Vitamin A – Deficiency and Toxicity
Vitamin A, in the strictest sense, refers to retinol. However, the oxidized metabolites, retinaldehyde and retinoic acid, are also biologically active compounds. The term retinoids includes all molecules (including synthetic molecules) that are chemically related to retinol. Retinaldehyde (11-cis) is the essential form of vitamin A that is required for normal vision, whereas retinoic acid is necessary for normal morphogenesis, growth, and cell differentiation. Retinoic acid does not function in vision and, in contrast to retinol, is not involved in reproduction. Vitamin A also plays a role in iron utilization, humoral immunity, T cell–mediated immunity, natural killer cell activity, and phagocytosis. Vitamin A is commercially available in esterified forms (e.g., acetate, palmitate) since it is more stable as an ester.
There are more than 600 carotenoids in nature, and approximately 50 of these can be metabolized to vitamin A. β-Carotene is the most prevalent carotenoid in the food supply that has provitamin A activity. In humans, significant fractions of carotenoids are absorbed intact and are stored in liver and fat. It is now estimated that 12 µg or greater of dietary β-carotene is equivalent to 1 µg of retinol, whereas 24 µg or greater of other dietary provitamin A carotenoids (e.g., cryptoxanthin, α-carotene) is equivalent to 1 µg of retinol.
The liver contains approximately 90% of the vitamin A reserves and secretes vitamin A in the form of retinol, which is bound to retinol-binding protein. Once this has occurred, the retinol-binding protein complex interacts with a second protein, transthyretin. This trimolecular complex functions to prevent vitamin A from being filtered by the kidney glomerulus, to protect the body against the toxicity of retinol and to allow retinol to be taken up by specific cell-surface receptors that recognize retinol-binding protein. A certain amount of vitamin A enters peripheral cells even if it is not bound to retinol-binding protein. After retinol is internalized by the cell, it becomes bound to a series of cellular retinol-binding proteins, which function as sequestering and transporting agents as well as co-ligands for enzymatic reactions. Certain cells also contain retinoic acid–binding proteins, which have sequestering functions but also shuttle retinoic acid to the nucleus and enable its metabolism.
Retinoic acid is a ligand for certain nuclear receptors that act as transcription factors. Two families of receptors (RAR and RXR receptors) are active in retinoid-mediated gene transcription. Retinoid receptors regulate transcription by binding as dimeric complexes to specific DNA sites, the retinoic acid response elements, in target genes. The receptors can either stimulate or repress gene expression in response to their ligands. RAR binds all-trans retinoic acid and 9-cis retinoic acid, whereas RXR binds only 9-cis retinoic acid.
The retinoid receptors play an important role in controlling cell proliferation and differentiation. Retinoic acid is useful in the treatment of promyelocytic leukemia and is also used in the treatment of cystic acne because it inhibits keratinization, decreases sebum secretion, and possibly alters the inflammatory reaction. RXRs dimerize with other nuclear receptors to function as coregulators of genes responsive to retinoids, thyroid hormone, and calcitriol. RXR agonists induce insulin sensitivity experimentally, perhaps because RXR is a cofactor for the peroxisome-proliferator-activated receptors (PPARs), which are targets for the thiazolidinedione drugs such as rosiglitazone and troglitazone
The retinol activity equivalent (RAE) is used to express the vitamin A value of food. One RAE is defined as 1 µg of retinol (0.003491 mmol), 12 µg of β-carotene, and 24 µg of other provitamin A carotenoids. In older literature, vitamin A was often expressed in international units (IU), with 1 RAE being equal to 3.33 IU of retinol and 20 IU of β-carotene, but these units are no longer in current scientific use.
