Hypervitaminosis A refers to any number of a large amount of toxic effects from ingesting too much preformed vitamin A. Symptoms may result from effects, including altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervitaminosis A is believed to have occurred in early humans and the problem still persists.
Toxicity may result from ingesting too much preformed vitamin A from the diet, supplement intake, or prescription medication, and can be prevented by not ingesting more than guideline amounts.
Diagnosis is difficult, as serum retinol is not sensitive to toxic levels of vitamin A, although some tests are available. Hypervitaminosis A is usually treated by stopping high vitamin A intake. Most people fully recover.
High intake of provitamin carotenoids, such as beta carotene, does not cause hypervitaminosis A, as conversion to the active form of vitamin A is highly regulated.
Signs and symptoms
Symptoms may include:
- Abnormal softening of the skull bone (craniotabesâ€"infants and children)
- Blurred vision
- Bone pain or swelling
- Bulging fontanelle (infants)
- Changes in consciousness
- Decreased appetite
- Dizziness
- Double vision (young children)
- Drowsiness
- Headache
- Gastric mucosal calcinosis
- Heart valve calcification
- Hypercalcemia
- Increased intracranial pressure (may be referred to as Idiopathic intracranial hypertension)
- Irritability
- Liver damage
- Nausea
- Poor weight gain (infants and children)
- Skin and hair changes
- Cracking at corners of the mouth
- Hair loss
- Higher sensitivity to sunlight
- Oily skin and hair (seborrhea)
- Premature epiphyseal closure
- Skin peeling, itching
- Spontaneous fracture
- Yellow discoloration of the skin (aurantiasis cutis)
- Uremic pruritus
- Vision changes
- Vomiting
Causes
Hypervitaminosis A results from excessive intake of preformed vitamin A. A genetic variance in tolerance to vitamin A intake may occur. Children are particularly sensitive to vitamin A, with daily intakes of 1500 IU/kg body weight reportedly leading to toxicity.
Types of vitamin A
- Provitamin carotenoids - such as beta carotene - are “largely impossible†to cause toxicity, as conversion to retinol is a highly regulated. No vitamin A toxicity has been reported from ingestion of excessive amounts. Overconsumption of beta carotene can, however, cause carotenosis, a benign condition in which the skin turns orange.
- Preformed vitamin A absorption and storage in the liver occur very efficiently until a pathologic condition develops. When ingested, 70-90% of preformed vitamin A is absorbed and used.
Sources of toxicity
- Diet - liver is high in vitamin A. The liver of certain animals â€" including the polar bear, bearded seal, walrus, moose, and husky â€" are particularly toxic.
- Supplements - usually when taken above recommended dosages - can be toxic. Cod liver oil is particularly high in vitamin A.
- Medications - at high doses of vitamin A - are often used on long-term basis in numerous preventive and therapeutic medical applications, which may lead to hypervitaminosis A
Types of toxicity
- Acute toxicity occurs over a period of hours or a few days, and is less of a problem than chronic toxicity.
- Chronic toxicity - ingestion of high amounts of preformed vitamin A for months or years - results from daily intakes greater than 25,000 IU for 6 years or longer and more than 100,000 IU for 6 months or longer - are considered toxic.
Mechanism
Absorption and storage in the liver of preformed vitamin A occur very efficiently until a pathologic condition develops.
Delivery to tissues
Absorption
When ingested, 70-90% of preformed vitamin A is absorbed and used.
Storage
About 80% of the total body reserves of vitamin A are in the liver. Fat is another significant storage site, while the lung and kidneys may also be capable of storage.
Transport
Once in the liver, retinol binds to retinol-binding protein (RBP) and is transported from the liver to tissues as the holo-RBP complex. The range of serum retinol concentrations under normal conditions is 1â€"3 μmol/l. Elevated amounts of retinyl ester (i.e., > 10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans. Candidate mechanisms for this increase include decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells.
Effects
Effects include increased bone turnover and altered metabolism of fat-soluble vitamins. More research is needed to fully elucidate the effects.
Increased bone turnover
Retinoic acid suppresses osteoblast activity and stimulates osteoclast formation in vitro, resulting in increased bone resorption and decreased bone formation. It is likely to exert this effect by binding to specific nuclear receptors (members of the retinoic acid receptor or retinoid X receptor nuclear transcription family) which are found in every cell (including osteoblasts and osteoclasts).
