Release Date: March 15, 2008
Expiration Date: March 15, 2009 
TARGET AUDIENCE
Internists, family practitioners, geriatricians, cardiologists, and others who care for older patients. 
MEDIUM USED & METHOD OF PARTICIPATION
Read the article, complete the evaluation and post-test, and return both to: NACCME via fax at (610) 560-0502. You will receive your certificate in 6-8 weeks. If you would like to print your certificate immediately, go to http://cme.naccme.com, register as a NACCME user and access the activity test and evaluation online.
 
SUCCESSFUL COMPLETION
Successful completion entails participants obtaining a score of at least 70% on the post-test. A certificate of completion will be mailed to the address listed on your post-test/evaluation form within 6-8 weeks of receipt of the documents.
 
ACCREDITATION
MD/DO:
This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
 
SPONSOR
This activity is sponsored by The North American Center for Continuing Medical Education.
 
DISCLOSURES
All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.
 
Drs. Thomas and Gambert have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of their article.

Reviewer: Dr. Christmas has disclosed no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article.

Editor: M. Edwards has disclosed no significant financial relationship. 

All NACCME employees involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.
 
CONFLICT OF INTEREST RESOLUTION-CONTENT VALIDATION
In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the Advisory Board in December, 2007 for clinical content validity, to ensure that the activity’s materials are fair, balanced, and free of bias toward the commercial supporters of the activity, and that activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community
 
 
 
Learning Objectives
Upon completion of this educational activity, participants should be able to:
1. Discuss the most commonly ingested minerals, trace elements, and fat-soluble vitamins in the United States.
2. Identify the dietary sources of minerals, trace elements, and fat-soluble vitamins.
3. Describe the nutritional importance of the most commonly used supplements.
4. Explain the main hazardous side effects of the most commonly used over-the-counter supplements.

This is Part I of a two-part article. Part II will examine water-soluble vitamins, essential fatty acids, and herbs.

In an attempt to live healthier and longer lives, millions of Americans are increasingly purchasing organic foods and “natural” supplements, vitamins, minerals, and herbs from health food stores. While under certain circumstances these products may have beneficial effects, in many cases there is little evidence to support their use. In fact, they may have significant health risks associated with their use—and may even be life-threatening. Not everything bought in a health food store is “healthful,” as illustrated by the following case.

Mrs. S was an 86-year-old woman who had immigrated to America from Russia 60 years earlier. Throughout her life, she practiced home remedies and believed in living a “natural life.” She and her husband enjoyed reading popular health food magazines, and they found a local health food store that sold them a variety of vitamins, minerals, and other supplements that they had read about that week. They had two shelves in their kitchen: one with the products and the other with cross-referenced articles that listed claimed “benefits” for each item stored on their other shelf.

