Vitamin Toxicity 

More than 60,000 instances of vitamin toxicity are reported annually to US poison control centers.^{[1, 2]} According to National Health and Nutrition Examination Survey (NHANES) data, in 2003–2006 33% of the United States population aged 1 year and older took a multivitamin supplement in a given month.^[3] In a 2009 survey, 56% of US consumers said they take vitamins or supplements, with 44% saying they take them daily.^[4] (See Pathophysiology and Etiology.)

Owing to their ability to accumulate in the body, fat-soluble vitamins have a higher potential for toxicity than do water-soluble vitamins. Iron-containing vitamins are the most toxic, especially in pediatric acute ingestions. (See Prognosis, Workup, Treatment, and Medication.)

Vitamin A

An important fat-soluble vitamin, vitamin A’s basic molecule is a retinol, or vitamin A alcohol. After absorption, retinol is transported via chylomicrons to the liver, where it is either stored as retinol ester or reexported into the plasma in combination with retinol-binding protein for delivery to tissue sites.

Dietary vitamin A is obtained from preformed vitamin A (or retinyl esters), which is found in animal foods (liver, milk, kidney, fish oil), fortified foods, and drug supplements. Dietary vitamin A is also obtained from provitamin A carotenoids from plant sources, principally carrots. Dietary vitamin A is available mainly as preformed vitamin A in western countries and as provitamin A carotenoids in developing countries.

Supplements are typically 10,000-50,000 international units (IU) per capsule. Fish-liver oils may contain more than 180,000 IU/g. The acute toxic dose of vitamin A is 25,000 IU/kg, and the chronic toxic dose is 4000 IU/kg every day for 6-15 months. (Beta-carotene [ie, provitamin A] is converted to retinol but not rapidly enough for acute toxicity.)

IU is not a Joint Commission on Accreditation of Healthcare Organizations [JACHO]–approved abbreviation, and it must be spelled out on patients' charts and in prescriptions.

RDAs

Because the body can make use of both preformed vitamin A and provitamin A carotenoids that it converts into vitamin A (retinol), and these substances have different bioactivity levels, the recommended dietary allowances (RDAs) for vitamin A are given as mcg of retinol activity equivalents (RAE). The RDAs for vitamin A are as follows^[5] :

• Males (>14 y) - 900 mcg RAE
• Females (>14 y) - 700 mcg RAE
• Pregnancy (14-18 y) - 750 mcg RAE
• Pregnancy (19-50 y) - 770 mcg RAE
• Lactation (14-18 y) - 1200 mcg RAE
• Lactation (19-50 y) - 1300 mcg RAE

The RDAs for children is as follows:

• 0-6 months - 400 mcg RAE
• 7-12 months - 500 mcg RAE
• 1-3 years - 300 mcg RAE
• 4-8 years - 400 mcg RAE
• 9-13 years - 600 mcg RAE

Vitamin B-1

Vitamin B-1 (ie, thiamine) is found in organ meats, yeast, eggs, and green, leafy vegetables. Vitamin B-1 supplements usually contain 50-500 mg of vitamin B-1 per tablet. This vitamin is a cofactor for pyruvate dehydrogenase in the Krebs cycle. The RDA is 1.5 mg (0.7 mg for children aged 1-4 y).

Vitamin B-2

The RDA for vitamin B-2 (riboflavin) is 1.7 mg (0.8 mg for children aged 1-4 y). Supplements usually are 25-100 mg.

Vitamin B-3

Vitamin B-3 (ie, niacin) is found in green vegetables, yeast (pumpernickel bagels may contain 190 mg of niacin), animal proteins, fish, liver, and legumes. Supplements are usually 20-500 mg per tablet.

Vitamin B-3 synthesis requires tryptophan. Niacin is converted to nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are coenzymes for dehydrogenase-type reactions. In large doses, niacin decreases synthesis of LDL cholesterol level. The RDA is 20 mg (9 mg for children aged 1-4 y).

Vitamin B-6

Vitamin B-6 (ie, pyridoxine) is found in poultry, fish, pork, grains, and legumes. Supplements usually are 5-500 mg per tablet.

