Author: Chris Masterjohn

Topics: Nutrition

All information is attributed to the author. Except in the case where we may have misunderstood a concept and summarized incorrectly. These notes are only for reference and we always suggest reading from the original source.

Contents

Comprehensive Nutritional Screening

• Tests

The Fat-Soluble Vitamins and Related Minerals

• General Concerns for Fat-Soluble Vitamins and Saponifiable Minerals
• Vitamin A
• Vitamin D, Calcium, and Phosphorus
• Magnesium
• Vitamin K

B Vitamins Involved in Energy Metabolism

• Thiamin (Vitamin B1)
• Riboflavin (Vitamin B2)
• Niacin (Vitamin B3)
• Pantothenic Acid (B5)
• Vitamin B6
• Biotin (Vitamin B7)

B Vitamins Involved in Methylation

• Signs and Symptoms of Imbalances
• Risk Factors for Imbalances
• Effects of Common Genetic Polymorphisms
• Testing for Methylation-Related Nutrients
• Guide to Using the Genova Methylation Panel
• Testing Caveats
• Correcting Imbalances in Methylation-Related Nutrients
• Molybdenum and Sulfur Catabolism

Antioxidant Vitamins and Minerals

• General Testing for Oxidative Stress
• Vitamin E
• Vitamin C
• Manganese
• Zinc
• Copper
• Selenium
• Iron
• Glutathione

Iodine

Electrolytes: Sodium, Potassium, and Chloride

Correcting Electrolyte Imbalances

• Suggestions for Increasing Salt
• Suggestions for Increasing Potassium and Decreasing Salt
• Diets Rich in Fruits and Vegetables
• Diets Low in Fat, Moderate in Grains, and Free of Refined Carbohydrates
• Low-Carbohydrates, High Fat Diets
• Summary of the Dietary Options
• Potassium Supplements
• Vomiting and Diarrhea
• Altered Electrolyte Concentrations

Other Minerals

Essential Fatty Acids

• Signs and Symptoms of Arachidonic Acid Deficiency
• Signs and Symptoms of DHA Deficiency
• Testing for Essential Fatty Acids
• Correcting Essential Fatty Acid Imbalances

Index of Signs and Symptoms

Comprehensive Nutritional Screening

Blood should be drawn for the ION panel, parathyroid hormone, and 1,25(OH)2D at the same time if possible. Get the tests when your supplement regime has been stable for at least four weeks, and avoid supplements the day of the test and during any longer period of fasting that might be recommended. This way, the results reflect what you normally do. However, any supplements containing biotin, especially doses greater than 300 micrograms per day, should be removed for four days to ensure high biotin levels do not interfere with any lab results.

Tests (see original source for interpretation)

• Genova ION Profile + 40 amino acids
• From the HDRI site, on their requisition form, the following tests: ETKA, EGR, NADH/NADPH, EGOT, sulphur panel, GSH ox+red
• Complete Blood Count (CBC) (LabCorp, Quest)
• Comprehensive metabolic panel (LabCorp, Quest)
• Parathyroid Hormone (LabCorp, Quest)
• 1,25(OH) 2 D (LabCorp, Quest)
• Serum magnesium (LabCorp, Quest)
• Whole blood vitamin B1 (LabCorp)
• Whole blood vitamin B2 (LabCorp)
• Vitamin B5 (LabCorp, Quest)
• Plasma vitamin B6 (LabCorp, Quest)
• Vitamin B7 (LabCorp, Quest)
• Serum and RBC Folate (single test: LabCorp; Quest offers serum and RBC separately)
• Serum B12 (LabCorp, Quest)
• Uric Acid (LabCorp, Quest)
• Plasma ascorbate (LabCorp, Quest)
• Manganese in whole blood (LabCorp) or red blood cells (Quest)
• Plasma selenium (LabCorp)
• Iron panel (LabCorp, Quest)
• Serum transferrin (LabCorp, Quest)
• Total Glutathione (LabCorp)
• 24-hour urine iodine (LabCorp, Quest)
• Optional Add-On: Hair Elements (Doctor’s Data)
• Optional Add-On: obtain a 23andMe or Ancestry genetic analysis and run the raw data file through his choline calculator.

The Fat-Soluble Vitamins and Related Minerals

General Concerns for Fat-Soluble Vitamins and Saponifiable Minerals

These are fat soluble but we still absorb some of them even without the presence of fat in our meal. Just not as much.

Because these vitamins are absorbed along with fats, disorders that cause fat malabsorption can cause deficiencies of all four vitamins. Fat malabsorption can also cause deficiencies of saponifiable minerals.

• Saponification is the process of a mineral binding to a fatty acid. Fatty acids are negatively charged, and they can be saponified by minerals that form positively charged ions. This is only nutritionally relevant if those ions are formed in large quantities in the digestive tract. The most relevant minerals include sodium, potassium, calcium, and magnesium, and to some extent iron, zinc, copper, and manganese may also be affected.
• Disorders of fat malabsorption include abetalipoproteinemia, hypobetalipoproteinemia, Crohn’s disease, celiac disease, cystic fibrosis, some disorders of the liver, pancreas, gall bladder, bile ducts, and small intestine.

There are three hints of such disorders that might be uncovered during the course of nutritional testing:

• Low levels of all four fat-soluble vitamins, rather than low levels of only one. You can use Genova’s fat-soluble vitamin panel for this, and the Genova ION Profile + 40 amino acids. It has markers of A, D, and E, but not K.
• Alternatively, you can look at each vitamin individually. Of these, vitamin D the most likely to be normal because it can be made in the skin during sun exposure without the need to absorb it from the diet.
• A standard lipid panel showing cholesterol and other blood lipids below the reference range.
• High levels of fecal fat. Fecal fat is often a component of more stool panels as well.

Vitamin A

Signs and Symptoms of Deficiency

Poor night vision; dry eyes; hyperkeratosis around hair follicles, or appearing as bumps on the skin that can be mistaken for goosebumps or acne, or on the surface of the conjunctiva (Bitot’s spots); poor immunity to infectious diseases.

Less Well Established but Plausible Signs and Symptoms of Deficiency

Kidney stones; disrupted circadian rhythm and an inability to use light therapy to entrain a healthy circadian rhythm; autoimmune disorders; asthma and allergies; food intolerances; low sex hormones; and delayed puberty.

Risk Factors for Deficiency

• Diets that do not contain at least one of the following: a weekly serving of liver; regular use of cod liver oil, a multivitamin, or another supplement providing 100% of the US RDA for vitamin A as retinol.
• If the diet is also poor in dairy products and eggs, and does not contain several servings per day of red, orange, yellow, or green vegetables.
• Diets where fats come from polyunsaturated vegetable oils are more likely to produce vitamin A deficiency than diets where the fat is mostly saturated or monounsaturated.
• A low-fat diet will not intrinsically produce vitamin A deficiency, but it will increase its likelihood by leading to lower absorption of vitamin A from food.
• Long-term use of glucocorticoids, high-protein diets, and high-dose vitamin D may contribute to vitamin A deficiency in combination with poor dietary intake.

Signs and Symptoms of Toxicity

Most commonly, nausea, vomiting, and headache. In extremes, anorexia, blurred vision, scaling skin, hair loss (alopecia), organ damage, death.

Osteopenia and osteoporosis can be worsened by vitamin A at non-toxic levels when vitamin D and calcium are deficient. You should keep vitamin A below 10,000 IU per day during the first eight weeks of pregnancy due to a possible risk of birth defects unless blood measurements, signs, and symptoms justify higher intakes to prevent deficiency.

Risk Factors for Toxicity

Months or years of consistently taking at least 165 IU per kilogram body weight per day, and in the majority of cases greater than 2300 IU per kilogram body weight per day.

When vitamin D is taken alongside vitamin A, the majority of vitamin A toxicity cases involve months or years of consistently taking more than 4620 IU vitamin A per kilogram body weight per day, which for a person weighing 70 kilograms is 323,400 IU per day. Almost all vitamin A is prepared in oil; however, vitamin A preparations that are water-soluble, emulsified, or solid may cause toxicity in weeks rather than months and at ten times lower doses.

Testing for Vitamin A Deficiency

• Serum vitamin A: This should be kept toward the middle of the reference range (third quintile) and low-normal results do not necessarily rule out a problem.
• Retinol-binding protein: Can be measured alongside serum vitamin A, but may be affected by a greater number of variables unrelated to vitamin A status (it is increased in insulin resistance and type 2 diabetes, and decreased in type 1 diabetes, systemic inflammation, and a variety of liver and kidney diseases).

Testing for Vitamin A Toxicity

• Serum vitamin A will be high in most cases.
• In descending order of likelihood, the following tests may show elevations:
  • γ-glutamyltransferase, triglycerides, alkaline phosphatase, prothrombin time, cholesterol, aspartate aminotransferase, bilirubin, and calcium.

Testing Caveats

• Zinc deficiency should always be considered as an explanation for an apparent case of vitamin A deficiency that does not respond well to dietary and supplemental strategies, regardless of whether serum vitamin A is altered.
• Adiposity may cause cellular vitamin A deficiency without lowering serum levels. Fatty liver disease compromises the liver’s ability to store vitamin A and may raise serum levels.
• Drugs that are vitamin A derivatives (known as retinoids; e.g., isotretinoin, marketed as Accutane) may cause vitamin A deficiency signs by hurting the body’s utilization of natural vitamin A.
• Chronic alcohol abuse and protein deficiency also hurt vitamin A utilization.

Correcting Vitamin A Deficiency

You should rule out deficiencies of other nutrients, especially vitamin D, before taking high-dose vitamin A.

Supplements providing 25,000-50,000 IU per day appear to be well within the margin of safety for short-term use (several weeks) in an adult, and may help resolve a deficiency more quickly, but should not be used without close monitoring of serum vitamin A.

Correcting Vitamin A Toxicity

The only well-established treatment for vitamin A toxicity is the removal of the toxic dose of vitamin A.

Vitamin D, Calcium, and Phosphorus

Osteopenia and Osteoporosis

• Osteopenia is a less severe form of osteoporosis and both involve decreased bone mineral density and increased risk of fracture.
• A DXA scan is required for early diagnosis and without one signs and symptoms may not be apparent.
• Elevated parathyroid hormone (PTH) is a major factor in these conditions, and it is raised by deficiencies of vitamin D or calcium, or by excess phosphorus.
• These disorders are caused by deficiencies of calcium or vitamin D, or an excess of phosphorus.

Rickets and Osteomalacia

• Rickets is the childhood version of osteomalacia.
• Key sign and symptoms include bone pain, muscle weakness, fragile bones, and skeletal deformities such as thickened wrists and ankles, compressed vertebrae and pelvis, and bowed legs. Skeletal deformities are more common and obvious in children.
• An X-ray would show poorly mineralized, overgrown bone matrix, and, in children, expanded growth plates. These are driven by hypocalcemia (low blood calcium) or hypophosphatemia (low blood phosphorus),
• Deficiencies of vitamin D, calcium, or phosphorus can cause rickets.

Tetany

A neuromuscular condition resulting from hypocalcemia. It can involve muscle twitching, tremors, or spasms; confusion; and in extreme cases seizures, coma, and death.

Since tetany is driven by hypocalcemia, deficiencies of vitamin D or calcium cause it. A large excess of phosphorus may also contribute to tetany by depleting blood levels of calcium. It is low ionized calcium rather than low total calcium that drives the condition, and alkalosis or high albumin may decrease ionized calcium even when total calcium is normal.

Soft Tissue Calcification

Deposits of calcium in tissues other than the bones and teeth can take many forms, including kidney stones and cardiovascular disease. In children, early calcification of cartilage interferes with growth. Soft tissue calcification can be caused by hypercalcemia or hyperphosphatemia. In the urinary system, it may be caused by high levels of calcium or phosphorus in the urine, known as hypercalciuria and hyperphosphaturia.

Excesses of vitamin D, calcium, and phosphorus can cause it. Nevertheless, calcium at healthy intakes protects against kidney stones because it prevents excess phosphorus absorption and favors net movement of phosphorus into bone rather than kidney.

Hypercalcemia

• High levels of ionized calcium in the blood can be caused by excess calcium or vitamin D, but not phosphorus. They are usually driven by a high amount of total calcium, but acidosis or low albumin may increase ionized calcium even when total calcium is normal.
• Chronic excess of vitamin D will cause more persistent hypercalcemia than chronic excess of calcium when either are present on their own. However, excess calcium can cause persistent hypercalcemia in the presence of alkalosis and impaired kidney function.
• In addition to soft tissue calcification, hypercalcemia can lead to frequent thirst and urination, confusion, lethargy, fatigue, depression, bradycardia (slow heart rate), arrhythmia, palpitations, or fainting.
• Hypercalcemia may be driven in part by calcium moving from bone to blood, especially in response to vitamin D toxicity, in which case it will be accompanied by lower bone mineral density.

Hyperphosphatemia

Phosphate binds to calcium, causing the calcium phosphate to leave the blood as it deposits in other tissues, both in healthy ways (e.g., bone) and unhealthy ways (e.g., kidney stones). Thus, hyperphosphatemia can cause tetany (deficient calcium available to the nervous and muscular systems) and soft tissue calcification (excess calcium phosphate deposited in soft tissues) but not osteomalacia (deficient calcium phosphate available to bone). 

Osteopetrosis

An extremely rare condition of increased bone mineral density and brittle bones.

Considered genetic, but it has been induced in animals by giving excess calcium.

Less Well Established but Plausible Signs of Vitamin D and Calcium Deficiency

High blood pressure, poor immunity to infectious diseases, autoimmune conditions (especially psoriasis, multiple sclerosis, and type 1 diabetes), asthma and allergies, certain cancers (estrogen-responsive breast cancer, and cancers of the prostate, colon, rectum, ovary, and endometrium), low sex hormones, high androgens in women, insomnia, and cardiovascular disease.

Primarily driven by vitamin D deficiency. CVD, asthma, allergies, and cancer are also possible consequences.

Less Well Established but Plausible Signs of Phosphorus Deficiency

Fatigue, weakness, and carbohydrate intolerance.

Risk Factors for Vitamin D Deficiency, Excess, and Toxicity

Deficiency:

An indoor lifestyle combined with a low dietary fatty fish, pasture-raised egg yolks, cod liver oil, and vitamin D supplements. If you spend a lot of time outdoors, you may still develop deficiency if you use sunscreen and sunblock, clothing that covers most or all of your skin, or if environmental factors such as clouds, pollution, atmospheric ozone, and tall buildings block your exposure to UV-B rays. Inflammation (from infection or from recovery from injury or surgery), excess phosphorus or vitamin A, and calcium deficiency can all deplete vitamin D levels. Disorders of fat malabsorption hurt the ability to absorb vitamin D in the diet, but do not hurt the ability to obtain it from sunlight.

Excess:

He considers vitamin D supplementation that raises your 25(OH)D higher than 50, and especially 60, ng/mL presents an increased risk of soft tissue calcification even if you have no evidence of hypercalcemia.

Toxicity:

Hypercalcemia is the hallmark of vitamin D toxicity. Case reports have associated it with 25(OH)D levels as low as 56 ng/mL, but most cases are associated with levels higher than 200 ng/mL.

Risk Factors for Calcium Deficiency and Excess

Deficiency:

A diet low in dairy products, edible bones (e.g., those in canned fish), green vegetables, calcium-containing multivitamins, or calcium supplements is the primary risk factor. Excess phosphorus inhibits calcium absorption and may aggravate a dietary deficiency.

Excess:

The tolerable upper intake limit (TUIL) set by the Institute of Medicine for calcium is 2.5 grams per day for adults under the age of 50 and 2 grams per day for adults over this age. This is based on the risk of calcium-alkali syndrome, where hypercalcemia occurs alongside alkalosis and impaired renal function. This requires causes of alkalosis and impaired renal function in addition to high calcium intakes.

