Forms of Vitamin E

Vitamin E exists in a variety of forms (e.g., alpha-tocopherol, beta-tocopherol, alpha-tocotrienol), each of which has multiple stereoisomers. However, only four stereoisomers are found in our blood, all of them variants of alpha-tocopherol. These isomers are designated RRR-, RRS-, RSR-, and RSS-alpha-tocopherol. Of the four, only RRR-alpha-tocopherol occurs naturally in foods. However, all four can be found in fortified foods and dietary supplements. Why are other forms of vitamin E absent from blood? Because they are unable to bind to alpha-tocopherol transfer protein (alpha-TTP), the hepatic protein required for secretion of vitamin E from the liver and subsequent transport throughout the body.

Sources

Most dietary vitamin E comes from vegetable oils (e.g., corn oil, olive oil, cottonseed oil, safflower oil, canola oil). The vitamin is also found in nuts, wheat germ, whole-grain products, and mustard greens.

Requirements

The RDA for vitamin E, for men and women, is 15 mg/day (22.5 IU). RDAs increase for women who are breastfeeding, but not for those who are pregnant. Taking more than 200 mg/day increases the risk for hemorrhagic stroke. Accordingly, this limit should be exceeded only when there is a need to manage a specific disorder (e.g., advanced macular degeneration) and only when advised by a health care professional.

Deficiency

Vitamin E deficiency is rare. In the United States deficiency is limited primarily to people with an inborn deficiency of alpha-TTP and to those who have fat malabsorption syndromes and hence cannot absorb fat-soluble vitamins. Symptoms of deficiency include ataxia, sensory neuropathy, areflexia, and muscle hypertrophy.

Potential Benefits

Vitamin E has a role in protecting red blood cells from hemolysis. There is evidence that 200 IU of vitamin E daily may reduce the risk for colds in older adults, and 400 IU daily (in combination with vitamin C, beta-carotene, zinc, and copper) may delay progression of age-related macular degeneration. The higher dose associated with halting macular degeneration carries substantial risk, as detailed in the discussion that follows.

Potential Risks

High-dose vitamin E appears to increase the risk for hemorrhagic stroke by inhibiting platelet aggregation. According to a 2010 report, for every 10,000 people taking more than 200 IU of vitamin E daily for 1 year, there would be 8 additional cases of hemorrhagic stroke. Accordingly, doses higher than 200 IU/day should generally be avoided.

Some studies have demonstrated a relationship between high doses of vitamin E (400 IU daily) and increased cancer risk or poor cancer outcomes. These results are consistent with the theory that high doses of antioxidants may cause cancer or accelerate cancer progression.

Studies have also linked high-dose vitamin E therapy with an increased risk for death, especially in older people. Others have demonstrated higher mortality with long-term vitamin E therapy at doses above 400 IU (266 mg). Accordingly, recommendations have been put forward to decrease the current UL of 1500 IU daily to 200 IU daily.

Finally, high-dose vitamin E (in combination with vitamin C) can blunt the beneficial effects of exercise on insulin sensitivity. Under normal conditions, exercising enhances cellular responses to insulin. However, among subjects who took vitamin E (400 IU/day) plus vitamin C (500 mg twice daily), exercising failed to yield this benefit.

Forms and Sources of Vitamin K

Vitamin K occurs in nature in two forms: (1) vitamin K₁, or phytonadione (phylloquinone), and (2) vitamin K₂. Phytonadione is present in a wide variety of foods. Vitamin K₂ is synthesized by the normal flora of the gut. Two other forms—vitamin K₄ (menadiol) and vitamin K₃ (menadione)—are produced synthetically. At this time, phytonadione is the only form of vitamin K available for therapeutic use.

Requirements

Human requirements for vitamin K have not been precisely defined. In 2002 the Food and Nutrition Board set the AI for adult males at 120 mcg and the AI for adult females at 90 mcg. AIs for other life-stage groups are shown in Table 65.1. For most individuals, vitamin K requirements are readily met through dietary sources and through vitamin K synthesized by intestinal bacteria. Because bacterial colonization of the gut is not complete until several days after birth, levels of vitamin K may be low in newborns.

