Vitamin A

Vitamin A is a generic term for a large number of related compounds. Retinol (an alcohol) and retinal (an aldehyde) are often referred to as preformed vitamin A. Retinal can be converted by the body to retinoic acid, the form of vitamin A known to affect gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. Beta-carotene and other carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids. Hundreds of different carotenoids are synthesized by plants, but only about 10 % of them are provitamin A carotenoids. The following discussion will focus mainly on preformed vitamin A and retinoic acid.

Function

Vision

The retina is located at the back of the eye. When light passes through the lens, it is sensed by the retina and converted to a nerve impulse for interpretation by the brain. Retinol is transported to the retina via the circulation, where it moves into retinal pigment epithelial cells (diagram). There, retinol is esterified to form a retinyl ester, which can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis retinol, which can be oxidized to form 11-cis retinal. 11-cis Retinal can be shuttled across the interphotoreceptor matrix to the rod cell, where it binds to a protein called opsin to form the visual pigment, rhodopsin (visual purple). Rod cells with rhodopsin can detect very small amounts of light, making them important for night vision. Absorption of a photon of light catalyzes the isomerization of 11-cis retinal to all-trans retinal and results in its release. This isomerization triggers a cascade of events, leading to the generation of an electrical signal to the optic nerve. The nerve impulse generated by the optic nerve is conveyed to the brain where it can be interpreted as vision. Once released all-trans retinal is converted to all-trans retinol, which can be transported across the interphotoreceptor matrix to the retinal epithelial cell to complete the visual cycle (2). Inadequate retinol available to the retina results in impaired dark adaptation, known as "night blindness."

Regulation of gene expression

Retinoic acid (RA) and its isomers act as hormones to affect gene expression and thereby influence numerous physiological processes. All-trans RA and 9-cis RA are transported to the nucleus of the cell bound to cytoplasmic retinoic acid-binding proteins (CRABP). Within the nucleus, RA binds to retinoic acid receptor proteins (diagram). All-trans RA binds to retinoic acid receptors (RAR) and 9-cis RA binds to retinoid receptors (RXR). RAR and RXR form RAR/RXR heterodimers, which bind to regulatory regions of the chromosome called retinoic acid response elements (RARE). A dimer is a complex of two protein molecules. Heterodimers are complexes of two different proteins, while homodimers are complexes of two of the same protein. Binding of all-trans RA and 9-cis RA to RAR and RXR respectively allows the complex to regulate the rate of gene transcription, thereby influencing the synthesis of certain proteins used throughout the body. RXR may also form heterodimers with thyroid hormone receptors (THR) or vitamin D receptors (VDR). In this way, vitamin A, thyroid hormone, and vitamin D may interact to influence gene transcription. Through the stimulation and inhibition of transcription of specific genes, retinoic acid plays a major role in cellular differentiation, the specialization of cells for highly specific physiological roles. Most of the physiological effects attributed to vitamin A appear to result from its role in cellular differentiation.

Immunity

Vitamin A is commonly known as the anti-infective vitamin, because it is required for normal functioning of the immune system. The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) function as a barrier and form the body's first line of defense against infection. Retinol and its metabolites are required to maintain the integrity and function of these cells. Vitamin A and retinoic acid (RA) play a central role in the development and differentiation of white blood cells, such as lymphocytes that play critical roles in the immune response. Activation of T-lymphocytes, the major regulatory cells of the immune system, appears to require all-trans RA binding of RAR.

Growth and development

Both vitamin A excess and deficiency are known to cause birth defects. Retinol and retinoic acid (RA) are essential for embryonic development. During fetal development, RA functions in limb development and formation of the heart, eyes, and ears. Additionally, RA has been found to regulate expression of the gene for growth hormone.

Red blood cell production

Red blood cells, like all blood cells, are derived from precursor cells called stem cells. These stem cells are dependent on retinoids for normal differentiation into red blood cells. Additionally, vitamin A appears to facilitate the mobilization of iron from storage sites to the developing red blood cell for incorporation into hemoglobin, the oxygen carrier in red blood cells.

Nutrient interactions

Zinc

Zinc deficiency is thought to interfere with vitamin A metabolism in several ways: 1) Zinc deficiency results in decreased synthesis of retinol binding protein (RBP), which transports retinol through the circulation to tissues (e.g., the retina). 2) Zinc deficiency results in decreased activity of the enzyme that releases retinol from its storage form, retinyl palmitate, in the liver. 3) Zinc is required for the enzyme that converts retinol into retinal. At present, the health consequences of zinc deficiency on vitamin A nutritional status in humans are unclear.

