Monday, 21 October 2019

Vitamin A

Vitamins A

What is Vitamin A?



Vitamin A or retinol is an essential micronutrient for all vertebrates. It is required for normal vision, reproduction, embryonic development, cell and tissue differentiation, and immune function. Many aspects of the transport and metabolism of vitamin A, as well as its functions, are well conserved among species. Dietary vitamin A is ingested in two main forms preformed vitamin A (retinyl esters and retinol) and provitamin A carotenoids (β-carotene, α-carotene, and β-cryptoxanthin) although the proportion of vitamin A obtained from each of these forms varies considerably among animal species and among individual human diets. These precursors serve as substrates for the biosynthesis of two essential metabolites of vitamin A: 11-cis-retinal, required for vision, and all-trans-retinoic acid, required for cell differentiation and the regulation of gene transcription in nearly all tissues.

Vitamin A is referred to as compounds with the biological activity of retinol. These include the provitamin A carotenoids, principally β-carotene, α-carotene, and β-cryptoxanthin, which are provided in the diet by green and yellow or orange vegetables and some fruits and preformed vitamin A, namely retinyl esters and retinol itself, present in foods of animal origin, mainly in organ meats such as liver, other meats, eggs, and dairy products.

History and Discovery of Vitamins A


Vitamin A was discovered in the early 1900s by McCollum and colleagues at the University of Wisconsin and independently by Osborne and Mendel at Yale. Osborne and Mendel both groups were studying the effects of diets made from purified protein and carbohydrate sources, such as casein and rice flour, on the growth and survival of young rats. The groups observed that the animals died and growth ceased unless the diet was supplemented with fish oils, butter or a quantitatively minor ether soluble fraction extracted from these substances, from milk, or from meats.

Retinoid


The name retinoid was coined to describe synthetically produced structural analogs of the naturally occurring vitamin A family, but the term is now used for natural as well as synthetic compounds. Retinoids and carotenoids are defined based on molecular structure. According to the International Union of Pure and Applied Chemistry and International Union of Biochemistry and Molecular Biology (IUPAC–IUB), retinoids are ‘‘a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner’’

Vitamins A Deficiency and Prevention


Prevention of Xerophthalmia


Xerophthalmia


Vitamin A deficiency is a primary cause of xerophthalmia, which is manifested as night blindness and corneal abnormalities softening of the cornea (keratomalacia) and ulceration leading to irreversible blindness. In the early 1990s, the WHO estimated that approximately 3 million children, most living in India, parts of Southeast Asia, and sub-Saharan Africa, had some form of xerophthalmia annually, and, on the basis of blood retinol levels, another 250 million were subclinically deficient. The use of vitamin A to prevent or treat xerophthalmia represents an important success story in the nutritional sciences.

Actions of Vitamin A in the Eye

Thebiologicalbasisforthepreventionofxerophthalmiaistwofold:11-cis-retinal is specifically required for the production of rhodopsin in rods and analogous proteins in cones [206], whereas retinoic acid is required for the maintenance and integrity of the corneal epithelium, a role similar to the one it plays in many other epithelial tissues.

Retina

Night blindness is often the first detectable sign of vitamin A deficiency. It is experienced as a loss of the ability to quickly readapt to the dark after the retina is exposed to bright light. The absorption of light by rhodopsin in the photoreceptor cells results in the instantaneous isomerization of its 11-cis-retinal moiety to all-trans-retinal, and this photoisomerization event initiates a signal cascade to nearby retinal ganglion cells, which is propagated to the visual cortex of the brain. For normal vision to continue, the all-trans-retinal, just released from rhodopsin, must be converted back to 11-cis-retinal and recombined with opsin, a process known as dark adaptation. 

Dark adaptation occurs through an elegant series of reactions, known as the visual cycle or retinoid cycle, which involves both RPE and photoreceptor cells and the cycling of retinoids between them. However, the reactions of the visual cycle take place over minutes, as compared with milliseconds for photoisomerization, and thus dark adaptation would be slow were it not for the ability of the retina to very quickly generate new molecules of 11-cis-retinal using retinyl esters stored in the RPE as substrate. Retinyl esters previously formed by LRAT are rapidly hydrolyzed and isomerized to 11-cis-retinol. 

