Practice Essentials
Over 50,000 instances of vitamin toxicity were reported to US poison control centers in 2021. [1] According to National Health and Nutrition Examination Survey (NHANES) data, in 2017-2018, use rates of multivitamin/mineral supplements (MVMs) were 11% in children up to age 2 years, 34.6% at 2-5 years, 29.5% at 6-11 years, and 17.3% at 12–19 years. After age 19, use rates increased by age so that by age 71 years or older, 44% of women and 41% of men were taking MVMs. [2]
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.
Pathophysiology and Etiology
Fat-soluble vitamins (vitamins A, D, and E) are stored to a variable degree in the body and consequently are, making it more likely to cause toxicity when taken in excess amounts. In contrast, water-soluble vitamins (vitamins B, C, and K) are generally excreted in the urine and stored only to a limited extent; hence, adverse effects occur only when extremely large amounts are taken.
Vitamin A
The bioavailability of retinol is generally more than 80%, whereas the bioavailability and bioconversion of carotenes (ie, provitamin A) are lower. [14] 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. [15] It has been suggested that earlier estimates of daily human requirements of vitamin A be revised downward. [16]
Excess 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, 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 two compounds are similar. Birth defects (when taken during pregnancy), intracranial hypertension, depression, and suicidal ideation have been reported with isotretinoin. [17] A careful drug history to uncover the possibility of isotretinoin use is important in patients presenting with manifestations suggestive of vitamin A intoxication.
B Vitamins
Vitamin B1 (thiamine) and vitamin B2 (riboflavin) generally are nontoxic.
Vitamin B3
Vitamin B3 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 1500-6000 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 B6
Over time, 300-500 mg/day of vitamin B6 may be neurotoxic (patients with impaired kidney function may be more susceptible). The acute toxic dose has generally not been established.
Hadtsteinand and Vrolijk have suggested that a possible pathological mechanism of toxicity is related to PDXK (pyridoxal kinase) inhibition by vitamin B6 resulting in convulsions and reductions in gamma-aminobutyric acid (GABA) biosynthesis and the development of peripheral neuropathy. [18]
Vitamin B9
A toxic dose has not been established, but folate is generally nontoxic. Intakes more than 5000 mcg/day mask pernicious anemia.
Vitamin B12
The toxic dose for vitamin B12 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, 1000 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. [19, 20] (Concomitant use of vitamin E and anticoagulants can also increase the risk of bleeding complications). [19, 20]
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 levels of the HDL subfraction HDL2 that otherwise occur with niacin and simvastatin therapy. [21, 22]
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). [10]
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. [23]
Most studies using up to 3200 IU/d of vitamin E did not observe significant acute clinical or biochemical adverse effects. [24] Vitamin E supplementation does not seem to significantly increase or decrease cardiovascular events, [25, 26, 27, 28] although it may increase the risk of mortality. [11, 10]
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). [29]
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. [30, 31, 32, 33, 34, 27, 35, 36]
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. [37]
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. [38, 39]
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 K3 (menadione) supplements have been banned by the US Food and Drug Administration (FDA) because of their high toxicity.
Epidemiology
Occurrence in the United States
The Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS) documents the number of exposures for each class of vitamins (eg, adult and pediatric multiple vitamins, individual vitamins), the outcomes, and the fatalities from that ingestion. In 2021, the NPDS reported 50,120 single exposures to vitamins, with 1830 minor adverse outcomes, 185 moderate outcomes, 7 major outcomes, but no deaths. [1]
Regarding vitamin D toxicity, a retrospective analysis of NPDS data from 2000 through June 30, 2014 found that the mean number of exposures, which was 196 per year from 2000 to 2005, increased 1600% between 2005 and 2011 to a new annual mean of 4535 exposures per year. Nevertheless, a decline occurred in the percentage of patients treated in a health care facility and of patients with serious medical outcome, and one death was reported. [40]
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.
Prognosis
The prognosis is generally excellent in patients with vitamin toxicity. [11] 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.
Patient Education
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.
