Hypervitaminosis: A Global Concern

U.S. Pharm. 2021;46(10):47-50.

Vitamins are essential in regulating various metabolic and biologic activities in the human body. However, overconsumption and prolonged use of pharmaceutical forms of both water-soluble and fat-soluble vitamins may lead to accumulation and toxicity. In cases of acute poisoning resulting from vitamin supplements or drugs, emergency assistance is required to detoxify the effects and to restore the function of the body’s organs. To manage any type of hypervitaminosis, proper diagnosis is essential in expediting elimination of the supplement from the body.^1,2

Generally, vitamins and dietary supplements are taken to improve health or well-being. However, they are not necessarily safe for everyone. Like regular drugs, supplements with active ingredients provide a physiologic or pharmacologic effect that can also cause adverse effects in susceptible individuals. Therefore, attention to adverse effects and potential interactions is necessary to avoid serious medical problems. Medical providers are aware that a large percentage of the population takes dietary supplements, and they request information from patients about supplement intake to provide optimal medical care.²

In the United States, the FDA regulates the efficacy and safety of all pharmaceuticals on a regular basis. The FDA does not require any documentation of efficacy for vitamins and supplements. As a result, the safety of dietary supplements is only ensured through reporting of adverse events and rarely through intervention. Consumers should be aware that vitamins and supplements may in fact contain actual pharmaceuticals or nothing of biological value and have significant toxic potential. Toxicity due to large-volume use of vitamins is called hypervitaminosis and has been a global concern for a long time.^1,2

Type of Vitamins 

The human body cannot make vitamins on its own. Therefore, it becomes essential to obtain sufficient amounts of vitamins through the diet to ensure a healthy lifestyle. Vitamins are present in small concentrations in foods. They regulate physiologic functions and help maintain the metabolic rate of the body. A poor diet can cause various deficiency diseases which, if untreated with adequate supplementation, may lead to serious illness or even death.²

Vitamins are categorized into two groups, fat-soluble vitamins and water-soluble vitamins.

Vitamins A, D, E, and K are fat-soluble vitamins. They can be stored in the body, particularly in the liver. Vitamin B complex and vitamin C are water-soluble vitamins. They are dissolved easily in water during cooking, and a portion of these vitamins may be destroyed by heating. They cannot be stored in the body and therefore must be consumed daily in foods or via supplementation. Extra quantities of water-soluble vitamins taken in one day are eliminated in the urine as waste by the body.²

Vitamins are available in different formulations by pharmaceutical and supplement companies in the form of syrups, tablets, capsules, and powder packets.

Hypervitaminosis General Symptoms

Many people take vitamin supplements daily, believing that excess vitamins are harmless and will be excreted from the body. This misconception and the prolonged intake of vitamins may cause toxic effects or hypervitaminosis. A large intake of highly fortified foods can also lead to the accumulation of fat-soluble vitamins in the liver. Natural foods have not been associated with any toxicity.^1,2 

In the United States, an account submitted by poison control centers reported that annually more than 60,000 people, including children under the age of 6, are subjected to life-threatening outcomes due to vitamin toxicities.^2,3

Research studies have reported that in well-nourished individuals, prolonged intake of the antioxidant supplements, including vitamin A and vitamin E, may increase mortality.² Conversely, vitamin D₃ supplements have been shown to decrease mortality in elderly people who are living independently or in institutional care.²

Hypervitaminosis may be acute or chronic with very specific or general clinical symptoms. Acute hypervitaminosis is the result of a very high dose of one or more multiple vitamin preparations/supplements. Chronic hypervitaminosis results due to the gradual development of clinical symptoms over extended periods of time.

Certain symptoms of intoxication are common to all the forms of hypervitaminosis, such as headache, severe weakness, dizziness, inability to exercise, inability to perform daily routine, nausea, sensations of internal tremor, constipation, or diarrhea. Hypervitaminosis due to fat-soluble vitamins has a more pronounced course because these vitamins accumulate in the body tissues and cause severe intoxication. Hypervitaminosis due to water-soluble vitamins has a less pronounced manifestation and is not life-threatening. Therefore, it can be normalized by increasing the urinary output and restricting the intake of such supplements.^2,4

Hypervitaminosis A

Hypervitaminosis A occurs due to prolonged ingestion of too much of preformed vitamin A from foods (fish oil, animal liver and kidney, and plant sources like carrots). The amount of vitamin A in supplements per capsule is typically 10,000-50,000 international units (IU). Cod-liver oils may contain more than 180,000 IU/g. The acute toxic dose of vitamin A is 25,000 IU/kg, whereas the chronic toxic dose is 4,000 IU/kg every day for 6 to 15 months.^2,5

