratio (these foods must be balanced with appropriate amounts of copper from other food sources):

• Oysters
• Muscle meat
• Breakfast cereal
• Cow’s milk
• Prepackaged meat
• Mollusks/shellfish

Foods with a low Zinc:Copper Ratio (these will need to be paired with foods higher in zinc):

• Organ meats/liver
• Seaweed/spirulina
• Lentils/beans/chickpeas
• Dark chocolate/cacao
• Vegetables

The takeaway is that you shouldn’t make these high zinc:copper ratio foods are the only ones that you eat in your diet. Additionally, you should not overconsume high copper containing foods either, like eating 3 oz. of liver every day. As a rule of thumb, eat around 0.5 to 1 oz. of liver/day for copper and at least 12 oz. of red meat for zinc, iron, B12 and protein.

Exercise and Zinc:Copper

Exercise stimulates the growth of muscle and bone, which are made-up of larger amounts of zinc compared to copper (zinc/copper ratios 56 and 120, respectively) and thus exercise tends to protect against a diet higher in zinc to copper (i.e., more zinc gets directed towards muscle and bone growth). This may be why weightlifters are somewhat protected from their high intake of meat, as zinc is needed for muscle and bone growth. This also suggests that weightlifters need more zinc, in order to develop larger muscles and stronger bones. Thus, zinc requirements go up when building muscle, and this is likely why many weightlifters crave muscle meat (for the high zinc content).

Copper and Molybdenum

Another copper inhibitor is molybdenum (Mo). It is a mineral found in foods like pork, lamb, beef, beans, eggs and cereal grains in small amounts. Molybdenum and copper have been found to have antagonistic roles with each other. Indeed, a Mo/Cu ratio of 2.5/1 in animals can lead to copper deficiency and altered immune responses during infection.

Patients with type-2 diabetes have been shown to have higher serum and urine copper levels due to molybdenum removing it from tissues and eliminating it through urine. Those with severe nephropathy have a higher urine level of Cu/Mo. Thus, excess molybdenum, when combined with sulfur, may promote the excretion of copper through urine or bile via binding with protein-bound and free copper.

Copper Absorption

Copper is absorbed in the gastrointestinal tract and is transported to the liver.

Liver damage, cirrhosis or fibrosis increase the demand for copper and decrease its absorption. Fibrate medications (such as bezafibrate, fenofibrate, gemfibrozil) may be able to restore low copper levels in NAFLD disease and increase concentrations of hepatic Cu-Zn SOD. Malabsorption diseases like celiac disease, short bowel syndrome and IBS also reduce copper absorption. Copper deficiency has been seen in patients with celiac disease and it can cause anemia and thrombocytopenia. Gastric bypass surgery or colon removal can cause copper deficiency.

The oral bioavailability of copper can range from 12-75%, depending on the amount of copper in the diet. The average bioavailability of most normal diets is between 30-40% on the typical Western diet. That number can be lower in the presence of excess zinc, molybdenum, iron or fructose/added sugars. The refining of grains and cereals can reduce the copper content by up to 45%.

Indiscriminate use of multivitamins that often contain zinc and iron can be problematic for people low in copper.

Copper absorption occurs in the stomach and the small intestine, but the most efficient absorption takes place in the ileum and duodenum. For optimal absorption, copper needs acid from the stomach to be liberated from food. During absorption, excess copper is transiently stored in the enterocytes by binding to metallothionine. Once inside the enterocyte, cuprous ions bind to different copper chaperones to be distributed to various organelles and cell compartments. Thus, damage to the microvilli of enterocytes, which contain micronutrient absorption transporters, will decrease copper absorption. It has been shown that the overconsumption of refined sugar and fructose damages the enterocytes, which will likely reduce copper absorption.

• Iron can compete with copper for absorption via the DMT1 (divalent metal transporter 1) transporter. Iron deprivation or iron deficiency due to chronic disease or malnutrition, can lead to copper overload, possibly due to absorption increases in ATP7A, which brings copper into the portal circulation. Zinc also competes with copper absorption via DMT1.
• Sodium may enhance copper absorption or retention and people on amiloride may need more copper as it appears to reduce copper and sodium absorption in the intestine. Thus, low salt diets may reduce, whereas normal salt diets may improve copper absorption.
• In the presence of excess copper, CTR1 reduces copper absorption by enterocytes. However, when enterocytes are damaged because of intestinal tract injuries, copper deficiency may occur.
• Fructose increases the requirements for copper and exacerbates the effects of copper deficiency. Thus, added sugars are a tax on copper status.

Approximately 0.5-2.5 mg of copper is excreted via feces every day. Biliary copper secretion cannot be reabsorbed, as it is prevented by binding to bile salts and comes out in the feces. Thus, the body has the ability to get rid of copper excess through bile excretion, which is regulated by the liver (liver cells excrete excess copper into bile). Low blood copper levels, or low ferritin levels, leads to copper being released into the blood circulation. To prevent copper overload, surplus copper can be excreted through the natural shedding of the intestinal epithelial cells.

Copper absorption in the stomach is stimulated by an acidic pH and is inhibited by zinc and cadmium. Stomach acid frees up copper bound to food and facilitates peptic digestion, which releases copper from natural organic complexes. That is why proton pump inhibitors or other acid suppressing over the counter therapies or medications can reduce copper absorption as it reduces the release of copper from natural organic complexes in food.

Cadmium is a common toxic heavy metal that has accumulated in the environment due to pollution. Ironically, zinc helps to reduce the absorption of cadmium.

Vitamin C can enhance, or inhibit, copper absorption. If taken prior to (around 75 minutes before) or with copper, vitamin C reduces copper absorption by blocking the binding of copper to metallothionein. However, if vitamin C is taken after copper ingestion (75 minutes after) it increases ceruloplasmin and lysyl oxidase activity. Vitamin C also seems to help facilitate the transfer of copper ions into cells, reacting with the copper carrying protein ceruloplasmin, reducing cupric copper (CuII+) to cuprous copper (CuI+) making the bound copper atoms more freely available and facilitating their cross-membrane transport. Moreover, histidine may aid the transport of copper from albumin into certain cells. Additionally, glutathione appears to help facilitate the transfer of copper to metallothionine and superoxide dismutase. Thus, cysteine and glycine, which help to increase glutathione levels, may also help with copper transport in the body.

In large doses, vitamin C may decrease copper status by increasing iron and zinc absorption. However, there may not be enough vitamin C in whole foods like fruit and vegetables to inhibit copper absorption or deplete it.

• That is why it is better to focus on getting vitamin C and potassium from whole foods and use supplemental doses only acutely during sickness or an infection. On the flip side, Vitamin C + E can also combat copper toxicity-induced lipid peroxidation and liver damage. They have also been shown to reduce the oxidation of HDL cholesterol caused by excess copper.

Copper homeostasis is maintained in the liver. Importantly, the thyroid gland regulates more than 5% of all the genes expressed in the liver, including copper metabolism.