Pharmacokinetics

Intestinal absorption of the natural forms of vitamin K (phytonadione and vitamin K₂) is adequate only in the presence of bile salts. Menadione and menadiol do not require bile salts for absorption. After absorption, vitamin K is concentrated in the liver. Metabolism and secretion occur rapidly. Very little is stored.

Deficiency

Vitamin K deficiency produces bleeding tendencies. If the deficiency is severe, spontaneous hemorrhage may occur. In newborns, intracranial hemorrhage is of particular concern.

An important cause of deficiency is reduced absorption. Because the natural forms of vitamin K require bile salts for their uptake, any condition that decreases availability of these salts (e.g., obstructive jaundice) can lead to deficiency. Malabsorption syndromes (sprue, celiac disease, cystic fibrosis of the pancreas) can also decrease vitamin K uptake. Other potential causes of impaired absorption are ulcerative colitis, regional enteritis, and surgical resection of the intestine.

Disruption of intestinal flora may result in deficiency by eliminating vitamin K–synthesizing bacteria. Hence deficiency may occur secondary to use of antibiotics. In infants, diarrhea may cause bacterial losses sufficient to result in deficiency.

The normal infant is born vitamin K deficient. Consequently, to rapidly elevate prothrombin levels and reduce the risk for neonatal hemorrhage, the American Academy of Pediatrics and the Centers for Disease Control and Prevention recommend that all infants receive a single injection of phytonadione (vitamin K₁) immediately after delivery. This previously routine prophylactic intervention has recently been challenged by parents who believe that the risks outweigh benefits. Subsequent to increases in parents declining prophylaxis, there has been an increase in life-threatening vitamin K deficiency bleeding in recent years.

As discussed in Chapter 44, the anticoagulant warfarin acts as an antagonist of vitamin K and thereby decreases synthesis of vitamin K–dependent clotting factors. As a result, warfarin produces a state that is functionally equivalent to vitamin K deficiency. If the dosage of warfarin is excessive, hemorrhage can occur secondary to lack of prothrombin.

Intravenous (IV) phytonadione can cause serious reactions (shock, respiratory arrest, cardiac arrest) that resemble anaphylaxis or hypersensitivity reactions. Death has occurred. Consequently, phytonadione should not be administered by the IV route unless other routes are not feasible, and then only if the potential benefits clearly outweigh the risks.

Therapeutic Uses and Dosage

Vitamin K has two major applications: (1) correction or prevention of hypoprothrombinemia and bleeding caused by vitamin K deficiency and (2) control of hemorrhage caused by warfarin.

Preparations and Routes of Administration

Phytonadione (vitamin K₁) is available in 5-mg tablets, marketed as Mephyton, and in parenteral formulations (2 and 10 mg/mL) sold generically. Parenteral phytonadione may be administered by IM, subcutaneous (subQ), and IV route. However, because IV administration is dangerous, this route should be used only when other routes are not feasible and only if the perceived benefits outweigh the substantial risks. For example, this might be indicated in management of life-threatening bleeding due to vitamin K antagonists (e.g., poisoning by coumarins in rodenticides).

Sources

The main dietary sources of ascorbic acid are citrus fruits and juices, tomatoes, potatoes, strawberries, melons, spinach, and broccoli. Orange juice and lemon juice are especially rich sources.

Requirements

Current RDAs for vitamin C are shown in Table 65.1. As in the past, RDAs increase for women who are pregnant or breastfeeding. For smokers, the RDA is increased by 35 mg/day.

Deficiency

Deficiency of vitamin C can lead to scurvy, a disease rarely seen in the United States. Symptoms include faulty bone and tooth development, loosening of the teeth, gingivitis, bleeding gums, poor wound healing, hemorrhage into muscles and joints, and ecchymoses (skin discoloration caused by leakage of blood into subcutaneous tissues). Many of these symptoms result from disruption of the intercellular matrix of capillaries and other tissues.

Adverse Effects

Excessive doses can cause nausea, abdominal cramps, and diarrhea. The mechanism is direct irritation of the intestinal mucosa. To protect against gastrointestinal (GI) disturbances, the Food and Nutrition Board has set 2 g/day as the adult UL for vitamin C.

Therapeutic Use

The only established indication for vitamin C is prevention and treatment of scurvy. For severe, acute deficiency, parenteral administration is recommended.