Vitamin B-6 functions in protein and amino acid metabolism. Pyridoxine is the treatment of choice for isoniazid overdose. It is also used by bodybuilders, as well as for the treatment, with varying results, of the following^[6] :

• Premenstrual syndrome (PMS)
• Carpal tunnel syndrome
• Schizophrenia
• Childhood autism
• Attention deficit hyperactivity disorder (ADHD)

The RDAs for vitamin B-6 are as follows:

• Age 19-50 years - 1.3 mg
• Age 51 years and older (males) - 1.7 mg
• Age 51 years and older (females) - 1.5 mg
• Pregnancy (19-50 y) - 1.9 mg
• Lactation (19-50 y) - 2 mg

The RDAs for children are as follows:

• Age 0-6 months (adequate intake) - 0.1 mg
• Age 7-12 months (adequate intake) - 0.3 mg
• Age 1-3 years - 0.5 mg
• Age 4-8 years - 0.6 mg
• Age 9-13 years - 1 mg
• Age 14-18 years (males) - 1.3 mg
• Age 14-18 years (females) - 1.2 mg
• Pregnancy (14-18 years) - 1.9 mg
• Lactation (14-18 years) - 2 mg

Vitamin B-12

Vitamin B-12 (ie, cyanocobalamin), which requires an intrinsic factor for absorption, is found in milk products, eggs, fish, poultry, and meat. Supplements usually contain 25-250 mcg of the vitamin per tablet. Vitamin B-12 is a treatment of pernicious anemia and cyanide poisoning.

RDAs

The RDAs for vitamin B-12 are as follows^[7] :

• Age 14 years and older - 2.4 mcg
• Pregnancy (14 y and older) - 2.6 mcg
• Lactation (14 y and older) - 2.8 mcg

The RDAs in children are as follows:

• Age 0-6 months (adequate intake) - 0.4 mcg
• Age 7-12 months (adequate intake) - 0.5 mcg
• Age 1-3 years - 0.9 mcg
• Age 4-8 years - 1.2 mcg
• Age 9-13 years - 1.8 mcg

Vitamin C

Vitamin C (ie, ascorbic acid) is found in citrus fruits and vegetables. An antioxidant and reducing agent, its controversial uses include treatment of upper respiratory tract infections and cancer.^[8] Supplements are usually 100-2000 mg per capsule.

RDAs

The RDAs for vitamin C are as follows (it has been found that individuals who smoke need an additional 35 mg/day)^[9] :

• Adult males (19 y or older) - 90 mg
• Adult females (19 y or older) - 75 mg
• Pregnancy (19 y or older) - 85 mg
• Lactation (19 or older) - 120 mg

The RDAs for vitamin C in children are as follows:

• Age 0-6 months (adequate intake) - 40 mg
• Age 7-12 months (adequate intake) - 50 mg
• Age 1-3 years - 15 mg
• Age 4-8 years - 25 mg
• Age 9-13 years - 45 mg
• Age 14-18 years (males) - 75 mg
• Age 14-18 years (females) - 65 mg
• Pregnancy (14-18 y) - 80 mg
• Lactation (14-18 y) - 115 mg

Vitamin D

Vitamin D (ie, cholecalciferol) is present in most dairy products, egg yolks, liver, and fish. It increases serum calcium levels by facilitating calcium absorption and mobilizing calcium from bone. Supplements usually are 400 IU per tablet. The RDAs for vitamin D are as follows^[10] :

• Age 0-12 months (adequate intake) - 10 mcg (400 IU)
• Age 1-70 years (including lactation and pregnancy) - 15 mcg (600 IU)
• Age >70 years - 20 mcg (800 IU)

Vitamin E

Vitamin E is any of a group of at least 8 related fat-soluble compounds with similar biological antioxidant activity, particularly alpha-tocopherol but also including other isomers of tocopherol and the related compound tocotrienol. Vitamin E is found in vegetable oil, nuts, sunflower, wheat, green leafy vegetables, and fish. It is a fat-soluble vitamin that acts as an antioxidant and free-radical scavenger in lipophilic environments. Bile is required for absorption; 25% of vitamin E is absorbed orally. Storage of the vitamin occurs in adipose tissue, the liver, and muscle.

Vitamin E may block absorption of vitamins A and K. In addition, it decreases low-density lipoprotein (LDL) cholesterol level at doses more than 400 IU/day.

One milligram of synthetic vitamin E (all-rac-alpha-tocopherol acetate) is equivalent to 1 IU of vitamin E. One milligram of natural vitamin E (RRR–alpha tocopherol) is equivalent to 0.45 IU of vitamin E.

In a 2000 report, the Food and Nutrition Board of the National Academy of Sciences specified the RDA of vitamin E as 15 mg/day and listed the tolerable upper intake level (UL) of any alpha-tocopherol form as 1000 mg/day (1500 IU/day). The UL is the upper level that is likely to pose no risk of adverse health effects to almost all people in the general population.

