Chapter 205: Vitamins and Herbals

Vitamins and herbal preparations, particularly those sold in health food stores, are considered by many to be innocuous but may have potential toxicity when taken in excessive amounts over a period of time. Also, herbal preparations may contain toxic contaminants that can cause acute poisoning.

Hypervitaminosis from the fat-soluble vitamins A, D, and E can produce chronic toxicity (after weeks to months of excessive ingestion) or subacute toxicity (after days to a few weeks). Of the water-soluble vitamins, niacin, pyridoxine, and ascorbate are associated with toxicity (Table 205-1).

Dietary vitamin A is usually found in two forms: retinyl palmitate (an ester) from animal sources or carotenoids found in plants. After ingestion, the ester form is hydrolyzed in the gastrointestinal tract to retinol. Retinol is then absorbed into intestinal mucosal cells, where it then combines with a fatty acid to again become a retinyl ester. Carotenoids are dark-colored compounds found in plants. Plants containing the carotenoids have β-carotene, which is the vegeTable compound most efficiently converted to retinol. The liver contains approximately 95% of body vitamin A stores.

Vitamin A forms part of the visual pigments of the retina (rhodopsin and iodopsin), is important for the formation of mucus-secreting cells in the columnar epithelium, maintains bone growth, and maintains cellular membrane stability. The recommended dietary allowance ranges from 4000 international units (IU) for women to 5000 IU for men.

Hypervitaminosis A generally occurs in either the supplement or dietary forms.¹ The chronic form of vitamin A toxicity is usually due to excessive supplement use, although there have been case reports of acute toxicity due to ingestion of mammal organs (e.g., fish liver).² When the total dose is similar, water-miscible preparations are more toxic than oily preparations because of better absorption.³ There is variability among patients in the amounts necessary to develop hypervitaminosis; hemodialysis patients can develop hypercalcemia with lower doses of vitamin A supplementation due to decreased renal clearance of retinol.⁴ Thus the minimum dose that may cause toxicity in humans is not established.

Symptoms of hypervitaminosis A include blurred vision, appetite loss, abnormal skin pigmentation, loss of hair, dry skin, pruritus, long-bone pain, and an increased incidence of bone fractures. Massive doses can additionally cause pseudotumor cerebri, hypercalcemia, and hepatic failure.⁵

The treatment of hypervitaminosis A includes discontinuation of the vitamin and supportive care. Acute ingestions may be treated with oral activated charcoal.

β-Carotene, a precursor of vitamin A, may be rarely associated with toxicity but does not generally cause hypervitaminosis A. In diabetic patients and patients with hypothyroidism, however, large doses of β-carotene can cause a yellowish discoloration of the skin, which fades once β-carotene is stopped. This phenomenon is occasionally seen in infants and toddlers who consume large amounts of carrots and other pigmented vegetables.

Dietary vitamin D is ingested as a provitamin, either ergocalciferol (vitamin D₂) or cholecalciferol (vitamin D₃). Both forms are essentially bioequivalent. These provitamins are then converted to calcitriol (1, 25-dihydroxycholecalciferol), the physiologically active form of vitamin D. The major function of calcitriol is to elevate plasma calcium and phosphorus levels, enabling normal bone mineralization.

The recommended dietary allowance for vitamin D is approximately 400 IU, and therapeutic doses sometimes exceed 5000 IU. Infants may develop hypercalcemia from doses as low as 2000 IU, but adults require much higher doses before toxicity develops.^6,7 The main toxicity from hypervitaminosis D is hypercalcemia, and clinical findings include anorexia, nausea, abdominal pain, lethargy, weight loss, polyuria, constipation, confusion, and coma. Symptoms from massive doses of 1000 to 3000 IU/kg per day can develop in 2 to 8 days.

Treatment of hypervitaminosis D includes discontinuation of vitamin D, reduction of the calcium intake, and reduction of serum calcium levels. Pamidronate disodium, a bisphosphonate, inhibits osteoclastic bone resorption and can be used to treat the hypercalcemia.^10,11

Vitamin E activity is not limited to one compound; eight different fat-soluble, naturally occurring alcohols (called tocopherols and tocotrienols) have vitamin E activity, but α-tocopherol is the most active form. Because it is rapidly oxidized, α-tocopherol protects other molecules from being oxidized and thus is termed an antioxidant.¹⁰ Foods high in vitamin E include wheat germ, corn, soybean, sunflower seed, cod liver, and others.

Vitamin E is absorbed and distributed through the body similarly to other fat-soluble vitamins: from the intestines and then through lymphatic chylomicrons. The recommended dietary allowance is about 15 milligrams (or 22.4 IU) of α-tocopherol in adults with an increase to 19 milligrams per day during lactation.