It was a cold, snowy night when the telephone rang, asking me (SRG) to make a house call to see Mrs. S. That morning, she had awoken with a headache, and by afternoon she was “not her usual self,” according to her family. I remember ringing the doorbell and the front door opening to her apartment; I immediately smelled vinegar and heard an older woman moaning. Upon entering the living room, I saw Mrs. S sitting naked and draped in dish towels that had been soaked in vinegar, “a home remedy” that her family claimed she frequently used; her feet were placed in a bucket of ice water. I asked the family to help her lie down on the sofa and cover her with a blanket while I went into the kitchen to discard the bucket of water. On the way into the kitchen, I tripped over two 100-pound bags of kelp—seaweed to some, sodium iodide to me—and then I saw the shelves. There, carefully arranged in alphabetical order, was a cornucopia of vitamins and minerals from A to zinc. I remembered learning in medical school about the “cold pressor test”; the ice water likely contributed to her high blood pressure, now 240/120 mm Hg. Mrs. S was in severe congestive heart failure; not helped by her daily intake of two cups of kelp she took in an attempt to be “healthy.” We took her to the hospital, where she was also found to have renal failure, hyperkalemia, and hypermagnesemia, among other toxicities. Mrs. S died shortly thereafter.
Ever since this encounter, when asked by a patient whether a “vitamin would be worth taking,” I cannot help but ask, “What do you mean by a vitamin?” While it is beyond the scope of this two-part series to review in detail all aspects of the products mentioned, the articles do address the key aspects of each, with a particular focus on potential comorbidities, side effects, and hazards that may result from taking some commonly available products sold at health food stores. Part I discusses commonly used minerals and trace elements and fat-soluble vitamins. Part II (to be published in the next issue of Clinical Geriatrics) will discuss commonly used water-soluble vitamins, essential fatty acids, and herbs. It is important to ask patients to bring all of their medications, both prescription and off-the-shelf, as well as any health food product or supplement they are taking whenever they come for a visit. Be prepared to discuss the potential consequences of its use.
Minerals and Trace Elements
Calcium 
An adequate intake of calcium is essential for proper bone health as well as a variety of body functions, including cardiac and skeletal muscle contraction, blood clotting, and the transmission of nerve impulses. Calcium is found in highest concentrations in milk and dairy products, with approximately 300 mg of calcium per 8 ounces of milk or 1 ounce of cheese. Dark green leafy vegetables and sardines with bones are also good dietary sources of calcium. The Recommended Dietary Allowance (RDA) for calcium is 800-1500 mg per day, with variation regarding age, sex, and underlying disease. Those individuals at most risk of developing osteoporosis should aim for 1500 mg per day, as should persons over the age of 60 due to an age-related decline in calcium absorption from the intestine. Since many persons cannot take this quantity through dietary sources alone, supplements are being used with increased frequency. Calcium has even been added to certain bottled waters, juices, and other foods. In general, these doses are well tolerated and do not result in toxicity.
The primary side effects related to a high calcium intake are dyspepsia and constipation. Constipation appears to be the main risk, though ingestion of greater than 1500 mg of elemental calcium may lead to hypercalciuria and increase the risk of kidney stone formation. This may be particularly problematic if someone is prone to developing calcium oxalate stones, consumes diets rich in oxalate, or ingests greater than 250 mg of vitamin C. Foods that are high in oxalate include spinach, tea, nuts, chocolate, beets, rhubarb, strawberries, and wheat bran, amongst others. Due to our ability to excrete excess amounts of ingested calcium and our own homeostatic process involving parathyroid hormone, vitamin D, and phosphorus, hypercalcemia is a very rare occurrence in the absence of some underlying parathyroid abnormality or coincident ingestion of alkali. This latter phenomenon has been referred to as the “milk-alkali syndrome” and results when there is prolonged and excessive intake of calcium and some form of soluble alkali-like antacid, such as calcium carbonate or sodium bicarbonate. The triad of hypercalcemia, metabolic alkalosis, and renal insufficiency has characterized this problem. Fortunately, newer methods to reduce gastric acid, such as proton pump inhibitors and H2 blockers, have lessened the dependency on calcium-containing antacid treatments, and, therefore, milk-alkali syndrome is less prevalent than it was in the past. Calcium carbonate, however, has had a resurgence as a source of calcium for those concerned with osteopenia and osteoporosis prevention. While the amount of calcium carbonate required to be ingested per day in order to cause milk-alkali syndrome varies greatly, cases have been reported with as low as 4 grams per day, or a little over 1.5 grams of elemental calcium. Hypercalcemia, though rare, may remain asymptomatic until serious damage has occurred, with renal failure a possible outcome. High levels of calcium may also lead to cardiac conduction disturbances, pancreatitis, and neurological dysfunction. Unless permanent damage has resulted from nephrocalcinosis, this toxicity is reversible with a reduction of the calcium and alkali consumption.