While in most healthy adults, short-term supplementation with up to 1600 IU of vitamin E appears to be well tolerated and have minimal side effects, the long-term safety is questionable.^{[11, 12]} Data suggest a possible increase in mortality and in the incidence of heart failure with long-term use of vitamin E (400 IU or more), especially in patients with chronic diseases.^[11] Therefore, a UL of 1000 mg/day may be too high, especially if only the alpha-tocopherol form of vitamin E is used (vitamin E consists of 8 compounds and supplementing only one form can be detrimental). Supplements usually are 100-1000 IU per capsule.

RDAs

The RDAs for vitamin E are as follows^[13] :

• Age 14 years and older - 15 mg
• Pregnancy (14 y and older) - 15 mg
• Lactation (14 y and older) - 19 mg

The RDAs for children are as follows:

• Age 0-6 months (adequate intake) - 4 mg
• Age 7-12 months (adequate intake) - 5 mg
• Age 1-3 years - 6 mg
• Age 4-8 years - 7 mg
• Age 9-13 years - 11 mgM

Vitamin K

Vitamin K (ie, phytonadione) is produced by intestinal bacteria (vitamin K-2) and is found in green, leafy vegetables; cow's milk; and soy oil (vitamin K-1). Vitamin K-1 supplements are usually 2.5-10 mg. Phytonadione promotes liver synthesis of factors II, VII, IX, and X.

Adequate intakes

Measured in terms of adequate intake (as opposed to RDA), the recommendations for daily intake of vitamin K are as follows^[14] :

• Age 19 years or older (males) - 120 mcg
• Age 19 years or older (females) - 90 mcg
• Pregnancy and lactation (19-50 y) - 90 mcg

Adequate intakes in children are as follows:

• Age 0-6 months - 2 mcg
• Age 6-12 months - 2.5 mcg
• Age 1-3 years - 30 mcg
• Age 4-8 years - 55 mcg
• Age 9-13 years - 60 mcg
• Age 14-18 years - 75 mcg (including pregnancy and lactation)

Folic acid

Folic acid, which is found in oranges and green, leafy vegetables, decreases the risk of neural tube defects and may reduce serum homocysteine levels (which are a coronary artery disease risk factor). It may also have a therapeutic role as an adjuvant therapy for the treatment of methanol toxicity, since it enhances the elimination of formate.

RDAs

The RDAs for folic acid are as follows^[14] :

• Age 14 years and older - 400 mcg
• Pregnancy (14-50 y) - 600 mcg
• Lactation (14-50 y) - 500 mcg

The RDAs in children are as follows:

• Age 0-6 months (adequate intake) - 65 mcg
• Age 6-12 months (adequate intake) - 80 mcg
• Age 1-3 years - 150 mcg
• Age 4-8 years - 200 mcg
• Age 9-13 - 300 mcg

Vitamin A

Being fat-soluble, vitamin A is stored to a variable degree in the body, making it more likely to cause toxicity when taken in excess amounts.^[15] In contrast, water-soluble vitamins are generally excreted in the urine and stored only to a limited extent; hence, adverse effects occur only when extremely large amounts are taken.

The bioavailability of retinol is generally more than 80%, whereas the bioavailability and bioconversion of carotenes (ie, provitamin A) are lower. These may be affected by species, molecular linkage, amount of carotene, nutritional status, genetic factors, and other interactions.

While in general the body absorbs retinoids and vitamin A very efficiently, it lacks the mechanisms to destroy excessive loads. Thus, the possibility of toxicity exists unless intake is carefully regulated.^[16] It has been suggested that earlier estimates of daily human requirements of vitamin A be revised downward.^[17]

Vitamin A is highly teratogenic in pregnancy, especially in the first 8 weeks with daily intake more than 10,000 IU; however, it is also a cofactor in night vision and bone growth.

Carotenemia is the result of excessive intake of vitamin A precursors in foods, mainly carrots. Other than the cosmetic effect, carotenemia has no adverse consequences, because the conversion of carotenes to retinol is not sufficient to cause toxicity.

Isotretinoin (Accutane), a drug used for the treatment of severe forms of acne, is closely related to the chemical structure of vitamin A, which means that the pharmacology and toxicology of these 2 compounds are similar. Birth defects (when taken during pregnancy), intracranial hypertension, depression, and suicidal ideation have been reported with isotretinoin. A careful drug history to uncover this possibility of isotretinoin use is important in patients presenting with manifestations suggestive of vitamin A intoxication.

Vitamin B-1

Thiamin generally is nontoxic.

Vitamin B-2

Vitamin B-2 (riboflavin) generally is nontoxic.