Populations at risk for this syndrome are pregnant women, elderly women, and bulimics.

In these populations, calcium supplementation contributes to the syndrome when it takes the form of calcium oxide, hydroxide, or carbonate, or when it is accompanied by antacids, diuretics, ACE inhibitors, or NSAIDs.

Risk Factors for Phosphorus Deficiency and Excess

Deficiency:

• High levels of calcium in the diet may interfere with phosphorus absorption, but the reverse problem is far more likely.
• Hungry bone syndrome involves the movement of phosphorus into bone when bone mineral content starts increasing suddenly after the correction of a bone resorption disorder, for example by surgical removal of the parathyroid gland. Hypocalcemia and low levels of magnesium (hypomagnesemia) also develop during hungry bone syndrome.
• Refeeding syndrome occurs after aggressive correction of starvation or of chronic malnutrition, as might occur in alcoholism, eating disorders, or illnesses that impact food intake.
• Dietary phosphorus drops to low levels or even zero, the loss of lean mass causes loss of phosphorus stores, and the drop in carbohydrate metabolism causes the loss of the phosphorus needed for that process. Serum phosphate tends to remain stable during malnutrition. During refeeding, however, insulin and the rise in carbohydrate metabolism bring phosphate into cells, causing hypophosphatemia to develop. This is aggravated by the large demand for cellular repair and rebuilding of phosphorus stores. Hypomagnesemia and low levels of potassium (hypokalemia) also occur during refeeding syndrome.

Excess:

• The principal cause of hyperphosphatemia is chronic kidney disease.
• Excess dietary phosphorus, however, contributes to low bone mineral density and the risk of kidney stones.
• Phosphorus is more bioavailable from animal products than from plant products, and unlike bones and dairy products, animal flesh contains very little calcium. A diet rich in animal flesh may therefore may provide sufficient phosphorus to aggravate a deficient level of calcium. The main dietary risk factor, however, is a diet rich in processed foods.

Testing for Vitamin D, Calcium, and Phosphorus Status

25(OH)D (calcidiol)

Recommended to maintain this marker between 30-40 ng/mL, and to be concerned if under 25 ng/mL or over 50 ng/mL. To convert these units to nmol/L, multiply by 2.5. To convert nmol/mL back to ng/mL, divide by 2.5. 25(OH)D is very responsive to vitamin D status, but is decreased by calcium deficiency, excess phosphorus, vitamin A, inflammation, and genetic factors that increase its conversion to calcitriol or its inactivation.

Parathyroid Hormone (PTH)

• Calcium and vitamin D suppress PTH, while phosphorus raises it. If PTH is maximally suppressed, the body perceives calcium and vitamin D as adequate and does not perceive any crisis of excess phosphorus. The point of maximal suppression appears to be approximately halfway through the normal range (around 30 pg/mL) and may be as low as 20 pg/mL.
• A PTH higher than 35 pg/mL is a cause for nutritional action.
• If PTH is maximally suppressed, there is likely no need for action even if 25(OH)D appears low (unless magnesium deficient).

1,25(OH)2D (calcitriol)

• During vitamin D deficiency, calcitriol remains normal until the deficiency is beyond the degree needed to cause serious rickets and osteomalacia, at which point it may become elevated briefly and finally become low. By contrast, in calcium deficiency calcitriol rises linearly with the degree of deficiency. Phosphorus tends to have no net effect on calcitriol levels.
• If low, but in range, vitamin D is likely more deficient. If high, but in range, calcium is more likely deficient. If PTH is high, excess phosphorus may be the issue regardless of calcitriol level. Elevations are best interpreted when high-sensitivity CRP is measured.

High Sensitivity C-Reactive Protein

• Inflammation causes the conversion of calcidiol to calcitriol.
• Values of 1-3 suggest chronic, low-grade chronic inflammation, and values above 3, especially those above 10, suggest an acute infection or serious inflammatory disorder. hs-CRP values associated with low-grade inflammation could be considered likely to make a modest contribution to low 25(OH)D, especially if calcitriol is on the higher end of normal.

Calcitonin and FGF23

Excess calcium will raise calcitonin, and excess phosphorus will raise FGF23.

Total Calcium, Ionized Calcium, and Phosphorus

• Serum calcium declines in deficiencies of vitamin D or calcium that are severe enough to cause rickets. It rises in clinical hypercalcemia caused by excesses of these two nutrients.
• Only ionized calcium is biologically relevant. Total calcium usually reflects ionized calcium, and we usually use it because it is easier to collect the blood and cheaper. Nevertheless, total calcium will underestimate ionized calcium during acidosis or in the presence of low albumin, and it will overestimate it during alkalosis or in the presence of high albumin.
• Phosphorus levels decline in phosphorus deficiency and rise in phosphorus excess.

Other Nutrient Deficiencies

• Although zinc is not as prominent in vitamin D metabolism as it is in vitamin A metabolism, the activity of the vitamin D receptor is dependent on zinc, so zinc deficiency may cause resistance to vitamin D and cause clinical signs of deficiency to develop at normal 25(OH)D levels.
• Magnesium is critical to all aspects of vitamin D and calcium metabolism, and deficiency of magnesium will cause hypocalcemia (thereby contributing to tetany and osteomalacia) and interfere with the interpretation of the blood markers. For example, PTH may be low in magnesium deficiency even though the hypocalcemia that accompanies this deficiency should raise it.
• A deficiency of vitamin K will contribute to osteopenia or osteoporosis without affecting any of these blood markers.

Pregnancy

• Pregnancy lowers 25(OH)D, calcium, and PTH, and raises calcitriol. These are probably adaptations to supply calcium to the fetus while minimizing the risk of bone loss to the mother. Total calcium may drop as low as 8.2 mg/dL, which is below the typical bottom of the reference range.
• Pregnancy may induce a mild acidosis that keeps ionized calcium normal while total calcium drops. PTH is typically between 10 and 25 pg/mL. Alterations to 25(OH)D and calcitriol mainly occur in the second and third trimesters, where 25(OH)D is cut in half and calcitriol is doubled.

Kidney Disease

The excretion of phosphate declines, which causes calcium levels to fall. The hyperphosphatemia and hypocalcemia elicit a rise in PTH.

Requires medical treatment and nutritional management.

Sarcoidosis

A poorly understood overactivation of the immune system. Calcitriol is high, 25(OH)D is often low, and hypercalcemia may occur. It requires medical attention.

Tumors and Genetic Disorders

Blood markers that otherwise do not seem to make sense. For example, a deficiency of vitamin D or calcium will cause a rise in PTH that brings calcium levels up to normal. High PTH should therefore be associated with normal or low calcium. If high PTH is associated with high calcium, PTH is being overproduced, raising calcium higher than normal, and this is likely the result of a medical condition.

Excess phosphorus will raise FGF-23 and this will bring phosphorus levels down to normal. High FGF-23 should be associated with normal or high phosphorus. If high FGF-23 is associated with low phosphorus, FGF-23 is being overproduced, causing hypophosphatemia, and this is another likely case of a medical condition.

Correcting Nutritional Imbalances in Vitamin D, Calcium, and Phosphorus

• Low 25(OH)D, indoor lifestyle, low dietary vitamin D, normal calcium intake, low hs-CRP, and middle-of-the-range calcitriol. Vitamin D deficiency is most likely.
• Low 25(OH)D, outdoor lifestyle, adequate dietary vitamin D, low calcium intake, low hs-CRP, and calcitriol on the high end of the range. Calcium deficiency is most likely.
• Low 25(OH)D, outdoor lifestyle, adequate dietary vitamin D, adequate calcium, high hs-CRP, and calcitriol on the high end of the range. Inflammation is most likely.
• Low or normal 25(OH)D, outdoor lifestyle, adequate dietary vitamin D, adequate calcium, high intake of processed foods, calcitriol normal or low, calcium normal or low, phosphorus normal or high, and high FGF-23. Excessive intake of phosphorus is most likely.
• Alternatively, PTH may be normal or low in a case of excess vitamin D, and the earliest sign may be an elevated 25(OH)D. Very elevated 25(OH)D and hypercalcemia would be the principal markers of vitamin D toxicity.

Reasonable Daily Targets

A half hour a day of outdoor sun exposure with at least the hands and face; vitamin D intake in the range of 600-2000 IU; 800 to 1200 milligrams of calcium; minimal processed foods. Due to the large variation in endogenous vitamin D synthesis with lifestyle and environment, the vitamin D intake target may have to be modified substantially according to blood work.

If inflammation is the cause of low vitamin D in a person with frequent or chronic infections, it is recommended to still achieve these targets.

Magnesium

Signs and Symptoms of Deficiency

Cardiac arrhythmia, palpitations, weakness and fatigue, ataxia (loss of full control over body movements), muscle twitches and spasms, low blood levels of calcium (hypocalcemia) and related disorders such as tetany and osteomalacia, low blood levels of potassium (hypokalemia), apparent vitamin D deficiency and resistance to standard treatment.

Moderate magnesium deficits may contribute to the following disorders: osteopenia and osteoporosis, soft tissue calcification (such as kidney stones), high blood pressure (hypertension), preeclampsia and eclampsia, migraines, and many aspects of cardiovascular disease.

Risk Factors for Deficiency

• A diet low in plant foods or high in refined foods
• Malabsorption of magnesium: proton pump inhibitors and other antacids, vomiting and diarrhea, ulcerative colitis, pancreatitis, and any disorders that cause fat malabsorption.
• Urinary magnesium excretion is proportional to urinary volume and is increased by anything that causes increased urination, such as diabetes or diuretics. A number of other pharmaceutical drugs including epidermal growth factor blockers and some antibiotics and antifungal medications increase urinary magnesium loss.
• Chronic alcohol abuse causes both malabsorption and urinary wasting of magnesium.
• Sweating and burn injury.
• Hungry bone syndrome involves the movement of magnesium into bone when bone mineral content starts increasing suddenly after the correction of a bone resorption disorder, for example by surgical removal of the parathyroid gland. Low levels of calcium (hypocalcemia) and phosphorus (hypophosphatemia) also develop during hungry bone syndrome.
• Refeeding syndrome results from the aggressive correction of starvation or chronic malnutrition. Dietary magnesium drops to low levels and possibly zero, and loss of lean mass causes loss of magnesium stores. During refeeding, insulin brings magnesium into cells, causing hypomagnesemia to develop. This is aggravated by the large demand for cellular repair and rebuilding of magnesium stores. Low levels of hypophosphatemia and low levels of potassium (hypokalemia) also occur during refeeeding syndrome.

Signs and Symptoms of Toxicity

• Hypermagnesemia can lower blood pressure to dangerous levels. Both bradycardia (slow heart rate) and tachycardia (fast heart rate) may occur. Paradoxically, hypermagnesemia can cause hypocalcemia, one of the major features of clinical magnesium deficiency.
• In those with poor kidney function, supplementation can cause hypermagnesemia. One example of this is administration of magnesium to prevent convulsions in preeclampsia and eclampsia.
• For magnesium as a nutritional supplement, the upper limit of 350 mg/d should be used as a rough indicator of potential risk in the context of poor kidney function.

Testing for Magnesium Status

• Serum magnesium declines in deficiency and rises in toxicity, but it is less sensitive than red blood cell and urine to changes in magnesium status.
• Red blood cell magnesium may be low when serum is not, and while this could indicate an early deficiency, it could also indicate a deficiency in factors needed for bringing magnesium into cells, such insulin signaling, energy production, and sodium.
• Urine magnesium will be low in nutritional deficiency, but high in deficiencies caused by urinary loss.

Testing Caveats:

Since RBCs are higher in magnesium than serum, hemolysis will falsely elevate serum magnesium. 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. If serum is implausibly high, especially when urine and RBCs are normal, the serum measurement may have been falsely elevated from hemolysis and should be repeated.

There is a collection of rare genetic disorders that cause poor magnesium absorption, urinary magnesium loss, or both. Many of the signs and symptoms of magnesium deficiency are results of hypocalcemia or disordered calcium handling, and many result from hypokalemia.

Correcting Magnesium Deficiency

If your diet is low in unrefined plant foods, your first approach should be to eat more magnesium-rich foods. If this is not possible, practical, or sufficient to reverse signs, symptoms, and blood work, you can use a supplement, such as magnesium glycinate or malate.

Correcting Toxicity

If hypermagnesemia is found, poor kidney function is a likely cause and must be addressed with appropriate medical treatment. Nutritionally, supplemental magnesium should be removed.

Vitamin K

Signs and Symptoms of Deficiency

• Defective blood clotting. Easy bruising or blood accumulating at the surface of the skin may be most apparent, but widespread internal bleeding and hemorrhage are possible.
• May contribute to osteopenia, osteoporosis, short stature in children, soft tissue calcification (e.g., calcified atherosclerotic plaque; calcification of the vascular media that occurs in diabetes, kidney disease, and with age; kidney stones).
• Even less well established but plausible signs and symptoms include insulin resistance, inadequate insulin and hyperglycemia, low testosterone and fertility in men, high androgens in women, poor exercise performance or tolerance, and cancers of the liver, lung, and prostate.

Risk Factors for Deficiency

• Vitamin K1 occurs mainly in greens. Vitamin K2 refers to a collection of compounds known as menaquinones that are individually designated menaquinone-n, abbreviated MK-n, where n is a number between 4 and 13. MK-4 is found primarily in animal products, and MK-7 through MK-13 are found primarily in fermented foods.
• A severe vitamin K deficiency of dietary origin is rare, and would require a diet devoid of green plants, animal foods, and fermented foods. However, far less vitamin K2 is present in the diet than K1, and K2 is more effective at supporting most functions of vitamin K besides clotting. Most diets contain inadequate K2 to support these functions and, in this sense, moderate vitamin K deficiency may be the norm.
• Humans are able to convert other forms of vitamin K into MK-4, but cholesterol-lowering statins decrease this conversion and presumably make it more important to obtain MK-4 in the diet.
• High-dose vitamin E supplementation increases the breakdown of vitamin K and may contribute to deficiency.
• Vitamin D, chronic kidney disease, and anything else that causes soft tissue calcification raises the need for vitamin K. Any disorders leading to fat malabsorption may induce deficiency. The vitamin K status of newborns is often deficient because of inadequate intake by the mother during pregnancy.
• Drugs known as 4-hydroxycoumarins, such as warfarin (Coumadin), inhibit vitamin K recycling.
• Severe deficiencies of vitamin K can be produced by an overdose of anticoagulant medication, or accidental poisoning with rodenticides in the case of children and pets.

Special Note on Anticoagulant Medication

Vitamin K2 better supports the non-clotting functions of vitamin K than K1 does, and since it is present in the diet in much lower quantities than K1, low-dose K2 supplementation (e.g., 45 micrograms per day of MK-7) may be a safe way of supporting these other functions.

It doesn’t appear to interfere with warfarin and the like (Bruce Ames Triage Theory). Eat natto.

Excess and Toxicity

High-dose vitamin K stimulates the breakdown of vitamin E and has the potential to deplete glutathione, both of which are critical components of the antioxidant system. High doses also inhibit bone resorption, which may help preserve bone mass but may also interfere with blood sugar control, sex hormone balance, and energy utilization during exercise.

Testing for Vitamin K Status

Serum Vitamin K

• Reflects recent intake. Also, low even after intake or supplementation if deficiency is caused by malabsorption.

Prothrombin time

• A functional marker of blood clotting. It is used to calculate the international normalized ratio (INR), a value used to adjust the dose of anticoagulant medication. In the absence of 4-hydroxycoumarin treatment, it could reflect vitamin K deficiency, but could also reflect many other factors that interfere with blood clotting.