Phosphorus
Phosphorus is an essential component of bone mineral and also plays a significant role in the ability of oxygen to dissociate from hemoglobin through 2,3-diphosphoglycerate, the creation of energy from adenosine triphosphate, and muscle contraction. In steady state, renal excretion of phosphate is so efficient in normal subjects that balance can be maintained with only a minimal rise in serum phosphate concentration, even if phosphate intake is increased to 4000 mg per day.1 The RDA of phosphorus for healthy adults is 700 mg per day. Dietary sources of phosphorus include protein-rich foods such as fish and cereal grains, eggs, nuts, dry beans, peas, and lentils. While milk, cheese, and green leafy vegetables contain significant quantities of phosphorus, they contain more calcium, with the ratio of calcium to phosphorus in cow’s milk at 1.3:1. Deficiency is rare, though may result from persons ingesting aluminum hydroxide as an antacid or from various chemotherapies. An excess intake of phosphorus, as may occur from excessive use of certain cathartics or from supplements, may lead to a reduction in blood calcium levels, though this rarely occurs in adults. Diarrhea may also result from the use of supplemental phosphorus. Any cause of marked tissue breakdown can lead to release of intracellular phosphate into the extracellular fluid, as phosphate is the major intracellular anion. This hyperphosphatemia may potentially lead to symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues.
Magnesium
The majority of the body’s magnesium is contained in muscles, soft tissues, extracellular fluid, and the skeleton. Magnesium is essential for metabolic processes including glycolysis, formation of cyclic AMP, and membrane transport, among other activities. Primarily, the kidney regulates plasma magnesium levels. Dietary sources include seeds, nuts, legumes, leafy green vegetables, and unmilled grains. The RDA for adults of both sexes is 4.5 mg/kg. Persons with normal renal function can excrete excessive amounts of magnesium. Individuals with renal insufficiency or older persons with age-related declines in renal function, however, are at risk if they exceed the RDA, either through dietary sources or, more commonly, with the use of magnesium supplements or magnesium-containing antacids, cathartics, or calcium products used for the treatment of osteoporosis. Hypermagnesemia may be associated with nausea, vomiting, and hypotension as the earliest manifestations. Bradycardia, vasodilation, electrocardiographic changes, hyporeflexia, and central nervous system depression are more serious manifestations potentially leading to respiratory depression, coma, asystole, and death.
Iron
Iron is a necessary component of hemoglobin, myoglobin, and various enzymes. Approximately 30% of the iron stored in the body is in the form of ferritin and hemosiderin, mainly in the bone marrow, liver, and spleen, and as part of the blood transport protein transferrin. Dietary sources of iron are in the ferrous form; an acid environment in the stomach allows this to be converted to the ferric form that is more readily absorbed. Iron is primarily derived from meat, poultry, and fish; iron is also commonly added to cereals. To a lesser degree, iron can also be found in various fruits, vegetables, and juices. The percentage of iron absorbed from a meal decreases as the amount of iron present increases. Absorption of iron also depends on the iron status of the individual, with absorption relatively low when body stores are high. The average loss of iron in a healthy adult man is approximately 1 mg per day. Adult women who are menstruating will average an additional 0.5 mg per day, with variation depending on menstrual flow. As a woman ages, there is a reduction in the loss of iron through this process. In general, a daily intake of 10-11 mg of iron from the typical U.S. diet is thought to be sufficient for most women, with the current RDA set at 15 mg per day. For adult men, 10 mg per day is considered to be sufficient to replace losses that should not exceed 1.5 mg per day. Intake of 15 mg per day leads to approximately 1.5-2.2 mg of iron being absorbed. Postmenopausal women have the same iron requirements as men, and therefore the RDA is adjusted downward to 10 mg per day, similar to men at this time in life. While dietary intake for adults of up to 75 mg per day should not cause toxicity, some have argued that this increased intake may lead to cardiac abnormalities, especially in persons genetically at risk of developing hemochromatosis.2,3 This disease is associated with an autosomal recessive gene and affects between 3% and 7% of the population, with up to 14% being heterozygous for this disorder. Parenteral iron provided above that needed, as may occur from transfusions, does have significant risk and may result in cardiac, hepatic, and pancreatic dysfunction. Iron supplements may cause gastric discomfort and constipation and turn stools dark.
