PMC:7589163 / 7185-14781 JSONTXT

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Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

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Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T35","span":{"begin":1391,"end":1401},"obj":"Disease"},{"id":"T36","span":{"begin":2400,"end":2420},"obj":"Disease"},{"id":"T37","span":{"begin":2544,"end":2564},"obj":"Disease"},{"id":"T38","span":{"begin":3273,"end":3293},"obj":"Disease"},{"id":"T39","span":{"begin":3369,"end":3389},"obj":"Disease"},{"id":"T40","span":{"begin":3799,"end":3819},"obj":"Disease"},{"id":"T41","span":{"begin":3821,"end":3836},"obj":"Disease"},{"id":"T42","span":{"begin":3827,"end":3836},"obj":"Disease"},{"id":"T43","span":{"begin":4141,"end":4150},"obj":"Disease"},{"id":"T44","span":{"begin":4155,"end":4167},"obj":"Disease"},{"id":"T45","span":{"begin":4304,"end":4316},"obj":"Disease"},{"id":"T46","span":{"begin":4432,"end":4452},"obj":"Disease"},{"id":"T47","span":{"begin":4732,"end":4755},"obj":"Disease"},{"id":"T48","span":{"begin":5348,"end":5360},"obj":"Disease"},{"id":"T49","span":{"begin":5447,"end":5467},"obj":"Disease"},{"id":"T50","span":{"begin":5522,"end":5542},"obj":"Disease"},{"id":"T51","span":{"begin":5602,"end":5617},"obj":"Disease"},{"id":"T52","span":{"begin":5608,"end":5617},"obj":"Disease"},{"id":"T53","span":{"begin":5626,"end":5633},"obj":"Disease"},{"id":"T54","span":{"begin":5830,"end":5839},"obj":"Disease"},{"id":"T55","span":{"begin":5888,"end":5908},"obj":"Disease"},{"id":"T56","span":{"begin":6261,"end":6269},"obj":"Disease"},{"id":"T57","span":{"begin":6274,"end":6281},"obj":"Disease"},{"id":"T58","span":{"begin":6490,"end":6510},"obj":"Disease"},{"id":"T59","span":{"begin":6954,"end":6982},"obj":"Disease"},{"id":"T60","span":{"begin":7080,"end":7117},"obj":"Disease"},{"id":"T61","span":{"begin":7102,"end":7117},"obj":"Disease"},{"id":"T62","span":{"begin":7108,"end":7117},"obj":"Disease"},{"id":"T63","span":{"begin":7224,"end":7252},"obj":"Disease"},{"id":"T64","span":{"begin":7491,"end":7511},"obj":"Disease"},{"id":"T65","span":{"begin":7582,"end":7595},"obj":"Disease"}],"attributes":[{"id":"A35","pred":"mondo_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A36","pred":"mondo_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A37","pred":"mondo_id","subj":"T37","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A38","pred":"mondo_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A39","pred":"mondo_id","subj":"T39","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A40","pred":"mondo_id","subj":"T40","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A41","pred":"mondo_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/MONDO_0004588"},{"id":"A42","pred":"mondo_id","subj":"T42","obj":"http://purl.obolibrary.org/obo/MONDO_0001941"},{"id":"A43","pred":"mondo_id","subj":"T43","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A44","pred":"mondo_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A45","pred":"mondo_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A46","pred":"mondo_id","subj":"T46","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A47","pred":"mondo_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A48","pred":"mondo_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/MONDO_0005275"},{"id":"A49","pred":"mondo_id","subj":"T49","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A50","pred":"mondo_id","subj":"T50","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A51","pred":"mondo_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/MONDO_0005108"},{"id":"A52","pred":"mondo_id","subj":"T52","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A53","pred":"mondo_id","subj":"T53","obj":"http://purl.obolibrary.org/obo/MONDO_0004619"},{"id":"A54","pred":"mondo_id","subj":"T54","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A55","pred":"mondo_id","subj":"T55","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A56","pred":"mondo_id","subj":"T56","obj":"http://purl.obolibrary.org/obo/MONDO_0001673"},{"id":"A57","pred":"mondo_id","subj":"T57","obj":"http://purl.obolibrary.org/obo/MONDO_0004619"},{"id":"A58","pred":"mondo_id","subj":"T58","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A59","pred":"mondo_id","subj":"T59","obj":"http://purl.obolibrary.org/obo/MONDO_0024355"},{"id":"A60","pred":"mondo_id","subj":"T60","obj":"http://purl.obolibrary.org/obo/MONDO_0001577"},{"id":"A61","pred":"mondo_id","subj":"T61","obj":"http://purl.obolibrary.org/obo/MONDO_0005108"},{"id":"A62","pred":"mondo_id","subj":"T62","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A63","pred":"mondo_id","subj":"T63","obj":"http://purl.obolibrary.org/obo/MONDO_0024355"},{"id":"A64","pred":"mondo_id","subj":"T64","obj":"http://purl.obolibrary.org/obo/MONDO_0007016"},{"id":"A65","pred":"mondo_id","subj":"T65","obj":"http://purl.obolibrary.org/obo/MONDO_0020598"}],"text":"3. Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