Des-γ-carboxy Prothrombin

• DCP or protein induced by vitamin K absence or antagonism-II (PIVKA-II) rises when the vitamin K status of the liver is inadequate to support blood clotting. In the absence of 4-hydroxycoumarin treatment, high PIVKA-II strengthens the interpretation that prothrombin time is elevated because of vitamin K deficiency. PIVKA-II will rise during treatment with 4-hydroxycoumarins and this is expected. In the absence of 4-hydroxycoumarin treatment, elevated PIVKA-II suggests a relatively severe deficiency of vitamin K.

The vitamin K status of extrahepatic tissues

• The ideal tests of vitamin K status for routine screening and disease prevention. Not yet available clinically.

Correcting Vitamin K Deficiency

If the diet is devoid of leafy greens, they should be added to the diet at one or two servings per day. If this is not possible or practical, supplemental vitamin K1 (phylloquinone) can be added at a dose of 100-500 micrograms per day. Most people who do not consume natto or goose liver, and do not consume a lot of egg yolks and cheese, would benefit from supplementing with 200-1000 micrograms per day of K2, preferably as a mix of MK-4 and MK-7. Individuals with chronic kidney disease, and diseases involving soft tissue calcification, need at least 500 micrograms per day of supplemental K2 and probably more than one milligram per day.

Caveats

Thiamin is required for the recycling of vitamin K and should be considered if there is a reason to suggest thiamin deficiency. Glucose 6-phosphate dehydrogenase (G6PD) deficiency can also impair vitamin K recycling.

B Vitamins Involved in Energy Metabolism

All B vitamins are water-soluble. As a result, excessive fluid loss, as in the frequent urination that accompanies diabetes, can be a source of deficiency. Additionally, cooking foods in water that is then discarded will cause some loss of most B vitamins.

With the exception of vitamin B6, these vitamins have no known toxicity syndromes.

Thiamin (Vitamin B1)

Symptoms of Deficiency

• Beriberi. Peripheral neuropathy (weakness, numbness, pain, or tingling in the hands and feet), impairment of reflexes, with or without cardiovascular signs that include enlarged heart, elevated heart rate (tachycardia) and cardiac output, and congestive heart failure.
• Wernicke’s Encephalopathy. Weakness, paralysis, or disordered movement in the muscles around the muscles of the eye (ocular palsies, ophthalmoplegia, nystagmus) ataxia (loss of full control over body movements), confusion, often with peripheral neuropathy.
• Korsakoff’s Psychosis. Amnesia, confabulation (fabricated, distorted, or misinterpreted memories), decreased spontaneity and initiative. This is often but not always a progression of Wernicke’s encephalopathy.
• Very severe thiamin deficiency may cause seizures, paralysis, and death.
• Poor glucose tolerance may occur in less severe thiamin deficits. Less well established but plausible signs and symptoms include improvements in energy or neurological health on a low-carbohydrate diet, low levels of neurotransmitters, and apparent deficiencies of folate and vitamin K that do not respond well to dietary or supplemental corrections.

Risk Factors for Deficiency

• Dietary thiamin deficiency occurs when the diet does not contain several 100-gram servings per day of meat, legumes, whole grains, or enriched grains.
• Persistent vomiting, alcoholism, gastrointestinal diseases that cause malabsorption, liver diseases that impair hepatic thiamin storage, and HIV/AIDS.
• Diabetes increases the need for thiamin.
• Less common but well-established causes of thiamin deficiency include thiamin antagonists that occur in raw fish and shellfish, seasonally in ferns, and in the edible larvae of the African silkworm.
• Less well established but plausible causes include sulfite accumulation, which may be driven by molybdenum deficiency and high intake of animal protein or sulfite used as a food additive; thiamin-destroying bacteria and fungi in the human gut; thiamin-destroying amoebas that may pollute water; and perhaps thiamin antagonists produced during infections or from exposure to toxic indoor molds.

Testing for Thiamin Status

• Whole blood thiamin pyrophosphate: Low
• Erythrocyte transketolase activity: Low
• Alanine measured on a plasma amino acid profile: High
• Lactate and possibly pyruvate are elevated in the blood.
• Alpha-ketoglutarate, also known as 2-oxoglutarate, lactate, and possibly pyruvate is elevated on a urinary organic acid analysis

Testing Caveats

Transketolase activity is subject to genetic polymorphisms that may impact its activity, and alcoholism may cause epigenetic decreases in its activity; these caveats do not rule out the sensibility of supplementing thiamin when transketolase activity is low, since it may be responsive to extra thiamin, but they complicate a straightforward interpretation of thiamin deficiency.

If only one or two metabolites are high, the interpretation is less clear. Most thiamin-dependent enzymes also depend on lipoic acid and are subject to inhibition by oxidative stress and heavy metals, which may mimic the metabolite pattern of thiamin deficiency.

Correcting Thiamin Deficiency

• If the diet is poor in thiamin, thiamin-rich foods should be introduced.
• Many disease states cause thiamin deficiency that must be addressed independently with appropriate medical care. Thiamin supplementation is safe even at high doses and may help resolve a dietary deficiency more quickly or compensate for poor absorption or a high rate of urinary loss.
• If deficiencies of other B vitamins have not been adequately screened for, you should include a B complex alongside thiamin.
• Thiamin hydrochloride is likely adequate in most cases. Benfotiamine may be beneficial for the neuropathy of diabetes and alcoholism but its superiority over thiamin hydrochloride has not been clearly demonstrated. Thiamin pyrophosphate (thiamin diphosphate) is the active form of thiamin, and supplements of this form could plausibly overcome impairments in thiamin activation, which are known to occur in alcoholism.

Riboflavin (Vitamin B2)

Signs and Symptoms of Deficiency

• Red, crusty skin on the outer edges of the lips (cheilosis) or cracks at the corners of the mouth that may fissure (angular stomatitis); inflammation of the tongue (glossitis); redness, bleeding, and swelling inside the mouth (hyperemia and edema of the oral cavity); seborrheic dermatitis (red, scaly, itchy, painful, greasy skin affecting the outer edges of the nostrils, outer ears, eyelids, and genitals); pain or hypersensitivity to touch or temperature in the hands and feet (peripheral neuropathy); conjunctivitis; normocytic, normochromic anemia (low red blood cells but normal hemoglobin and MCV).
• Suboptimal riboflavin status may cause iron deficiency anemia that responds poorly to iron, elevated homocysteine, cataracts, high blood pressure, oxidative stress, migraines, fatigue, exercise intolerance, preeclampsia, and difficulty using fat for fuel.

Risk Factors for Deficiency

• Diets low in animal products, especially organ meats, and enriched flours, especially if they are also high in sugar or fat and do not include riboflavin supplements or riboflavin-containing multivitamins. Vegetarians and vegans have lower intakes and a greater risk of deficiency.
• Anorexics and alcoholics have poor intake, and alcohol impairs the absorption and utilization of riboflavin.
• Low stomach acid, impaired protein digestion, and intestinal inflammation impair riboflavin absorption.
• Light therapy, tanning beds, and extensive sun exposure deplete riboflavin.
• Exposure of food to light depletes riboflavin from food.
• Low thyroid and adrenal hormones impair the retention and use of riboflavin in the body.
• Diabetes, trauma, stress, and dialysis increase the excretion of riboflavin. Diabetes, cancer, and heart disease can precipitate or exacerbate a deficiency.
• The ideal riboflavin intake is likely to be higher than the RDA, at 2-5 mg/d. High-fat diets, exercise, and weight loss each increase the riboflavin requirement by 20-60% and have an additive effect when combined.

Testing for Riboflavin Status

• Whole blood total riboflavin, which is mainly intracellular riboflavin in its active form, is low in deficiency.
• Whole blood total riboflavin and a CBC at the same time: The author has a calculator that estimates the erythrocyte riboflavin concentration and correlates it with the gold standard marker of riboflavin status, the erythrocyte glutathione reductase activity coefficient (EGRAC). Values above 0.7 are good, while 0.5 indicates early deficiency and 0.4 indicates severe deficiency.

Testing Caveats

• Rare genetic disorders in fatty acid oxidation or riboflavin metabolism may induce signs of riboflavin deficiency but require highly specialized diagnosis and medical treatment.
• Some of the signs and symptoms of riboflavin deficiency, especially the skin lesions, are due to deficient metabolic activation of the form of vitamin B6 found in plant foods, and are seen in vitamin B6 deficiency as well.

Correcting Riboflavin Deficiency

• Organ meats
• Free riboflavin is preferable over riboflavin 5’-phosphate. 5 mg would be an ideal dose but most supplements have 100-400 mg and these high doses are harmless. Doses of 200-400 mg have been used to reduce migraines frequency and duration. Riboflavin should always be taken with food and should be spread out across meals as evenly as possible to maximize absorption and retention.

Niacin (Vitamin B3)

Signs and Symptoms of Niacin Deficiency

• Dermatitis, diarrhea, dementia.
• The dermatitis of niacin deficiency occurs only on sun-exposed tissue. It begins with reddening and progresses to scaling and dark color. It most commonly impacts the backs of the hands and the wrists, forearms, face, and neck.
• The diarrhea is associated with generalized malabsorption that might cause deficiencies of many other nutrients and celiac-like atrophy of the intestinal villi.
• The so-called “dementia” can be simple depression in its earliest stages, but progresses to schizophrenia-like psychosis, with auditory and visual hallucinations, and paranoid, suicidal, or aggressive behavior. Insomnia, headaches, and dizziness may be present early on. Later, tremors or muscular rigidity, loss of tendon reflexes, numbness and weakness may occur.
• Suboptimal niacin status may contribute to fatigue, exercise intolerance, or poor exercise performance; accelerated aging, especially of the skin in response to the sun, cancer and inflammation of the esophagus, vulnerability to leukemia, increased genetic mutations, and skin cancer.

Risk Factors for Niacin Deficiency

• Niacin is found in the diet and also synthesized from tryptophan using iron, riboflavin, and vitamin B6.
• Niacin in grains and seeds is poorly bioavailable unless they are soaked in an alkaline solution or fermented for 8 or more hours.
• Diets based on unprocessed whole grains, or based on sugar or fat, or that are very low in non-collagen protein, are likely to lead to poor niacin status.
• Hartnup’s disease is a rare genetic disorder of tryptophan malabsorption.
• Crohn’s disease and megaduodenum also cause malabsorption.
• Serotonin-producing tumors known as carcinoid tumors can divert tryptophan to serotonin and away from niacin. Drugs that impair niacin synthesis include isoniazid (anti-tuberculosis), Imuran and 6-mercaptopurine (immunosuppressives), 5-fluorouracil (anti-cancer), levadop/carbidopa (Parkinson’s) and alcohol.
• Alcoholism is also associated with poor intake.
• HIV/AIDS is associated with poor niacin status as a result of cellular damage that depletes niacin.
• Anything that lowers ATP levels (e.g., hypothyroidism, metformin, berberine) theoretically may hurt niacin status.
• Anything that directs tryptophan into building muscle tissue (e.g., working out or taking leucine or its metabolite, HMB) or serotonin synthesis (e.g., using carbohydrate to boost mood and improve sleep) may hurt niacin status.
• Any form of cellular damage, ranging from normal sunlight exposure to injury, disease states, and aging, depletes niacin for repair processes.

Niacin Excess and Toxicity

• Niacin used to lower blood lipids causes a flushing reaction involving redness and itching, possibly progressing to a brown color of the skin. It also may raise homocysteine, worsen glucose tolerance, and occasionally contribute to diabetes. Very high doses cause liver toxicity, resulting in nausea, vomiting, headache, elevated liver enzymes, hepatitis, jaundice, and in extreme cases encephalopathy and liver failure. Occasionally it results in blurred vision or lazy eye that reverses upon withdrawal.
• Excess niacin is detoxified through methylation, and the liver results from severe drainage of the methyl pool. At non-toxic doses, niacin still drains methyl groups, which might lower creatine synthesis or interfere with the regulation of neurotransmitters.

Risk Factors for Niacin Toxicity

• Both nicotinic acid and nicotinamide are toxic to the liver, but nicotinic acid is more toxic. Among preparation of nicotinic acid, slow-release is the most hepatotoxic form, while immediate release and extended release are less toxic.
• Elevated liver enzymes and jaundice have occurred at intakes as low as 750 mg/d nicotinic acid, but almost all severe cases 3-9 g/d. Nausea, vomiting, and headache have been reported from nicotinamide at doses as low as 3000 mg/d but severe signs very rare and only reported over 10 g/d.
• Toxicity has not been characterized for newer supplements such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), but they probably are slightly less toxic than nicotinamide. Individuals are most likely to experience toxic effects of niacin if they have a history of liver disease, diabetes, active peptic ulcers, gout, cardiac arrhythmia, IBD, migraines, alcoholism.
• To minimize toxicity, he recommends pairing nicotinic acid with glycine (100 mg of glycine or 300 mg of collagen for every 200 mg of nicotinic acid) and pairing all forms of niacin with trimethylglycine (TMG, 100 mg TMG for every 100 mg nicotinic acid or nicotinamide; 100 mg TMG for every 200 mg NMN or NR).
• Additionally, high-dose nicotinic acid appears to have a 1 in 43 chance of causing diabetes and the best protection against this is likely to avoid snacking on carbohydrates in the 2–6-hour period after each dose.

Testing for Niacin Deficiency

In deficiency, NADP(H) stays constant while NAD(H) falls. The “niacin number” can be calculated by dividing the concentration of NAD(H) by NADP(H) and multiplying by 100. Healthy adults not taking niacin supplements have a niacin number close to 175. Niacin supplementation can raise this over 600, while 5 weeks of moderate, experimental niacin deficiency drops it to 60.

As the niacin number declines under 175, deficiency should be considered progressively more likely, and this can be used as a target for correcting deficiency.

Correcting Niacin Deficiency

• Niacin-rich foods, protein, vitamin B6, or iron, depending on what the cause of deficiency is.
• Nicotinamide riboside (NR) supplements are the best choice for improving tissue levels, but high doses will tax the methylation system so care to optimize methylation status should be used in this approach, and he recommends supplementing 100 mg trimethylglycine (TMG) for every 200 mg NR.

Pantothenic Acid (Vitamin B5)

Signs and Symptoms of Pantothenate Deficiency

• Numbness, especially in the toes, burning in the feet, irritability, restlessness, disturbed sleep, and gastrointestinal distress.
• Considered extremely unlikely.
• Additional signs that should be considered plausible in more moderate deficits could include a vulnerability to hyperammonemia (which would make someone feel sick and fatigued on a high-protein diet), general fatigue and weakness, improved health and well-being on a low-fat diet, and the pain associated with rheumatoid arthritis.

Risk Factors for Deficiency

• Pantothenate is also produced by gut microbes, which may protect against deficiency on low-pantothenate diets.
• Yeast, liver, eggs, and mushrooms stand out as excellent sources.
• Diets high in refined grains and devoid of pantothenate-rich foods will be low in pantothenate and this may contribute to moderate deficits when pantothenate supplements or pantothenate-containing multivitamins are not used. The contribution of gut pantothenate production to nutritional status is not well characterized, but gut dysbiosis might be seen as a plausible contributor to deficiency.

Testing for Pantothenate Status

Plasma levels of pantothenate decline in nutritional status.

Correcting Pantothenate Deficiency

If other B vitamin deficiencies have not been ruled out, supplementation is best as a component of a B complex. Nevertheless, there is no known toxicity and supplements of one gram per day of calcium pantothenate have shown promise in rheumatoid arthritis. Calcium pantothenate is about half pantothenate and one gram of it provides approximately 50 times the RDA.