Zinc
Zinc has received a great deal of attention as a way to improve wound healing and fight the common cold. Despite this, there are few data to support its use in persons who already have sufficient amounts of zinc in their diets. Zinc is a necessary component of many enzymes in the body. The pool of available zinc is quite small, and there is a rapid turnover rate. The body is capable of absorbing zinc more efficiently when taken in small quantities and when deficient in the body. The majority of zinc is derived from animal products, such as meat, liver, eggs, and seafood. Cereals are also a source of zinc, though in relatively smaller amounts. Diets containing high concentrations of phytate and dietary fiber may impair the utilization of zinc; dietary intake of phosphorus, protein, and iron may also increase zinc requirements by reducing zinc absorption. It has been suggested that 12-15 mg of zinc per day for men and 12 mg per day for women is necessary to ensure proper zinc balance for persons consuming the standard U.S. diet. Acute toxicity from oral ingestion may lead to gastrointestinal (GI) irritation and vomiting. This is particularly problematic when oral intake exceeds 2 grams.4 Individuals who consume as little as 18.5 mg per day chronically, however, may develop a deficiency state for copper, and persons taking 10-20 times the RDA of zinc chronically may develop hypocupremia, microcytosis, and neutropenia. Doses of zinc exceeding 20 times the RDA have been associated with impaired immune responses.5 Daily doses of between 80 mg to 150 mg for several weeks may affect lipoprotein metabolism, leading to a reduction in high-density lipoprotein cholesterol.6 Chronic ingestion of zinc supplements exceeding 15 mg per day is not advised.
Iodine
Iodine is an essential component of the diet and is necessary for the normal production of thyroid hormone. Iodine is found in the diet as iodide and is rapidly absorbed and transported to the thyroid gland for synthesis into thyroid hormones, and to salivary and gastric glands and kidneys to be excreted. All iodide secreted into the GI tract is reabsorbed, and thus the main excretory route is in the urine. Although iodide is widely available, not all soils contain sufficient quantities to meet our needs through the diet; saltwater fish also contain significant amounts of iodine. For this reason, iodized salt containing 76 mcg per gram of salt has been available since the 1920s in this country. Iodine is present in many types of bread, as it is used to oxidize dough. Dairy products may contain iodine that is present in the feed provided to cows; it is also used in the milk production process.
The recommended allowance for adults of both sexes is currently 150 mcg per day, with doses up to 2 mg per day considered to be relatively safe. Excess dietary intake may, however, lead to thyrotoxicosis in individuals who have underlying disorders of thyroid hormone formation, or who have compensated to an iodine-deficient state by altering their thyroid hormone metabolism. An acute, self-limiting depression of thyroid function may also occur after consuming large quantities of iodine. Caution is advised for those who consume kelp, a form of seaweed, as a source of iodine, as this product contains very large quantities of sodium with its own inherent risks. Daily consumption of iodide in doses between 200 mg/kg and 500 mg/kg of body weight has been associated with death in animals, though no similar reports exist in humans.
Selenium
Selenium has received a great deal of interest for its antioxidant properties. It is necessary for the proper functioning of glutathione peroxidase, an enzyme that catalyzes the degradation of hydroperoxides. Low levels of selenium have been associated with cardiomyopathy. Selenium is present in seafood and organ meat in relatively large quantities and, to a lesser extent, is present in all meat. The RDA for selenium is 70 mcg and 55 mcg per day, respectively, for men and women. It is known that ingestion of 5 mg or more per day can result in hair loss and changes in the fingernails. Other symptoms from excessive intake of selenium may include nausea, diarrhea, nail and hair changes, abdominal pain, peripheral neuropathy, fatigue, and irritability. There have been several studies in persons with diabetes that have suggested that supplementation with selenium may help to prevent vascular complications,7 and that patients with diabetes may have a relatively lower level of selenium as compared to individuals without diabetes.8 Other studies have shown no effect of supplementation on blood glucose levels.9 In a randomized, placebo-controlled trial of over 1000 subjects, chronic ingestion of 200 mcg per day of selenium supplementation failed to prevent new-onset type 2 diabetes and, in fact, was associated with a statistically higher risk for developing type 2 diabetes.10 This has significant ramifications, as most individuals who take selenium supplements use a dose of 30-200 mcg daily.
Fluoride  