Iron

Vitamin A deficiency may exacerbate iron deficiency anemia. Vitamin A supplementation has been shown to have beneficial effects on iron deficiency anemia and improve iron nutritional status among children and pregnant women. The combination of vitamin A and iron seems to reduce anemia more effectively than either iron or vitamin A alone.
Deficiency

Vitamin A deficiency and vision

Vitamin A deficiency among children in developing nations is the leading preventable cause of blindness. The earliest evidence of vitamin A deficiency is impaired dark adaptation or night blindness. Mild vitamin A deficiency may result in changes in the conjunctiva (corner of the eye) called Bitot's spots. Severe or prolonged vitamin A deficiency causes a condition called xeropthalmia (dry eye), characterized by changes in the cells of the cornea (clear covering of the eye) that ultimately result in corneal ulcers, scarring, and blindness.

Vitamin A deficiency and infectious disease

Vitamin A deficiency can be considered a nutritionally acquired immunodeficiency disease. Even children who are only mildly deficient in vitamin A have a higher incidence of respiratory disease and diarrhea, as well as a higher rate of mortality from infectious disease, than children who consume sufficient vitamin A. Supplementation of vitamin A has been found to decrease the severity of and deaths from diarrhea and measles in developing countries, where vitamin A deficiency is common. HIV-infected women who were vitamin A deficient were three to four times more likely to transmit HIV to their infants. The onset of infection reduces blood retinol levels very rapidly. This phenomenon is generally believed to be related to decreased synthesis of retinol binding protein (RBP) by the liver. In this manner, infection stimulates a vicious cycle, because inadequate vitamin A nutritional status is related to increased severity and likelihood of death from infectious disease.

Disease Prevention

Cancer

Studies in cell culture and animal models have documented the capacity for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites. However, the results of human studies examining the relationship between the consumption of preformed vitamin A and cancer are less clear.

Lung cancer

At least ten prospective studies have compared blood retinol levels at baseline among people who subsequently developed lung cancer and those who did not. Only one of those studies found a statistically significant inverse association between serum retinol and lung cancer risk. The results of the Beta-Carotene And Retinol Efficacy Trial (CARET) suggest that high-dose supplementation of vitamin A and beta-carotene should be avoided in people at high risk of lung cancer. About 9,000 people (smokers and people with asbestos exposure) were assigned a daily regimen of 25,000 IU of retinol and 30 milligrams of beta-carotene, while a similar number of people were assigned a placebo. After four years of follow up the incidence of lung cancer was 28% higher in the supplemented group. Presently, it seems unlikely that increased retinol intake decreases the risk of lung cancer, although the effects of retinol may be different for nonsmokers compared to smokers.

Breast cancer

Retinol and its metabolites have been found to reduce the growth of breast cancer cells in the test tube, but observational studies of dietary retinol intake in humans have been less optimistic. The majority of epidemiological studies have failed to find significant associations between retinol intake and breast cancer risk in women, although one large prospective study found total vitamin A intake to be inversely associated with the risk of breast cancer in premenopausal women with a family history of breast cancer. Blood levels of retinol reflect the intake of both preformed vitamin A and provitamin A carotenoids like beta-carotene. Although a recent case-control study found serum retinol levels and serum antioxidant levels to be inversely related to the risk of breast cancer, two recent prospective studies did not observe significant associations between blood retinol levels and the subsequent risk of developing breast cancer. Presently, there is little evidence in humans that increased intake of preformed vitamin A or retinol reduces breast cancer risk.

Disease Treatment

Pharmacologic doses of retinoids

It is important to note that treatment with high doses of natural or synthetic retinoids overrides the body's own control mechanisms, and therefore carries with it risks of side effects and toxicity. Additionally, all of these compounds have been found to cause birth defects. Women who have a chance of becoming pregnant should avoid treatment with these medications. Retinoids tend to be very long acting; side effects and birth defects have been reported to occur months after discontinuing retinoid therapy. The retinoids discussed below are prescription drugs, and should not be used without medical supervision.

Retinitis pigmentosa

Retinitis pigmentosa describes a broad spectrum of genetic disorders that result in the progressive loss of photoreceptor cells (rods and cones) in the eye's retina. Early symptoms of retinitis pigmentosa include impaired dark adaptation and night blindness, followed by the progressive loss of peripheral and central vision over time. The results of a randomized controlled trial in more than 600 patients with common forms of retinitis pigmentosa indicated that supplementation with 4,500 mcg (15,000 IU)/day of preformed vitamin A (retinol) significantly slowed the loss of retinal function over a period of 4-6 years. In contrast, supplementation with 400 IU/day of vitamin E increased the loss of retinal function by a small but significant amount, suggesting that patients with common forms of retinitis pigmentosa may benefit from long term vitamin A supplementation but should avoid vitamin E supplementation at levels higher than those found in a typical multivitamin. Up to 12 years of follow-up in these patients did not reveal any signs of liver toxicity as a result of excess vitamin A intake. High dose vitamin A supplementation to slow the course of retinitis pigmentosa requires medical supervision and must be discontinued if there is a possibility of pregnancy (see Safety).