Vitamin B6

Signs and Symptoms of B6 Deficiency

• Convulsive seizures; cognitive symptoms such as irritability, depression, and confusion; vulnerability to infection, lesions similar to those of riboflavin deficiency (cheilosis, angular stomatitis, glossitis, oral hyperemia and edema), and sideroblastic anemia.
• More moderate deficits of B6 elevate homocysteine, contribute to cardiovascular disease, and contribute to chronic low-level inflammation.
• Less well established but plausible signs and symptoms of moderate B6 deficits include cognitive decline, depression, anxiety, insomnia, hypoglycemia, oxalate kidney stones, and the morning sickness of pregnancy.
• Vitamin B6 is needed for the endogenous synthesis of niacin, and may contribute to niacin deficiency in the presence of other predisposing factors. It is also needed for the metabolic activation of essential fatty acids, and may contribute to essential fatty acid deficiency in the presence of other predisposing factors.

Risk Factors for B6 Deficiency

• There are rare genetic defects that cause dramatic increases in the need for vitamin B6 to prevent either seizures or sideroblastic anemia.
• Diets low in animal foods, low in riboflavin, low in raw foods, or dominated by overcooked foods may contribute to deficiency.
• Gut flora and the enzyme pyridoxine 5’-phosphate oxidase (PNPO) are important for deriving B6 from plant foods, and variations in these factors may contribute to deficiency.
• Inflammation raises the need for B6 and also increases its degradation.
• Oral contraceptives, high estrogen levels, NSAIDs, and drugs used to treat tuberculosis and Parkinson’s increase the need for B6.
• Sulfite accumulation, which may be driven by molybdenum deficiency and a high intake of animal protein or sulfite used as a food additive, contributes to B6 deficiency.

Vitamin B6 Toxicity

Long-term use of doses above 500 milligrams per day of pyridoxine may cause ataxia (loss of full control over body movements), and sensory neuropathy, with symptoms such as numbness to touch or temperature change, tingling, burning, or pain in the extremities.

Testing for B6 Status

• Plasma B6: Low
• Erythrocyte transaminase activity: Low
• The combination of elevated xanthurenate, k ynurenate, and quinolinate on a urinary organic acids profile is robust evidence of B6 deficiency. In early deficits, xanthurenate is most likely to be elevated and quinolinate is least likely.

Testing Caveats

Oral contraceptives, and presumably high estrogen, may cause the signs of B6 deficiency to appear on an organic acid profile, but it is not clear whether higher doses of B6 will correct them. It is therefore unclear whether this should be regarded as B6 deficiency. Nevertheless, anecdotally, 100 mg/d of pyridoxal 5’-phosphate seems to mitigate the insomnia that sometimes accompanies high estrogen levels.

Correcting B6 Deficiency

• Increasing the proportion of animal foods in the diet, using more gentle cooking techniques, and including more raw foods may all help improve B6 status. Among plant foods, bananas are an excellent source of B6 because it is easy to eat them raw and because their B6 is absorbed more effectively than the B6 in most other plant foods.
• Pyridoxal 5’-phosphate is the ideal supplement because it does not require riboflavin-dependent metabolic activation in the liver. 5 milligrams per day should be adequate to correct a deficiency that results from poor dietary intake. However, many factors disrupt B6 metabolism, and doses between 30-100 milligrams per day may be needed to reverse signs of deficiency in some individuals. Because of the risk of toxicity, doses this high should be used with care and only when there is clear justification. 

Correcting B6 Toxicity

Neurological problems induced by toxic doses of B6 generally resolve when B6 is withdrawn. Nevertheless, signs and symptoms of toxicity should always be reported to a physician as they could require medical care or be mistaken for other conditions that require medical care.

Biotin (Vitamin B7)

Signs and Symptoms of Deficiency

• Scaly, red dermatitis around the nose, mouth, and perineum, hair loss, conjunctivitis, ataxia, depression, lethargy, paresthesia.
• Biotin deficiency during pregnancy may contribute to birth defects.

Risk Factors for Biotin Deficiency

• Egg yolks and liver, which are far more abundant in biotin than any other foods; egg whites, which contain a heat-sensitive compound known as avidin that impairs biotin absorption; and pregnancy, which raises the need for biotin.
• The consumption of egg white, especially raw and when consumed without equal numbers of egg yolks and without biotin supplements or biotin-containing multivitamins. Even though cooking degrades avidin, substantial proportions remain in cooked egg white. Whole eggs do not pose a risk of deficiency, and this is probably true even if raw. On the other hand, egg whites should not be consumed without the yolks unless biotin supplements are also used. The same is true for egg white protein powders.
• Pregnancy raises the need for biotin, and about one-third of mothers become temporarily biotin deficient during pregnancy.

Testing Biotin Status

• Urinary 3-hydroxyisovalerate (beta-hydroxyisovalerate): The most sensitive and robust marker of marginal biotin deficiency.
• Blood levels of biotin decline in deficiency, but they are less sensitive than urinary 3-hydroxyisovalerate.

Correcting Biotin Deficiency

Thoroughly cooking egg whites or consuming fewer of them. Liver and egg yolks are the best food sources of biotin. Liver can be consumed up to two 3.5-ounce servings per week, and 3-4 egg yolks per day can be used for most people, but may need to be moderated for individuals with elevated blood cholesterol.

B Vitamins Involved in Methylation

The B vitamins most centrally involved in methylation include folate (vitamin B9), vitamin B12, choline, and betaine. Amino acids – methionine, serine, and glycine are also central to the system. Finally, the system of energy metabolism directly supports the methylation system, with especially prominent roles for thiamin, riboflavin, niacin, and vitamin B6.

Most of the nutrients in this pathway act as methyl donors: folate, B12, choline, betaine, methionine, and serine. However, glycine acts as a methyl buffer, removing excess methyl groups from the system to prevent over-methylation. Methylation remains adequate and in balance when all parts of the system are optimized.

Signs and Symptoms of Imbalances

Signs and Symptoms of Deficient Methylation

• Fatty liver disease, neural tube birth defects, elevated homocysteine and associated cardiovascular risk, fatigue, poor exercise capacity, histamine intolerance, difficulty ignoring negative thoughts and thought patterns, depression, anxiety, obsessive compulsive disorder, histamine intolerance, inability to adequately eliminate arsenic, inability to properly utilize selenium or excrete excess selenium.
• Severe deficiencies in methylation could contribute to deficiencies of zinc, copper, and perhaps other positively charged minerals. As with excessive methylation, possibly cancer.

Signs and Symptoms of Excessive Methylation

Among the best supported: distractibility, difficulty focusing, impulsivity, and substance abuse.

More speculative: difficulty breaking free from psychological conditioning, difficulty falling asleep or poor-quality sleep, and faster aging skin. As with deficient methylation, possibly cancer.

Signs and Symptoms Specific to B12 and Folate Deficiencies

Macrocytic, megaloblastic anemia. This is independent of their role in methylation. This may be asymptomatic, or may make you feel tired, weak, short of breath on exertion, and cause heart palpitations and paleness.

Signs and Symptoms Specific to B12 Deficiency

• Vitamin B12 deficiency causes neurological degeneration that is largely independent of its role in methylation and does not involve folate. Mental changes include memory loss, changes of personality or mood, and in the most severe cases delirium and psychosis.
• Changes generally begin in the feet and work their way upwards with lost sense of position and vibration and paresthesia (tingling, numbness, or a feeling of something crawling on the skin), possibly progressing to ataxia (loss of full control over the muscles), spasticity (constant contraction) and gait abnormalities (difficulty walking correctly).
• Other signs and symptoms include optic neuritis, visual disturbances, and autonomic dysfunction, which may manifest as dizziness or faintness upon standing in the case of orthostatic hypotension, or exercise intolerance if the heart rate does not appropriately adjust to exercise.

Risk Factors for Imbalances

Folate Deficiency

• Meeting the folate requirement requires two to three 100-gram servings of liver, legumes, or greens per day. Liver should not be used more than twice a week in most cases and legumes and greens can be used to meet the remainder of the requirement. Folate is stable in liver when frozen and in legumes when dried, but not in frozen vegetables.
• Reliance on frozen vegetables as a source of folate without realizing that most of the natural folate in these foods has degraded before consumption may also be a major contributor.
• Preventing deficiency may take 3-5 servings of plant foods rather than 2-3 if they are cooked and the cooking water is discarded.
• There is also a rare genetic defect in the primary intestinal folate transporter known as hereditary folate malabsorption.

Folate Excess

• First, it can mask B12 deficiency by preventing the associated anemia without doing anything to prevent the degeneration of the nervous system.
• Second, although the mechanism is poorly understood, folate supplementation has been associated with the onset of nervous system degeneration in B12-deficient patients and could be the factor that provoked the degeneration.
• Third, supplementation with as low as 1 milligram per day of folate has provoked hypersensitivity reactions in some individuals.

Vitamin B12 Deficiency

• The major cause of vitamin B12 deficiency is poor absorption.
• Pernicious anemia occurs in 0.1% of the general population and close to 2% of the elderly. It consists of an autoimmune attack on components of the digestive system specific to B12 absorption. Chronic gastritis, on the other hand, is usually caused by H. pylori, may affect half or more of the population, begins in childhood, and advances with age. In the elderly, gastritis may be severe enough to cause vitamin B12 deficiency in 10-15% of the population.
• Signs of B12 deficiency are found in over 70% of vegetarians and 90% of vegans, due to low intake without supplementation. B12 is found almost exclusively in animal products, and the bioavailability in eggs is low, making milk the only food source for most lacto-ovo-vegetarians.
• Some research indicates that there is B12 in a small selection of vegan foods: shiitake, chanterelle, and black trumpet mushroom; and chlorella and green or purple nori (laver). Nevertheless, most mushrooms and edible bacteria or algae do not contain B12 and the levels found in chlorella have been shown to be extremely inconsistent.
• Some animal products, such as liver and clams, have far more than the RDA for B12, but you can only absorb one day’s worth of B12 in each meal. If you eat one large serving of clams, your data may indicate that you’ve eaten enough for at least the week and maybe even the month, but you’ve only absorbed enough for the day. Thus, a diet that does not contain, on average, at least seven B12-rich meals per week and meet the RDA for an average intake, is at risk of suboptimal B12 status.

Choline and Betaine Deficiency

• Within the methylation system, choline is converted to betaine, and betaine acts as the direct methyl donor.
• Choline is much more abundant in liver and egg yolks than in any other foods. Meeting the requirement for choline requires 2-3 egg yolks per day if obtained exclusively from egg yolks. One 100-gram serving of liver provides the equivalent of two egg yolks, and one 100-gram serving of most cruciferous vegetables or nuts provides the equivalent of half an egg yolk.
• Choline fulfills other functions outside of methylation that betaine cannot fulfill.
• One egg yolk’s worth of choline can be obtained in betaine using any of the following: 100 grams of spinach (measured raw), 100 grams of raw beets or 50 grams of cooked or canned beets, or 25 grams of wheat germ.

Choline Excess

Excess choline may be converted in the colon to trimethylamine oxide (TMAO), which may contribute to cardiovascular disease. This can be minimized by 1) spreading choline out across meals rather than taking it all at once, and 2) getting choline mainly from food, and if using supplemental choline to use phosphatidylcholine.

Amino Acid Deficiencies

• Serine and glycine can be synthesized by the body, while methionine cannot. Nevertheless, endogenous synthesis of any amino acids only occurs adequately when total protein requirements are met.
• As long as the protein comes from animal products or from plant products that are well diversified (for example, does not come exclusively from legumes), methionine and serine needs will be met.
• Methionine, present in all proteins and especially rich in animal protein, increases the need for glycine. Therefore, this extra glycine requirement is best fulfilled by the inclusion of collagen in the diet, which is much higher in glycine than other proteins and quite low in methionine. 5 grams of glycine could be obtained from ⅔ of an ounce of bone meal, or with one to two servings of hydrolyzed collagen.

Amino Acid Excesses

• Excess protein generates ammonia, which is toxic if it accumulates but is usually safely converted to urea. Rare genetic disorders or urea-degrading microbes in the gut may impair the disposal of ammonia but for most people the ability to dispose of ammonia is not overwhelmed until protein intakes reach 8 grams per kilogram body weight, which cannot be obtained from food and would be extremely difficult to achieve even with protein supplements.
• Methionine increases the need for glycine, and high intakes of animal protein or supplementation with S-adenosylmethionine (SAMe) may deplete glycine to suboptimal levels.
• Collagen supplementation has the potential to increase oxalate accumulation and could pose a risk of kidney stones. Individuals at risk of kidney stones should be careful with collagen and preferably monitor oxalate levels. Oxalate excretion in response to collagen is more likely to occur if you are deficient in B6.
• The oxalate is produced mainly from the hydroxyproline in collagen, not the glycine, so if you cannot resolve increased oxalate excretion in response to collagen supplementation, you should try supplemental glycine as an alternative.

Effects of Common Genetic Polymorphisms

MTHFR:

• MTHFR enables the production of methylfolate, which allows folate to support the methylation process. Methylfolate is also the off switch for the glycine buffer system, so low methylfolate levels cause increased wasting of glycine as methylated metabolites. This depletes glycine and methyl groups, even if there is an inadequate supply of methyl groups.

There are two common polymorphisms: A1298C and C677T.

• One A1298C allele decreases MTHFR activity by 17%.
• One C677T decreases it 33%. Two A1298C decrease it by 39%. One of each decrease it 53%.
• Two C677T decrease it by 75%.

A 75% decrease in MTHFR activity has several important impacts on nutritional requirements:

• The requirement for riboflavin is increased by 1.6 milligrams per day.
• The choline requirement is doubled to about 900-1200 mg/d, which is the equivalent of 4-5 egg yolks.
• Methylfolate production is lower. This cannot be compensated for with methylfolate supplements. A typical folate molecule is recycled 18,000 times per day, and it is not safe to take 18,000 times the RDA for folate. Nevertheless, it is important to maintain enough methylfolate to switch off the glycine buffer system and using between 400 and 1000 micrograms of supplemental methylfolate may be helpful.
• Since almost half of methylation is used to synthesize creatine, 3-5 grams per day of supplemental creatine may cut the methylation demand in half and help to better conserve methylfolate to more effectively stop glycine wasting. Ideally the dose is taken with meals spread throughout the day but usually it is more practical to take it with a single meal per day. The full effects take 4-6 weeks to set in.
• Glycine requirements are presumably higher. Putting more emphasis on obtaining dietary sources of collagen makes sense, and you may try supplements providing 3-10 grams of glycine (such as one to three servings of hydrolyzed collagen).
• Excess methionine from high animal protein intake or from S-adenosylmethionine (SAMe) supplementation will exacerbate glycine wasting. Unless there are specific athletic goals requiring higher protein intakes, you should keep your protein intake below 2 grams per kilogram body weight and diversify it among animal and plant proteins.

SLC19A1 and MTHFD1:

• SLC19A1 is needed to transport folate into cells and MTHFD1 is an enzyme that produces methylenefolate, a precursor to methylfolate and the form of folate that is required to prevent anemia. Unlike MTHFR, which plays no role in preventing macrocytic anemia, both of these could increase the risk of anemia because they can both impair the intracellular supply of methylenefolate. Homozygosity for the G80A allele of SLC19A1 decreases its activity 50%, and homozygosity for the of the G1958A allele of MTHFD1 decreases its activity by 34%.
• If 50% of folate enters the cell and 66% is converted to methylenefolate, from which 61% is converted to methylfolate, presumably this lowers methylfolate production to 0.5*0.66*0.61= 20% of normal.
• Since these polymorphisms also impact the supply of methylenefolate, folate supplements, if they are used, should be a mix of folinic acid (formylfolate) and methylfolate, since folinic acid will be more easily converted into methylenefolate.

