View source for Vitamin A

{{Short description|Essential nutrient}}
{{About|the family of [[vitamer]]s|the form usually used as a supplement|Retinol}}
{{Good article}}
{{Use dmy dates|date=December 2024}}
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{{Infobox drug
| image             = All-trans-Retinol2.svg
| image_class       = skin-invert-image
| width             =
| alt               =
| image2            = Retinol 3D balls.png
| image_class2      = bg-transparent 
| width2            =
| alt2              =
| caption           = Retinol (depicted) and retinal play a biological role in vision, but most of the effects of vitamin A are exerted by retinoic acid, which binds to nuclear receptors and regulates gene transcription.
<!-- Clinical data -->
| pronounce         = 
| tradename         =
| Drugs.com         = {{Drugs.com|monograph|vitamin-a}}
| MedlinePlus       =
| DailyMedID        = Retinol
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment = 
| pregnancy_category = 
| routes_of_administration = [[By mouth]], [[Intramuscular injection|intramuscular]]<ref name=AHFS2016>{{cite web|title=Vitamin A|url=https://www.drugs.com/monograph/vitamin-a.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161230232204/https://www.drugs.com/monograph/vitamin-a.html|archive-date=30 December 2016}}</ref>
| class             = [[Vitamin]]
| ATC_prefix        = A11
| ATC_suffix        = CA01
| ATC_supplemental  = {{ATC|D10|AD02}}, {{ATC|R01|AX02}}, {{ATC|S01|XA02}}

<!-- Legal status -->
| legal_AU_comment  = 
| legal_BR          = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C5, D1, D2, E, F1, F2, F3, F4 -->
| legal_BR_comment  = 
| legal_CA          = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment  = 
| legal_DE          = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment  = 
| legal_NZ          = <!-- Class A, B, C -->
| legal_NZ_comment  = 
| legal_UK          = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment  = 
| legal_US          = OTC
| legal_US_comment  = /&nbsp;Rx-only<ref>{{cite web | title=Aquasol A - vitamin a palmitate injection, solution | website=DailyMed | date=14 August 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ec825f1c-c15f-44de-ad46-8ab9c49ec21c | access-date=18 January 2024 | archive-date=18 January 2024 | archive-url=https://web.archive.org/web/20240118075117/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ec825f1c-c15f-44de-ad46-8ab9c49ec21c | url-status=live }}</ref>
| legal_EU          = 
| legal_EU_comment  = 
| legal_UN          = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment  = 
| legal_status      = <!-- For countries not listed above -->

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| onset             = 
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<!-- Identifiers -->
| index2_label = mixture
| CAS_number        = 68-26-8
| CAS_supplemental  =
| CAS_number2 = 11103-57-4
| PubChem           = 1071
| IUPHAR_ligand     = 4053
| DrugBank          =
| ChemSpiderID      = 393012
| UNII              = G2SH0XKK91
| UNII2 = 81G40H8B0T
| KEGG              =
| ChEBI             = 17336
| ChEMBL            = 986
| NIAID_ChemDB      =
| synonyms          =

<!-- Chemical and physical data -->
| IUPAC_name        = (2''E'',4''E'',6''E'',8''E'')-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol
| C=20
| H=30
| O=1
| SMILES            = OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)/CCCC1(C)C
| StdInChI          = 1S/C20H30O/c1-16(8-6-9-17(2)13-15-21)11-12-19-18(3)10-7-14-20(19,4)5/h6,8-9,11-13,21H,7,10,14-15H2,1-5H3/b9-6+,12-11+,16-8+,17-13+
| StdInChIKey       = FPIPGXGPPPQFEQ-OVSJKPMPSA-N
| density           =
| density_notes     =
| melting_point     = 62–64
| melting_high      =
| melting_notes     =
| boiling_point     = 137–138
| boiling_notes     = ({{val|e=-6|u=mm Hg}})
| solubility        =
| sol_units         = 
| specific_rotation =
}}

