Vitamin A toxicity; Vitamin A - 80-90% of the total body reserves of vitamin A are in the liver

Absorption

When ingested, 70-90% of preformed vitamin A is absorbed and used.

Storage

80-90% of the total body reserves of vitamin A are in the liver (with 80-90% of this amount being stored in hepatic stellate cells and the remaining 10-20% being stored in hepatocytes). Fat is another significant storage site, while the lung and kidneys may also be capable of storage.

Transport

Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids.

The range of serum retinol concentrations under normal conditions is 1–3 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 of excess Vitamin A

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.

Mitochondrial toxicity

Vitamin A exerts several toxic effects regarding redox environment and mitochondrial function.


Signs and symptoms of Vitamin A toxicity 

Symptoms may include:[1]

Abnormal softening of the skull bone (craniotabes—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[2]
Heart valve calcification[3]
Hypercalcemia
Increased intracranial pressure manifesting as cerebral edema, papilledema, and headache[4] (may be referred to as Idiopathic intracranial hypertension)
Irritability
Liver damage[5][6][7][8][9][10][11][12][13]
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[14][15][16][17][18]
Skin peeling, itching
Spontaneous fracture[19][20]
Yellow discoloration of the skin (aurantiasis cutis)
Uremic pruritus[21]
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 their conversion to retinol is highly regulated. No vitamin A toxicity has ever been reported from ingestion of excessive amounts. Overconsumption of beta carotene can only cause carotenosis, a harmless and reversible cosmetic 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.[20]

Sources of toxicity

Diet - liver is high in vitamin A. The liver of certain animals — including the polar bear, bearded seal,[24][25] walrus,[26] moose,[27] — 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.

https://en.wikipedia.org/wiki/Hypervitaminosis_A#cite_note-2006Review-20