MTRR:

• MTRR is an enzyme that repairs vitamin B12 when it has been damaged by oxidative stress. Homozygosity for A66G or C524T lowers the activity of the enzyme 3-4-fold. This may cause no problems if oxidative stress is minimal. Under conditions of oxidative stress, however, individuals with these polymorphisms may become more vulnerable to vitamin B12 deficiency. These mutations do not directly impact nutritional requirements, but reinforce the need to be proactive about measuring B12 status.

PEMT:

• PEMT is an enzyme that uses the methylation system to produce phosphatidylcholine.
• If you have decreased PEMT activity, you will have a higher risk specifically of fatty liver and liver damage when you do not follow the choline recommendations.

Testing for Methylation-Related Nutrients

• Homocysteine in amino acid profiles: The homocysteine levels associated with optimal health are 5-9 micromoles per liter. If your homocysteine is elevated, it could be due to a deficiency of one or more methyl donors (B12, folate, choline/betaine), a deficiency of vitamin B6, which is needed for its catabolism, or a deficiency of any of the B vitamins that enable the production of methylfolate (thiamin, riboflavin, niacin, B6).
• Methionine on an amino acid profile: If methionine is low when homocysteine is high, it makes it more likely that homocysteine is high as a result of deficient methyl donors. If methionine is mid-range when homocysteine is high, homocysteine is more likely high as a result of deficient B6. If methionine is high and homocysteine is low, it suggests that there is a backup in the conversion of methionine to its activated form, S-a denosylmethionine (SAMe). This may be caused by rare genetic mutations that are not included in the common genetic polymorphism section above, or to deficiencies of magnesium or ATP, and it would be a good reason to try SAMe supplementation at doses ranging from one tablet or up to 1600 milligrams per day. This interpretation would be strengthened if methionine is high or high-normal while SAMe is low or low-normal.
• Glycine and sarcosine on an amino acid profile: Ideally glycine should be toward the middle or higher end of the normal range, and sarcosine should be close to zero. If glycine is low, it suggests that more glycine is needed. However, if sarcosine is elevated, even toward the middle or higher end of the normal range, it suggests that low methylfolate levels are causing glycine wasting, which calls for strict implementation of the MTHFR-specific recommendations above (these should be tried even in the absence of MTHFR polymorphisms if sarcosine is elevated).
• Mean Corpuscular Volume (MCV) on a complete blood count (CBC): High MCV is a sign of macrocytic anemia and suggests a deficiency of folate or vitamin B12. Deficiencies of other nutrients may elevate MCV, such as copper, thiamin, riboflavin, niacin, and vitamin B6, but folate and B12 are much more common, especially if there are no independent indications that these other nutrients may be deficient. Choline/betaine should not impact MCV. It is, therefore, more specific to folate and B12 than the alterations of homocysteine and methionine listed above. Rare mutations in dihydroflate reductase (DHFR), and possibly common polymorphisms may increase MCV.
• Serum and RBC Folate: Folate in red blood cells reflects total folate status, while folate in plasma or serum reflects almost exclusively methylfolate. If total folate status is low, it suggests a general folate deficiency. If only serum (or plasma) folate is low, it suggests a specific deficiency of methylfolate due to impaired MTHFR activity, or a deficiency of any of the B vitamins that enable the production of methylfolate (thiamin, riboflavin, niacin, B6). Excess intake of methionine or supplementation with S-adenosylmethionine will inhibit MTHFR activity and may also contribute to low methylfolate levels.
• Urinary FIGlu on a urinary organic acid profile: Formiminoglutamate (FIGlu) is a functional marker specific to folate that is independent of the methylation process and other methylation-related nutrients and rises in folate deficiency.
• Serum B12: If serum B12 is low, it shows B12 is deficient. Serum B12 should not be used as the only marker of B12 status, however, because adequate serum levels do not show that B12 is getting into cells and fulfilling its function, and a suitable functional marker, methylmalonic acid, is described below.
• Methylmalonic acid in urine or in blood: Methylmalonic acid (MMA) is a functional marker specific to B12 that is independent of the methylation process and other methylation-related nutrients and rises in B12 deficiency. If the increase is moderate and the kidneys are healthy, it is more likely to be found in the urine, but an impairment in kidney function could make it more apparent in the blood, so it is better to measure both.

Guide to Using the Genova Methylation Panel

Diversions from optimal methylation are likely to show up as one or more of four patterns on the Genova Methylation Panel (See book for lines and more information):

• Deficient remethylation of homocysteine, with a low methylation index, methionine, and S-adenosylmethionine; along with high homocysteine and S-adenosylhomocysteine.
• Excess methylation of glycine, with low glycine and high dimethylglycine and sarcosine.
• A high rate of trans-sulfuration, with high cyst(e)ine and taurine, and possibly high cystathionine.
• A low rate of methionine activation, with high methionine but low S-adenosylmethionine.

If deficient remethylation of homocysteine is found, the cause may be deficiencies of folate, B12, or betaine/choline. The following points should be considered:

• Assessing folate and B12 deficiencies requires the tests above.
• If betaine and choline are deficient in the diet, they will both be low.
• If the betaine/choline ratio is high, this is likely from deficient folate or B12, or from poor MTHFR activity.
• If the betaine/choline ratio is low, this is likely from low choline dehydrogenase activity, and is a strong argument for using trimethylglycine (TMG, betaine) instead of choline to support methylation.
• If betaine and choline are both high, this could be from low BHMT activity and suggests that neither choline nor TMG may be able to adequately support remethylation, increasing reliance on folate and B12.
• If both MTHFR and BHMT activity are low, however, it may be harder than expected to use folate, B12, TMG, or choline to support remethylation. If methionine levels are also low and undermethylation symptoms are the primary concern, this is an argument for increasing dietary methionine, which can be achieved through increased total protein, increased animal protein (which is twice as rich in methionine as plant protein), or supplementation with L-methionine. However, if lowering homocysteine is the primary concern, it may be necessary to decrease dietary methionine. If high homocysteine, low methionine, and undermethylation symptoms are all important concerns, the best strategy would be to use vitamin B6 to try to increase the amount of methionine that can be tolerated without a rise in homocysteine, and to adjust the dietary methionine to what best achieves the balance between fixing undermethylation and keeping homocysteine low.

If excess methylation of glycine is found, it could reflect high levels of SAMe and inadequate glycine, or it could reflect low levels of methylfolate. The following points should be considered:

• If methionine and S-adenosylmethionine are elevated, the best strategy is to improve the balance of methionine to glycine within the diet. A good default is 5 grams of glycine for every 75 grams of non-collagen protein. 5 grams of glycine can be obtained from glycine powder, or from 15 grams of gelatin or collagen.
• If excess methylation of glycine accompanies deficient remethylation of homocysteine as described earlier, then the likely cause of the glycine methylation is low levels of methylfolate, due either to folate deficiency or to low MTHFR activity. This could be confirmed using markers of folate status. In this case, the primary strategy should be to restore methylfolate levels. If serum folate is low, this indicates that methylfolate levels are low. If it is also true that RBC folate is low or FIGlu is high, then more dietary folate is needed. If these others markers are normal, however, the problem is likely to be mainly with MTHFR activity. In this case the recommendations in the “Effects of Common Genetic Polymorphisms” section should be implemented.

If a high rate of transsulfuration is found, this could reflect high levels of SAMe or oxidative stress. The following points should be considered:

• If methionine and S-adenosylmethionine are elevated and glutathione is normal or high, then this may not be a problem (unless it causes sulfur intolerance).
• If glutathione is low, then the high rate of transsulfuration is likely due to oxidative stress. If this is accompanied by low methionine, S-adenosylmethionine, and homocysteine, then oxidative stress is likely severe enough to be compromising methylation and contributing to undermethylation symptoms. In this case, see Antioxidant Vitamins and Minerals.
• If a high rate of transsulfuration accompanies symptoms of sulfur intolerance, such as allergy-like symptoms or symptoms of glutamate intolerance, regardless of the other methylation markers, see Molybdenum and Sulfur Catabolism.

If a low rate of methionine activation is found, this could be caused by magnesium deficiency, any deficiencies or disorders of energy metabolism, or impairments in the MAT enzyme. If the underlying cause is genetic or cannot be easily resolved, this is a strong argument for supplementing with SAMe at doses ranging from one tablet or up to 1600 milligrams per day.

Testing Caveats

Numerous reactions in the methylation pathway require magnesium and ATP. Magnesium deficiency or metabolic disruptions that affect ATP production such as hypothyroidism, diabetes, insulin resistance could contribute to methylation imbalances, and this becomes more likely if no nutrient deficiencies can be supported. Extra niacin is excreted in methylated form, and high-dose niacin supplements (in any form: niacin, niacinamide, or nicotinamide) may be the cause of an apparent deficiency in methylation.

Correcting Imbalances in Methylation-Related Nutrients

• There are no satisfactory tests of choline status, but most people do not consume enough choline and the choline recommendations listed above should be implemented in most cases. Lack of evidence for deficiencies of other nutrients should also point attention to choline when the data suggest a deficiency of methyl donors.
• If the cause is a medical issue, such as a malabsorption disorder, it will need appropriate medical treatment.
• If the cause is poor diet, the dietary targets, or supplements within the ranges listed in “Causes of Deficiencies and Imbalances” should be used, with doses adjusted over time to bring blood markers in range.
• If creatine is used to reduce the methylation demand, it should be noted that, anecdotally, some people develop over-methylation symptoms such as insomnia. This appears to be a temporary effect, and it may take up to 6 weeks for the full effects of creatine to settle in.

Molybdenum and Sulfur Catabolism

• The transsulfuration pathway is closely connected to the methylation pathway and represents the intersection between the methylation pathway and the antioxidant system by providing the amino acid cysteine for the synthesis of glutathione.
• The pathway is activated by high methionine inputs, serving to get rid of the excess (as would occur after a high-protein meal), and by oxidative stress, serving to increase the synthesis of glutathione when it is most needed. If the sole need is to get rid of excess methionine, the cysteine is catabolized to taurine and sulfate. If the sole need is to increase glutathione synthesis, it is directed into that pathway.
• The amino acid serine and vitamin B6 are needed for its production from homocysteine. The conversion always generates alpha-ketobutyrate as a byproduct, which is the major source of methylmalonic acid, discussed above as a marker of vitamin B12 status. The methylmalonic acid requires biotin to be produced, and vitamin B12 to be eliminated. The synthesis of glutathione from cysteine requires glycine, magnesium, and ATP. On its way to sulfate, cysteine first generates sulfite. Sulfite is toxic and its accumulation can cause deficiencies of thiamin and vitamin B6. The conversion of sulfite to sulfate requires molybdenum.

Signs and Symptoms of Molybdenum Deficiency

• Seizures, mental retardation, and dislocated lenses within the eye, all occurring in the newborn, and is unlikely to be informative for what moderate deficits in molybdenum might look like.
• More moderate sulfite accumulation may impair thiamin and B 6 status and cause the signs and symptoms discussed in those sections.
• Presumably, molybdenum deficits could contribute to sulfite sensitivity as well, which results in allergy-like reactions (dermatitis, hives, flushing, low blood pressure, abdominal pain, diarrhea, anaphylaxis, asthma) to the sulfites used as food additives.

Risk Factors for Molybdenum Deficiency

• Molybdenum is very rich in legumes. The need for molybdenum increases with high intakes of protein, especially of animal proteins, as a result of their high methionine content. Thus, a diet rich in animal proteins and low in legumes is likely to lead to significantly lower molybdenum status than the opposite pattern.
• The need for molybdenum appears to also increase during pregnancy, where the production of hydrogen sulfide, essential to the growth of the placenta and embryo, provides an additional source of sulfite. The morning sickness of pregnancy may result from sulfite-induced B6 deficiency that occurs on the background of low molybdenum intakes.

Molybdenum Excess

The upper limit is set at 30 micrograms per day per kilogram bodyweight, which in a 70-kilogram individual is 2100 micrograms per day. There is no reason to use doses higher than this, and supplements often contain as little as 150 micrograms and rarely contain more than one milligram.

Testing for Molybdenum Status

• Serum or Whole Blood Molybdenum: HDRI tests report an exact value within a normal range.
• Uric Acid: In addition to converting sulfite to sulfate, molybdenum is also necessary to make uric acid. Uric acid is low in molybdenum deficiency.
• Urinary Sulfite and Sulfate: High urinary sulfite and low urinary sulfate indicates a molybdenum deficiency.
• Serum Sulfate and the Cysteine-to-Sulfate Ratio: Low serum sulfate and a high cysteine-to-sulfate ratio may indicate molybdenum deficiency.

Correcting a Molybdenum Deficiency

Increasing legumes and decreasing animal protein may help correct a molybdenum deficit, but animal protein is nutritionally important and some individuals do not tolerate legumes well. If dietary measures are unfeasible or insufficient, 500-1000 micrograms per day of molybdenum supplementation should be more than adequate, and this can likely be dropped to 100-200 micrograms per day as a maintenance dose once markers and signs and symptoms resolve.

Antioxidant Vitamins and Minerals

While vitamins E and C are best known as antioxidants, the antioxidant system also depends on the following minerals: zinc, copper, manganese, iron, and selenium. Glutathione is not a nutrient, but it is the master antioxidant and serves as the interface between the antioxidant system and the system of energy metabolism, allowing glucose to act as the ultimate antioxidant. Glutathione synthesis also interacts with the methylation system through the transsulfuration pathway.

General Testing for Oxidative Stress

Useful markers include lipid peroxides, a measure of oxidative damage to lipids, and 8-hydroxy-2-deoxyguanosine, a marker of oxidative damage to DNA. Additionally, in panels that include citric acid cycle metabolites, the following can be seen as indicating oxidative stress:

• A high citrate-to-isocitrate ratio is the earliest sign of oxidative stress.
• High alpha-ketoglutarate suggests more severe oxidative stress, but if isocitrate is extremely low this sign may not be observed.
• High succinate, when found alongside a high citrate-to-isocitrate ratio, suggests the most severe oxidative stress.

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

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.

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 especially cigarette smoke, 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

• If dietary intake is infeasible or insufficient, supplementation with 200 milligrams per day of ascorbic acid is adequate in most cases.
• 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. 

Manganese

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

Industrial exposure to manganese through coal mining or the inhalation of gasoline vapors when manganese additives are used can cause manganese to deposit in the brain and cause a variety of neurological problems including headaches, dopamine depletion, and Parkinson-like symptoms. Drinking water is sometimes contaminated with toxic levels of manganese.

Testing Manganese Status

Manganese should be measured in whole blood or red blood cells and not in plasma or serum.

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 the 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. He recommends cutting these in half or taking them every other day, or taking a daily supplement with 3-5 milligrams.

Zinc

Signs and Symptoms of Zinc Deficiency

• The earliest sign of zinc deficiency is usually patches of dry skin. 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.

Risk Factors for Zinc Deficiency

• Zinc is most abundant in oysters, red meat, and cheese, and the its 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.

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 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.

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

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.

Risk Factors for Copper Deficiency

• The best food sources of copper are liver, oysters, shiitake mushrooms, pure chocolate, and spirulina. Other good sources are most 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 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

• Serum Copper: Serum copper declines in deficiency and is more sensitive and perhaps more specific than ceruloplasmin. Serum is preferable, but plasma is also acceptable.
• Ceruloplasmin: Ceruloplasmin declines in deficiency but is less sensitive and perhaps less specific than serum copper.
• Urinary Copper: Increased in Wilson’s disease.

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

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.

Signs and Symptoms of Selenium Deficiency

• Keshan disease is the 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.

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.

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

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. The 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.