• Thyroid hormones stimulate the synthesis and export of ceruloplasmin from the liver into the serum. Thus, being hypothyroid may hinder copper homeostasis and utilization in the body.

One of the biggest chelators of copper is glyphosate. Deficiencies in trace minerals like iron, molybdenum, copper and others are associated with celiac disease and it can also be attributed to glyphosate’s ability to chelate these metals. Glyphosate is one of the most common pesticides in the U.S. used on almost all types of fruit and vegetables. Not only does it reduce the mineral content of the vegetation, but it also disrupts the microbiome potentially promoting malabsorption diseases.

• Glyphosate is a strong chelator thanks to its ability to form strong complexes with transition metals. Glyphosate has also been shown to decrease iron, magnesium, manganese and calcium levels in non-GMO soybeans.

Copper-Dependent Enzymes and Functions and the Consequences of a Deficit

Copper-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Cytochrome c oxidase: Cellular respiration: Decreased energy production
• Superoxide dismutase: Dismutation of superoxide anion radical: Increased oxidative stress
• Catalase: Catalyze the conversion of hydrogen peroxide into water: Increased oxidative stress and lipid peroxidation in the heart
• Glutathione: Scavenge free radicals: Increased oxidative stress
• Glutathione peroxidase: Eliminates hydrogen peroxide: Increased oxidative stress
• NADPH: Free radical protection and increase nitric oxide: Reduction in glutathione and increased oxidative stress
• Tyrosinase: Converts tyrosine to dopamine: Depression
• Dopamine-B-hydroxylase: Converts dopamine to norepinephrine: Depression, decreased “fight or flight response”, potentially decreased ability to survive stressful events, obesity
• Peptidylglycine alpha-amidating monooxygenase: Neuropeptide synthesis and peptide hormone processing: Brain processing problems
• Lysyl oxidase: Conversion of procollagen to tropocollagen and of pro-elastin to elastin in the connective tissues: Decreased strength of blood vessels, cartilage, heart, bones, enamel, ligaments and damage to these tissues
• Cartilage matrix glycoprotein: Formation of extracellular matrix and copper transport in cartilage cells: Decreased tendon strength, loss of cartilage tissue and osteoarthritis
• Soluble pyridoxal-dependent monoamine oxidase: Oxidation of catecholamines to aldehydes: Reduced glucose uptake in fat cells and reduced leukocyte transmigration into endothelium decreasing pathogen killing
• Ceramide galactosyl transferase: Myelinogenesis: Myelopathies and neurological disorders
• Prostaglandin GG2 or GH2 reductase: Synthesis of prostaglandin F2- alpha: Inflammation, growth deficiency
• Beta-oxidation: Governs fat burning: Metabolic syndrome, obesity & insulin resistance
• Ceruloplasmin: Copper and iron transportation: Anemia, fatigue, iron overload
• Hemoglobin: Tissue oxygenation and energy production: Anemia, fatigue, poor energy production
• Hepcidin/Hephaestin: Intestinal iron absorption/oxidation of ferrous to ferric iron: Anemia

In humans, copper levels are high in the organs during childhood and start declining throughout later stages of life. During old age, hepatic and aortic copper decreases substantially, which is inversely associated with the concentration of calcium in the arteries.

Signs and Symptoms of Copper Deficiency

Anemia that may mimic iron deficiency or B12/folate deficiency, malabsorption of iron causing actual iron deficiency, leukopenia, neutropenia, high cholesterol, osteoporosis, histamine intolerance, hypopigmentation of skin and hair, neurotransmitter imbalances such as low adrenaline or high serotonin.

Patients with an acquired copper deficiency and lack of ceruloplasmin can get liver iron overload, diabetes, neurological issues and retinal degeneration. People with non-alcoholic fatty liver disease (NAFLD) have significantly lower copper levels in the liver, which suggests that copper deficiency likely contributes to the iron accumulation in the liver of those with NAFLD. Iron overload is associated with many diseases like arthritis, cancer, tumor growth, diabetes, heart failure and liver damage. Studies link excess heme iron with colon cancer. By reducing iron overload, copper may slow down the aging process. Furthermore, iron overload can induce copper deficiency. 

• Anemia
• Defective keratinization of the oral cavity
• Neutropenia
• Hypopigmentation of hair and skin
• Abnormal bone formation/bone fragility
• Cartilage damage, joint pain and arthritis
• Reduced immunity
• Vascular/blood vessel issues
• Cardiac hypertrophy
• Heart murmurs and valvular regurgitation
• Fragile collagen/elastin (fragile organs/tissues) – tendon/tissue ruptures/tears
• Aneurysms of blood vessels (rupture of heart/blood vessels)
• Increased lipid accumulation in the heart
• Abnormal EKG – changes in ST segments, prolonged PR intervals and R wave duration and amplitude
• His Bundle electrical abnormalities
• Increased QT intervals, inversion of the T wave and increased QRS amplitudes and notching
• Decrease in ATP levels and energy
• Increased lactic acid
• Decreased ventricular contractility in the heart

Risk Factors for Copper Deficiency

• The best food sources of copper are liver, oysters, shiitake mushrooms, pure chocolate, and spirulina. Other good sources are shellfish, whole grains, legumes, and potatoes. Diets low in these foods will predispose an individual toward copper deficiency.
• Soil variation is large, and low soil copper is another major factor predisposing toward deficiency.
• Improperly formulated infant formula and total parenteral nutrition have resulted in copper deficiency.
• Zinc supplementation can cause copper deficiency, especially if the dose is over 45 milligrams or if the ratio of zinc to copper is greater than 15.
• Impaired methylation, antacids, proton pump inhibitors, gastric bypass surgery, and any digestive problems affecting the stomach or upper intestine can cause copper malabsorption.
• High doses of vitamin C may impair copper metabolism but evidence for this is limited.
• Menkes disease is a very rare defect in copper metabolism that causes copper accumulation in some tissues but overall presents as systemic copper deficiency.
• Copper deficiency can reduce the function of superoxide dismutase (SOD) increasing oxidative stress and oxidized lipids in the body. Furthermore, copper is needed to strengthen collagen and hence a lack of copper may reduce the health of the arteries and the heart. A lack of copper also reduces the body’s ability to use iron and can lead to anemias commonly thought to be due to iron deficiency.
• Copper deficient diets can reduce cytochrome c oxidase activity and heme synthesis from iron and protoporphyrin. This reduction in cytochrome c oxidase limits the reduction of Fe3+ iron to Fe2+ iron to form heme. Thus, copper deficiency reduces iron utilization by the mitochondria.