Vitamin B-3

Vitamin B-3 does not have a toxic dose established for humans. However, adverse effects such as skin flushing can occur at doses of 50 mg/day or greater. While therapeutic doses are considered to typically range from 1,500-6,000 mg/day, these doses carry a risk of liver toxicity, especially if not titrated slowly or in the presence of any preexisting liver disease.

Vitamin B-6

Over time, 300-500 mg/day of vitamin B-6 may be neurotoxic (patients with impaired renal function may be more susceptible). The acute toxic dose has generally not been established.

Vitamin B-12

The toxic dose for vitamin B-12 is not established.

Vitamin C

The acute toxic dose for vitamin C has not been determined. The chronic toxic dose is more than 2 g/day.

Vitamin D

The acute toxic dose for vitamin D has not been established. The chronic toxic dose is more than 50,000 IU/day in adults. In infants younger than 6 months, 1,000 IU/day may be considered unsafe. However, a wide variance in potential toxicity exists for vitamin D.

Vitamin E

Vitamin E can prolong the prothrombin time (PT) in animal models by inhibiting vitamin K–dependent carboxylase, although administration of vitamin K corrects this. High doses of vitamin E increase the vitamin K requirement; coagulopathy can occur in patients who are deficient in vitamin K.^{[18, 19]} (Concomitant use of vitamin E and anticoagulants can also increase the risk of bleeding complications).^{[18, 19]}

Vitamin E at dosages of 1600 IU/day reduces platelet thromboxane production. Vitamin E supplementation may impair the hematologic response to iron in children with iron-deficiency anemia.

In the Heart Protection Study, a combination of vitamin E (600 IU alpha-tocopherol only), vitamin C, and beta-carotene did not affect mortality. However, it did cause a significant, albeit small, increase in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, as well as a decrease in high-density lipoprotein (HDL) cholesterol. In 2 randomized trials, an antioxidant cocktail that included vitamin E (form not specified) blunted the beneficial increase in HDL2 levels associated with niacin and simvastatin therapy.^{[20, 21]}

Vitamin E can depress leukocyte oxidative bactericidal activity and mitogen-induced lymphocyte transformation.

Although adverse effects usually are observed only at very high dosages of vitamin E, a meta-analysis showed a possible increase in mortality at dosages of 400 IU/d and higher (alpha-tocopherol only).^[11]

Complications

Note that these published studies have used only the alpha-tocopherol form of vitamin E and not a balanced mixture of the 8 different forms of vitamin E that naturally occur and have important physiologic functions. Supplementing with only one form of vitamin E has been shown to suppress the other 7 forms, resulting in physiological dysfunction, which may account for some of the negative studies presented here.^[22]

Most studies using up to 3200 IU/d of vitamin E did not observe significant acute clinical or biochemical adverse effects.^[23] Vitamin E supplementation does not seem to significantly increase or decrease cardiovascular events,^{[24, 25, 26, 27]} although it may increase the risk of mortality.^{[12, 11]}

Vitamin E supplementation was shown to increase the risk of prostate cancer in healthy men, in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).^[28]

In the Heart Outcomes Prevention Evaluation (HOPE-TOO) study, a randomized trial examining the effects of 400 IU of vitamin E versus those of a placebo in patients with diabetes or vascular disease, vitamin E did not decrease the incidence of cancer deaths or vascular events during follow-up (mean 7.2 y). Evidence indicated, however, that it did increase the incidence of heart failure.^{[29, 30, 31, 32, 33, 26, 34, 35]}

An increased risk of bleeding has been observed with coadministration of vitamin E and warfarin, with an increased PT due to the depletion of vitamin K–dependent clotting factors. This does not occur in healthy individuals with normal vitamin K levels. Increased gingival bleeding also was observed in patients taking vitamin E and aspirin.^[36]

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study showed that, compared with placebo, alpha-tocopherol at dosages of 50 mg/day increased the risk of fatal subarachnoid hemorrhage by 181% in men aged 50-69 years who smoked cigarettes. The risk of cerebral infarction was decreased by 14% in the vitamin E group, with no significant net effect of vitamin E on mortality from total strokes. These results had not been found in previous studies.^{[37, 38]}

An increased risk of sepsis occurred in a clinical trial (14% vs 6%) in which vitamin E was administered to premature neonates with a birthweight of less than 1500 g. When high-dose vitamin E of up to 30 mg/kg/day was administered to this population to prevent retrolental fibroplasia, necrotizing enterocolitis occurred. The incidence of necrotizing enterocolitis increased 2-fold (12%) in 2 studies; however, others have shown no difference. These findings may be secondary to the compounding effects of prematurity and the effect of vitamin E on the immune system. No other population has demonstrated these findings.

