Vitamin A (retinol, retinal, and retinoic acid) is a fat-soluble vitamin that is the foundation of the visual cycle (where retinal is the chromophore of rhodopsin and the cone opsins), of immune function (where retinoic acid regulates the differentiation of immune cells and the production of antibodies), and of epithelial cell differentiation (where retinoic acid regulates the differentiation of the epithelial cells of the skin, the gut, the respiratory tract, and the genitourinary tract). Vitamin A deficiency is one of the most common nutritional deficiencies in the world — it affects approximately 250 million preschool-aged children in the developing world, and it is the leading cause of preventable blindness in children, producing xerophthalmia (dry eyes), night blindness, Bitot spots, keratomalacia, and in severe cases, permanent blindness. The prevention of vitamin A deficiency through supplementation and through the fortification of staple foods with vitamin A is one of the most cost-effective public health interventions available, and it has been estimated that vitamin A supplementation in children under 5 years of age prevents approximately 500,000 cases of blindness and reduces all-cause mortality by approximately 25%.
The Visual Cycle and the Rhodopsin System
The visual cycle is the process by which the chromophore 11-cis-retinal (derived from vitamin A) is regenerated following its isomerisation to all-trans-retinal during the bleaching of rhodopsin by light. In the dark, 11-cis-retinal is bound to the opsin protein in the rhodopsin molecule, forming the light-sensitive visual pigment rhodopsin. When a photon of light strikes the rhodopsin molecule, the 11-cis-retinal absorbs the photon and is isomerised to all-trans-retinal, triggering a conformational change in the opsin protein that initiates the visual signal transduction cascade. The all-trans-retinal is then released from the opsin and must be recycled back to 11-cis-retinal for the rhodopsin molecule to be regenerated. This recycling process involves the reduction of all-trans-retinal to all-trans-retinol, the transport of all-trans-retinol to the retinal pigment epithelium, the enzymatic conversion of all-trans-retinol to 11-cis-retinol, the oxidation of 11-cis-retinol to 11-cis-retinal, and the transport of 11-cis-retinal back to the photoreceptor outer segment for recombination with opsin. Without adequate vitamin A, the regeneration of 11-cis-retinal is impaired, the rhodopsin content of the rod cells is reduced, and the sensitivity of the rod cells to light is diminished — producing the night blindness that is one of the earliest and most characteristic symptoms of vitamin A deficiency.
The clinical importance of vitamin A for the visual cycle is underscored by the observation that vitamin A supplementation reverses night blindness within days — the rapid restoration of dark adaptation following vitamin A supplementation is one of the most dramatic therapeutic effects in all of nutritional medicine and is the basis for the WHO recommendation for the mass distribution of vitamin A supplements in areas where vitamin A deficiency is endemic.
Vitamin A and Immune Function
Vitamin A is also essential for immune function — retinoic acid (the active metabolite of vitamin A that is formed by the oxidation of retinol) is one of the most important regulators of immune cell differentiation and of the immune response to infection. Retinoic acid is required for the differentiation of the epithelial cells of the gut, the respiratory tract, and the genitourinary tract, and it is required for the production of the mucins and the antimicrobial peptides that form the first line of defence against pathogens at the mucosal surfaces. Retinoic acid is also required for the differentiation and the function of the T lymphocytes, including the regulatory T cells (Tregs) that prevent autoimmunity and the Th1 and Th2 subsets that coordinate the cellular and humoral immune responses. The importance of vitamin A for immune function is underscored by the observation that vitamin A deficiency is associated with an increased susceptibility to infection (particularly to the measles virus, to diarrhoeal diseases, and to respiratory infections) and that vitamin A supplementation reduces the incidence and the severity of these infections in vitamin A-deficient children.
Practical Application
For general vitamin A supplementation, the evidence-based approach is to supplement with vitamin A at 3,000-10,000 IU daily (as retinol or retinyl palmitate, the two most common supplemental forms), which is approximately the RDA of 3,000 IU daily for adult men and 2,300 IU daily for adult women. For the prevention of vitamin A deficiency in areas where it is endemic, the WHO recommendation is to supplement children under 5 years of age with 100,000-200,000 IU of vitamin A every 4-6 months, which is sufficient to prevent the clinical manifestations of deficiency. Chronic supplementation with more than 25,000 IU daily of vitamin A should be avoided during pregnancy because of the risk of teratogenicity (vitamin A is a known teratogen, and high doses of vitamin A during early pregnancy can produce birth defects). Beta-carotene (the provitamin A carotenoid that is found in fruits and vegetables) is a safer alternative to preformed vitamin A because it is converted to vitamin A only as needed and does not accumulate to toxic levels. For comprehensive immune support, vitamin A pairs well with vitamin D (which has complementary immunomodulatory effects), with zinc (which is required for the retinol-binding protein that transports vitamin A in the blood), with the omega-3 fatty acids (which have anti-inflammatory effects and which support the epithelial integrity that is maintained by vitamin A), and with the carotenoid antioxidants (lutein, zeaxanthin, astaxanthin) which protect the retinal pigment epithelium from oxidative damage.
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