Copper Toxicity

• In theory, excess copper may cause oxidative stress and contribute to Alzheimer’s disease and other neurodegenerative diseases. However, the only well-established syndrome of copper toxicity is Wilson’s disease, which is a genetic defect in the ability to excrete copper into the bile. This results in unregulated copper absorption, impaired transport into some tissues causing local deficiency, but net copper overload and deposition of excess copper in the liver, brain, and cornea, where it causes oxidative damage. 
• Copper-rich diets are unlikely to meet the upper limit, and they are also rich in zinc, which protects against copper toxicity. Supplemental copper should be kept under 10 milligrams per day, and ideally should be kept under 3 milligrams per day unless higher doses are needed to correct a deficiency or to prevent the zinc-to-copper ratio from exceeding 15. Copper may contaminate water at doses that exceed the upper limit, but this will make you nauseated and turn your laundry, sinks, toilets, and bathtubs light blue or green.
• Filtering the water or running it for a minute before consumption will eliminate a large amount of contaminating copper. Infants cannot regulate their copper absorption and should not be given copper supplements.

Testing Copper Status

C-reactive protein has been associated with an elevation of copper. Usual plasma copper tests are insensitive and not entirely accurate. Low copper levels in the liver would likely be a better determinant but a more practical strategy would be to measure leukocyte copper levels, which are more reflective of total body copper status and are depleted in those with significant atherosclerosis or coronary artery disease.

Unfortunately, measuring copper levels in the liver requires a biopsy and hence it is not very practical. Hair mineral analysis is a potential option to add to other measurements for an overall assessment of trace mineral status. Scalp hair remains isolated from other metabolic activities and is a unique indicator of elements concentrated in an individual at a given time point. Hair analysis has been used for successful assessment of heavy metal toxicity. Red blood cell copper may also be a better indicator of copper status versus serum levels and may reveal an undiagnosed pandemic of copper deficiency.

Best to Worst Ways to Diagnose Copper Deficiency:

1. Liver copper levels
2. Leukocyte copper levels
3. Red blood cell copper levels
4. Blood copper levels and ceruloplasmin

Testing Caveats

• Ceruloplasmin is increased by inflammation and estrogen. Since most copper within serum is bound to ceruloplasmin, this tends to elevate serum copper as well, but to a lesser degree.
• Pregnancy nearly doubles the levels of these markers. Lactation has a significant but weaker effect.
• Supplemental estrogen increases copper by 30 to 90%.
• Whether these markers remain suitable for assessing copper deficiency during these conditions and how the ranges should be altered has not been studied.

Correcting Copper Deficiencies

• 7 milligrams of supplemental copper per day for two months have been shown to fully correct anemia and neutropenia associated with celiac-induced copper deficiency.
• Ideally copper-rich foods should be emphasized, but this can serve as a general strategy for supplementation. The aim should be to normalize blood markers and resolve any related signs and symptoms.
• If the cause is zinc supplementation, the zinc should be removed until the deficiency is fixed, and the dose should be lowered or its ratio to copper should be improved if the supplement is reintroduced. If the cause is antacids or proton pump inhibitors, alternative strategies for improving these symptoms should be sought if possible. Malabsorption disorders require medical treatment.

Correcting Copper Toxicity

Wilson’s disease requires chelation therapy. However, chelation therapy may cause deficiencies of other minerals, so screening for other deficiencies is advised. The rare cases of outright copper poisoning require close medical attention. Other potential harms of excess copper are speculative and if suspicions are raised, improving zinc status is likely the best protection.

Selenium

Summary

Selenium is an essential mineral important for hormonal production, antioxidant defense and redox homeostasis (balancing oxidative stress). It’s also a cofactor for the antioxidant glutathione peroxidase – boosting its expression and activity. Viral infections can increase the need for selenium due to increased production of reactive oxygen species.

Selenium is involved in repairing oxidized methionine residues, thus playing a role in oxidized protein repair systems. Cooking protein-rich food like meat at high temperatures creates carcinogenic compounds called heterocyclic amines and polycyclic aromatic hydrocarbons, which might be mitigated in the presence of adequate selenium.

Selenium deficiency is linked to pathogenicity of multiple viruses. Deficient selenium enhances the pathology of influenza infection. Sufficient selenium improves survival from influenza-induced pneumonia. Getting more dietary selenium protects against influenza. The host’s selenium status is a determining factor in influenza virus mutations. Supplementing 200 mcg of selenium for 8 weeks in selenium-deficient people increased cytotoxic lymphocyte-mediated tumor cytotoxicity by 118% and natural killer cell activity by 82.3% compared to baseline. The best source of selenium appears to be yeast.

Selenium is contained in over two dozen selenoproteins in the body, many of which have roles in cell redox homeostasis and antioxidant defense. Selenium has two forms: inorganic (selenate and selenite) and organic (selenomethionine and selenocysteine) both of which are good dietary sources of selenium.

Sodium-Selenium-Iodine (SSI) Connection

Selenoproteins are involved with thyroid hormone metabolism and antioxidant defense. Selenium is present in selenoproteins as selenocysteine, which is essential for enzymatic activities. In addition to iodine, the thyroid gland is also the highest concentrated source of selenium per gram of tissue in the body due to a high number of selenoproteins.

The main selenoproteins, namely glutathione peroxidase, thioredoxin reductase and deiodinases are expressed in the thyroid gland in large quantities.

How Selenoproteins Affect Thyroid Function

• Glutathione peroxidases (GPx) are selenoenzymes that regulate thyroid hormone synthesis, contributing to the high content of selenium in the thyroid. They also protect thyroid cells against hydrogen peroxide and other free radicals, which would otherwise inhibit thyroid function. Selenium deficiency reduces glutathione peroxidase levels. A study noted that there was an association between higher TSH and decreased selenium/glutathione peroxidase activity.
• Thioredoxin reductases (TrxR) are essential for antioxidant defense and regulation of certain transcription factors. So far, there have been three selenoenzymes in the thioredoxin reductase family identified – TrxR1, TrxR2 and TrxR3. They help protect the thyroid against oxidative damage.
• Deiodinases (DIO) scavenge iodide from iodinated tyrosine inside the thyroid gland during thyroid hormone biosynthesis and are a family of thioredoxin proteins. The breakdown of thyroglobulin (Tg) during thyroid hormone biosynthesis produces 6-7 times more iodinated tyrosine than thyroid hormones; deiodinases are then available to salvage iodide from iodinated tyrosine. Without deiodinase, iodide and left-over iodinated tyrosine would be excreted through urine, reducing thyroid hormone biosynthesis. In fact, mutations in deiodinases cause iodine deficiency and selenium directly controls deiodinase activity. TSH stimulates the conversion of T4 into T3 via deiodinases.

Thus, selenium is important for not only activating thyroid hormones, but also recycling them. In other words, iodine does not work without selenium and sodium and a lack of any of these essential nutrients will worsen thyroid function.

Chronic lymphocytic thyroiditis (CLT) can be improved with selenium at a dose of 200 mcg/day given for 3-12 months by decreasing anti-thyroperoxidase (TPO) antibodies. The suppression of antibodies appears to require doses above 100 mcg/day to maximize glutathione peroxidase. CLT is the most common autoimmune thyroid disease in which iodine status is adequate and where genetic factors of selenium deficiency are present. Giving 200 mcg of selenium/day as selenomethionine might help to reduce postpartum thyroiditis by reducing thyroid antibodies. Selenium given at 80 mcg/day for 12 months has also been observed to significantly lower anti-TPO antibodies in patients with Hashimoto’s thyroiditis with normal T4 and TSH levels.