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Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

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Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T20","span":{"begin":19,"end":29},"obj":"http://purl.obolibrary.org/obo/GO_0008152"},{"id":"T21","span":{"begin":634,"end":641},"obj":"http://purl.obolibrary.org/obo/GO_0051235"},{"id":"T22","span":{"begin":911,"end":932},"obj":"http://purl.obolibrary.org/obo/GO_0000981"},{"id":"T23","span":{"begin":911,"end":924},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T24","span":{"begin":1140,"end":1146},"obj":"http://purl.obolibrary.org/obo/GO_0007601"},{"id":"T25","span":{"begin":1148,"end":1160},"obj":"http://purl.obolibrary.org/obo/GO_0016049"},{"id":"T26","span":{"begin":1148,"end":1154},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T27","span":{"begin":1633,"end":1659},"obj":"http://purl.obolibrary.org/obo/GO_0051047"},{"id":"T28","span":{"begin":1650,"end":1659},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T29","span":{"begin":1854,"end":1863},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T30","span":{"begin":2058,"end":2073},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T31","span":{"begin":2222,"end":2237},"obj":"http://purl.obolibrary.org/obo/GO_0045730"},{"id":"T32","span":{"begin":2362,"end":2373},"obj":"http://purl.obolibrary.org/obo/GO_0016049"},{"id":"T33","span":{"begin":2367,"end":2373},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T34","span":{"begin":2649,"end":2677},"obj":"http://purl.obolibrary.org/obo/GO_0045064"},{"id":"T35","span":{"begin":2907,"end":2929},"obj":"http://purl.obolibrary.org/obo/GO_0002456"},{"id":"T36","span":{"begin":2907,"end":2929},"obj":"http://purl.obolibrary.org/obo/GO_0002449"},{"id":"T37","span":{"begin":2969,"end":2986},"obj":"http://purl.obolibrary.org/obo/GO_0042110"},{"id":"T38","span":{"begin":2971,"end":2986},"obj":"http://purl.obolibrary.org/obo/GO_0001775"},{"id":"T39","span":{"begin":3065,"end":3075},"obj":"http://purl.obolibrary.org/obo/GO_0023052"},{"id":"T40","span":{"begin":4155,"end":4167},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T41","span":{"begin":4304,"end":4316},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T42","span":{"begin":5602,"end":5617},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T43","span":{"begin":5750,"end":5766},"obj":"http://purl.obolibrary.org/obo/GO_0016032"}],"text":"3. Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T7","span":{"begin":1384,"end":1401},"obj":"Phenotype"},{"id":"T8","span":{"begin":2400,"end":2420},"obj":"Phenotype"},{"id":"T9","span":{"begin":2544,"end":2564},"obj":"Phenotype"},{"id":"T10","span":{"begin":3273,"end":3293},"obj":"Phenotype"},{"id":"T11","span":{"begin":3369,"end":3389},"obj":"Phenotype"},{"id":"T12","span":{"begin":3799,"end":3819},"obj":"Phenotype"},{"id":"T13","span":{"begin":3821,"end":3836},"obj":"Phenotype"},{"id":"T14","span":{"begin":3852,"end":3863},"obj":"Phenotype"},{"id":"T15","span":{"begin":4432,"end":4452},"obj":"Phenotype"},{"id":"T16","span":{"begin":5052,"end":5075},"obj":"Phenotype"},{"id":"T17","span":{"begin":5150,"end":5165},"obj":"Phenotype"},{"id":"T18","span":{"begin":5340,"end":5360},"obj":"Phenotype"},{"id":"T19","span":{"begin":5447,"end":5467},"obj":"Phenotype"},{"id":"T20","span":{"begin":5522,"end":5542},"obj":"Phenotype"},{"id":"T21","span":{"begin":5888,"end":5908},"obj":"Phenotype"},{"id":"T22","span":{"begin":6261,"end":6269},"obj":"Phenotype"},{"id":"T23","span":{"begin":6490,"end":6510},"obj":"Phenotype"},{"id":"T24","span":{"begin":6948,"end":6982},"obj":"Phenotype"},{"id":"T25","span":{"begin":7218,"end":7252},"obj":"Phenotype"},{"id":"T26","span":{"begin":7491,"end":7511},"obj":"Phenotype"},{"id":"T27","span":{"begin":7578,"end":7595},"obj":"Phenotype"}],"attributes":[{"id":"A7","pred":"hp_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/HP_0032169"},{"id":"A8","pred":"hp_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A9","pred":"hp_id","subj":"T9","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A10","pred":"hp_id","subj":"T10","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A11","pred":"hp_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A12","pred":"hp_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A13","pred":"hp_id","subj":"T13","obj":"http://purl.obolibrary.org/obo/HP_0000662"},{"id":"A14","pred":"hp_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/HP_0007462"},{"id":"A15","pred":"hp_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A16","pred":"hp_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A17","pred":"hp_id","subj":"T17","obj":"http://purl.obolibrary.org/obo/HP_0001518"},{"id":"A18","pred":"hp_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/HP_0006528"},{"id":"A19","pred":"hp_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A20","pred":"hp_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A21","pred":"hp_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A22","pred":"hp_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/HP_0002014"},{"id":"A23","pred":"hp_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A24","pred":"hp_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/HP_0002783"},{"id":"A25","pred":"hp_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/HP_0002783"},{"id":"A26","pred":"hp_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/HP_0004905"},{"id":"A27","pred":"hp_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/HP_0002630"}],"text":"3. Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