'''Vitamin A''' is a [[fat-soluble]] [[vitamin]] that is an [[essential nutrient]]. The term "vitamin A" encompasses a group of chemically related [[organic compounds]] that includes [[retinol]], retinyl [[ester]]s, and several [[provitamin]] (precursor) [[carotenoid]]s, most notably [[Β-Carotene|β-carotene]] (''beta''-[[carotene]]).<ref name="ods">{{cite web|title=Vitamin A Fact Sheet for Health Professionals|url=https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/|publisher=Office of Dietary Supplements, US National Institutes of Health|date=March 2021|access-date=8 August 2021|archive-date=12 December 2016|archive-url=https://web.archive.org/web/20161212224704/https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/|url-status=live}}</ref><ref name="lpi">{{cite web |url=http://lpi.oregonstate.edu/mic/vitamins/vitamin-A |title=Vitamin A |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis |date=1 July 2016 |access-date=21 December 2021 |archive-date=27 April 2021 |archive-url=https://web.archive.org/web/20210427223156/https://lpi.oregonstate.edu/mic/vitamins/vitamin-A |url-status=live }}</ref><ref name="DRI VitA"/><ref name=PKIN2020VitA>{{cite book |vauthors=Blaner WS |title = Present Knowledge in Nutrition | edition = Eleventh |chapter = Vitamin A | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London |pages = 73–92 |isbn=978-0-323-66162-1}}</ref> Vitamin A has multiple functions: growth during [[embryo]] development, maintaining the [[immune system]], and healthy vision. For aiding vision specifically, it combines with the protein [[opsin]] to form [[rhodopsin]], the light-absorbing molecule necessary for both low-light ([[scotopic]] vision) and [[color vision]].<ref name="Wolf2001">{{cite journal | vauthors = Wolf G | title = The discovery of the visual function of vitamin A | journal = The Journal of Nutrition | volume = 131 | issue = 6 | pages = 1647–1650 | date = June 2001 | pmid = 11385047 | doi = 10.1093/jn/131.6.1647 | doi-access = free | title-link = doi }}</ref>

Vitamin A occurs as two principal forms in foods: A) retinoids, found in [[Animal source foods|animal-sourced foods]], either as retinol or bound to a [[fatty acid]] to become a retinyl ester, and B) the carotenoids [[Α-Carotene|α-carotene]] (''alpha''-carotene), β-carotene, [[Γ-Carotene|γ-carotene]] (''gamma''-carotene), and the [[xanthophyll]] [[beta-cryptoxanthin]] (all of which contain β-[[ionone]] rings) that function as provitamin A in [[herbivore]] and [[omnivore]] animals which possess the [[enzyme]]s that cleave and convert provitamin carotenoids to retinol.<ref name=Wu2016/> Some [[carnivore]] species lack this enzyme. The other carotenoids do not have retinoid activity.<ref name=PKIN2020VitA/>

Dietary retinol is absorbed from the [[digestive tract]] via [[Passive transport|passive diffusion]]. Unlike retinol, β-carotene is taken up by [[enterocyte]]s by the membrane transporter protein [[SCARB1|scavenger receptor B1]] (SCARB1), which is upregulated in times of [[vitamin A deficiency]] (VAD).<ref name=PKIN2020VitA/> Retinol is stored in [[lipid droplet]]s in the [[liver]]. A high capacity for long-term storage of retinol means that well-nourished humans can go months on a vitamin A-deficient diet, while maintaining [[blood]] levels in the normal range.<ref name=lpi/> Only when the liver stores are nearly depleted will signs and symptoms of deficiency show.<ref name=lpi/> Retinol is reversibly converted to [[retinal]], then irreversibly to [[retinoic acid]], which activates hundreds of [[gene]]s.<ref name="Kedish2016"/>

Vitamin A deficiency is common in developing countries, especially in [[Sub-Saharan Africa]] and [[Southeast Asia]]. Deficiency can occur at any age but is most common in pre-school age children and pregnant women, the latter due to a need to transfer retinol to the fetus. Vitamin A deficiency is estimated to affect approximately one-third of children under the age of five around the world, resulting in hundreds of thousands of cases of [[Visual impairment|blindness]] and deaths from childhood diseases because of immune system failure.<ref name=UNICEFvitaminA/> Reversible [[Nyctalopia|night blindness]] is an early indicator of low vitamin A status. Plasma retinol is used as a [[biomarker]] to confirm vitamin A deficiency. Breast milk retinol can indicate a deficiency in nursing mothers. Neither of these measures indicates the status of liver reserves.<ref name=PKIN2020VitA/>

The [[European Union]] and various countries have set recommendations for dietary intake, and upper limits for safe intake. Vitamin A toxicity also referred to as [[hypervitaminosis A]], occurs when there is too much vitamin A accumulating in the body. Symptoms may include nervous system effects, liver abnormalities, [[fatigue]], muscle weakness, bone and skin changes, and others. The adverse effects of both acute and chronic toxicity are reversed after consumption of high dose supplements is stopped.<ref name=PKIN2020VitA/>