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 other six 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 decrements 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 the 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 supplements he recommends 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. He recommends using the above iron supplements at one dose three times per day with a meal. They provide 10-15 milligrams per dose, which is 30-45 milligrams per day. This is similar to what you can get from eating clams twice a day and is within the tolerable upper intake level set by the Institute of Medicine on the basis of the gastrointestinal side effects of ferrous sulfate. 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, he recommends using blood donation. 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 the other minerals in this guide, 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

Signs and Symptoms of Poor Glutathione Status

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

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. His confidence that HDRI conducts this test properly is decreasing. Pending further investigation of the blood collection procedures, he may remove this recommendation. At present, it is included because it is the only test he knows of that measures glutathione in its reduced and oxidized forms.
• 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 the testing in the previous section suggests that glutathione synthesis is compromised and pyroglutamate is not elevated, then the following possibilities should be given the most weight:

• 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 given the most weight:

• 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 and their diagnosis and treatment are beyond the scope of this guide.

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.

Iodine

It is the only mineral that becomes part of thyroid hormone. The thyroid gland has the highest need for antioxidant protection in the body, however. Thyroid hormone also regulates the rate of ATP production, and ATP is needed to support the antioxidant system through the synthesis of glutathione.

Signs and Symptoms of Iodine Deficiency

• When iodine deficiency occurs during pregnancy and the first year of life, it results in cretinism. This causes a general stunting of physical and neurological development with a lifelong decrease in IQ.
• Hypothyroidism at any age during development will slow growth, and will prevent the development or maintenance of fertility. More generally, hypothyroidism causes signs such as fatigue, brain fog, cold hands and feet, increased sensitivity to cold in general, hair loss, and swelling (edema), especially in the face.
• Iodine deficiency hypothyroidism may be accompanied by goiter, which manifests as a swelling in the neck due to an enlargement of the thyroid gland, and may feel like a lump in the throat.
• Hypothyroidism compromises immune function, and iodine itself is antimicrobial; either of these may account for increased vulnerability to infections. Poor digestive function, including constipation, small intestinal bacterial overgrowth (SIBO), and fat malabsorption may could be considered plausible results of hypothyroidism due to a slowing of gastric motility.
• Fibrocystic breast disease may also be a manifestation of iodine deficiency.

Risk Factors for Iodine Deficiency

• Consuming foods grown in low-iodine soil, not consuming many seafoods, not using iodized salt, and not using iodine supplements or iodine-containing multivitamins.
• Women who are pregnant or lactating, and probably women with large breasts, have increased iodine needs.
• High exposure to thiocyanate, a compound that inhibits the transport of iodine into the thyroid and mammary glands. Thiocyanate is produced during the detoxification of cyanide from cigarette smoke or from the cyanogenic glycosides in many plant foods, and is produced from glucosinolates found in cruciferous vegetables. The most important sources of cyanogenic glycosides are cassava, lima beans, sorghum sprouts, flax, the seeds of apples and pears, and the leaves, fruit and seeds of black cherries, cherries, almonds, plums, peaches and apricots. The most widely used cruciferous vegetables include broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard, rutabaga, turnip, and bok choy. Other crucifers include arugula, horseradish, radish, wasabi, watercress, and maca. Sulforaphane, used as a supplement to promote detoxification, generates isothiocyanate.
• Isoflavones derived from soy also bind to iodine and prevent its utilization for the production of thyroid hormone. Fluoride and bromine compete with iodine for transport and utilization. Fluoride is found mainly in toothpaste and fluoridated water. Bromine is put to a multitude of uses, such as flame retardants, dyes, insecticides, furniture foam, gasoline, and the casings of electronics, and is thus ubiquitous in the modern environment.

Signs and Symptoms of Iodine Excess

• Acute administration of iodine to individuals with underlying thyroid diseases, especially those resulting from iodine deficiency, may cause transient hyperthyroidism. Iodine supplementation above 1 milligram per day increases TSH over the course of two weeks, with no established clinical consequences. While a theoretical risk, prolonged elevation of TSH could contribute to goiter or thyroid cancer. Exposure to grams of iodine at once causes acute poisoning. This is extremely rare, but results in abdominal pain, fever, nausea, vomiting, and possibly coma. Allergies to iodine are possible, but very rare.
• Iodermia is a rare reaction to iodine that causes skin eruptions that appear as acne, itching (pruritis), and hives (urticaria).

Risk Factors for Iodine Excess

Consumption of very iodine-rich seaweeds in their raw state (mainly kelp, which is also known as kombu, haidai, or by various scientific names beginning with Laminariales) could lead to iodine excess. Boiling for 15-30 minutes removes the iodine risk. Consuming one gram per day of raw kelp provides more than 1 milligram per day of iodine, and consuming 8 grams per day provides more than 20 milligrams. Use of iodine supplements or topical use of iodine could also provide excess.

Testing for Iodine Status

The best marker of iodine status is urinary iodine excretion. Iodine is excreted in the urine when the body perceives that dietary iodine exceeds the body’s needs. This makes it more reliable than blood levels of iodine. Urinary iodine will fluctuate widely according to recent dietary intake. He recommends using 24-hour urine iodine and taking it as reflective of the iodine status produced by the diet consumed on the day of and the day before the test, providing that the individual has not recently made a dramatic change to their iodine intake.

Testing Caveats

Urinary iodine assesses iodine intake, but it cannot assess whether iodine intake is sufficient to overcome iodine antagonists. If these antagonists stop iodine from getting into the thyroid gland, this does not necessarily stop it from being excreted in the urine.

Correcting Iodine Deficiency

Take a kelp supplement providing 2-300 micrograms per day. Maine Coast Sea Seasonings also sells shakers of kelp granules or of salt and spices with added seaweed that can be used in foods to ensure adequate iodine. Also, avoid goitrogens and other iodine antagonists.

Correcting Iodine Excess

If adverse effects on thyroid health accompany the use of high-dose iodine, the main nutritional strategy is to remove the source of iodine. Since the thyroid gland has the highest antioxidant needs in the body, optimizing the nutrients in the antioxidant section can be used to augment this strategy.

Electrolytes: Sodium, Potassium, and Chloride

An electrolyte is a substance that dissolves into ions in a solvent, enabling the conduction of electricity in the presence of an electrode. In human physiology, the major electrolytes are sodium, potassium, calcium, magnesium, chloride, phosphate, and bicarbonate. Bicarbonate is produced endogenously and is not an essential nutrient. Sodium, potassium, and chloride are the three essential minerals whose primary purpose is to serve as electrolytes.

Signs, Symptoms, and Risk Factors for Electrolyte Imbalances

Signs and Symptoms of Sodium and Chloride Deficiency

• Insulin resistance and elevated total cholesterol, LDL cholesterol, and triglycerides.
• Overactivation of the sympathetic nervous system and increased vulnerability to developing anxiety, dehydration and weakness, and poor intestinal absorption of many nutrients.
• The nutrients most likely to be affected are glucose, vitamin C, biotin, pantothenic acid, phosphorus, magnesium, and iodine. Calcium, niacin, and thiamin could also be affected.
• Chloride is required for the secretion of stomach acid (which is hydrochloric acid, made from hydrogen and chloride) and low chloride intakes presumably compromise digestion by causing hypochloridia (low stomach acid).
• Hyponatremia refers to low blood levels of sodium and should be seen as distinct from inadequate dietary sodium. Signs and symptoms include nausea, vomiting, headache, confusion, weakness and fatigue, cramping, muscle spasms, ataxia (loss of full control over body movements) restlessness, irritability, and in extreme cases seizures or coma.
• Hypochloremia refers to low blood levels of chloride. It is far rarer than hyponatremia and very rarely occurs to a clinically important extent on its own. It causes metabolic alkalosis, especially if produced from loss of stomach acid during extended vomiting. This can mimic the symptoms of hypocalcemia by decreasing the concentration of ionized calcium in the blood and can cause hypokalemia by driving potassium from the serum into cells. Possible signs and symptoms of hypocalcemia and hypokalemia include muscle spasms, twitching, tremors, cardiac arrhythmia, palpitations, bradycardia (slow heart rate), and confusion. In severe cases seizures, coma, and death could result but this has never been documented from isolated hypochloremia. Isolated chloride deficiency has only been produced from errors in the production of infant formula, where it produced growth failure, irritability, anorexia, gastrointestinal distress, and weakness, and in some cases metabolic alkalosis and hypokalemia. None of the infants died and the only sign that persisted after correction of the diet was delayed speech development and language skills.

Risk Factors for Sodium and Chloride Deficiency

• Sodium and chloride are also found in fresh foods in roughly equal proportions, although meat, fish, and eggs are somewhat richer in sodium, while nuts, vegetables, fruits, and grains are somewhat richer in chloride. A mix of natural foods that is diversified among plant and animal foods and among land and sea foods may provide sufficient sodium and chloride for many individuals, but it is also possible that chronic stress increases the need for salt beyond what natural, unprocessed foods can provide.
• The amount of salt recommended as sufficient for adults by the Institute of Medicine translates to two thirds of a teaspoon of regular table salt per day. 
• Unless you suffer from high blood pressure or a high risk of kidney stones or osteoporosis you should be liberal with salt and salt your food to taste, while also trying to eat a potassium-rich diet for balance.
• All electrolytes, especially sodium, chloride, and potassium, are lost in vomit, diarrhea, sweat, and urine. Common causes of fluid loss are foodborne illnesses, gastrointestinal infections, diuretics, diabetes, sauna use, and intense physical activity. Persistent vomiting will disproportionately cause alkalosis and loss of chloride because of the expulsion of stomach acid. Untrained individuals will lose large amounts of sodium when engaging in exercise that causes intense sweating. As individuals train, especially in hyperthermic conditions, they adapt by excreting less sodium into sweat.
• Mixing some electrolytes into water as a workout fuel, such as 1/16th teaspoon of salt and the juice of one quarter lemon per bottle of water, and consuming a diet that is salted to taste, should protect against this.

Signs and Symptoms of Excess Sodium and Chloride

A high salt-to-potassium ratio increases blood pressure and may also increase extracellular fluid in general, contributing to edema (swelling). It also contributes to a chronic acid burden, which lowers bone mineral density and increases the risk of osteopenia, osteoporosis, and kidney stones.

Hypernatremia is sometimes caused by a defect in the sense of thirst. Weakness, nausea, and loss of appetite are other early symptoms. In severe cases, it may lead to cerebral edema and shrinkage of brain cell volume, muscle twitching or spasming, confusion, seizures, coma, and death.

Risk Factors for Excess Sodium and Chloride

The Institute of Medicine set the tolerable upper intake limit at one teaspoon of salt as well, though acknowledging that increased sweating may increase needs. The value of salt restriction is hotly contested in the scientific literature, however, and both known physiology and clinical evidence suggest that consuming adequate potassium is far more important than restricting salt for blood pressure.

Signs and Symptoms of Potassium Deficiency

• Inadequate potassium elevates the salt-to-potassium ratio. A high ratio contributes to high blood pressure, edema (swelling), and chronic acid burden (leading to increased risk of osteopenia, osteoporosis, and kidney stones). Potassium stimulates insulin, and it is plausible to suggest a high-carbohydrate meal would destabilize blood sugar more when it is also l ow in potassium.
• Low-potassium diets can contribute to hypokalemia, but are rarely the cause all on their own. Hypokalemia leads to a slower heart rate (bradycardia); cardiac arrhythmia or palpitations; reduced intestinal motility (which could lead to constipation and theoretically to small intestinal bacterial overgrowth, SIBO); muscle spasms and twitches; lower levels of insulin secretion, leading to hyperglycemia; low blood pressure (hypotension) and in severe cases, hypokalemia can result in skeletal muscle necrosis (cell death), rhabdomyolysis (damaged muscles spilling their contents into the blood), and life-threatening changes in heart function. 

Risk Factors for Potassium Deficiency

• The primary dietary risk factors are a low intake of fruits and vegetables, high intake of added fats and oils and of refined carbohydrates, and discarding the juices of meat and the cooking water used for plant foods. Additionally, foods prepared in brines reduce the potassium content of the diet because brines exchange sodium for potassium.
• Refeeding syndrome is a major cause of hypokalemia. During starvation or chronic malnutrition (as might occur in alcoholism, eating disorders, or illnesses that impact food intake), catabolism releases intracellular potassium stores and causes loss of potassium from the body. During refeeding, insulin brings potassium into cells, lowering its concentration in the serum, causing hypokalemia. The high rate of cellular repair and need to rebuild intracellular potassium stores aggravates the hypokalemia. Low levels of magnesium (hypomagnesemia) and phosphorus (hypophosphatemia) are also found in refeeding syndrome.
• Diarrhea and vomiting both cause direct loss of potassium. Vomiting also causes alkalosis from the loss of stomach acid, and alkalosis drives potassium into cells and increases its excretion in the urine, both of which lower its concentration in the serum. During illnesses that cause vomiting and diarrhea, dietary potassium is usually low, making it difficult to replenish serum levels. 

Signs and Symptoms of Excess Potassium

Supplemental potassium on an empty stomach could stimulate insulin secretion and lower blood sugar, contributing to hypoglycemia. Symptoms of hypoglycemia include hunger, fatigue, shakiness, irritability, anxiety, sweating, and in extreme cases confusion, visual disturbances, seizures, and loss of consciousness. Extreme hypoglycemia causing seizures has not been documented from potassium supplementation, however.

Hyperkalemia can cause fast heart rate (tachycardia) and cardiac arrhythmia, and palpitations. Confusion, paresthesia (tingling, numbness, or a feeling of something crawling on the skin) may also occur. In severe cases, hyperkalemia causes weakness, paralysis, and cardiac arrest, and can be fatal.

Risk Factors for Excess Potassium

• Potassium supplements are generally safe for healthy adults. Potassium chloride supplements have caused gastrointestinal distress when provided in a wax matrix or microencapsulated gelatin capsule, but not as a powder mixed with water. Supplemental potassium has been used in amounts as high as 15.6 grams per day in healthy adults without causing any instances of hyperkalemia.
• Dietary potassium may contribute to hyperkalemia in diabetes or insulin resistance, where the insulin response to potassium is inadequate. It may also contribute to hyperkalemia in cases of drugs or medical conditions that impair the excretion of potassium into the urine, which include Addison’s disease, a selective deficiency in adrenal production of aldosterone, and therapy with heparin, ACE inhibitors, beta-blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs). In these cases, supplemental potassium is more dangerous than food potassium because it raises blood levels of potassium faster. Acidosis, cellular damage, low ATP production from hypothyroidism or diabetes, and digitalis overdose can all shift potassium from the cells into the blood, causing hyperkalemia.
• Potassium supplements can be taken in multiple servings, and bulk powders can make it easy to do so. 15 grams per day have been used safely in trials, potassium-rich foods may provide 5 to 15 grams per day, and a healthy adult has the capacity to excrete up to 33 grams of potassium per day. On an empty stomach, high-dose potassium supplements may cause hypoglycemia. Taken with a meal and spread evenly through the day, however, they are safe for healthy individuals. Nevertheless, the conditions that impair potassium excretion are numerous, and some of them — insulin resistance and NSAID usage — are common. If you are using potassium supplements that provide more than a gram per day spread evenly across meals, he recommends consulting your physician to ensure healthy insulin secretion and sensitivity, healthy kidney function, and that you are not taking drugs that contraindicate the use of potassium supplements.

Testing for Electrolytes

Electrolytes being in the normal range does not rule out nutritional imbalances. Rather, dietary analysis, blood pressure, and edema should be considered the primary nutritional markers:

• Dietary Analysis: Intake of potassium should be higher than 4.7 grams per day and may safely reach double or triple this. Intake of sodium should be at least 1.5 grams per day. Intake of sodium above 2.3 grams per day may pose a risk when potassium is deficient, but is unlikely to pose a risk when potassium is adequate. Chloride follows sodium closely enough that it can be ignored.
• Blood Pressure: Repeated measurements showing blood pressure higher than 130/80 suggest the need for dietary strategies to reduce the salt-to-potassium ratio.