This change in bone turnover is likely to be the reason for numerous effects seen in hypervitaminosis A, such as hypercalcemia and numerous bone changes such as bone loss that potentially leads to osteoporosis, spontaneous bone fractures, altered skeletal development in children, skeletal pain, radiographic changes, and bone lesions.
Altered fat-soluble vitamin metabolism
Vitamin A is fat-soluble and high levels have been reported affect metabolism of the other fat-soluble vitamins D, E, and K.
The toxic effects of vitamin A might be related to altered vitamin D metabolism, concurrent ingestion of substantial amounts of vitamin D, or binding of vitamin A to receptor heterodimers. Antagonistic and synergistic interactions between these two vitamins have been reported, as they relate to skeletal health.
Stimulation of bone resorption by vitamin A has been reported to be independent of its effects on vitamin D.
Diagnosis
Tests
Tests may include:
- bone X-rays
- blood calcium test
- cholesterol test
- liver function test
- blood test for vitamin A
Relevance of blood tests
Retinol concentrations are nonsensitive indicators
Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are not sensitive indicators in this range of liver vitamin A reserves. The range of serum retinol concentrations under normal conditions is 1â€"3 μmol/l and, because of homeostatic regulation, that range varies little with widely disparate vitamin A intakes
Retinol esters have been used as markers
Retinyl esters can be distinguished from retinol in serum and other tissues and quantified with the use of methods such as high-performance liquid chromatography.
Elevated amounts of retinyl ester (i.e., > 10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans and monkeys. This increased retinyl ester may be due to decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells.
Prevention
Hypervitaminosis A can be prevented by not ingesting more than the US Institute of Medicine Daily Tolerable Upper Level of intake for Vitamin A. This level is for synthetic and natural retinol ester forms of vitamin A. Carotene forms from dietary sources are not toxic. The dose over and above the RDA is among the narrowest of the vitamins and minerals. Possible pregnancy, liver disease, high alcohol consumption, and smoking are indications for close monitoring and limitation of vitamin A administration.
Daily Tolerable Upper Level
Treatment
In humans
- Stopping high Vitamin A intake is the standard treatment. Most people fully recover.
- Vitamin E may alleviate hypervitaminosis A.
- Liver transplantation may be a valid option if no improvement occurs.
Since cytochrome p450, and especially CYP3A4, is responsible for oxidizing excess retinol, these factors should be considered to eliminate any side effects: Vitamin D intake (a known CYP3A4-inducer), iron intake (CYP3A4 has an iron center). Copper and vitamin C are also critical, for their roles in iron metabolism.
In animals
These treatments have been used to help treat or manage toxicity in animals. Although not considered part of standard treatment, they might be of some benefit to humans.
- Vitamin E appears to be an effective treatment in rabbits, prevents side effects in chicks
- Taurine significantly reduces toxic effects in rats. Retinoids can be conjugated by taurine and other substances. Significant amounts of retinotaurine are excreted in the bile, and this retinol conjugate is thought to be an excretory form, as it has little biological activity.
- Cholestin - significantly reduces toxic effects in rats.
- Vitamin K prevents hypoprothrombinemia in rats and can sometimes control the increase in lasma/cell ratios of vitamin A.
In vitro
These treatments help prevent toxic effects in vitro.
- Taurine, zinc, and vitamin E protect cells from retinol-induced injury.
- Cholesterol prevents retinol-induced Golgi apparatus fragmentation.
History
Vitamin A toxicity is known to be an ancient phenomenon; fossilized skeletal remains of early humans suggest bone abnormalities may have been caused by hypervitaminosis A.
Vitamin A toxicity has long been known to the Inuit and has been known by Europeans since at least 1597 when Gerrit de Veer wrote in his diary that, while taking refuge in the winter in Nova Zemlya, he and his men became severely ill after eating polar bear liver.
In 1913, Antarctic explorers Douglas Mawson and Xavier Mertz were both poisoned (and Mertz died) from eating the livers of their sled dogs during the Far Eastern Party (another study suggests, however, that exhaustion and diet change are more likely to have caused the tragedy).
Other animals
Some Arctic animals demonstrate no signs of hypervitaminosis A despite having 10-20 times the level of vitamin A in their livers than other Arctic animals. These animals are top predators and include polar bear, Arctic fox, bearded seal, and glaucous gull. This ability to efficiently store higher amounts of vitamin A may have contributed to their survival in the extreme environment of the Arctic.
See also
- Vitamin poisoning
- Far Eastern Party
- Retinoic acid syndrome
- Piblokto
References
External links
- Facts about Vitamin A and Carotenoids, from the National Institutes of Health's Office of Dietary Supplements.
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