Vitamin C has been advocated for therapy of many conditions unrelated to deficiency, including cancers, asthma, osteoporosis, and the common cold. Claims of efficacy for several of these conditions have been definitively disproved. Other claims remain unproved. Studies have shown that large doses of vitamin C do not reduce the incidence of colds, although the intensity or duration of illness may be decreased slightly. Research has failed to show any benefit of vitamin C therapy for patients with advanced cancer, atherosclerosis, or schizophrenia. Vitamin C does not promote healing of wounds.

Preparations and Routes of Administration

Vitamin C is available in formulations for oral and parenteral administration. Oral products include tablets (ranging from 25–1000 mg), timed-release capsules (500−1500 mg), and syrups (20 and 100 mg/mL), as well as granules, crystals, powders, effervescent powders, and wafers. Parenteral administration may be subQ, IM, or IV.

Physiologic Actions

Before it can exert physiologic effects, niacin must first be converted into nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP then act as coenzymes in oxidation-reduction reactions essential for cellular respiration.

Sources

Nicotinic acid (or its nutritional equivalent, nicotinamide) is present in many foods of plant and animal origin. Particularly rich sources are liver, poultry, fish, potatoes, peanuts, cereal bran, and cereal germ.

In humans, the amino acid tryptophan can be converted to nicotinic acid. Hence proteins can be a source of the vitamin. About 60 mg of dietary tryptophan is required to produce 1 mg of nicotinic acid.

Requirements

RDAs for nicotinic acid are stated as niacin equivalents (NEs). By definition, 1 NE is equal to 1 mg of niacin (nicotinic acid) or 60 mg of tryptophan. Current RDAs for niacin are provided in Table 65.1.

Deficiency

The syndrome caused by niacin deficiency is called pellagra, a term that is a condensation of the Italian words pelle agra, meaning “rough skin.” As suggested by this name, a prominent symptom of pellagra is dermatitis, characterized by scaling and cracking of the skin in areas exposed to the sun. Other symptoms involve the GI tract (abdominal pain, diarrhea, soreness of the tongue and mouth) and central nervous system (irritability, insomnia, memory loss, anxiety, dementia). All symptoms reverse with niacin replacement therapy.

Adverse Effects

Nicotinic acid has very low toxicity. Small doses are completely devoid of adverse effects. When taken in large doses, nicotinic acid can cause vasodilation with resultant flushing, dizziness, and nausea. Using flushing as an index of excess niacin consumption, the Food and Nutrition Board has set 50 mg as the adult UL. Toxicity associated with high-dose therapy is discussed in Chapter 42.

Nicotinamide, a compound that can substitute for nicotinic acid in the treatment of pellagra, is not a vasodilator, and this does not produce the adverse effects associated with large doses of nicotinic acid. Accordingly, nicotinamide is often preferred to nicotinic acid for treating pellagra.

Therapeutic Uses

In its capacity as a vitamin, nicotinic acid is indicated only for the prevention or treatment of niacin deficiency. It is used off-label for treatment of pellagra.

Preparations, Dosage, and Administration

Nicotinic acid (niacin) is available in immediate-release tablets (50–500 mg), extended-release tablets (250–1000 mg), and extended-release capsules (250–500 mg). Dosages for mild deficiency range from 10 to 20 mg/day. For treatment of pellagra, daily doses may be as high as 500 mg/day; however, the usual dose is 50-100 mg every 6-8 hours. Dosages for hyperlipidemia are given in Chapter 42.

Nicotinamide (niacinamide) is available in 100- and 500-mg tablets. The usual dosage for treatment of pellagra is 100 mg every 6 hours initially. Once major signs and symptoms have resolved, dosing can be decreased to 10 mg every 8-12 hours until resolution of skin lesions. Unlike nicotinic acid, nicotinamide has no effect on plasma lipoproteins and hence is not used to treat hyperlipidemias.

Sources and Requirements

In the United States most dietary riboflavin comes from milk, yogurt, cheese, bread products, and fortified cereals. Organ meats are also rich sources. RDAs for riboflavin are listed in Table 65.1.

Toxicity

Riboflavin appears devoid of toxicity to humans. When large doses are administered, the excess is rapidly excreted in the urine. Because large doses are harmless, no UL has been set.