Fluoride is present in small quantities in most soils, water supplies, plants, and animals, with highest dietary sources being tea and ocean fish consumed with their bones. Fluoride is, however, frequently added to water sources to provide higher amounts than is generally available in the diet as a way of improving dental health in growing children. Although some have advocated the use of supplemental fluoride for bone health, data suggest that the increased bone density described may actually result in more “brittle” bone formation and increased risk for bone fractures. Average daily intake in the United States varies from approximately 0.9 mg per day to 1.7 mg per day, depending on whether the water supply has been fluoridated.
Fluoride is toxic when consumed in excessive quantities. Chronic toxicity, or fluorosis, affects bones, kidney function, muscles, and nerves. This usually occurs after years of daily exposure to doses between 20 mg and 80 mg of fluoride, a range not uncommonly used by persons taking supplements for presumed bone health. Children exposed to excessive fluoride may have “mottled” teeth, though this is not a problem in adults. While some have argued that fluoride intake may increase the risk of developing cancer, there are no data to support this claim. Death has been reported with ingested doses in excess of 5 grams of sodium fluoride.
Chromium
Chromium is a necessary cofactor for insulin activity and plays a role in the metabolism of carbohydrates and fatty acids. This has led some to advocate for the use of chromium supplements as a way to improve glucose homeostasis in persons with diabetes or impaired glucose tolerance, as well as a way to augment capacity for exercise by improving muscle and skeletal mass; little evidence is available to favor its use for this purpose. The recommended dietary intake of chromium for the general population is between 50 mcg and 200 mcg per day, with the highest content found in calf liver and other organ meats, American cheese, dark-meat turkey, broccoli, grapes, and wheat germ. While there is little chance of toxicity from chromium taken in through the diet as it is in the trivalent form, supplements in the form of chromium salts may lead to toxic states and have been reported to cause dermatitis, GI ulcers, and even irreversible liver and kidney damage. Occupational exposure to chromate, the hexavalent form of chromium, has been associated with lung cancer; dietary sources and supplemental forms that are not of this type, however, have never been associated with the development of cancer.
Potassium
Potassium is an intracellular cation that is found in cell water at a concentration of 145 mEq/L. This is more than 30 times the concentration of potassium in plasma, where it is at 3.8-5.0 mEq/L. Potassium plays a key role in skeletal muscle contraction, nerve conduction, and the regulation of blood vessels and blood pressure. The kidney largely regulates potassium, with potassium loss occurring mostly through the urine and GI tract. Approximately 90% of ingested potassium is absorbed from the GI tract, with the highest amounts present in fruits, vegetables, and fresh meats. The minimum requirement for the person with normal renal function is thought to be between 1600 mg and 2000 mg (40-50 mEq) per day. Acute intoxication leading to hyperkalemia and cardiac arrest may occur with intakes of 18 grams or more per day, even in the absence of renal insufficiency. In persons with reduced renal function, however, hyperkalemia may occur with much lower intakes, and caution is advised. Since renal function declines with increasing age, potassium intake may present a problem to those individuals of advanced age, even in the absence of kidney disease. This is further compounded in those who are on diets that are “salt-restricted”. Salt substitute products may contain potassium chloride (KCl) instead of sodium chloride (NaCl), and may present a challenge to those who are unaware of the potassium content of the salt substitute they are using. Fortunately, many alternative products are on the market that are both sodium- and potassium-free. Patients should be advised to read labels carefully and choose products that both taste good and do not contain potassium. 
Copper
Copper plays a significant role in various disorders of metabolism, as it is a ligand to a number of enzymes. Major sources of copper in the United States include legumes, meats, and nuts.11 Dietary copper is primarily absorbed in the small intestine and the stomach. Copper deficiency is rare in humans; if present, patients can present with anemia, arthritis, and leukopenia. Serum copper and ceruloplasmin levels are increased with any inflammatory process, pregnancy, coronary artery disease, diabetes, malignancies, and renal failure.12 Copper levels are elevated in Wilson’s disease, a defect in a copper-transporting protein in the liver. Situations involving accidental consumption by children, contaminated water sources, suicide attempts, and topical creams for burn treatment that contain copper salts can potentially lead to copper toxicity.13 Severe toxicity can lead to hepatic necrosis, coma, renal failure, hypotension, and death. Symptoms such as nausea, vomiting, and abdominal pain can occur in lower degrees of toxicity. The RDA of copper is 1.5-3 mg per day for adults.
Aluminum