Vitamin E is thought to be nontoxic at daily doses of up to 600 IU. The most significant clinical effect of vitamin E at doses higher than 1000 IU per day taken on a long-term basis is the ability to antagonize the effects of vitamin K.¹¹ Specifically, vitamin E acts as a competitive inhibitor of vitamin K–dependent γ-carboxylation. This effect is only clinically significant in those patients taking warfarin.¹² Additionally, through the production of thromboxane, high levels of vitamin E inhibit platelet aggregation. Patients being treated with warfarin should be cautioned about ingesting large amounts of vitamin E. Patients not undergoing treatment with warfarin may rarely have bleeding from large amounts of vitamin E. Other effects in adults who take large doses for a long period of time include nausea, fatigue, headache, weakness, and blurred vision.¹³ These symptoms resolve weeks after discontinuation of the vitamin.

Vitamin K activity is found in several compounds of varied origin: phylloquinone or vitamin K₁, which is naturally produced by plant sources; menaquinone or vitamin K₂, which is produced by bacterial sources; and menadione or vitamin K₃, a synthetic chemical that is a vitamin precursor of vitamin K₂. Because large doses of menadione are toxic, the use of menadione supplements is banned in the United States for human use but can still be found in animal feed. The gastrointestinal absorption of vitamin K requires the presence of bile and pancreatic juice. Between 10% and 80% of ingested vitamin K is absorbed. It is thought that most of the vitamin K stores in the body are derived from plant sources (K₁). Furthermore, if one has an adequate dietary intake of vitamin K₁, eradication of the gut bacteria will not lead to a deficiency of vitamin K.¹⁴ The recommended dietary allowance of vitamin K is small, about 1 microgram/kg per day. Because most adults consume a diet that contains 300 to 500 micrograms, vitamin K deficiency states are uncommon. In contrast to the other fat-soluble vitamins, vitamin K is not stored in the body to any significant extent.

Vitamin K is required for the production of several factors involved in the coagulation cascade: factor II (prothrombin), factor VII (proconvertin), factor IX (Christmas factor), and factor X (Stuart-Prower factor), and proteins C, S, and Z. Warfarin compounds inhibit vitamin K activity, thereby producing a coagulopathy.

The main concern about vitamin K toxicity is the adverse reactions seen with the IV form. The only recommended form of vitamin K for both oral and parenteral use is K₁. Because vitamin K is fat soluble, it must be given parenterally in a lipid-soluble form. Toxicity from IV vitamin K₁ injection is due to the aqueous colloidal suspension formulation¹⁵ producing rare anaphylactoid reactions and reported deaths.¹⁶

The absorption of IM vitamin K₁ is erratic and therefore not recommended. PO vitamin K is equal in efficacy to the SC route. Therefore, SC injection of vitamin K is recommended only when the patient is hemodynamically sTable and unable to take the oral form. The IV form is usually reserved for serious or life-threatening bleeding due to warfarin.¹⁷

Toxicity from oral vitamin K is rare, although doses exceeding 500 micrograms per day are associated with skin rashes. Treatment from excessive vitamin K includes stopping the drug and monitoring prothrombin times for patients on warfarin.

Vitamin B₁, or thiamine, is converted by the body to thiamine pyrophosphate, which acts as a cofactor for several metabolic reactions, including transketolations. Food sources of thiamine include fruits, grain, meats, fish, and milk, among others. The recommended dietary allowance for thiamine is 1.5 milligrams.¹⁸

Intestinal absorption of thiamine is greatest in the jejunum. Thiamine is not stored in the body to any significant extent. Because of renal excretion (water solubility), there is no toxicity to the ingestion of large doses of thiamine over prolonged periods.

The two main clinical concerns with thiamine include the precipitation of Wernicke's encephalopathy and anaphylactoid reactions. Older literature observed the "precipitation" of Wernicke's encephalopathy in patients with thiamine deficiency with prolonged (not acute) treatment with hypertonic IV glucose.¹⁹ However, there was no observed precipitation of Wernicke's encephalopathy from a single or repeated bolus of IV glucose, even in patients with an altered mental status.²⁰ Furthermore, thiamine uptake into nerve cells is slower than that of glucose uptake, making pretreatment with thiamine low in efficacy in the prevention of a Wernicke's encephalopathy.²¹ In summary, IV glucose is unlikely to precipitate Wernicke's encephalopathy in patients with altered mental status.

The issue of IV thiamine toxicity is based on older literature that noted anaphylactoid reactions, likely due to the diluent and contaminants.²² The current pure aqueous forms of thiamine for IV use very rarely result in anaphylactoid adverse reactions.²³ Therefore, IV use of thiamine is both safe and clinically efficacious. Conversely, PO and IM thiamine is absorbed unpredictably in the emergency setting.