• Anti-TPO antibodies promote the production of inflammatory cytokines by thyroid lymphocytes, making the effects of selenium more pronounced during episodes of inflammation.

Graves’ disease is also correlated with lower selenium levels and selenium is necessary for protecting against the increased oxidative stress that occurs during this condition. Selenium supplementation has also been shown to improve the quality of life in patients with Graves’ orbitopathy.

Selenium supplementation in those who have a baseline deficiency likely provides significant benefits, whereas consuming over 300 mcg/day of selenium may potentially lead to negative consequences:

• Generally, the majority of observational studies and meta-analyses see an inverse relationship between selenium/selenoprotein status and cardiovascular disease risk. The main mechanism appears to be due to selenoproteins’ ability to inhibit oxidative stress, lower inflammation and protecting vascular cells against apoptosis or calcification. Selenoproteins regulate redox and calcium homeostasis. Selenoproteins increase resistance to oxidative stress, whereas selenium deficiency increases damage from oxidative stress.
• Selenoproteins can prevent the oxidation of lipids, which reduces the potential for atherosclerosis. The oxidation of LDL is a bigger risk factor for atherosclerosis and heart disease than total or LDL cholesterol levels alone. Furthermore, lipoproteins become oxidized when oxidative stress exceeds the body’s antioxidant capacity. Supplemental selenium at doses of 100-300 mcg/day has been shown to lower total cholesterol and raise HDL cholesterol, which may help clear the blood from potentially oxidizable lipids. 
• Glutathione peroxidase-3 (GPx3) deficiency, which is a selenium-dependent enzyme, promotes platelet thrombosis and vascular dysfunction. GPx3 can also inhibit the oxidation of LDL cholesterol by eliminating hydroperoxides, thus preventing vascular inflammation and atherogenesis. GPx4 has similar effects. Selenium levels are directly correlated with GPx activity.
• Impairment of selenoproteins during selenium deficiency may be a contributing factor in congestive heart failure and cardiomyopathy. Low selenium status is associated with future cardiovascular death in patients with acute coronary syndrome (someone who has had a heart attack). Selenium deficiency in heart failure patients is independently associated with impaired exercise tolerance and a 50% higher mortality rate.
• Thioredoxins also regulate cardiac function and cardiovascular disease risk. They also affect cardiac remodeling. Trx-1 has been shown to reduce oxidative stress and cardiac hypertrophy in response to oxidative stress.

People with lower selenium status are more likely to experience cognitive decline and neurodegeneration because of increased oxidative stress. Low selenium in the elderly also correlates with worse memory. In France, supplementation with antioxidants, including selenium, has been shown to improve episodic memory and semantic fluency in subjects aged 45-60.

Heavy Metals

Selenium has detoxifying effects on several heavy metals, such as cadmium, mercury and lead. The mechanisms are mediated by glutathione peroxidases and other antioxidants that help to eliminate these toxic compounds. Mercury toxicity can inhibit selenoenzymes that are needed to combat oxidative stress. Thus, selenium might be a cornerstone mineral for preventing the damage that occurs from heavy metal toxicity.

• This is also one of the reasons why seafood that has higher levels of selenium poses a lower risk for mercury toxicity. Tuna actually contains selenoneine, which is a potent antioxidant. The ratio of selenium to mercury matters more as selenium counteracts the harms from mercury. The consumption of fish can contribute up to 16.7% of the dietary protein intake for humans worldwide.
• The addition of selenium fertilizers has been shown to reduce the accumulation of cadmium and lead into crops like lettuce. Fruit stays firm and ripe longer if sprayed with foliar selenium, possibly due to an increased protection against oxidation. Selenium also protects plants against environmental stressors like UV-B radiation and extreme temperatures.
• However, in large amounts, selenium can act as an environmental pollutant, killing fish. In most cases, high selenium in the environment is the result of activities like coal burning and mining.

Requirements

The RDA for selenium is 15 mcg for infants, 20-40 mcg for children and 55 mcg for adults. During pregnancy and lactation, the RDA for selenium increases to 60-70 mcg/day, respectively. Selenium toxicity or selenosis generally occurs if you exceed 400 mcg/day (although the actual level that induces toxicity is likely at 800mcg/day or higher).

Large doses of selenium in individuals without selenium deficiency may promote hyperglycemia and insulin resistance. Symptoms of too much selenium consumption include a metallic taste in the mouth, garlic odor, hair and nail loss and brittleness. Diarrhea, nausea, fatigue and skin lesions are also common.

The low selenium content of New Zealand’s diet was fixed by increasing the import of high-selenium wheat. Selenium levels are well known to be lower in smokers and the elderly.

Things that Raise the Requirement for Selenium

• Hemodialysis removes selenium from blood
• HIV patients have lower levels of selenium because of malabsorption
• Certain medications like cisplatin lower selenium in hair and serum
• Malabsorption conditions like IBS, intestinal permeability, etc.
• Aging
• Heavy metal toxicity and pollution
• Living in a low selenium soil environment
• Hypothyroidism
• Chronic inflammatory conditions like diabetes and cardiovascular disease

General Note on Selenium

Due to the extremely wide variation of soil selenium and the fact that hardly anyone knows exactly where all of their food comes from, it’s assumed that everyone is at approximately equal risk of having too much or too little selenium, and believe everyone should measure their plasma selenium to confirm their actual selenium status. Deficiency and toxicity look very similar to one another, underscoring the need to measure selenium status even further.

Availability from Food

Brazil nuts, wild salmon, kidneys, mutton, egg yolk. 

How much selenium is in food depends on the amount of selenium in the soil. The soil consists of inorganic selenium that the plants obtain and convert into the organic form. Selenocysteine and selenite promote selenoprotein biosynthesis by getting reduced to hydrogen selenite, which is then converted to selenophosphate which supports selenoprotein biosynthesis. In animal and human tissues, selenium is in the form of selenomethionine and selenocysteine.

Ocean waters and rivers also contain quite a lot of selenium, which is why meat, fish and seafood are generally much higher in selenium than plants.

2-3 Brazil nuts per day will achieve daily requirements. Other options for daily selenium consumption are consuming seafood 2-3 times per week since that will also provide iodine, omega-3s and protein. The majority of selenium is absorbed in the small intestine (50-80%) and excreted by kidneys (60%). Thus, your selenium status is also determined by the state of your digestive and excretory organs.