The declining use of aluminum-containing antacids has resulted in a low incidence of abnormal aluminum levels among patients. The patient undergoing hemodialysis can be exposed to aluminum in medications and in the dialysate water. Osteomalacia, bone and muscle pain, iron-resistant microcytic anemia, hypercalcemia, and neurologic abnormalities can occur with the accumulation of aluminum over time.14,15 Patients with aluminum excess complain of generalized bone and joint pain and muscle weakness, often due to osteomalacia.14,15 The joint pain may reflect elevation in the aluminum concentrations in the synovial fluid.16 Interestingly, the risk of aluminum-related bone disease is increased in persons with diabetes.17 Bone marrow aluminum accumulation can result in a reversible microcytic anemia without evidence of iron deficiency and is resistant to iron supplementation.18,19 Hypercalcemia due to aluminum should be considered in the differential diagnosis of hypercalcemia.18,19 Acute aluminum neurologic toxicity is characterized by mental status changes, coma, and seizures, and is potentially fatal.18,19
Fat-Soluble Vitamins
Vitamin A
Vitamin A has received a great deal of attention for its antioxidant properties and as a possible way to reduce “free-radical” damage to cells, a process that has been potentially linked to a variety of age-related illnesses, and even to some of the effects of aging itself. Supplements are sold in most groceries and health food stores, and come in a variety of formulations and dosages. Vitamin A consists of a group of compounds that are necessary for proper growth, cell differentiation and proliferation, vision, reproduction, and immune function. Active vitamin A, primarily in the form of a retinyl ester, is found in animal sources and is especially high in fish oil from cod, halibut, salmon, and shark. It is also found in beef and chicken livers, eggs, and dairy products. Beta-carotene, a precursor for vitamin A, is found only in green and yellow-orange fruits and vegetables, including carrots, kale, kohlrabi, parsley, spinach, turnip greens, dandelion greens, apricots, and cantaloupe.
Vitamin A, frequently referred to as retinol, belongs to the family of retinoids that includes naturally occurring retinol, retinaldehyde, and retinoic acid, as well as a large number of synthetic products; all of these have varying amounts of vitamin A activity. The body’s need for vitamin A can be met by dietary intake of preformed retinoids or by consumption of carotenoid precursors of vitamin A, such as beta-carotene, alpha-carotene, and cryptoxanthin, which is present in some plants.
Ingested beta-carotene is converted to retinol and then to retinyl esters by the intestine’s mucosal cells. These products are taken up by the liver and stored as retinyl esters, with the liver containing over 90% of the total body stores of vitamin A. The recommended minimum daily requirement for vitamin A in adults is between 800 mcg (women) and 1000 mcg (men).
Vitamin A toxicity results when high doses are ingested either acutely or chronically. Vitamin A toxicity has been known to affect Arctic explorers, who often need to survive on polar bear and seal livers. Symptoms may include headache, vomiting, diplopia, alopecia, dry mucous membranes, desquamation, bone abnormalities, and liver damage. Often referred to as pseudotumor cerebri, vitamin A toxicity can mimic a space-occupying lesion in the brain. Toxicity usually results when intake from both foods and supplements exceeds 15,000 mcg of “retinol equivalents” (RE; 50,000 IU) per day for adults. This is approximately 10 times the RDA and would be hard to obtain from the ingestion of food alone, unless one were ingesting large amounts of beef or chicken liver or fish liver oils. Spontaneous abortions and birth defects have also been associated with daily doses of retinyl esters or retinol greater than 6000 RE or 20,000 IU. A meta-analysis evaluating the effects of antioxidant supplements suggested that treatment with varying doses of vitamin A may increase mortality.20 It should be noted that the use of carotenoids, even in large doses, has not been associated with the toxicity common to vitamin A due to its relatively limited conversion to vitamin A by the intestine, liver, and other organs. It does, however, result in coloring of adipose tissue, including the subcutaneous fat, and thus results in a yellow appearance of the skin, especially of the palms of the hands and soles of the feet. This gradually disappears upon discontinuation of the product.
Vitamin D 
Vitamin D (calciferol) is essential for normal maturation of the skeleton and regulation of calcium and phosphorus in the body. Vitamin D3 (cholecalciferol) is formed when ultraviolet light catalyzes its synthesis from 7-dehydrocholesterol in the skin. Ultraviolet light also converts ergosterol in plants to form vitamin D2, or ergocalciferol. Vitamin D is metabolized in the liver to form 25-hydroxyvitamin D (25[OH]D or calcidiol). This is further hydroxylated in the kidney to yield 1,25-dihydroxyvitamin D (1,25[OH]2D or calcitriol). Each of these metabolic products is more potent than its precursor. In general, vitamin D requirements can be met by exposing the skin to a sufficient amount of sunlight or artificial ultraviolet light. This assumes, however, that the liver and kidney are able to adequately convert vitamin D to its more active formulations. Due to fears of the harmful effects of sunlight, however, many individuals avoid this exposure or use sunscreens.