Hypervitaminosis A may be acute or chronic. An acute form is extremely rare, and the symptoms may manifest as headache, vomiting, short-term loss of consciousness, dizziness, irritability, nausea, abdominal pain, fever, skin rashes all over the body without clear localization, and visual disturbances like diplopia. The chronic forms are associated with symptoms such as dry patchy skin, dry fissured lips, hair loss, and brittle nails. Hypervitaminosis A also affects the osteoarticular structure by altering bone metabolism, accompanied by stiffness in movements and pain and swelling of periarticular soft tissues. In pregnant women, long-term use may cause severe teratogenic effects in the fetus, including malformations of eyes, skull, lungs, and heart.²

In elderly people, symptoms may manifest as decreased vision, imbalance of lipid profile, arrhythmia, common arthralgia, and chronic hepatic and renal failure. Carotenodermia (harmless condition in which skin turns orange) has been reported in men from long-term intake of beta-carotene. This can be reversed by discontinuing the intake of beta-carotene. Toxicity due to vitamin A supplements has also been reported in children. Management is by discontinuation of supplements and taking only prescribed doses.^2,5

Hypervitaminosis D

Hypervitaminosis D is caused by prolonged and/or excessive intake of prescribed medications such as calcium along with vitamin D. Excessive exposure to sunlight does not result in excessive levels of vitamin D. Recently, concern about vitamin D deficiency has led to the overconsumption of various forms of vitamin D supplements. The acute toxic dose for vitamin D has not been reported. The chronic toxic dose in adults is higher than 50,000 IU/day. In infants younger than 6 months, 1,000 IU/day may be considered unsafe. The tolerable upper-intake level for all groups older than age 1 year is 2,000 IU/day. Therefore, there is wide variation in the potential toxicity for vitamin D. Toxicity is much more likely to occur from high intakes of dietary supplements containing vitamin D.^2,6

Signs of acute toxicity include tremors of distal parts of the extremities, a sharp pain syndrome in the muscles of back and extremities, general dehydration of the body, and subcutaneous hemorrhages of various forms and to different extents. In pregnant women, there is the risk for the development of bone-structure anomalies.

Long-term high-dose D supplement intake may result in adverse health effects, increase in mortality, greater risk of pancreatic cancer, cardiovascular events, and increased falls and fractures in the elderly. In children, hypervitaminosis D has been associated with dental enamel hypoplasia and focal pulp calcification.

The protective effect of vitamin A in hypervitaminosis D₃ is its ability to downregulate matrix Gla proteins in the soft tissues and prevent calcification in renal tissue.^2,6

Hypervitaminosis E

Vitamin E is naturally present in vegetable oils, unprocessed cereal grains, nuts, and seeds. No adverse side effects have been reported after consuming vitamin E in natural foods. People have been taking vitamin E supplements on a regular basis because of its known antioxidant, antiatherogenic, antisterility, and antiaging properties. The recommended daily dose is 3 to 25 mg/day, and the side effects are observed at doses above 1 g/kg.^2,7

Healthy individuals taking vitamin E daily at a dose of 100 mg or more for prolonged duration (1 year) are likely to exhibit hypervitaminosis E. A daily dose at 150-200 mg/kg body weight/day may result in cystic fibrosis abetalipoproteinemia. The number and severity of side effects are directly proportional to the dose and duration of vitamin E intake. High doses of alpha-tocopherol supplements can affect blood clotting by inhibiting vitamin K–dependent carboxylase, which leads to increased bleeding, inhibited platelet aggregation by reducing the platelet thromboxane production, hemorrhages, and an impaired immune system caused by decreasing phagocyte activity of the leucocytes. The cardiovascular effects associated with hypervitaminosis E are aggravation of angina, hypertension, and acceleration of atherogenesis. Fatigue, weakness, headache, gastrointestinal disturbance, diarrhea, intestinal cramps, and delayed wound healing have also been associated with vitamin E toxicity. Management is by discontinuing the supplements, and consuming only the daily recommended dose.^2,7,8

Hypervitaminosis K

Vitamin K₁ and vitamin K₂ are the two common forms of vitamin K. Vitamin K₁ is produced in green leafy vegetables like spinach, cabbage, broccoli, and brussels sprouts and is also found in cow’s milk, soy oil, cottonseed oil, canola oil, and olive oil. Vitamin K₂ is synthesized by intestinal bacteria in the body and can be found in dairy, fermented foods, and animal products. Both forms are likely safe for most people when taken by mouth or injected into the vein. Side effects are negligible in most people who take a physician’s recommended amount each day.