Frequency of Deficiency

Mild deficiency is common

Selenium-Dependent Enzymes, Functions and Consequences of a Deficit

Selenium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

• Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
• Thioredoxin reductase: Antioxidant defense, peroxynitrite protection, convert T4: Oxidative stress, atherosclerosis and lipid peroxidation
• Deiodinases: Convert T4 into T3 and iodine transport in thyroid cells: Hypothyroidism
• Thyroid Hormones: Regulate metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
• Glutathione: Scavenge free radicals: Increased oxidative stress

Signs and Symptoms of Selenium Deficiency

• Keshan disease is a classical deficiency disorder. It includes hepatic cirrhosis, white nail beds and fingernails falling out, and cardiac insufficiency with fibrosis and necrosis.
• Generally, selenium deficiency increases the vulnerability to infections, toxins, and other nutrient imbalances, especially to those that cause oxidative stress, such as vitamin E deficiency and iron overload.
• Less well established but plausible signs of selenium deficiency include the following: poor production of T3, the active thyroid hormone, from its precursor, T4; Hashimoto’s thyroiditis; and cancer, especially prostate, colorectal, and lung cancers. While not clearly documented, white spots and streaks in the fingernails might occur in deficiency; however, these are more clearly documented in toxicity.
• Selenium deficiency increases thyroid size and risk for goiter. Lower selenium levels are associated with increased thyroid volume and nodule formation. Thus, adequate selenium may protect against goiter as well as thyroid disease. The incidence of goiter in children is associated with the amount of selenium in the local soil – i.e., low selenium in soil, low selenium in food, selenium and iodine deficiency, hypothyroidism and goiter. Fixing iodine deficiency in children with goiter and selenium deficiency does not reduce the volume of goiter or improve thyroid function.
• Selenium deficiency leads to the activation of oncogenes (cancer causing genes) due to an increased formation of reactive oxygen species. Thus, selenium might have a role in the prevention of cancer due to its antioxidant and immunomodulatory properties.

Risk Factors for Selenium Deficiency

• Selenium content is richest in organ meats and seafoods. Brazil nuts are rich in selenium but more variable than animal foods. Diets lower in these foods are more likely to produce selenium deficiency than diets high in them.
• However, the overwhelming risk factor for selenium deficiency is deficient levels of selenium within the soils where most of the foods are grown. Deficient methylation should not lower blood levels of selenium but might impair the utilization of selenium for biological functions.

Signs and Symptoms of Selenium Toxicity

• High soil content: Hepatic cirrhosis, hair loss (alopecia), and nails that are brittle with white spots and streaks and may fall out.
• In cases of acute poisoning due to errors in formulating supplements: muscle cramps, nausea, diarrhea, irritability, fatigue, loss of the hair and nails, and peripheral neuropathy (weakness, numbness, pain, or tingling in the hands and feet).
• More moderate excesses of selenium may increase the risk of diabetes.

Risk Factors for Selenium Toxicity

High soil levels are the main cause of toxicity, but in the past, poisoning has occurred from mistakes in the formulation of supplements. Deficient methylation may impair the ability to excrete excess selenium.

Testing for Selenium Status

Plasma selenium is the ideal marker of selenium status. Serum and whole blood are likely to be equivalent, but plasma selenium is better studied and preferred. Plasma selenium should be kept between 90 and 140 μg/L, with the possible sweet spot being 120. For units, μg/L and ng/mL are interchangeable.

Correcting a Selenium Deficiency

• Organ meats, seafood, and Brazil nuts can be used in the diet to increase selenium intakes, but it must be kept in mind that Brazil nuts are extremely variable in their selenium content. Some sources may advocate using mushrooms, but selenium is poorly bioavailable from mushrooms.
• For supplements, selenomethionine should be used. Selenite and selenate are acceptable but not preferable. Methylselenocysteine should be avoided. 100 micrograms per day is fully adequate to correct a deficiency, but 200 micrograms per day could be used for 3-4 weeks if faster progress is desired. Regardless, five months should be given to see the full effect.
• If plasma levels cannot be sustained in the optimal range with diet alone, the long-term maintenance dose of a supplement should be 100 micrograms per day for adults, or 1-1.5 micrograms per kilogram body weight per day for children. It is important to follow up plasma selenium to ensure the target range has been reached and not exceeded.
• Selenium – 50-200 mcg daily improves glutathione peroxidase and immune cell proliferation.
• Taking 200 mcg of selenium has been shown to increase glutathione peroxidase in patients with chronic kidney failure. Over 400 mcg/day of selenium, however, can be toxic and cause nausea.
• Selenium supplementation without prior iodine replenishment may exacerbate hypothyroidism because there isn’t enough glutathione peroxidase to clean up the hydrogen peroxide that gets created during iodine-deficient hypothyroidism. Those unleashed free radicals will then begin to damage thyroid cells and interfere with thyroid health. Thyroid function has not been shown to change in healthy subjects receiving additional supplemental selenium if they have no parameters of hypothyroidism.

Note on Selenium Supplementation

Selenium supplements mostly come in the form of selenomethionine, selenium-enriched yeast, sodium selenite or sodium selenate. The human body can absorb up to 70-90% of selenomethionine but only 50% of selenium from selenite. Thus, selenomethionine is the best organic selenocompound for improving selenium status because it is incorporated into proteins in a non-specific way. However, selenomethionine needs to be reduced to hydrogen selenide (H2Se) by selenocysteine beforehand, making it less efficient metabolically. Nevertheless, organic selenocompounds like selenomethionine cause less acute toxicity, which is why they are more preferred in short-term therapy.

Plasma or serum selenium levels at 8 mcg/dL or above are enough to meet the requirements for selenoprotein biosynthesis. The average serum selenium concentration in U.S. adults over 40 years old is 13.67 mcg/dL. Males tend to have higher selenium levels than females and whites more than African Americans. Blood and urine selenium reflect only recently consumed selenium. Measuring glutathione peroxidase can be an indirect measurement of selenium status. Selenoprotein P may be one of the best markers for measuring total body selenium status.

Correcting Selenium Toxicity

• In the case of toxicity, liver damage and other complications will require close medical care.
• For less severe excesses of selenium, the source of excess selenium, whether supplements or foods, should be removed. Since excess selenium causes oxidative stress, the other nutrients in the antioxidant section should be examined and optimized.

Iron

It forms hemoglobin, comprises proteins throughout the body, and regulates cell growth and differentiation. It even helps maintain brain function, metabolism, endocrine function, and immune function and plays a role in the production of ATP. However, if you consume too much, you can develop hemochromatosis (particularly dangerous for men who don’t get rid of excess, via menstruation, and sedentary individuals who don’t turn over as many RBCs). As your cells create energy, they create low, manageable levels of superoxide, which enzymes convert into hydrogen peroxide to be converted to water and oxygen. When iron interacts with superoxide or hydrogen peroxide it leads to a chemical reaction that produces a free radical known as hydroxyl radical. Too many of these can lead to age-related chronic conditions like Alzheimer’s, Parkinson’s, cancer, heart disease, and diabetes.

Iron is a cofactor to many DNA repair and replication proteins like Pol #, Rad 3/XPD and Dna2. Mutations of iron-requiring proteins are associated with diseases of DNA repair defects in mammals. Base excision repair glycosylases that remove damaged bases contain the iron-sulfur cluster protein cofactor. Hence, good iron (and thus by default copper) and sulfur status are important for DNA repair.