Use in Riboflavin Deficiency

Riboflavin is indicated only for prevention and correction of riboflavin deficiency, which usually occurs in conjunction with deficiency of other B vitamins. In its early state, riboflavin deficiency manifests as sore throat and angular stomatitis (cracks in the skin at the corners of the mouth). Later symptoms include cheilosis (painful cracks in the lips), glossitis (inflammation of the tongue), vascularization of the cornea, and itchy dermatitis of the scrotum or vulva. Oral riboflavin is used for treatment. The dosage is 10 to 15 mg/day.

Use in Migraine Headache

As discussed in Chapter 23, riboflavin can help prevent migraine headaches; however, prophylactic effects do not develop until after 3 months of treatment. The daily dosage is 400 mg—much higher than the dosage for riboflavin deficiency.

Sources

In the United States the principal dietary sources of thiamine are enriched, fortified, or whole-grain products, especially breads and ready-to-eat cereals. The richest source of the natural vitamin is pork.

Deficiency

Severe thiamine deficiency produces beriberi, a disorder having two distinct forms: wet beriberi and dry beriberi. Wet beriberi is so named because its primary symptom is fluid accumulation in the legs. Cardiovascular complications (palpitations, electrocardiogram abnormalities, high-output heart failure) are common and may progress rapidly to circulatory collapse and death. Dry beriberi is characterized by neurologic and motor deficits (e.g., anesthesia of the feet, ataxic gait, footdrop, wristdrop); edema and cardiovascular symptoms are absent. Wet beriberi responds rapidly and dramatically to replacement therapy. In contrast, recovery from dry beriberi can be very slow.

In the United States thiamine deficiency occurs most commonly among people with chronic alcohol consumption. In this population, deficiency manifests as Wernicke-Korsakoff syndrome rather than frank beriberi. This syndrome is a serious disorder of the central nervous system, having neurologic and psychological manifestations. Symptoms include nystagmus, diplopia, ataxia, and an inability to remember the recent past. Failure to correct the deficit may result in irreversible brain damage. Accordingly, if Wernicke-Korsakoff syndrome is suspected, parenteral thiamine should be administered immediately.

Adverse Effects

When taken orally, thiamine is devoid of adverse effects. Accordingly, no UL for the vitamin has been established.

Therapeutic Use

The only indication for thiamine is treatment and prevention of thiamine deficiency.

Preparations, Dosage, and Administration

Thiamine is available in standard tablets (50, 100, and 250 mg) and in solution (100 mg/mL) for IM or IV administration. For mild deficiency, oral thiamine is preferred. Parenteral administration is reserved for severe deficiency states (wet or dry beriberi, Wernicke-Korsakoff syndrome). The dosage for beriberi is 5 to 30 mg/day orally in single or divided doses 3 times/day for 1 month. For critically ill patients, therapy is initiated at the same dosage but via the IM or IV route 3 times/day. For Wernicke’s encephalopathy, typical dosage is 100 mg IV initially followed by 50 to 100 mg/day IM or IV until the patient begins eating a balanced diet. In some instances, dosage may need to be increased.

Requirements

Current RDAs for pyridoxine are listed in Table 65.1. RDAs increase significantly for women who are pregnant or breastfeeding.

Sources

In the United States the principal dietary sources of pyridoxine are fortified, ready-to-eat cereals; meat, fish, and poultry; white potatoes and other starchy vegetables; and noncitrus fruits. Especially rich sources are organ meats (e.g., beef liver) and cereals or soy-based products that have been highly fortified.

Deficiency

Pyridoxine deficiency may result from poor diet, isoniazid therapy for tuberculosis, and inborn errors of metabolism. Symptoms include seborrheic dermatitis, anemia, peripheral neuritis, convulsions, depression, and confusion.

In the United States dietary deficiency of vitamin B₆ is rare, except among people who abuse alcohol on a long-term basis. Within this population, vitamin B₆ deficiency is estimated at 20% to 30% and occurs in combination with deficiency of other B vitamins.

Isoniazid (a drug for tuberculosis) prevents conversion of vitamin B₆ to its active form and may thereby induce symptoms of deficiency (peripheral neuritis). Patients who are predisposed to this neuropathy (e.g., people with diabetes or alcoholism) should receive daily pyridoxine supplements.