==Definition==
Vitamin A is a [[fat-soluble]] [[vitamin]], a category that also includes [[Vitamin D|vitamins D]], [[Vitamin E|E]] and [[Vitamin K|K]]. The vitamin encompasses several chemically related naturally occurring compounds or metabolites, i.e., [[vitamer]]s, that all contain a β-[[ionone]] ring.<ref name=lpi/> The primary dietary form is [[retinol]], which may have a [[fatty acid]] molecule attached, creating a retinyl [[ester]], when stored in the liver. Retinol {{ndash}} the transport and storage form of vitamin A {{ndash}} is interconvertible with [[retinal]], catalyzed to retinal by [[retinol dehydrogenase]]s and back to retinol by retinaldehyde reductases.<ref>{{cite journal | vauthors = Lidén M, Eriksson U | title = Understanding retinol metabolism: structure and function of retinol dehydrogenases | journal = The Journal of Biological Chemistry | volume = 281 | issue = 19 | pages = 13001–13004 | date = May 2006 | pmid = 16428379 | doi = 10.1074/jbc.R500027200 | doi-access = free | title-link = doi }}</ref>
:retinal + [[nicotinamide adenine dinucleotide phosphate|NADH]] + H<sup>+</sup> {{eqm}} retinol + NAD<sup>+</sup>
:retinol + [[nicotinamide adenine dinucleotide|NAD]]<sup>+</sup> {{eqm}} retinal + NADH + H<sup>+</sup>
Retinal (also known as retinaldehyde) can be irreversibly converted to ''all-trans''-[[retinoic acid]] by the action of [[retinal dehydrogenase]]
:retinal + NAD<sup>+</sup> + H<sub>2</sub>O → retinoic acid + NADH + H<sup>+</sup>
Retinoic acid is actively transported into the [[cell nucleus]] by CRABp2 where it regulates thousands of genes by binding directly to gene targets via [[Retinoic acid receptor alpha|retinoic acid receptors]].<ref name=PKIN2020VitA/>

In addition to retinol, retinal and retinoic acid, there are plant-, fungi- or bacteria-sourced [[carotenoid]]s which can be metabolized to retinol, and are thus vitamin A vitamers.<ref name=PKIN2020Carotenoids/>

There are also what are referred to as 2nd, 3rd and 4th generation [[retinoid]]s which are not considered vitamin A vitamers because they cannot be converted to retinol, retinal or ''all-trans''-retinoic acid. Some are prescription drugs, oral or topical, for various indications. Examples are [[etretinate]], [[acitretin]], [[adapalene]], [[bexarotene]], [[tazarotene]] and [[trifarotene]].<ref name="Becken2015">{{cite journal |vauthors=Beckenbach L, Baron JM, Merk HF, Löffler H, Amann PM |date=2015 |title=Retinoid treatment of skin diseases |journal=European Journal of Dermatology |volume=25 |issue=5 |pages=384–391 |doi=10.1684/ejd.2015.2544 |pmid=26069148 |s2cid=408725 |doi-access=free |title-link=doi}}</ref><ref name="Monograph">{{cite web |date=28 October 2019 |title=Trifarotene Monograph for Professionals |url=https://www.drugs.com/monograph/trifarotene.html |url-status=live |archive-url=https://web.archive.org/web/20210304102410/https://www.drugs.com/monograph/trifarotene.html |archive-date=4 March 2021 |access-date=23 May 2021 |website=Drugs.com}}</ref>

==Absorption, metabolism and excretion==
Retinyl esters from [[Animal source foods|animal-sourced foods]] (or synthesized for dietary supplements for humans and domesticated animals) are acted upon by retinyl ester hydrolases in the [[Lumen (anatomy)|lumen]] of the small intestine to release free retinol. Retinol enters [[enterocyte]]s by [[Passive transport|passive diffusion]]. Absorption efficiency is in the range of 70 to 90%. Humans are at risk for acute or chronic vitamin A toxicity because there are no mechanisms to suppress absorption or excrete the excess in urine.<ref name="DRI VitA"/> Within the cell, retinol is there bound to [[RBP2|retinol binding protein 2]] (RBP2). It is then enzymatically re-esterified by the action of [[lecithin retinol acyltransferase]] and incorporated into [[chylomicron]]s that are secreted into the [[lymphatic system]].