Acute promyelotic leukemia

Normal differentiation of myeloid stem cells in the bone marrow gives rise to platelets, red blood cells, and white blood cells, which are important for the immune response. Altered differentiation of those stem cells results in the proliferation of immature leukemic cells, giving rise to leukemia. A mutation of the retinoic acid receptor RAR has been discovered in patients with a specific type of leukemia called acute promyelotic leukemia (APL). Treatment with all-trans retinoic acid or high doses of all-trans retinyl palmitate restores normal differentiation, and leads to improvement in some APL patients.

Diseases of the skin

Both natural and synthetic retinoids have been used as pharmacologic agents to treat disorders of the skin. Etretinate and acitretin are retinoids that have been useful in the treatment of psoriasis, while tretinoin (Retin-A) and isotretinoin (Accutane) have been used successfully to treat severe acne. Retinoids most likely affect the transcription of skin growth factors and their receptors.

Safety in pregnancy

Although normal fetal development requires sufficient vitamin A intake, consumption of excess preformed vitamin A (retinol) during pregnancy is known to cause birth defects. No increase in the risk of vitamin A-associated birth defects has been observed at doses of preformed vitamin A from supplements below 3,000 mcg/day (10,000 IU/day). Since a number of foods in the U.S. are fortified with preformed vitamin A, pregnant women should avoid multivitamin or prenatal supplements that contain more than 1,500 mcg (5,000 IU) of vitamin A. Vitamin A from beta-carotene is not known to increase the risk of birth defects. Etretinate and isotretinoin (Accutane), synthetic derivatives of retinol, are known to cause birth defects and should not be taken during pregnancy or if there is a possibility of becoming pregnant. Tretinoin (Retin-A), another retinol derivative, is prescribed as a topical preparation that is applied to the skin. Because of the potential for systemic absorption of topical tretinoin, its use during pregnancy is not recommended.

Do high intakes of vitamin A increase the risk of osteoporosis?

The results of several recent prospective studies suggest that long term intakes of preformed vitamin A in excess of 1,500 mcg/day (5,000 IU/day) are associated with increased risk of osteoporotic fracture and decreased bone mineral density (BMD) in older men and women. Although this level of intake is greater than the RDA of 700-900 mcg/day (2,300-3,000 IU/day), it is substantially lower than the UL of 3,000 mcg/day (10,000 IU/day). Only excess intakes of preformed vitamin A (retinol), not beta-carotene, were associated with adverse effects on bone health. Although these observational studies cannot provide the reason for the association between excess retinol intake and osteoporosis, limited experimental data suggest that excess retinol may stimulate bone resorption or interfere with the ability of vitamin D to maintain calcium balance. In the U.S., retinol intakes in excess of 5,000 IU/day can be easily attained by those who regularly consume multivitamin supplements and/or fortified foods, including some breakfast cereals. At the other end of the spectrum, a significant number of elderly people have insufficient vitamin A intakes, which have also been associated with decreased BMD. One study of elderly men and women found that BMD was optimal at vitamin A intakes close to the RDA. Until supplements and fortified foods are reformulated to reflect the current RDA for vitamin A, it makes sense to look for multivitamin supplements that contain 2,500 IU of vitamin A or multivitamin supplements that contain 5,000 IU of vitamin A, of which at least 50% comes from beta-carotene (see example supplement label).

Drug Interactions

Chronic alcohol consumption results in depletion of liver stores of vitamin A, and may contribute to alcohol-induced liver damage. However, the liver toxicity of preformed vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics. Oral contraceptives that contain estrogen and progestin increase retinol binding protein (RBP) synthesis by the liver, increasing the export of RBP-retinol complex in the blood. Whether this increases the dietary requirement of vitamin A is not known. Retinoids or retinoid analogs, including acitretin, all-trans-retinoic acid, bexarotene, etretinate and isotretinoin (Accutane), should not be used in combination with vitamin A supplements, because they may increase the risk of vitamin A toxicity.

Linus Pauling Institute Recommendation

The RDA for vitamin A (2,300 IU/day for women and 3,000 IU/day for men) is sufficient to support normal gene expression, immune function, and vision. However, following the Linus Pauling Institute’s recommendation to take a multivitamin/multimineral supplement daily could supply as much as 5,000 IU/day of vitamin A as retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/multimineral supplement that provides no more than 2,500 IU of vitamin A or a supplement that provides 5,000 IU of vitamin A, of which at least 50% comes from beta-carotene (see example supplement label). High potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.

Older adults (65 years and older)

Presently there is little evidence that the requirement for vitamin A in older adults differs from that of younger adults. Additionally, vitamin A toxicity may occur at lower doses in older adults than in younger adults. Following the Linus Pauling Institute’s recommendation to take a multivitamin/multimineral supplement daily could supply as much as 5,000 IU/day of retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/multimineral supplement that provides no more than 2,500 IU of vitamin A or a supplement that provides 5,000 IU of vitamin A, of which at least 50% comes from beta-carotene (see example supplement label). High potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/