|Classification and external resources|
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, but not limited to, altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervitaminosis A is believed to have occurred in early humans and the problem persists up until the current day.
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, do not cause Hypervitaminosis A as conversion to the active form of Vitamin A is highly regulated.
- 1 Signs and symptoms
- 2 Causes
- 3 Mechanism
- 4 Diagnosis
- 5 Prevention
- 6 Treatment
- 7 History
- 8 Other animals
- 9 See also
- 10 References
- 11 External links
Signs and symptoms
Symptoms may include:
- Abnormal softening of the skull bone (craniotabes—infants and children)
- Blurred vision
- Bone pain or swelling
- Bulging fontanelle (infants)
- Changes in consciousness
- Decreased appetite
- Double vision (young children)
- Gastric Mucosal Calcinosis (GMC)
- Heart valve calcification
- Increased intracranial pressure (may be referred to as Idiopathic intracranial hypertension)
- Liver damage
- 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
- Uremic Pruritus
- Vision changes
Hypervitaminosis A results from excessive intake of preformed Vitamin A. There may be a genetic variance in tolerance to vitamin A intake. Children are particularly sensitive to vitamin A, with daily intakes of 1500 IU/kg body wt reportedly leading to toxicity.
Types of Vitamin A
- Provitamin carotenoids - such as Betacarotene. It is “largely impossible” to get toxicity from this type of Vitamin A as conversion to retinal is a highly regulated. There are no reports of Vitamin A toxicity from ingestion of excessive amounts. Overconsumption of Betacarotene can however cause carotenosis, a benign condition in which the skin turns orange.
- Preformed Vitamin A - Absorption and storage in the liver of preformed vitamin A occur very efficiently until a pathologic condition develops. When ingested, 70-90% of preformed vitamin A is absorbed and utilized.
Sources of toxicity
- Diet - liver is high in Vitamin A. The liver of certain animals — including the polar bear, bearded seal, walrus, moose, and husky — are particularly toxic.
- Supplements - Usually when taken above recommended dosages. Cod liver oil is particularly high in Vitamin A.
- Medication - 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 - such as over a period of hours or a few days. Less of a problem than chronic toxicity.
- Chronic - ingestion of high amounts of preformed vitamin A for months or years. Daily intakes of > 25 000 IU for > 6 y and > 100,000 IU for > 6 months are considered toxic
Absorption and storage in the liver of preformed vitamin A occur very efficiently until a pathologic condition develops.
Delivery to tissues
When ingested, 70-90% of preformed vitamin A is absorbed and utilized.
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 1–3 μmol/L. Elevated amounts of retinyl ester (ie, > 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 include, but are not limited to, increased bone turnover and altered metabolism of fat-soluble vitamins. More research is needed to fully elucidate the effects.
Increased bone turnover
It is known that 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. There have been reported antagonistic and synergistic interactions between these 2 vitamins as they relate to skeletal health.
It has been reported that stimulation of bone resorption by Vitamin A is independent of its effects on Vitamin D.
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 nonsensitive indicators in this range of liver vitamin A reserves. The range of serum retinol concentrations under normal conditions is 1–3 μmol/L and, because of homeostatic regulation, that range varies little with widely disparate vitamin A intakes
Retinol esters have been used as markers
Elevated amounts of retinyl ester (ie, > 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.
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
|Life stage group category||Upper Level (μg/day)|
- Stopping high Vitamin A intake - This 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, the following 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.
The following 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 it is believed this retinol conjugate is 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 Plasma/cell ratio's of Vitamin A.
These treatments help prevent toxic effects in vitro.
- Taurine, zinc and Vitamin E - protects cells from retinol-induced injury.
- Cholesterol - prevents retinol induced golgi fragmentation.
Vitamin A toxicity is known to be an ancient phenomenon and fossilized skeletal remains of early humans suggest that 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 suggest however that exhaustion and diet change are more likely to have caused the tragedy).
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.
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