There isn’t enough scientific information to determine recommended dietary allowances for vitamin K. It has been reported that if one is suffering from diabetes, monitoring of blood sugar level becomes necessary as vitamin K₁ might lower blood sugar level. Vitamin K toxicity can occur only with type K₃ that leads to hemolytic anemia by inhibiting the glutathione function that may lead to accumulation of reactive oxygen species. This may cause a rupture of the red blood cell membrane due to oxidative stress and lead to hemolytic anemia, jaundice, or liver damage. This is rarely observed in adults and is mostly seen in infants. People taking blood-thinning drugs or anticoagulants should limit their intake of foods with vitamin K, as excess vitamin K can alter blood-clotting times.^2,9  

Hypervitaminosis C

While the acute toxic dose for vitamin C has not been determined, the chronic toxic dose is more than 2 g/day. The maximum dose for adults should not exceed 90 mg/day. The symptoms of hypervitaminosis C in adults are manifested as feelings of weakness, dizziness, diarrhea, nausea, vomiting, insomnia, headache, allergic reactions to skin, heartburn, and stomachache. Overdoses of ascorbic acid have been reported to be associated with increased nervous excitability, itching, and rashes on the skin in children. Various serious consequences have also been reported with prolonged overdose of the supplement, such as kidney disease, gastritis, and stomach ulcer, deficiency of vitamin B complex, disturbance of the pancreas, increased blood pressure, progressive deterioration of vision, disturbance in menstrual cycle, decrease in the number of leucocytes, and hormonal disorders. An excess of vitamin C in the body stimulates the accumulation of oxalates and their deposition in the renal tissue and gall bladder. An overdose of vitamin C during pregnancy can cause severe disorders in the metabolism of the fetus. Management is by discontinuing the supplement use and increasing the urinary output.^2,10  

Hypervitaminosis B

Hypervitaminosis B-Complex: Hypervitaminosis of vitamin B complex causes the following symptoms: generalized hypersensitivity of skin, headache of varying degrees of intensity without limited localization, intestinal ulcers, occurrence of sleep disorders, fatty liver, hyperglycemia, hyperuricemia, nausea, and indigestion.^2,10,11 

Hypervitaminosis B₁: Overdose of thiamine (B₁) blocks nerve transmission and causes paralysis, restlessness, convulsions, respiratory paralysis, and cardiac failure. It also interferes with other B vitamins, insulin, and thyroid functions.^2,11 

Hypervitaminosis B₂ (Riboflavin): Prolonged use of this vitamin may result in liver dysfunction, photophobia, cracks and ulcers in the corners of the mouth, cardiomyopathies, vomiting, itching, numbness, burning or prickling sensation, hypotension, fatigue, and production of bright yellow urine.^2,11

Hypervitaminosis B₃ (Niacin): Some adverse effects, such as skin flushing, have been reported at a dose of 50 mg/day or greater. The therapeutic doses are considered to range from 1,500-1,600 mg/day. Prolonged use at a dose of 3 g/day may be associated with risk for liver toxicity, low blood pressure, light-headedness, insomnia, peptic ulcer, skin rash, hyperemia of skin, pruritus, gastrointestinal disturbances, aggravation of bronchial asthma, gout, and fasting hyperglycemia.^2,11

Hypervitaminosis B₅: Overdose of B₅ (pantothenic acid) may cause diarrhea, gastrointestinal problems, and water retention leading to edema.^2,11

Hypervitaminosis B₆: Hypervitaminosis B₆ (pyridoxine) is extremely rare. Prolonged use of supplements at a dose of 300 to 500 mg/day can cause severe and progressive sensory neuropathy with ataxia, painful skin rashes, photosensitivity, nausea, and heartburn. The severity of symptoms is dose-dependent. Excessive doses cause damage to sensory neurons resulting in paresthesia in the hands and feet, difficulty in walking, tiredness, and reduced sensation to touch. Discontinuing the use of vitamin B₆ may resolve symptoms unless irreversible damage has occurred to neurons.^2,11

Hypervitaminosis B₇ (Biotin): Side effects from an overdose of biotin (vitamin H/B₇) are rare, as it is easily excreted in urine and feces. Sometimes overdose may cause hyperkeratosis of superficial follicular epithelium.^2,11

Hypervitaminosis B₉ (Folic Acid): The symptoms of hypervitaminosis B₉ are specified by tonic convulsions in the gastric muscles that may occur at any time of the day, and inhibition of the function of hepatic alcohol dehydrogenase. Sleep, stomach, and skin problems are also associated with overdose.^2,11

Hypervitaminosis B₁₂ (Cobalamin): Hypervitaminosis B₁₂ occurs in the elderly who take it in the parenteral dosage for treating malignant anemia. Overdose may lead to various types of allergic reactions, congestive heart failure, pulmonary edema, reduction in the size of vascular-controlled reflexes, palpitations, tingling sensations, and numbness of limbs. The toxic dose for vitamin B₁₂ has not been specified.^2,11

Conclusion

In an effort to combat poor diets or vitamin deficiencies, people often take various vitamin supplements in excess without consulting medical practitioners, nutritionists, or dieticians. High intake of fat-soluble or water-soluble vitamins can lead to accumulation of vitamins in body tissues and fluids that cause toxicity and hypervitaminosis.

Whereas high intake of water-soluble vitamins generally does not impose a serious threat, the accumulation of fat-soluble vitamins A, D, E, and K may cause intoxication syndrome, resulting in more serious adverse health consequences. Hypervitaminosis can be normalized by increasing the urinary output and limiting the intake of vitamin supplements. Taking the advice of physicians, pharmacists, nutritionists, or dieticians before consuming vitamin supplements can limit the likelihood of adverse outcomes.

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