Liver, fish, and eggs are excellent food sources for preformed vitamin A; vegetable sources of provitamin A carotenoids include dark green and deeply colored fruits and vegetables. Moderate cooking of vegetables enhances carotenoid release for uptake in the gut. Carotenoid absorption is also aided by some fat in a meal. Infants are particularly susceptible to vitamin A deficiency because neither breast nor cow's milk supplies enough vitamin A to prevent deficiency. In developing countries, chronic dietary deficit is the main cause of vitamin A deficiency and is exacerbated by infection. In early childhood, low vitamin A status results from inadequate intakes of animal food sources and edible oils, both of which are expensive, coupled with seasonal unavailability of vegetables and fruits, and lack of marketed fortified food products. Concurrent zinc deficiency can interfere with the mobilization of vitamin A from liver stores. Alcohol interferes with the conversion of retinol to retinaldehyde in the eye by competing for alcohol (retinol) dehydrogenase. Drugs that interfere with the absorption of vitamin A include mineral oil, neomycin, and cholestyramine.
Vitamin A deficiency is endemic where diets are chronically poor, especially in Southern Asia, Sub-Saharan Africa, some areas of Latin America, and the Western Pacific, including parts of
Any stage of xerophthalmia should be treated with 60 mg of vitamin A in oily solution, usually contained in a soft-gel capsule. The same dose is repeated 1 and 14 days later. Doses should be reduced by half for patients 6–11 months of age. Mothers with night blindness or Bitot's spots should be given vitamin A orally, either 3 mg daily or 7.5 mg twice a week for 3 months. These regimens are efficacious, and they are less expensive and more widely available than injectable water-miscible vitamin A. A common approach to prevention is to supplement young children living in high-risk areas with 60 mg every 4–6 months, with a half-dose given to infants 6–11 months of age.
There are no specific deficiency signs or symptoms that result from carotenoid deficiency. It was postulated that β-carotene would be an effective chemopreventive agent for cancer because numerous epidemiologic studies had shown that diets high in β-carotene were associated with lower incidences of cancers of the respiratory and digestive systems. However, intervention studies in smokers found that treatment with high doses of β-carotene actually resulted in more lung cancers than did treatment with placebo. Non–provitamin A carotenoids, such as lutein and zeaxanthin, have been suggested to protect against macular degeneration. The non–provitamin A carotenoid lycopene has been proposed to protect against prostate cancer. However, the effectiveness of these agents has not been proven by intervention studies, and the mechanisms underlying these purported biologic actions are unknown.
Acute toxicity of vitamin A was first noted in Arctic explorers who ate polar bear liver and has also been seen after administration of 150 mg in adults or 100 mg in children. Acute toxicity is manifested by increased intracranial pressure, vertigo, diplopia, bulging fontanels in children, seizures, and exfoliative dermatitis; it may result in death. In children being treated for vitamin A deficiency according to the protocols outlined above, transient bulging of fontanels occurs in 2% of infants, and transient nausea, vomiting, and headache occur in 5% of preschoolers. Chronic vitamin A intoxication is largely a concern in industrialized countries and has been seen in normal adults who ingest 15 mg/d and children who ingest 6 mg/d of vitamin A over a period of several months. Manifestations include dry skin, cheilosis, glossitis, vomiting, alopecia, bone demineralization and pain, hypercalcemia, lymph node enlargement, hyperlipidemia, amenorrhea, and features of pseudotumor cerebri with increased intracranial pressure and papilledema. Liver fibrosis with portal hypertension and bone demineralization may result from chronic vitamin A intoxication. When vitamin A is provided in excess to pregnant women, congenital malformations have included spontaneous abortions, craniofacial abnormalities, and valvular heart disease. In pregnancy, the daily dose of vitamin A should not exceed 3 mg. Commercially available retinoid derivatives are also toxic, including 13-cis-retinoic acid, which has been associated with birth defects. As a result, contraception should be continued for a least 1 year, and possibly longer, in women who have taken 13-cis retinoic acid.
High doses of carotenoids do not result in toxic symptoms but should be avoided in smokers due to an increased risk of lung cancer. Carotenemia, which is characterized by a yellowing of the skin (creases of the palms and soles) but not the sclerae, may be present after ingestion of >30 mg of β-carotene daily. Hypothyroid patients are particularly susceptible to the development of carotenemia due to impaired breakdown of carotene to vitamin A. Reduction of carotenes from the diet results in the disappearance of skin yellowing and carotenemia over a period of 30–60 days.