Riboflavin is excreted through the urine, and toxicity has not been reported regardless of the amount ingested.²⁴

There are two active forms of niacin—nicotinic acid and nicotinamide—which, in conjunction with thiamine and riboflavin, have antipellagra activity. Niacin, thiamine, and riboflavin all function as coenzymes in energy metabolism. Niacin becomes part of the coenzymes nicotinamide-adenine dinucleotide and nicotinamide-adenine dinucleotide phosphate; both are required in all major metabolic pathways in which there is oxidative breakdown of amino acids, fatty acids, and other compounds, including the oxidation of ethanol.

Niacin is found primarily in poultry, meat, and fish, with lesser amounts in plants. Niacin deficiency causes changes first in cells of the skin, followed by impairment of nervous system and GI function. Deficiency states create symptoms such as anorexia, anxiety, depression, irritability, and weakness.

Nicotinic acid in the range of 100 to 200 times the recommended dietary allowance of 20 milligrams lowers serum cholesterol and β-lipoprotein, but nicotinamide does not. Large niacin doses can also deplete cardiac muscle glycogen and can cause liver toxicity. Some patients experience a frightening "niacin flush" when taking a dose of >100 milligrams. The niacin flush, caused by prostaglandin D₂ and E₂ release with subsequent vasodilation, is characterized by face, neck, and chest burning, itching, and erythema.²⁵ Rarely, hypotension may occur.²⁶ An adult-strength aspirin may decrease the prostaglandin surge caused by niacin.²⁷

Higher niacin doses may additionally cause nausea, abdominal cramping, diarrhea, and headache. Even higher doses >2000 milligrams per day over a prolonged period can produce abnormalities of liver function, impaired glucose tolerance, hyperuricemia, and skin changes such as dryness and discoloration. These subacute and chronic symptoms resolve within days to weeks after stopping treatment.

Vitamin B₆ is a necessary cofactor for many enzymatic processes. The active form of pyridoxine is pyridoxal-5-phosphate. Dietary deficiency of pyridoxine is classically characterized by cheilosis, glossitis, seborrheic dermatitis, and stomatitis. Severe dietary deficiency can lead to altered mental status and seizures.²⁷ Dietary deficiency in infants can result in seizures (as a consequence of a reduced synthesis of γ-aminobutyric acid), anemia (caused by impaired synthesis of heme), xanthurenic aciduria (because of reduced formation of hydroxyanthranilic acid), cystathioninuria (because of decreased cleavage of cystathionine to cysteine and homoserine), and homocystinuria (because of impaired formation of cystathionine). Deficiency states can be induced through ingestion of antagonists to vitamin B₆ such as isoniazid, hydrazines (rocket fuels and the toxic mushroom Gyromitra esculenta), cycloserine, and penicillamine.

Vitamin B₆ in high doses >1 gram/d over more than several weeks will cause nerve damage.^28,29,30 Initial symptoms are an unsTable gait and numbness of the feet. This is followed by similar symptoms in the hands and arms. There may be a marked loss of position and vibration senses. After withdrawal of the vitamin, recovery occurs within several months, although some patients may have residual neurologic impairment. There is no evidence that a single 5-gram IV dose of pyridoxine (the usual dose given for hydrazine exposure) will cause any type of nerve damage.³¹

Vitamin B₆ also can cause intestinal inactivation of levodopa in patients receiving that medication for Parkinson's disease. Patients should be instructed not to take this vitamin at the same time as the medication.

Vitamin B₁₂ deficiency can result in hematologic, neurologic, and psychiatric effects.³² The common hematologic disorders include megaloblastic anemia and pancytopenia. The neurologic disorders commonly observed include paresthesias, peripheral neuropathies, and dorsal spinal cord column demyelination. Psychiatric symptoms include depression, dementia, and psychosis.

Partially because of the size and complexity of the vitamin B₁₂ molecules, deficiencies of this water-soluble vitamin result more from absorption problems than from dietary insufficiencies.³² Absorption depends on the production of intrinsic factor by the parietal cells of the stomach. Vitamin B₁₂–intrinsic factor complexes are initially formed in the stomach. The complexes pass to the ileum, where the intrinsic factor attaches to the intestinal epithelium, facilitating the absorption of the vitamin B₁₂. Vitamin B₁₂ is stored in the liver in such quantities that it takes several years for pernicious anemia to develop in an individual who is a strict vegetarian and ingests little B₁₂ or in someone unable to produce intrinsic factor.³²