Frequency of Deficiency

Developing countries and some vegans. Celiac disease, Crohn’s disease and pregnancy are predisposing factors

Availability from Food

Blood, bovine liver, oysters, mussels, beef, sardines, dark green vegetables. Vitamin C promotes the absorption of iron.

Signs and Symptoms of Iron Deficiency

• Iron deficiency leads to anemia, which may be asymptomatic early on, but which can cause declining work performance, fatigue, weakness, pale skin, arrhythmia, palpitations, dizziness or lightheadedness, and muscle cramps. During anemia, blood is rerouted to supply the brain and heart at the expense of most other tissues, which causes a decline in many other bodily functions, such as digestion and skin health. Iron deficiency also causes hypothyroidism, leading to signs such as cold hands and feet, increased sensitivity to cold in general, hair loss, and swelling (edema) in the face.
• In children, iron deficiency causes short stature and permanent decrements in brain function manifesting as low IQ, and it is especially critical to catch it and correct it early. Iron deficiency also delays puberty.

Risk Factors for Iron Deficiency

• Loss of blood during menstruation and increased needs during childhood and pregnancy are the major risk factors for iron deficiency. Additionally, the absorption of iron is more reliable from animal foods than from plant foods, and the phytate found in whole grains, nuts, seeds, and legumes (especially abundant when these foods are not processed by fermentation, soaking, or sprouting) is a major inhibitor of iron absorption.
• Polyphenols, found generally in plants, and especially rich in fruits and vegetables, are also inhibitors of iron absorption. Thus, a dietary pattern low in animal foods and rich in plant foods is an additional risk factor for iron deficiency, especially when iron-containing supplements and iron-fortified foods such as enriched flour are not used.

Signs and Symptoms of Iron Overload

• Clinical iron overload is known as hemochromatosis. Classically, it is understood as causing four manifestations, known as a tetrad: hepatic cirrhosis, diabetes, hyperpigmentation of the skin, and cardiac failure. The hyperpigmentation increases in response to sun exposure and generally consists of brown, bronze, or gray coloring. It can be driven by iron deposits or increased melanin; however, iron overload is a major risk factor for a collection of disorders known as porphyrias, where intermediates in heme synthesis known as porphyrins may also accumulate in skin and generate brown or red coloration in response to sun exposure. Hyperpigmentation may also affect the teeth and be accompanied by enamel loss. Patients also report fatigue, joint pain, depression and mood swings, hair loss, chest pain, dizziness, impaired sexual function, menstrual problems, and abdominal pain. Iron overload appears to raise blood cholesterol and to contribute to Alzheimer’s, and possibly Parkinson’s. Iron overload causes oxidative stress, so general wear and tear on the tissues, problems associated with the deficiencies of other antioxidant nutrients, and aggravation of most chronic disease risk, should be expected.
• Production of reactive oxygen species during iron metabolism causes lipid peroxidation. High iron levels in the body increases the susceptibility to having greater levels of oxidized lipids. Iron overaccumulation promotes oxidative stress and is associated with many diseases like arthritis, cancer, tumors, diabetes, heart failure and liver damage. Too much ferritin also supports lipofuscin formation, which is one of the main age-related pigments that accelerates aging.

Risk Factors for Iron Overload

• In the HFE gene, there are two notable variants, C282Y and H63D. Globally, for C282Y, 7.5% are heterozygous and 0.5% are homozygous; for H63D, 17% are heterozygous and 2% are homozygous. Conventionally, homozygosity for C282Y is considered the major risk factor for hemochromatosis. However, clinical hemochromatosis does occur in patients homozygous for H63D.
• If one considers the oxidative stress of more moderate iron overload, then having any of these genotypes is a very significant risk factor. Although most hemochromatosis results from these mutations in the HFE gene, there are at least six other rarer genes in which mutations can be the cause, and tests for these genes are not accessible. It is therefore imperative to use blood tests as the major means of assessing iron status and to only use genetic tests as a means of explaining the results and determining what to do about them.
• Blood transfusions, hemodialysis, and liver diseases may also contribute to iron overload. Iron-rich diets, iron-containing supplements, and foods fortified with iron such as enriched flour, may make a contribution to iron overload but are unlikely to cause even moderate iron overload if there are not additional risk factors present.

Testing for Iron Status

• On a complete blood count (CBC) low hemoglobin, low mean corpuscular hemoglobin (MCH), and high red blood cell distribution width (RDW) are indicators of iron deficiency anemia. Mean corpuscular volume (MCV) is likely to be low (making the anemia microcytic), unless a deficiency of vitamin B12 or folate also exists.
• Reticulocyte hemoglobin (CHr) may decrease earlier than the other markers and may be particularly useful in children, where catching anemia early is critical to preserving the brain from irreversible decreases in function.
• Iron saturation can be found on an iron panel and is an estimate of transferrin saturation. Transferrin saturation can be calculated directly by getting the iron panel and serum transferrin at the same time. To calculate it, divide the serum iron from the iron panel by the serum transferrin and multiply by 70.9%. It is always preferable to use transferrin saturation over iron saturation because iron saturation often underestimates transferrin saturation and sometimes the gap is large. At a minimum, test both one or two times to determine whether iron saturation is a good proxy for transferrin saturation in your specific case and only substitute the former if it appears reliable for you. Ideally your transferrin saturation is between 30 and 40%. Consistent deviations from these percentages, even in the normal range, should be considered potential early signs of deficiency (under 30%) or overload (over 40%). Deviations out of the normal range should be considered very clear indicators of a current problem.
• Ferritin: Ferritin is a good indicator of long-term iron stores when oxidative stress and inflammation are not present. However, oxidative stress and inflammation both increase ferritin levels independently of iron status and can create a false impression of iron overload. Oxidative stress and inflammation may also keep ferritin normal when it would otherwise drop, masking cases of iron deficiency. When ferritin is normal or high and all other signs suggest iron deficiency anemia, this indicates anemia of chronic disease. It is harmful and potentially fatal to treat this as a case of iron deficiency and requires medical care. When there are no signs of oxidative stress or inflammation, low ferritin should be taken as a sign of iron deficiency and high ferritin as a sign of iron overload, especially when corroborated by transferrin saturation.
• High-Sensitivity C-Reactive Protein: hs-CRP is a marker of systemic inflammation. Inflammation may drive up ferritin but make all other markers look like iron deficiency. When ferritin is critical to the interpretation, hs-CRP should be measured to rule out a contribution of inflammation to the ferritin measurement. If hs-CRP is high, ferritin is normal or high, and all other markers look like iron deficiency, anemia of chronic disease should be considered and any nutritional treatment should pend proper medical diagnosis and care.