Clearly, the elderly are prone to deficiency states for the above reasons, as well as their tendency to avoid dairy products, usually fortified with vitamin D. 25-OH vitamin D is the storage form of vitamin D and should be present at a level between 30 ng/mL and 50 ng/mL to ensure proper bone health. In order to achieve this goal, most persons require between 400 IU and 800 IU of vitamin D (10-20 mcg of cholecalciferol) daily. Recently, 50,000 IU given as a once-per-month pill has been advocated to increase vitamin D levels, especially for those with metabolic bone disease. Since this dosage provides approximately twice that achieved through the previously recommended 800 IU taken daily, monitoring of the 25-OH vitamin D level is suggested in order to avoid toxicity.
Vitamin D is potentially toxic, with side effects including hypercalcemia and hypercalciuria. Individuals may not account for all of the sources of vitamin D they may be taking, and the amount ingested can quickly exceed a safe level. Calcium, antiresorptive agents, daily vitamins, and various food sources—even certain types of bottled water—now come with varying amounts of vitamin D that have been artificially added. Hypervitaminosis D may lead to calcium deposits in soft tissues, with resultant irreversible renal and cardiovascular damage. In children, as little as 45 mcg (1800 IU) of cholecalciferol per day has been associated with hypervitaminosis D. While it is unclear exactly how much vitamin D may result in toxicity due to a number of individual variations in its metabolism, caution is advised when exceeding recommended dosages.
Hypercalciuria may also be compounded by individuals taking more than 1500 mg of calcium through diet and supplements; excess calcium is excreted into the urine, raising the probability of renal stone formation. The immediate effects of a severe overdose of vitamin D is abdominal cramps, nausea, and vomiting, though most individuals do not acutely take such high quantities to induce these effects. Most cases will result from daily ingestion of vitamin D that exceeds requirements and an accumulation over time, leading to toxic levels in one’s fat stores. Once vitamin D toxicity does occur, however, due to vitamin D’s fat-soluble properties, toxic levels may remain for many months or even years, with unwanted side effects remaining a real risk for a prolonged period of time.
Vitamin E
Vitamin E is a popular vitamin due to its antioxidant properties and myths about it enhancing sexuality. While some argue that there are no toxic effects from taking megadoses of vitamin E, cases have been reported of headache, fatigue, diplopia, breast soreness, emotional disturbances, thrombophlebitis, and diarrhea following chronic intake of large quantities. Ingestion of large doses of vitamin E may also interfere with the absorption of other fat-soluble vitamins, leading to deficiencies in vitamins D, A, and K. A meta-analysis evaluating the effects of antioxidant supplements suggested that treatment with varying doses of vitamin E may increase mortality.20 Individuals taking warfarin should be cautious about ingesting high doses of vitamin E, greater than 100 mg daily, as international normalized ratio may be affected. Most adults appear to tolerate oral doses of vitamin E of 100-800 mg per day without signs of toxicity; 8 mg and 10 mg per day is the RDA for women and men, respectively.
Vitamin K
Vitamin K is the name for a group of compounds containing the 2-methyl-1,4-naphthoquinone moiety. Compounds with vitamin K activity are essential for the formation of prothrombin and at least five other proteins that include factors VII, IX, and X and proteins C and S, which are involved in the regulation of blood clotting. The only major sign of vitamin K deficiency is a defective coagulation of the blood. The best dietary source of vitamin K is green leafy vegetables, providing 50-800 mcg of vitamin K per 100 grams of food. Small but significant amounts of vitamin K are also present in dairy products, meats, eggs, cereals, fruits, and vegetables. Another potentially important source of vitamin K is the bacterial flora in the ileum and jejunum. A normal diet provides approximately 300-500 mcg of vitamin K daily. The RDA for vitamin K is 1 mcg/kg body weight. Even when large amounts of vitamin K are ingested over an extended period of time, toxic manifestations are rare in adults. Caution is advised for persons taking warfarin, however, due to vitamin K’s effect on the clotting process.
Conclusion
The risks and benefits of any drug should be reviewed collaboratively by clinician and patient. In addition, as many patients often take multiple medications and supplements together, obtaining the detailed medication history from the patient is critical. Subsequently, utilizing resources to assess for known potential drug interactions and toxicities is essential. Many of these interactions are not well described. As more patients seek out medicines that may be considered out of the mainstream (or out of the mainstream dosing), it becomes even more critical for the clinician to be well versed in the benefits and toxicities of these commonly used medicines.