Testing Caveats

• Maintaining healthy blood pressure also requires maintaining healthy body composition, a good physical activity routine, avoiding excess alcohol, proper stress management, and adequate intake of other minerals, such as calcium and magnesium. Blood pressure elevations are not specific indications of the salt-to-potassium ratio and are not necessarily related to diet or lifestyle.
• Edema may have many other causes, most notably hypothyroidism (especially when affecting the face) or diabetes (especially when affecting the lower legs).
• Toxic levels of barium and thallium may mimic potassium deficiency.

Correcting Electrolyte Imbalances

Suggestions for Increasing Salt

For individuals with high blood pressure, a high risk of kidney stones (having had a kidney stone in the past, or signs of high risk discovered on a urinalysis, such as a high presence of calcium oxalate crystals), or a high risk of osteoporosis (postmenopausal women, anyone with low bone mineral density), he recommends following the recommendations to construct a potassium-rich diet. If blood pressure is normal, salt your food to taste as you’re unlikely to salt your food beyond your actual needs.

Suggestions for Increasing Potassium and Decreasing Salt

• In the case of high blood pressure or edema, the first nutritional effort should be to raise the dietary potassium. This interpretation is especially strong if dietary potassium is under 4.7 grams, but could be plausible at almost any level. Salt should be restricted gradually if raising dietary potassium does not work.
• Three options for constructing a potassium-rich diet are provided below: 1) a diet very rich in fruits and vegetables, 2) a low-fat diet that is low in grains and free of refined carbohydrates, and 3) a low-carbohydrate, high-fat diet that emphasizes vegetables with high ratios of potassium to net carbs.

Diets Rich in Fruits and Vegetables

Fruits generally provide 100-500 mg of potassium per 100 gram serving, and vegetables generally provide 200-1000 mg per 100 gram serving. Try to consume them raw or to consume the cooking water and juices to prevent wasting potassium.

Diets Low in Fat, Moderate in Grains, and Free of Refined Carbohydrates

• Reducing the fat content of the diet, moderating grains, and eliminating refined carbohydrates can allow the broad selection of alternative foods to fulfill the potassium requirement.
• 300 Calories worth of beans or potatoes provides close to 1.5 grams of potassium each, which is about quadruple that provided by whole wheat. 300 Calories of fat-free milk provides 1.4 grams of potassium, whereas the same caloric load of whole milk provides only 715 milligrams, about half as much. 300 Calories of sirloin steak with all the fat trimmed off provides 700 mg of potassium. By contrast, beef tallow does not contain any potassium. In a single large egg, there are 67 mg of potassium, 80% of which is in the white. For each 300 Calories, egg whites provide over 1 gram of potassium, while whole eggs provide only 281 milligrams and egg yolks provide a dismal 103 milligrams.

Low-Carbohydrate, High-Fat Diets

The following is a list of mg potassium per gram net carb (total carbohydrate minus fiber) in some of the best choices for vegetables: watercress, 431; spinach, 399; purslane, 329; mustard greens, 221; bamboo shoots, 178; arugula, 176; red leaf lettuce, 170; celery, 144; white mushrooms, 138; green leaf lettuce, 129; zucchini, 119; Chinese cabbage, 119; asparagus, 106; common cabbage, 79; iceberg lettuce, 71; tomatoes, 66. If one were to eat 100 grams of each of these vegetables per day, this would yield 4.9 grams of potassium and less than 32 grams of net carbs. The lean portion of the protein would bring the total to anywhere from 5.6 to 6.9 grams of potassium and the remainder of the diet could be fat.

Summary of the Dietary Options

He does not recommend high-fat ketogenic diets unless there is a medical purpose. He does not recommend using egg whites without the yolks unless one also supplements with biotin, monitors biotin status, and ensures an adequate intake of choline through other foods. He does not recommend foods that have their natural fats removed, including yolk-free egg whites, unless one is using them temporarily to meet a body composition goal or one has demonstrated difficulties digesting or metabolizing fats. 

In Summary

• Consuming foods raw or consuming the cooking water and juices always helps improve potassium intake.
• Avoiding refined carbohydrates always helps improve potassium intake.
• The lean portions of meat, eggs, and dairy always make a significant contribution to potassium intake.
• If you are focusing on cutting calories, a high volume of fruits and especially vegetables are the best way to improve potassium intake.
• If you have difficulty eating high volumes of low-calorie foods due to time constraints, digestive difficulties, or difficulty meeting caloric requirements, then a diet with moderate amounts of whole grains and larger amounts of potatoes and legumes is the best way to improve potassium intake.
• If you have trouble digesting or metabolizing fats, or need to temporarily reduce fat to extreme levels for body composition goals, then consuming fat-free dairy products, lean cuts of meat, and egg whites supplemented with biotin and alternative sources of choline is the best way to improve potassium intake.
• If you are eating a low-carbohydrate, high-fat diet, selecting the foods with the highest potassium-to-net carb ratios and eating them in large volumes is the best way to improve potassium intake.
• Depending on your goals, any of the above strategies can be mixed and matched.

Potassium Supplements

If all of the above strategies prove infeasible or unsustainable, you can obtain a portion of the potassium requirement from supplements. In such cases, he recommends mixing potassium citrate powder in water for the least risk of gastrointestinal distress. Potassium should always be taken with a full meal and the dose should be spread out across the day. Potassium supplements should not be used by anyone with diabetes, insulin resistance, impaired kidney function, or who is using ACE inhibitors, beta-blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs), unless prescribed by a physician.

Vomiting and Diarrhea

• In cases of moderate, self-limiting illness, it makes sense to replete electrolytes once fluids can be kept down. ¼ teaspoon each of table salt, baking soda, and potassium bicarbonate, along with some juice containing natural sugars to balance the potassium, will replace the major electrolytes lost. If the fluid loss was overwhelmingly from vomiting rather than diarrhea, doubling the table salt and taking out the baking soda will help replete the lost chloride better, and apple cider vinegar can help replete the lost acid.
• Extended fluid loss may cause the loss of other electrolytes, such as calcium, magnesium, and phosphorus. Loss of bile in vomit or diarrhea can deplete zinc and copper, and thiamin deficiency is also found in persistent vomiting.

Altered Electrolyte Concentrations

Altered electrolyte concentrations almost always indicate deeper problems that are not nutritional in nature.

Other Minerals

Boron appears to support executive brain function, to improve testosterone in men, and to protect against prostate cancer in men and lung cancer and cervical dysplasia in women.

Chromium appears to support glucose tolerance, insulin sensitivity, and to raise HDL-cholesterol.

Evidence for beneficial effects of other trace elements is scant:

• Strontium has shown benefits to bone mineral density in osteoporotic women when supplemented as 2 grams per day of strontium ranelate, which provides about 340 milligrams of elemental strontium. There is no evidence on which to consider this a nutritional effect rather than a pharmacological effect, however, and it is not clear that strontium has an essential role in human biology.
• There are observational studies associating low-dose lithium in drinking water with benefits such as lower risks of dementia, homicide, and suicide, but also studies associating it with harms, such as impaired calcium metabolism. 
• Silicon might support bone health and nickel might support reproductive function and liver health, but the evidence for this is limited to animal experiments and there is no evidence supporting these roles in humans. 
• Vanadium supplementation has improved insulin sensitivity in people with diabetes, but it is not clear that it has any role as an essential nutrient and animal experiments suggest that it has a very narrow therapeutic window, causing harms at doses that are not much higher than the doses that cause benefits.
• While there is some evidence that arsenic deprivation in animals can produce deficiency signs, there is no evidence of this in humans, no known essential roles of arsenic in animal biology, and clear evidence of its toxicity.

Food selection is an unlikely cause of inadequate boron, but low plant food intake could contribute. Low accumulation in the food chain can be caused by low soil boron, low soil organic matter, or soil pH below 5.0 or above 6.5. Taking boron supplements does not eliminate the harms of eating low-boron foods, because low boron uptake into plant tissues also compromises their content of chlorophyll and fat-soluble vitamins. Nevertheless, supplemental boron at 3 milligrams per day has shown some promise for increasing testosterone levels in men.

Chromium is found in the highest concentrations in whole grains, unrefined sugars, and brewer’s yeast (but not other edible yeasts), and in lesser amounts in fruits and vegetables. Needs for chromium are probably proportional to carbohydrate intake. The refining of grains and sugars removes chromium and this may contribute to poor glucose tolerance on diets high in refined carbohydrates. It may be that choosing unrefined grains and unrefined sugars over their refined counterparts is adequate. Nevertheless, soil chromium varies and this influences the chromium stores of plants. Supplementation of 200 micrograms per day of chromium has shown some promise for improving glucose metabolism.

Zinc promotes the production of the endogenous metal chelator, metallothionein, even when provided over and above the levels needed to support all other aspects of zinc nutritional status. If hair mineral analysis shows elevated levels of heavy metals, zinc supplementation, along with careful evaluation of the status of zinc, copper, and the other positively charged minerals, may help promote detoxification. Arsenic is specifically detoxified using methylation, and if arsenic is elevated, nutritional support for the methylation process may promote its clearance. Barium is most effectively detoxified with sulfate, so support for sulfur amino acids, vitamin B6, and molybdenum may help promote its clearance.

Essential Fatty Acids

There are two fatty acids for which the evidence of essential roles in animals and humans is strong: arachidonic acid (AA) and docosahexaenoic acid (DHA). A third fatty acid, eicosapentaenoic acid (EPA), has demonstrated benefits at high doses for lowering extremely high triglyceride levels, but this is a pharmacological action, not a nutritional one. There is some evidence suggesting it improves mental health outcomes more effectively than DHA. Nevertheless, EPA can interfere with the function of AA and there is no clear evidence that it has essential roles in human nutrition.

Other fatty acids, such as linoleic acid (LA) and alpha-linolenic acid (ALA) are defined conventionally as “essential fatty acids” because we cannot synthesize them. By contrast, we synthesize AA from LA, and we synthesize EPA and DHA from ALA, so AA, EPA, and DHA are not considered essential. Nevertheless, there is no clear evidence that we require LA or ALA to be present in our bodies to support our health, and there is clear evidence that we require AA and DHA.

Signs and Symptoms of Arachidonic Acid Deficiency

The only well-established deficiency sign for arachidonic acid in humans is eczema. Mechanistic evidence suggests that arachidonic acid deficiency also increases the risk of food intolerances, infectious diseases, autoimmune disorders, and chronic, low-grade inflammation. Drugs that interfere with AA metabolism cause gastrointestinal distress. The blood thinning effect of fish oil results from EPA interfering with AA metabolism.

Risk Factors for AA Deficiency

AA is abundant in egg yolks and liver. It can be made from LA, which is found in small amounts in animal products and olive oil, and in larger amounts in vegetable oils, but the conversion depends on genetics, insulin sensitivity, protein, calories, calcium, zinc, biotin, and vitamin B6. Thus, a diet that lacks egg yolks and liver does not necessarily lead to AA deficiency but increases its risk due to the many difficulties synthesizing AA from LA. Oxidative stress and chronic inflammation deplete AA. Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere AA metabolism and may contribute to deficiency signs regardless of AA levels. High-dose EPA, as would be found in high-dose fish oil or used pharmacologically to lower triglycerides, causes a similar effect as NSAIDs. AA needs are highest during childhood growth, bodybuilding, pregnancy, lactation, and recovery from injury.

Signs and Symptoms of DHA Deficiency

DHA deficiency predisposes to low-grade, chronic inflammation, poor visual acuity, slower mental processing, learning deficits, and possibly Alzheimer’s disease and psychiatric conditions such as depression, anxiety, and attention deficit and hyperactivity disorder (ADHD).

Risk Factors for DHA Deficiency

DHA is found in large amounts in seafoods and in smaller amounts in egg yolks when chickens are raised on pasture. A diet low in seafood and based on grain-fed animal products is the major risk factor for low DHA levels. DHA can be made from EPA in fish oil and from ALA in plant oils but the conversion depends on genetics, insulin sensitivity, protein, calories, calcium, zinc, biotin, and vitamin B6. Oxidative stress and chronic inflammation deplete DHA. High intakes of LA from vegetable oils aggravate the effect of low DHA intakes by replacing DHA in tissues with a different fatty acid, docosapentaenoic acid (DPA).

Testing for Essential Fatty Acids

The Genova ION Profile + 40 amino acids and NutrEval offer comprehensive fatty acid analyses, but the p referred test is the Omega-3 Index Basic because it is measured in red blood cells rather than plasma, where the data will more accurately reflect long-term status.

Testing Caveats

Low essential fatty acids may indicate oxidative stress. If this is the case, optimizing the antioxidant nutrients should take precedence over repleting the fatty acids. If AA, and perhaps DHA, are specifically low, and high-sensitivity C-reactive protein is high, inflammation may be driving the utilization of these fatty acids. In this case the source of inflammation deserves independent attention, but dietary strategies to replete the fatty acids still deserve central importance because deficiencies of AA and DHA can be the cause of chronic inflammation.

Correcting Essential Fatty Acid Imbalances

• If AA is low, increase AA intake by consuming one 100 gram serving of liver per week and up to 3-4 whole eggs or egg yolks per day. If this is not feasible, an arachidonic acid supplement can be used at 250 milligrams per day with a meal.
• If the AA/EPA ratio is low as a result of high or high-normal EPA, first reduce or remove EPA supplements. If the EPA is needed for pharmacological management of high triglycerides, or if it is proving useful for management of a psychiatric condition, then work with a health care practitioner to find the minimum effective dose, and utilizing the strategies described above for boosting AA intake to see if the ratio can be normalized.
• He does not consider a high AA/EPA ratio worth acting on.
• If DHA is low, increase the intake from natural foods by using 3-4 whole eggs or egg yolks per day from chickens raised on pasture, consuming 2-3 100-gram servings of fatty fish per week, or using ½ teaspoon of cod liver oil per day. There is some evidence supporting the use of krill oil to improve the brain content of DHA more rapidly, which may be helpful for psychiatric conditions.

Index of Signs and Symptoms

This section is for finding associations and speculation for cause, effect, and symptom management. Use these suggestions to research deeper and then speak with a medical professional before jumping to conclusions and stating certainty.