Inborn errors of metabolism can prevent efficient utilization of vitamin B₆, resulting in greatly increased pyridoxine requirements. Among infants, symptoms include irritability, convulsions, and anemia. Unless treatment with vitamin B₆ is initiated early, permanent cognitive deficits may result.

Adverse Effects

At low doses, pyridoxine is devoid of adverse effects. However, if extremely large doses are taken, neurologic injury may result. Symptoms include ataxia and numbness of the feet and hands. To minimize risk, adults should not consume more than 100 mg/day, the UL for this vitamin.

Drug Interactions

Vitamin B₆ interferes with the utilization of levodopa, a drug for Parkinson disease. Accordingly, patients receiving levodopa should be advised against taking the vitamin.

Therapeutic Uses

Pyridoxine is indicated for prevention and treatment of all vitamin B₆ deficiency states (dietary deficiency, isoniazid-induced deficiency, pyridoxine dependency syndrome).

Preparations, Dosage, and Administration

Pyridoxine is available in solution (200 mg/5 mL), standard tablets (25, 50, 100, 250, and 500 mg), extended-release tablets (200 mg), and capsules (150 mg) for oral use. It is available in solution (100 mg/mL) for IM or IV administration. To correct dietary deficiency, the dosage is 10 to 20 mg/day for 3 weeks followed by 1.5 to 2.5 mg/day thereafter for maintenance. To treat deficiency induced by isoniazid, the dosage is typically 100 mg/day IM or IV for 3 weeks and then 30 mg/day as a maintenance dose. To protect against developing isoniazid-induced deficiency, the dosage is 25 to 50 mg/day. Pyridoxine dependency syndrome may require initial doses up to 600 mg/day followed by 25 to 50 mg/day for life.

Recommended Dietary Allowances and Tolerable Upper Intake Levels

RDAs for vitamin B₁₂ and folate are provided in Table 65.1. Because adults older than 50 years often have difficulty absorbing dietary vitamin B₁₂, they should ingest at least 2.4 mcg/day in the form of a supplement. A UL of 1000 mcg/day has been set for folic acid. Owing to insufficient data, no UL has been set for B₁₂.

Food Folate Versus Synthetic Folate

The form of folate that occurs naturally (food folate) has a different chemical structure than synthetic folate (pteroylglutamic acid). Synthetic folate is more stable than food folate and has greater bioavailability. In the presence of food, the bioavailability of synthetic folate is at least 85%. In contrast, bioavailability of food folate is less than 50%.

To increase folate in the American diet, the U.S. Food and Drug Administration requires that all enriched grain products (e.g., enriched bread, pasta, flour, breakfast cereal, grits, rice) must be fortified with synthetic folate—specifically, 140 mcg/100 g of grain. As a result of grain fortification, the incidence of folic acid deficiency in the United States has declined dramatically. Unfortunately, the incidence of birth defects from folate deficiency (see later) has only dropped by 32%.

Folic Acid Deficiency and Fetal Development

Deficiency of folic acid during pregnancy can impair development of the central nervous system, resulting in neural tube defects (NTDs), manifesting as anencephaly or spina bifida. Anencephaly (failure of the brain to develop) is uniformly fatal. Spina bifida, a condition characterized by defective development of the bony encasement of the spinal cord, can result in nerve damage, paralysis, and other complications. The time of vulnerability for NTDs is days 21 through 28 after conception. As a result, damage can occur before a woman recognizes that she is pregnant. Because NTDs occur very early in pregnancy, it is essential that adequate levels of folic acid be present when pregnancy begins; women cannot wait until pregnancy is confirmed before establishing adequate intake. To ensure sufficient folate at the onset of pregnancy, the U.S. Preventive Services Task Force (USPSTF) now recommends that all women who are capable of becoming pregnant consume 400 to 800 mcg of supplemental folic acid each day—in addition to the folate they get from food.

Folic Acid and Cancer Risk

There is evidence that folic acid in low doses may reduce cancer risk, whereas folic acid in higher doses may increase cancer risk—suggesting that cancer risk is increased by having either too little folic acid (folic acid deficiency) or by having too much folic acid (folic acid excess). The bottom line? Taking high-dose folic acid to reduce cancer risk is ineffective and should be discouraged. Women who might become pregnant should continue taking at least 400 mcg of folic acid every day to prevent NTDs.