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Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}

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Vitamin A\n\n3.1. Metabolism and Functions\nRetinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].\nThe functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.\nRegarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].\nVitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].\n\n3.2. Vitamin A Status\nVitamin A deficiency states in developed countries are rare, but many developing countries have vitamin A deficiency of public health significance, associated with overt signs of deficiency, or subclinical levels of vitamin A depletion with marginal liver reserves [27]. However, today, marginal vitamin A status is prevalent and difficult to diagnose. Vitamin A biomarkers have been developed to diagnose different degrees of vitamin A status [28]. There are biological and functional indicators, such as ophthalmic signs of vitamin A deficiency (night blindness, xerophtalmia, Bitot spots), and biochemical indicators. As biochemical indicators, serum retinol concentrations are the most common population indicator. Normal plasma levels are 20–50 µg/dL in infants and increase gradually as children become older. However, serum retinol concentration is affected by infection and inflammation because RBP is an acute phase protein, thus these conditions may mimic a lack of vitamin A. For this reason, RBP linked with markers of inflammation may be used to adjust serum retinol concentration even if the ratio of retinol to RBP is influenced by a status of vitamin A deficiency, because of the increased level of circulating unbound plasma RBP. Furthermore, serum retinol concentration is homeostatically controlled over a wide range of liver reserves, and thus does not reflect the vitamin A liver stores. However, in children, values \u003c10 µg/dL indicate a deficiency of vitamin A [29].\n\n3.3. Recommended Daily Allowance and Supplementation\nThe recommended daily allowance for vitamin A is 450 µg for infants up to 12 months of age. The dietary reference intakes in older children are different based on age-sex group (Table 1).\nCompared with those in adults, neonates present low levels of vitamin A, and lower vitamin A stores and plasma retinol concentrations are seen in low-birthweight infants and in preterm newborns. Thus, vitamin A is used in preterm infants, due to the demonstrated efficacy in improving respiratory function and preventing development of chronic lung disease [30,31]. Furthermore, supplementation with vitamin A is recommended in case of latent vitamin A deficiency using a dose of 1500 µg daily. In children at risk of vitamin A deficiency, rates of mobility and mortality, probably associated with viral infection such as measles, have been reduced by a weekly doses of vitamin A at the RDA level [29,32].\n\n3.4. Vitamin A Supplementation against Viral Infections\nVitamin A supplementation is correlated with a reducing in the infection-related morbidity and mortality associated with vitamin A deficiency (Table 2) [33,34,35,36,37,38,39,40,41,42,43].\nA meta-analysis of 47 studies that included 1,233,856 children found that vitamin A supplementation is associated with a reduction of all-cause mortality of 12% [33]. This association could be explained by the low-to-moderate evidence that vitamin A supplementation in children can reduce the incidence of diarrhea and measles [34,35]. In contrast with previous several trials [33], in a large cluster-randomized trial (DEVTA trial) that included more than 1 million pre-school children in North India, a region with high frequency of vitamin A deficiency, supplementation with high-dose vitamin A (200,000 UI every 6 months] did not achieve a significant mortality reduction. However, in the same article, a meta-analysis that included DEVTA plus eight previous randomised trials of supplementation yielded a weighted average mortality reduction of 11% [32]. Moreover, although it has been reported that there is a significant association between low serum concentration of retinol and acute lower respiratory tract infections [36], several studies in children, particularly regarding the role of vitamin A for treatment of respiratory syncytial virus infection [37,38,39], have shown that vitamin A supplementation is not effective in reducing the incidence of lower respiratory tract infections [40,41,42,43]. However, considering the evidence of the role of vitamin A in supporting an effective immune system, and of the effect of vitamin A on child mortality, supplementation should be offered to children in population at risk of vitamin A deficiency, which could also include patients with disorders associated with fat malabsorption."}