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Vitamin A Deficiencies and Excess
Overview of Vitamin A
Vitamin A is a fat-soluble micronutrient that cannot be synthesized de novo by mammals; thus it is an obligatory dietary factor. The term vitamin A is generally used to refer to a group of compounds that possess the biologic activity of all- trans retinol ( Fig. 61.1 ). As a fat-soluble micronutrient, vitamin A is recognized as being essential for all vertebrates for normal vision, reproduction, cell and tissue differentiation, and functions of the immune system. Vitamin A plays critical roles in neonatal development. It is required for normal embryonic development, hematopoiesis, immune response, metabolism, and growth and differentiation of many types of cells.
Vitamin A can be obtained from the diet from preformed vitamin A (retinyl esters, such as retinyl palmitate) primarily in foods of animal origin. Organ meats (especially liver, kidney) are very rich in vitamin A, whereas other meats, milk, and cheese contain moderate levels. Other sources of vitamin A include several provitamin A carotenoids, which are found naturally in many fruits and vegetables, especially yellow-orange vegetables (pumpkin, squash, sweet potato), and leafy green vegetables (chard, spinach, broccoli). One of the most abundant carotenoids is β-carotene. Several cultivars or biofortified forms of sweet potatoes have been introduced to elevate carotene intake in areas of the world where vitamin A deficiency still is prevalent. α-Carotene and oxygenated carotenoids, such as β-cryptoxanthin, found in oranges, also possess vitamin A activity, at a lower bioactivity. In the body, these precursors are used for the synthesis of 2 essential metabolites of vitamin A. All- trans retinoic acid is the form required for cell differentiation and regulation of gene transcription and is the most bioactive form of vitamin A; 11- cis retinal is the form required for vision as the light-absorbing chromophore of the visual pigments rhodopsin and iodopsin.
Metabolism of Vitamin A
Vitamin A compounds in foods must first be released through normal digestive processes. Retinyl esters must first be hydrolyzed in the intestinal lumen to liberate unesterified retinol for absorption across the mucosal barrier. Once in the enterocyte, most of the retinol is reesterified, forming new retinyl esters for inclusion in chylomicrons. Approximately 70–90% of dietary preformed vitamin A is absorbed provided there is ≥10 g fat in the meal; otherwise the absorption efficiency is lower. Chronic intestinal disorders or lipid malabsorption can result in vitamin A deficiency. Provitamin-A carotenoids are transported from the intestinal lumen into the enterocytes by specific transporters, then either incorporated intact into chylomicrons or cleaved to form retinal, a precursor for retinol; β-carotene becomes retinol through this process. The estimated efficiency of absorption of carotenoids is 20–50%, lower than for preformed vitamin A. Moreover, the efficiency is reduced when the body's vitamin A status is high, and because vitamin A status may vary, there is significant interindividual variability in absorption efficiency. The carotene cleavage enzyme β-carotene monooxygenase, present in the enterocyte and in other tissues at lower levels, exhibits certain single nucleotide polymorphisms (SNPs) that, at least in vitro, reduce the efficiency of conversion of β-carotene to retinol. Clinical studies suggest a similar effect in vivo.
Once retinol is esterified in the enterocyte, retinyl ester is then packaged into nascent chylomicrons, which are secreted into the lymphatic vessels, enter the systemic circulation, and are then transported to and taken up by various tissues. When vitamin A status is adequate, in most mammals, including humans, the liver is the major site of chylomicron vitamin A uptake and storage, with potentially high levels of retinyl esters within hepatic stellate cells (HSCs). As vitamin A status deteriorates into the deficient range, vitamin A stores are mobilized from the HSCs, such that the released retinol can be taken up and utilized by extrahepatic tissues. Circulating retinol is bound to a specific transport protein, retinol-binding protein (RBP) , which in turn binds to the thyroid hormone transport protein, transthyretin (TTR) ; this complex delivers plasma retinol (as well as the thyroid hormone) to a large number of vitamin A target tissues. The major physiologic mediator of retinol uptake by cells in many tissues is Stra6, a widely expressed multitransmembrane domain protein that functions as a cell surface receptor for retinol bound to RBP. Stra6 is not significantly expressed in the liver, but a homologous receptor may perform the similar function. Within target tissues, retinol is either esterified into retinyl esters for storage or oxidized into retinoic acid for function. In the eye, 11- cis -retinal is formed, bound to the protein rhodopsin (rods) or iodopsin (cones), where it functions as a light-sensing receptor.
Vitamin A Status in Neonates
Neonates begin life with low levels of vitamin A, in plasma, liver, and extrahepatic tissues, compared with those in adults. Normal plasma levels of retinol are 20-50 µg/dL in infants and increase gradually as children become older. Median serum retinol values are 1.19 µmol/L in both boys and girls ages 4-8 yr; 1.4 and 1.33 µmol/L in boys and girls, respectively, ages 9-13; and 1.71 and 1.57 µmol/L in boys and girls, ages 14-18 (for conversion, 1 µmol/L = 28.6 µg/dL). Values of 1.96 and 1.85 µmol/L are found in 19-30 yr old adult men and women, respectively. Fig. 61.2 shows the distribution of serum retinol concentrations in U.S. children.
Retinol levels are even lower in neonates in developing countries, where vitamin A intakes may be low and vitamin A deficiency is a common and significant nutritional problem. Lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Malnutrition, particularly protein deficiency, can cause vitamin A deficiency because of the impaired synthesis of RBP.
Inflammation Causing Low Plasma Retinol
Inflammation is a cause of reduced levels of plasma retinol as a result of reduced synthesis of RBP and TTR. This condition may mimic a lack of vitamin A, but will not be corrected by supplementation. In U.S. adults, those with moderately elevated levels of C-reactive protein (CRP), indicative of mild inflammation, had lower average plasma retinol levels. The extent to which inflammation is a factor in low plasma retinol in children is uncertain but likely significant in acute infectious diseases such as measles, and possibly in chronic inflammatory conditions such as cystic fibrosis.
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