• Abdominal pain: iron overload, iodine deficiency, acute iodine poisoning
• Acid-base imbalance: zinc deficiency, electrolyte imbalances
• Acne: zinc deficiency, vitamin A deficiency, rare reactions to iodine
• Adrenal hormones, resistance to: zinc deficiency
• Adrenaline, low: copper deficiency, vitamin C deficiency
• Allergies: risk is increased by vitamin A deficiency and deficiencies or excesses of vitamin D and calcium; may occur in response to iodine; allergy-like reactions to sulfites that result from molybdenum deficiency
• Alopecia: deficiencies of riboflavin, biotin, zinc, iron, or iodine; iron overload, selenium toxicity or vitamin A toxicity
• Alzheimer’s disease: DHA deficiency, copper toxicity, or iron overload
• Androgens in women, high: deficiencies of vitamin D and calcium or vitamin K
• Anemia, megaloblastic, macrocytic: deficiencies of folate, B12, or copper
• Anemia, microcytic: deficiencies of iron, copper or riboflavin
• Anemia, normocytic, normochromic: Riboflavin deficiency, vitamin B6 deficiency
• Anemia, sideroblastic: “”
• Anxiety: deficiency of methylation, vitamin B6, molybdenum, DHA, or salt; acute hypoglycemia in response to potassium on an empty stomach
• Arsenic, slow rate of detoxification: deficient methylation
• Asthma: deficiencies of glutathione or vitamin A; deficiencies or excesses of calcium and vitamin D; allergy-like reactions to sulfites that result from molybdenum deficiency
• Ataxia (loss of full control over body movements): deficiencies of magnesium, thiamin, biotin, vitamin B12, or vitamin E; hyponatremia; vitamin B6 toxicity; Friedrich’s ataxia, a genetic disorder in iron distribution
• Atherosclerosis: See cardiovascular disease
• Attention deficit: See distractibility.
• Autoimmune disorders: deficiencies of vitamin A, vitamin D and calcium, or arachidonic acid, excess EPA from fish oil
• Beard hair, reddened: manganese deficiency
• Bitot’s spots: vitamin A deficiency
• Bleeding disorders: Deficiencies of vitamin C, vitamin K, or arachidonic acid, excess vitamin E or EPA from fish oil
• Blisters: zinc deficiency, flushing reaction to niacin
• Blood pressure, high (hypertension): a high salt-to-potassium ratio, deficiencies of vitamin D and calcium, magnesium or riboflavin
• Blood pressure, low (hypotension): Excess choline or magnesium; orthostatic hypotension from vitamin B12 deficiency; allergy-like reactions to sulfites that result from molybdenum deficiency; hyponatremia; hypokalemia
• Blood sugar problems: deficiency or excess of vitamin K; oxidative stress and imbalances of antioxidant nutrients, especially zinc; chronic potassium deficiency or high-carbohydrate, low-potassium meals; acute hypoglycemia in response to potassium on an empty stomach; phosphorus deficiency; see also diabetes.
• Bone mineral content, low: deficiencies of manganese, vitamin C, glycine, calcium and vitamin D, and vitamin K; excess phosphorus and vitamin A; a high salt-to-potassium ratio
• Bone mineral content, high: Excess calcium
• Bone pain: In rickets and osteomalacia, deficient vitamin D, calcium, phosphorus, or magnesium
• Bradycardia (slow heart rate): hypercalcemia, hypermagnesemia, hypokalemia, hypochloremia,
• Brain fog: hypothyroidism due to iodine or iron deficiency (see also selenium); anemia due to deficiencies of iron, copper, B 6, B 12, or folate; methylation imbalances
• Breast, fibrocystic disease: Iodine deficiency
• Bruising: deficiencies of vitamin C or vitamin K
• Burning in the feet: pantothenic acid deficiency
• Cancer: Oxidative stress, deficient or excess calcium and vitamin D, deficient or excess methylation, selenium deficiency. vitamin K deficiency; niacin deficiency
• Cardiac arrhythmia or palpitations: hypercalcemia, hypochloremia, hypokalemia and hyperkalemia, magnesium deficiency, anemia due to deficiencies of iron, copper, B6, B12, or folate; methylation imbalances
• Cardiovascular disease: atherosclerosis and heart disease risk: oxidative stress, deficient or excess calcium and vitamin D, excess phosphorus, and deficiencies of methylation, magnesium, molybdenum, vitamin B6, or manganese; enlarged heart and elevated cardiac output in thiamin deficiency; cardiac insufficiency in selenium deficiency; cardiac failure in iron overload
• Cataracts: riboflavin deficiency
• Cheilosis: deficiencies of riboflavin or vitamin B6
• Chest pain: iron overload
• Cholesterol, high: deficiency of copper or salt, iron overload
• Cholesterol, low: manganese deficiency
• Circadian rhythm, disrupted: vitamin A deficiency
• Confusion: deficiencies of thiamin or vitamin B6; the delirium of B 12 deficiency; hypocalcemia or hypercalcemia, hyponatremia or hypernatremia, acute hypoglycemia in response to potassium on an empty stomach
• Conjunctivitis: deficiencies of biotin or riboflavin; increased risk of eye infections more generally in vitamin A deficiency
• Constipation: iodine deficiency, hypokalemia
• Cramping: Hyponatremia, selenium poisoning, magnesium deficiency
• Dehydration: sodium and chloride deficiency
• Depression: deficiencies of niacin, vitamin B6, biotin, methylation, DHA; iron overload, hypercalcemia
• Dermatitis: deficiencies of riboflavin, niacin, biotin, manganese, arachidonic acid, or molybdenum
• Diabetes: oxidative stress, iron overload, selenium toxicity, niacin toxicity; as an autoimmune disease, type 1 diabetes risk may be increased by deficiencies of vitamin A, vitamin D, or arachidonic acid
• Diarrhea: deficiency of zinc or niacin, excess magnesium or vitamin C, allergy-like reactions to sulfites that result from molybdenum deficiency
• Distractibility: excess methylation
• Dizziness or lightheadedness: Niacin deficiency; anemia due to deficiencies of iron, copper, B6, B12, or folate; upon standing, due to autonomic dysfunction in B12 deficiency; iron overload, zinc toxicity
• Eclampsia: magnesium deficiency
• Eczema: See dermatitis.
• Edema: hypothyroidism from deficiencies of iodine, selenium, or iron; high salt-to-potassium ratio; edema of the oral cavity, deficiencies of riboflavin or vitamin B6; cerebral edema, hypernatremia
• Enamel loss: iron overload
• Encephalopathy: Niacin toxicity
• Excessive sweating: manganese deficiency, acute hypoglycemia in response to potassium on an empty stomach
• Exercise, poor performance or intolerance: deficient methylation; deficient riboflavin or niacin; deficient or excess vitamin K; autonomic dysfunction from vitamin B12 deficiency; shortness of breath on exertion due to vitamin C deficiency, or to anemia resulting from deficiencies of iron, copper, B 6, B 12, or folate
• Eyes, dry: vitamin A deficiency
• Fatigue and weakness: deficient methylation, deficient riboflavin, folate and B12 deficiency, hypochloremia, hyperkalemia, hypernatremia, iodine deficiency, iron deficiency and overload, magnesium deficiency, pantothenic acid deficiency, biotin deficiency, phosphorus deficiency, selenium toxicity, sodium and chloride deficiency
• Fatty liver disease: deficient methylation, oxidative stress
• Fertility and Sex Hormones: deficiencies of vitamin A, vitamin D and calcium, vitamin K, zinc, vitamin E, iodine, or arachidonic acid; iron deficiency and overload
• Fibrocystic breast disease: See breast, fibrocystic disease.
• Fingernails, white spots, streaks, brittle, falling out: selenium deficiency or toxicity
• Food intolerances: deficiencies of vitamin A or arachidonic acid
• Gait abnormalities (difficulty walking correctly): See ataxia.
• Glossitis: Deficiencies of riboflavin or vitamin B6.
• Goiter: deficient or excess iodine
• Graves’ disease: excess iodine
• Hair and nail growth, slow: manganese deficiency
• Hair loss: See alopecia.
• Hair, corkscrew-shaped: vitamin C deficiency
• Hands and feet, cold: hypothyroidism due to deficiencies of iron or iodine (see also selenium)
• Hashimoto’s thyroiditis: selenium deficiency or excess iodine
• Headache: deficiencies of magnesium or riboflavin; deficiency or toxicity of niacin; toxicities of vitamin A or manganese, hyponatremia, histamine intolerance from deficient methylation or copper
• Heart palpitations: See cardiac arrhythmia or palpitations.
• Heavy metal toxicity, vulnerability to: zinc deficiency
• Heart rate, slow: See bradycardia.
• Heart rate, fast: See tachycardia.
• Hepatitis: Niacin toxicity
• Hepatic cirrhosis: iron overload, selenium deficiency and toxicity
• Histamine intolerance: copper deficiency, deficient methylation
• Hives (urticaria): See itching (pruritis) and hives (urticaria)
• Homocysteine, elevated: deficiencies of methylation, vitamin B6, thiamin, or riboflavin, deficient or excess niacin; see methylation testing for a full explanation
• Hypochloridia (low stomach acid): deficient salt
• Hypoglycemia: See blood sugar problems.
• Hypothyroidism: deficiencies of iron or iodine (see also selenium)
• Immunity to infection, poor: Deficiencies of vitamin A, vitamin D and calcium, vitamin B6, zinc, selenium, iodine, or vitamin C; oxidative stress
• Impulsivity: Excess methylation
• Inflammation, chronic systemic: Deficiencies of arachidonic acid, DHA, vitamin A, vitamin D and calcium, and vitamin B6
• Insomnia and related sleep problems: Methylation imbalances; deficiencies of vitamin A, vitamin D and calcium, niacin, vitamin B5, vitamin B6.
• Insulin: See blood sugar problems and diabetes.
• Itching (pruritis) and hives (urticaria): flushing reactions to niacin, rare reactions to iodine, allergy-like reactions to sulfites that result from molybdenum deficiency; histamine intolerance from deficient copper or methylation
• IQ, low: deficiencies of iron or iodine during childhood
• Irritability and restlessness: Deficiencies of vitamin B5 or vitamin B6, selenium poisoning, hypochloremia, hyponatremia, acute hypoglycemia in response to potassium on an empty stomach
• Jaundice: Niacin toxicity
• Joint pain: iron overload
• Kidney stones: a high salt-to-potassium ratio; deficiencies of vitamin A, vitamin B6, or magnesium; both deficiencies and excesses of calcium; excess vitamin D and phosphorus; excess collagen supplementation and vitamin C
• Lazy eye: Niacin toxicity
• Lethargy: See fatigue and weakness.
• Leukopenia: copper deficiency
• Lightheadedness: See dizziness and lightheadedness
• Light therapy, inability to benefit from: vitamin A deficiency
• Lips, lesions on the outside of (cheilosis): deficiencies of riboflavin or vitamin B6
• Liver failure: glutathione depletion, niacin toxicity
• Low-Fat and Low-Carb: Improved health on low-fat diets, deficiencies of riboflavin or pantothenic acid; improved health on low-carbohydrate diets, thiamin deficiency
• Malabsorption: from an autoimmune condition, deficient vitamin A or arachidonic acid; generalized, from pellagra, niacin deficiency; of many water-soluble nutrients with no intestinal damage, deficient salt
• Menstrual problems: See fertility and sex hormones.
• Mental and cognitive health: imbalances of methylation and deficiencies of related nutrients, electrolyte imbalances, hypocalcemia and hypercalcemia, deficiencies of thiamin, niacin, and vitamin B6
• Migraine: riboflavin deficiency
• Miliaria crystallina (a form of dermatitis resulting from blocked sweat glands that appear as tiny clear bubbles on the skin): manganese deficiency
• Mouth, lesions in and around: deficiencies of riboflavin or vitamin B6 in cases of cheilosis (lips), angular stomatitis (corners of mouth), glossitis (inflamed tongue), hyperemia and edema of the oral cavity (red, swollen, and bloody inside the mouth); biotin for dermatitis around the mouth; vitamin C deficiency for bleeding gums and other bleeding inside the mouth
• Muscle spasms and twitching: Magnesium deficiency, hypocalcemia, hypokalemia, hyponatremia and hypernatremia
• Nails: See fingernails, white spots, streaks, brittle, falling out.
• Nausea: vitamin A toxicity, niacin toxicity too much zinc on an empty stomach, excess copper in drinking water, hyponatremia and hypernatremia, poisoning with iodine or selenium
• Neural tube birth defects: deficient methylation
• Neutropenia: copper deficiency
• Night vision, poor: vitamin A deficiency
• Numbness: pantothenic acid deficiency
• Nutrient imbalances, vulnerability to: selenium deficiency
• Obsessive compulsive disorder: deficient methylation
• Optic neuritis: deficiency of thiamin or vitamin B12
• Osteomalacia: deficiencies of calcium, phosphorus, vitamin D, or magnesium
• Osteopenia: See bone mineral content, low.
• Osteopetrosis: See bone mineral content, high.
• Osteoporosis: See bone mineral content, low.
• Oxytocin, low: vitamin C deficiency
• Paleness: anemia due to deficiencies of iron, copper, B6, B12, or folate
• Palpitations: See cardiac arrhythmia or palpitations.
• Paralysis: thiamin deficiency or hyperkalemia
• Paresthesia (tingling, numbness, or a feeling of something crawling on the skin): biotin deficiency, vitamin B12 deficiency, hyperkalemia
• Parkinson-like symptoms: manganese toxicity
• Parkinson’s disease: iron overload
• Peripheral neuropathy: deficiencies of thiamin, riboflavin, and vitamin E; toxicity of selenium and vitamin B6
• Preeclampsia: magnesium deficiency
• Pregnancy, morning sickness: molybdenum deficiency, vitamin B6 deficiency
• Pruritis: See itching (pruritis) and hives (urticaria).
• Psychological conditioning, difficulty breaking free from: Excess methylation
• Puberty, delayed: deficiencies of vitamin A, iron, and zinc
• Psychosis: deficiencies of thiamin, niacin, and B12, hypocalcemia and hypercalcemia, hyponatremia
• Pustules: zinc deficiency
• Respiratory congestion: deficient glutathione
• Restlessness: See irritability and restlessness
• Retinopathy (damage to the eye’s retina): vitamin E deficiency
• Rhabdomyolysis (damaged muscles spilling their contents into the blood): hypokalemia
• Rheumatoid arthritis: pain pantothenic acid deficiency
• Rickets: deficiencies of calcium, phosphorus, vitamin D, or magnesium
• Scurvy: vitamin C deficiency
• Seizures: deficiencies of vitamin B1 or B6, hypocalcemia, hyponatremia and hypernatremia, hypochloremia, thiamin deficiency, hypoglycemia
• Sense of position and vibration, lost: vitamin B12 deficiency
• Sensitivity to cold in general, increased: Hypothyroidism from deficiencies of iron or iodine (see also selenium)
• Serotonin, high: copper deficiency
• Shortness of breath on exertion: vitamin C deficiency, or anemia due to deficiencies of iron, copper, B6, B12, or folate
• Skin aging, faster: Deficient vitamin C, glycine, or niacin; oxidative stress
• Skin and hair, hypopigmentation: copper deficiency
• Skin, dermatitis: See dermatitis.
• Skin, itching or hives: See itching (pruritis) and hives (urticaria).
• Skin, dry patches: zinc deficiency
• Skin, hyperpigmentation: iron overload
• Skin, scaling: vitamin A toxicity, arachidonic acid deficiency
• Sleeping problems: See insomnia and circadian rhythm
• Small intestinal bacterial overgrowth (SIBO): Hypothyroidism from deficiencies of iodine or iron (see also selenium), hypokalemia
• Soft tissue calcification: Deficiencies of magnesium, vitamin A, and vitamin K, deficient or excess calcium, excess phosphorus or vitamin D
• Sore throat: zinc deficiency
• Spasticity (constant muscle contraction): vitamin B12 deficiency
• Spasms: See muscle spasms and twitching.
• Substance abuse: Excess methylation
• Swelling in the face: Hypothyroidism from iron or iodine deficiency (see also selenium)
• Tachycardia (fast heart rate): thiamin deficiency, hypermagnesemia, hyperkalemia
• Tetany: Deficiency of calcium and vitamin D, or magnesium; excess phosphorus
• Thirst high: salt-to-potassium ratio, hypernatremia
• Thyroid hormone, resistance to: zinc deficiency
• Toxins, vulnerability to: Vulnerability to tissue damage from a wide variety of toxins, selenium deficiency; vulnerability to toxic metal accumulation, zinc deficiency
• Tongue, inflammation: See glossitis.
• Tremors: hypocalcemia
• Triglycerides, elevated: deficient salt
• Twitching: See muscle spasms and twitching.
• Urticaria: See itching (pruritis) and hives (urticaria).
• Visual disturbances: vitamin B12 deficiency, vitamin A toxicity, niacin, toxicity
• Wound healing, impaired: zinc deficiency