Fatigue and weakness were reported in 2 case series in which vitamin E was administered at dosages of 800 IU/day. The symptoms resolved with removal of the drug.

Transient nausea and gastric distress have been observed in a few patients taking high dosages (2000-2500 IU/day) of vitamin E. Diarrhea and intestinal cramps have been reported at a dosage of 3200 IU/day. Other nonspecific, adverse effects of vitamin E, although reported only rarely, include delayed wound healing and headache.

Vitamin K

A toxic dose amount for vitamin has not been established. However, vitamin K-3 (menadione) supplements have been banned by the US Food and Drug Administration (FDA) because of their high toxicity.

Folic acid

A toxic dose has not been established, but folic acid is generally nontoxic. Intakes more than 5000 mcg/day mask pernicious anemia.

Occurrence in the United States

The 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS) documented the total number of exposures for each class of vitamins, the number of patients with major adverse outcomes, and the number of fatalities from that ingestion,^[1] in 2012. The figures are as follows:

• Adult multiple vitamin tablets with iron but without fluoride - 4934 single exposures, with 159 minor outcomes, 16 moderate outcomes, one major outcome, and no deaths
• Adult multiple vitamin tablets without iron or fluoride - 3227 single exposures, with 155 minor outcomes, 37 moderate outcomes, three major outcomes, and no deaths
• Pediatric multiple vitamin tablets with iron but without fluoride - 5987 single exposures, with 255 minor outcomes, 9 moderate outcomes, and no major outcomes or deaths
• Pediatric multiple vitamin tablets without iron or fluoride - 26,484 single exposures, with 410 minor outcomes, 12 moderate outcomes, and no major outcomes or deaths
• Vitamin A - 443 single exposures, with 16 minor outcomes, two moderate outcomes, one major outcome, and no deaths
• Vitamin B-3 - 1902 single exposures, with 609 minor outcomes, 117 moderate outcomes, six major outcomes, and no deaths
• Vitamin B-6 - 220 single exposures, with five minor outcomes, one moderate outcome, and no major outcomes or deaths
• Other B complex vitamins - 4459 single exposures, with 89 minor outcomes, 15 moderate outcomes, no major outcomes, and one death
• Vitamin C - 1215 single exposures, with 63 minor outcomes, two moderate outcomes, one major outcome, and no deaths
• Vitamin D - 4494 single exposures, with 137 minor outcomes, 19 moderate outcomes, and no major outcomes or deaths
• Vitamin E - 534 single exposures, with 18 minor outcomes, one moderate outcome, and no major outcomes or deaths
• Overall, 59,028 single exposures to different types of vitamins (tablet and liquid) were reported to poison control centers across the United States in 2012, accounting for 2100 minor outcomes, 263 moderate outcomes, 12 major outcomes, and one death

Age-related demographics

Single vitamins are consumed more often by adults, while multivitamins are administered more frequently to children.

Premature infants with low birthweight have suffered life-threatening adverse effects from vitamin E, with sepsis and necrotizing enterocolitis having occurred in these infants but not in others.

A syndrome of ascites, hepatomegaly, and thrombocytopenia resulting in death occurred in the 1980s in association with an intravenous vitamin E preparation used in premature infants with low birthweight. The cause was presumably a polysorbate carrier of the vitamin, and the syndrome has not occurred since its removal.

The prognosis is generally excellent in patients with vitamin toxicity.^[12] Patients with vitamin E toxicity, for example, have an excellent prognosis once the supplements are discontinued. Patients with mild bleeding episodes are likely to fully recover once vitamin K is administered and the vitamin E supplements are discontinued.

Patients with vitamin E toxicity who develop an intracranial hemorrhage have an increased mortality rate; however, with proper diagnosis and management, many patients with this condition survive and recover some or all of their previous functions.

Morbidity and mortality

Morbidity and mortality from pure vitamins are rare. As stated above, the American Association of Poison Control Centers reported 59,028 single exposures to vitamins in 2012, but only one death resulted.^{[1, 12]}

Remind parents of children who ingested vitamins of the appropriate ways to childproof their homes, and emphasize the need to use child-resistant bottles.

Instruct adults who have unintentionally overdosed on vitamins as part of their megavitamin regimen on the serious adverse effects of such chemicals.

For patient education information, see the First Aid and Injuries Center, as well as Iron Poisoning in Children, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.