Until recently, it was believed that vitamin B₁₂ had a wide therapeutic index for harm. With the advent of the use of vitamin B₁₂ as an antidote for cyanide poisoning, there have been a few case reports of direct vitamin B₁₂ toxicity given in the recommended dose of 5 grams IV to adults, producing erythema of the skin, mucous membranes, urine, and serum.³³ Rare cases of anaphylactoid reactions have also been reported. Hydroxocobalamin can also interfere with colorimetric lab tests, including those that test for carbon monoxide.³⁴

Biotin is required by all organisms but can be synthesized only by bacteria, yeasts, molds, algae, and some plant species. Those taking chronic antibiotics and those on extremely low-calorie diets are at risk of developing a biotin deficiency. For such individuals, 100 to 300 micrograms of biotin per day is recommended. There is no known toxicity to biotin overdosage.³⁵

Folate or folic acid is essential for the production of DNA, RNA, and proteins. Folate is found in fresh leafy green vegetables, yeasts, and liver. Recommended daily allowance for folate in nonpregnant adults is 0.4 milligram. After ingestion, folate is actively absorbed in the small and large intestine. Both deficiencies of vitamin B₁₂ and folate can result in megaloblastic (macrocytic) anemia. Large doses of folic acid given to an individual with an undiagnosed vitamin B₁₂ deficiency could correct megaloblastic anemia but leave the individual at risk of developing irreversible neurologic damage. Such cases of neurologic progression in vitamin B₁₂ deficiency have been mostly seen at folate doses of 5 milligrams and above.³⁶

The major form of vitamin C, ascorbate or ascorbic acid, is a strong reducing agent that participates in hydroxylation reactions such as those necessary for the formation of collagen. Scurvy is due to vitamin C deficiency and results in collagen, protein, and lipid metabolism abnormalities. Additionally, the presence of vitamin C in the intestines increases the absorption rate of iron, so those with a vitamin C deficiency will also be iron depleted.

Vitamin C, which is found primarily in fruits and vegetables, is absorbed through the jejunum and ileum. Large doses of vitamin C can lower the frequency of gout attacks.³⁷ It is controversial whether high-dose vitamin C is responsible for an increased risk of oxylate renal kidney stones.³⁸ Intrarenal deposition of oxalate crystals has been reported to cause renal failure in patients with chronic high-dose ascorbate ingestion.³⁹ Large doses of vitamin C may produce diarrhea and abdominal cramps, which subside with discontinuation. Megadoses of vitamin C may result in false-negative guaiac testing of feces and may give falsely elevated glucose levels on dipstick testing.

Herbal preparations have long been used by traditional cultures, and their use appears to be increasing in developed countries.⁴⁰ In developed countries, herbal preparations have been looked upon as a natural and inexpensive alternative to common Western pharmaceuticals. Unfortunately, many studies funded by the National Center for Complementary and Alternative Medicine have not supported the use of herbal medications for treatment of depression (St. John's wort),⁴¹ dementia (Ginkgo biloba),⁴² prostatic hypertrophy (saw palmetto),⁴³ osteoarthritis (glucosamine and chondroitin),⁴⁴ and the common cold (Echinacea).⁴⁵ In addition, no herbal is completely free of adverse side effects or the potential for herb–drug interactions.⁴⁶ This can be a problem because many patients are reluctant to divulge that they are taking herbal preparations to medical providers.⁴⁷

Although the U.S. Food and Drug Administration (FDA) has some regulatory oversight of herbal preparations, regulation is not as strict as that for drugs. Instead, herbs are classified as dietary supplements by the Dietary Supplemental Health and Education Act of 1994.⁴⁸ Unlike drugs, where the manufacturer must prove safety before marketing, the FDA needs to show that a dietary supplement is unsafe before it may take steps to restrict its sale or remove it from the market. Herbal agents can be classified as generally safe, potentially toxic, and toxic (Table 205-2).^49,50,51,52 Many herbal agents have specific liver, eye, and cardiovascular toxicities.^53–58

Although herbal preparations can cause direct toxicity from the herb itself, it is much more common that the patient becomes ill from the contamination, misuse, overuse, or misidentification of the herbal preparation.⁵⁹ Herbal preparations can cause either direct toxicity (Table 205-3) or indirect toxicity from herb–drug interactions (Table 205-4).⁵² Reported contaminants in herbal preparations include lead, selenium, and cyanide.^{62,63,64,65,66}

Much of the available literature on herb–drug interactions is anecdotal and nonreproducible, but there are some herb–drug interactions that, because of numerous clinical reports, animal studies, and/or controlled clinical studies, can be deemed to be "likely" (Table 205-4).⁶¹ Although not usually of clinical relevance, certain herbals may also interfere with assays for therapeutic drugs.^67,68,69