Testing Caveats

• The anemia of other nutrient deficiencies, especially copper but possibly vitamin B6, may cause similar alterations to hemoglobin levels. Riboflavin and copper deficiencies may contribute to iron deficiency directly by impairing its absorption. Macrocytic anemia caused by vitamin B12 or folate deficiencies could coexist with iron deficiency and make the red blood cell measurements more difficult to interpret, especially the MCV. Anemia can have other causes such as kidney disease, bone marrow disease, thalassemia minor, sickle cell anemia, autoimmune disorders and exposure to certain toxic chemicals.
• Friedrich’s ataxia is a genetic disorder of iron distribution that causes some manifestations of deficiency and others of iron overload, but with normal iron markers. The ataxia (loss of full control over body movements) resembles that seen in vitamin E deficiency and the latter is often mistaken for the former.

Correcting an Iron Deficiency

• Temporarily reduce plant foods and use iron-rich foods such as clams, liver, and red meat multiple times a day. For vegetarians, sprouted legumes, greens, seaweed, and potatoes are the best food sources, and the iron will be best absorbed if accompanied by 500-1000 mg of vitamin C per meal. 
• Supplements that promote detoxification, such as sulforaphane or milk thistle, should be avoided until the deficiency is corrected.
• Iron supplements may often be needed. Ferrous sulfate is the most common, but it contributes to oxidative stress and bacterial dysbiosis in the intestines and causes constipation and other undesirable side effects. The recommended supplements (Testing Nutritional Status) to avoid the risk of these side effects are Iron Smart liposomal iron and Proferrin ES heme iron. A meal of clams can provide 10-20 milligrams of iron per meal. This alone meets the RDA for everyone except pregnant women, who require 27 milligrams per day. Retest monthly until markers are in range and then reduce the dose. Except for pregnant women the appropriate maintenance dose is twice a day. Iron supplements should not be given to infants under the age of six months.
• Iron deficiency that does not improve with iron supplementation may reflect a need to address copper or riboflavin deficiencies.
• The goals for correcting the deficiency, whether with foods or supplements, are to bring all anemia markers into the normal range, bring transferrin saturation between 30 and 40%, and bring ferritin up to at least 60 ng/mL and preferably 100-150 ng/mL.

Correcting Iron Overload

• Clinical hemochromatosis can cause organ failure and it is imperative to achieve a proper diagnosis and medical treatment, which may involve chelation or phlebotomy.
• When correcting more moderate iron overload, blood donation is a good option. This removes iron with little risk of causing deficiencies in other nutrients.
• Donate once every two months two or three times, and then recheck the iron markers four weeks after the last blood donation.
• The primary goal is to bring transferrin saturation under 40%, but not lower than the bottom of the reference range and not consistently under 30%. The secondary goal is to bring ferritin below 60 ng/mL, and as l ow as 20 mg/mL if it improves signs, symptoms, oxidative stress markers, or the individual’s subjective sense of wellbeing.
• Consuming 300 milligrams of calcium per meal and including sources of phytate such as whole grains, legumes, nuts, and seeds can help reduce iron absorption from food. If taking this approach, or if using chelation treatment, it is important to assess the status of zinc and other nutrients, since their absorption may suffer too.
• Additionally, detoxification-promoting supplements such as milk thistle or sulforaphane will help shuttle iron into ferritin, which is protective.

Glutathione (GSH)

Summary

Glutathione (GSH) is the body’s main antioxidant produced in the liver. It protects against free radicals, heavy metals and helps to eliminate lipid peroxides as well as toxins through Nrf2-mediated M1-like macrophage polarization. Immune cells work best with optimal glutathione levels that balance redox status. GSH is more powerful and practical than regular antioxidant supplements because the body self-regulates it in conjunction with the immune system. Glutathione will either stimulate or inhibit immune response to control inflammation, thus protecting against autoimmunity as well, by priming T cells for inflammation. However, endogenous glutathione not only limits inflammatory reactions but fine-tunes the innate immune response towards antiviral pathways in response to an infection independent of GSH’s antioxidant properties.

GSH shields cells and cellular molecules from damaging oxidants and facilitates the excretion of toxins from cells. You need adequate protein intake to form it (0.5-0.8g per pound of bodyweight). Consume foods with GSH precursors, including milk thistle, quality whey protein, arugula, broccoli, cauliflower, and kale, and foods that support methylation, such as avocado, lentils, liver, garbanzo beans, Brazil nuts, grass-fed beef, and spinach.

Glutathione promotes the regulation of nitric oxide by enhancing citrulline function. Without enough NADPH, your body can’t recharge glutathione after it becomes oxidized. This will put breaks on all the detoxification systems. Glutathione is extremely important for protecting red blood cells from oxidative stress and its levels are highly dependent on magnesium.

• Additionally, magnesium helps to provide the ATP required for glutathione synthesis and two ATP molecules are used for the biosynthesis of one glutathione molecule.
• Selenium is a cofactor for the antioxidant glutathione peroxidase, boosting its expression and activity, this is important for reducing inflammation during viral infections. Supplementing selenium replete humans with 200 mcg/day of selenium can improve T-lymphocyte mediated immune responses, increase cytotoxic lymphocyte-mediated tumor cytotoxicity and natural killer cell activity compared to baseline.
• Furthermore, taking 297 mcg/day vs. 13 mcg/day of selenium improves the activation and proliferation of B lymphocytes, enhances cytotoxic T lymphocytes and improves activated T cell function.
• Another antioxidant defense mechanism against free radicals is metallothioneins (MTs), which are small, cysteine-rich, heavy metal-binding proteins. They are mostly known for detoxifying heavy metals, in particular cadmium and maintaining metal ion homeostasis. Human cells with excessive MTs are resistant to cadmium poisoning. In mammals, MTs bind zinc but if there’s excess cadmium, MTs will bind cadmium instead of zinc. During stress, MTs release zinc when nitric oxide and ROS levels increase. Although zinc itself raises the zinc-binding activity of metallothionein, zinc is needed to upregulate MTs through metal regulatory transcription factor 1 (MTF-1). Thus, the antioxidant effects of MTs are dependent on zinc. Zinc is also needed for glutathione production, as revealed by studies wherein zinc deficiency is accompanied by a deficiency of glutathione and increased oxidative stress. Zinc also protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis.

Benefits of Glutathione

• Glutathione is a master antioxidant that neutralizes free radicals and keeps other antioxidants like vitamin C and E in their active form.
• Glutathione reduces oxidative stress, which in high amounts can lead to many diseases and cancers.
• Glutathione supports liver health and helps fight fatty liver disease. The liver being the most important detox organ, it greatly benefits from glutathione.
• Glutathione aids the immune system by controlling inflammation and regulating autoimmune responses.
• Glutathione promotes the regulation of nitric oxide by enhancing citrulline function. This improves blood flow and supports heart health. Citrulline levels typically plummet with acute respiratory distress, especially during sepsis, which can be an end-stage complication of viral infections. Improving citrulline levels can help with endothelial health due to increased nitric oxide levels and nitric oxide itself has numerous antiviral effects. Thus, maintaining good glutathione and citrulline levels should help to ensure sufficient nitric oxide and improved immune function.
• Glutathione regulates cell death and cell cycle. A deficiency of glutathione can result in apoptosis or cellular death.
• Glutathione is used for DNA repair, protein synthesis, amino acid transportation and enzyme activation. All of the body’s systems are affected by glutathione.