It has been proposed that these steps take place in a single enzymatic reaction catalyzed by isomerohydrolase, a unique enzyme expressed in the RPE. However, alternative mechanisms have also been suggested. In a subsequent reaction facilitated by CRALBP, 11-cis-retinol is oxidized to 11-cis-retinal. Then, in a transport stepfacilitatedbyIRBPthe11-cis-retinal molecule formed in the RPE is returned to the rod cell for combination with opsin, thereby taking the place of a molecule of rhodopsin that was bleached. 

If the storage of vitamin A in the RPE is not adequate, the synthesis of rhodopsin is necessarily delayed as the visual cycle is completed, and night blindness occurs as the functional outcome of this delay. Ultimately, an adequate supply of retinoids in the eye depends on the resupply of retinol by holo-RBP to the RPE, to refill the retinyl ester pool. Although the retinoid cycle is best understood for rod cells, a recently described cone retinoid cycle shares some of the same features. However, Mu¨ller glial cells located near the cones apparently store retinyl esters in the cone retinoid cycle, analogous to the role of the RPE in the rod retinoid cycle.

Cornea and Conjunctiva

The epithelial cells of the cornea and conjunctiva require retinoids for their differentiation and integrity. RBP is expressed in the lacrimal glands and present in tears, and retinol bound to RBP is likely to be used for the biogenesis of retinoic acid by the cornea. Retinoid deficiency results in a loss of secretory goblet cells in the conjunctival membranes, observable cytologically, and sometimes includes visible Bitoˆt’s spots (foamy, bacteria-laden deposits in the outer quadrants of the eye). These early changes typically can be reversed and gradually progress by vitamin A. However, when corneal lesions have advanced to the point of xerosis, further deterioration leading to corneal ulceration, loss of the lens, and scarring can occur rapidly. The need for vitamin A to avert irreversible blindness is urgent.

Morbidity and Mortality


Morbidity and Mortality


The association of vitamin A deficiency and increased risk of mortality was not fully appreciated until late in the twentieth century. In the early 1980s, Sommer and colleagues reported results from studies in Indonesia in which young children with what was referred to as mild xerophthalmia night blindness and Bitoˆt’s spots were found to have died at a higher rate than children with normal eyes. Follow-up intervention studies by these and other investigators, conducted in preschool-aged children in poor regions of Southeast Asia, India, and Africa, showed conclusively that the risk of mortality is reduced by preventing vitamin A deficiency (reviewed by Sommer. 

Sommer estimated that vitamin A administered at doses of 200,000 IU (60 mg retinol) every 6 months would reduce total mortality by 35% in preschool children, at a cost of a few cents per child per year, while a meta-analysis of eight epidemiological studies, including one in which vitamin A was administered weekly in amounts similar to the RDA, estimated a 23% reduction in mortality in children less than 6 years of age who received vitamin A. Subsequent studies have shown a similar decrease in mortality in newborns and pregnant women supplemented with vitamin A.

Subclinical Deficiency

Based on these observations, there is now increased interest in subclinical forms of vitamin A deficiency that, while not causing overt deficiency symptoms, may nonetheless increase the risk of developing diarrhea and respiratory infections, decrease growth rate, slow bone development, and decrease the likelihood of survival from a serious illness. In children at risk of vitamin A deficiency, providing vitamin A supplements, given most often as prophylaxis and in some instances for therapy during illness, has significantly reduced the severity of infectious diseases. Vitamin A reduced measles-related morbidity and mortality.

Immune System Changes

The ability of vitamin A to reduce mortality is widely thought to be due to effects on the immune system, which collectively may reduce the severity of disease and increase the likelihood of survival. A number of animal models have been used to better understand the effects of vitamin A deficiency, and repletion, on the immune system. In brief, vitamin A deficiency results in multiple abnormalities in innate and adaptive immunity involving cell differentiation, hematopoiesis and blood, and lymphoid organ cell populations, and the organism’s ability to respond to challenges with pathogens, antigens, and mitogens. 

Changes, either increase or decreases, in the numbers and functions of B-cells, T-cells, natural killer cells, antigen-presenting cells, and macrophages have all been reported. Responses are often imbalanced or dysregulated, evident as imbalances in the production of cytokines and type 1 or type 2 immune responses and alterations in cell proliferation and cell-cell interactions. Generally, these abnormalities are completely reversible by treatment with vitamin A or retinoic acid. In normal animals, retinoic acid has been shown to stimulate innate and adaptive immune responses.

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