Food Sources

Fruit and vegetables contribute up to 50% of dietary glutathione, whereas meat contributes 25% for an average diet. Direct food sources high in glutathione are freshly prepared meat, fruit and vegetables are moderate sources and dairy and cereal are low in glutathione. Freezing foods maintain relatively the same amount of glutathione as fresh food, but other preservation methods, such as fermentation or canning, lead to extensive losses. Whey protein is also a good source of cysteine and hence glutathione and has been shown to lower oxidative stress. Milk thistle can raise glutathione levels and has antioxidant properties. Turmeric and curcumin can also promote glutathione synthesis and inhibit inflammation.

Supplements that promote glutathione production are N-acetyl cysteine (NAC), alpha-lipoic acid and liposomal glutathione. Magnesium and vitamin C can also increase glutathione levels. Most glutathione supplements are destroyed by the digestive tract and they’re poorly absorbed when taken orally. To circumvent this, many advocate for liposomal glutathione. 

Signs and Symptoms of Poor Glutathione Status

Poor immune function, asthma, respiratory congestion, and in severe cases liver failure.

There are many things that deplete your body’s glutathione levels, such as environmental toxins, poor lifestyle habits, sleep deprivation, excessive alcohol, chronic stress, getting older, inflammatory foods and nutrient deficiencies.

Risk Factors for Poor Glutathione Status

• Acetaminophen (Tylenol) depletes glutathione, which is the mechanism by which it causes liver failure when overdosed.
• Glutathione levels decrease during fasting, and diets that are low in protein or carbohydrate decrease its synthesis.
• Glutathione is made from glutamate, cysteine, and glycine. Glutamate is rarely limiting except in disease states that consume it, such as cancer. Cysteine is often limiting, especially in the fasting state. Glycine is often limiting, especially after a meal rich in animal protein.
• Magnesium deficiency or metabolic disruptions that affect ATP production or insulin sensitivity such as hypothyroidism, diabetes, and insulin resistance decrease the synthesis of glutathione.
• Diets low in plant polyphenols also decrease the synthesis of glutathione. Deficiencies of glucose 6-phosphate dehydrogenase, thiamin, niacin, and riboflavin compromise the recycling of glutathione.
• Diets low in meat and in low-calorie fruits and vegetables provide less exogenous glutathione than diets high in these foods.
• Rare genetic defects can impair glutathione synthesis.

Testing for Glutathione Status

• Total Glutathione: If low, this test suggests low glutathione synthesis or loss of glutathione from the body due to detoxification processes. This test may miss having an oxidized glutathione pool due to oxidative stress or a poor rate of recycling.
• Oxidized and Reduced Glutathione: If the reduced glutathione is low, the oxidized glutathione is high, or both, this indicates that the glutathione pool is being oxidized faster than it can be recycled. The causes could be excess oxidative stress, poor recycling, or both. A low rate of synthesis also makes the glutathione pool become oxidized more easily, so this should also be considered. 
• Pyroglutamate (oxoproline): When elevated, pyroglutamate indicates that glycine is limiting for glutathione synthesis. When normal or low, and the other tests suggest a low rate of glutathione synthesis, cysteine is more likely to be limiting.

Further Testing

If glutathione synthesis is compromised and pyroglutamate is not elevated, then the following possibilities should be considered:

• Low total protein intake. Conduct a dietary analysis and ensure that daily protein meets at least one gram per kilogram body weight.
• Low conversion of methionine to cysteine. Consult the methylation, sulfur catabolism, and vitamin B6 sections. The combination of high methionine and low homocysteine supports this, as does the combination of high homocysteine and signs of vitamin B6 deficiency.
• Low insulin signaling. Fasting insulin is optimally 2-6 uIU/mL. If elevated above this range, insulin resistance could be compromising glutathione synthesis. 
• Magnesium deficiency.
• Low ATP. Insulin resistance, hypothyroidism, or diabetes could compromise the supply of ATP.
• Low intake of fruits and vegetables. A dietary analysis can be conducted to examine fruit and vegetable intake. If lower than five to nine servings per day, there may be inadequate polyphenol stimulation of glutathione synthesis.
• Glycine: If the previous tests suggest glutathione synthesis is compromised and pyroglutamate is elevated.

If the glutathione pool is oxidized (low reduced glutathione, elevated oxidized glutathione, or both), then the following possibilities should be considered:

• Glucose 6-phosphate dehydrogenase (G6PD) deficiency. This is the most common genetic defect in the world and compromises glutathione recycling.
• Thiamin
• Riboflavin
• Niacin

Testing Caveat

Many infections and serious illnesses requiring medical care may deplete glutathione.

Correcting Poor Glutathione Status

• Consuming at least one gram per kilogram body weight of protein, consuming >200 grams of carbohydrate per day (for someone without digestive or blood sugar issues prohibiting this), supplementing with one or two servings of hydrolyzed collagen, eating a diet rich in fruits and vegetables, implementing a good physical activity routine, and optimizing body composition are all good strategies to improve glutathione status.
• N-acetyl-cysteine at up to 1600 milligrams per day in divided doses has been used to increase glutathione status. This is most likely to be effective when glycine is not limiting, as in the fasting state or after a collagen-supplemented meal, and in individuals who do not show elevated pyroglutamate.
• Unpasteurized milk, raw egg white, and whey protein supplements all contain glutamylcysteine bonds that overcome the first step of glutathione synthesis. Consuming these foods to provide 30 grams or more of protein per day may be particularly advantageous if low insulin signaling, low polyphenol stimulation of glutathione synthesis, or genetic impairments in the first step of glutathione synthesis are at issue. Unpasteurized milk is considered a foodborne illness risk by the CDC and FDA, though all available data indicates that it is much safer than other foods commonly consumed, such as deli meats and hot dogs. Raw egg whites will cause a biotin deficiency if not accompanied by supplemental biotin and their protein is less bioavailable than from cooked egg white.
• Supplements designed to upregulate detoxification, such as milk thistle or sulforaphane, increase glutathione synthesis. These may be especially helpful if a diet rich in fruits and vegetables is infeasible, or to compensate for low insulin signaling.
• Glutathione supplements at 500-1000 milligrams per day overcome all possible problems in glutathione synthesis and may compensate to some degree for poor glutathione recycling. Non-liposomal glutathione is less expensive than liposomal. If cost is an issue, try non-liposomal first, and only using liposomal glutathione if markers of glutathione status, or certain signs and symptoms that you suspect are related to glutathione status, fail to improve. If speed of results is more important, start with liposomal glutathione since there is a chance it will be more effective than regular glutathione.