Unlike retinol, [[Β-Carotene|β-carotene]] is taken up by enterocytes by the membrane transporter protein [[SCARB1|scavenger receptor B1]] (SCARB1). The protein is upregulated in times of vitamin A deficiency. If vitamin A status is in the normal range, SCARB1 is downregulated, reducing absorption.<ref name=PKIN2020VitA/> Also downregulated is the [[enzyme]] [[beta-carotene 15,15'-dioxygenase]] (formerly known as beta-[[carotene]] 15,15'-monooxygenase) coded for by the BCMO1 gene, responsible for symmetrically cleaving β-carotene into retinal.<ref name=Wu2016/> Absorbed β-carotene is either incorporated as such into chylomicrons or first converted to retinal and then retinol, bound to RBP2. After a meal, roughly two-thirds of the chylomicrons are taken up by the liver with the remainder delivered to peripheral tissues. Peripheral tissues also can convert chylomicron β-carotene to retinol.<ref name="PKIN2020VitA"/><ref name="Chel2016">{{cite journal | vauthors = Chelstowska S, Widjaja-Adhi MA, Silvaroli JA, Golczak M | title = Molecular Basis for Vitamin A Uptake and Storage in Vertebrates | journal = Nutrients | volume = 8 | issue = 11 | page = 676 | date = October 2016 | pmid = 27792183 | pmc = 5133064 | doi = 10.3390/nu8110676 | doi-access = free | title-link = doi }}</ref>

The capacity to store retinol in the liver means that well-nourished humans can go months on a vitamin A deficient diet without manifesting signs and symptoms of deficiency. Two liver cell types are responsible for storage and release: [[hepatocyte]]s and [[hepatic stellate cell]]s (HSCs). Hepatocytes take up the lipid-rich chylomicrons, bind retinol to [[RBP4|retinol-binding protein 4]] (RBP4), and transfer the retinol-RBP4 to HSCs for storage in lipid droplets as retinyl esters. Mobilization reverses the process: retinyl ester hydrolase releases free retinol which is transferred to hepatocytes, bound to RBP4, and put into [[blood]] circulation. Other than either after a meal or when consumption of large amounts exceeds liver storage capacity, more than 95% of retinol in circulation is bound to RBP4.<ref name="Chel2016"/>

===Carnivores===
Strict [[carnivore]]s manage vitamin A differently than [[omnivore]]s and [[herbivore]]s. Carnivores are more tolerant of high intakes of retinol because those species have the ability to excrete retinol and retinyl esters in urine. Carnivores also have the ability to store more in the liver, due to a higher ratio of liver HSCs to hepatocytes compared to omnivores and herbivores. For humans, liver content can range from 20 to 30 μg/gram wet weight. Notoriously, [[polar bear]] liver is acutely toxic to humans because content has been reported in range of 2,215 to 10,400 μg/g wet weight.<ref name=Green2016>{{cite journal | vauthors = Green AS, Fascetti AJ | title = Meeting the Vitamin A Requirement: The Efficacy and Importance of ''β''-Carotene in Animal Species | journal = TheScientificWorldJournal | volume = 2016 | issue = | article-number = 7393620 | date = 2016 | pmid = 27833936 | pmc = 5090096 | doi = 10.1155/2016/7393620 | doi-access = free | title-link = doi }}</ref> As noted, in humans, retinol circulates bound to RBP4. Carnivores maintain R-RBP4 within a tight range while also having retinyl esters in circulation. Bound retinol is delivered to cells while the esters are excreted in the urine.<ref name=Green2016/> In general, carnivore species are poor converters of ionone-containing carotenoids, and pure carnivores such as [[felidae]] (cats) lack the cleaving enzyme entirely. They must have retinol or retinyl esters in their diet.<ref name=Green2016/>

===Herbivores===
Herbivores consume ionone-containing carotenoids and convert those to retinal. Some species, including cattle and horses, have measurable amounts of β-carotene circulating in the blood, and stored in [[body fat]], creating yellow [[fat cell]]s. Most species have [[white fat]] and no β-carotene in circulation.<ref name=Green2016/>

===Activation and excretion===
In the liver and peripheral tissues of humans, retinol is reversibly converted to retinal by the action of alcohol dehydrogenases, which are also responsible for the conversion of [[ethanol]] to [[acetaldehyde]]. Retinal is irreversibly oxidized to retinoic acid (RA) by the action of aldehyde dehydrogenases. RA regulates the activation or deactivation of genes. The oxidative degradation of RA is induced by RA – its presence triggers its removal, making for a short-acting gene transcription signal. This deactivation is mediated by a [[cytochrome P450]] (CYP) enzyme system, specifically enzymes [[CYP26A1]], [[CYP26B1]] and [[CYP26C1]]. CYP26A1 is the predominant form in the human liver; all other human adult tissues contained higher levels of CYP26B1. CYP26C1 is expressed mainly during embryonic development. All three convert retinoic acid into 4-oxo-RA, 4-OH-RA and 18-OH-RA. [[Glucuronic acid]] forms water-soluble glucuronide conjugates with the oxidized metabolites, which are then excreted in urine and feces.<ref name="Kedish2016">{{cite book |vauthors=Kedishvili NY |title=The Biochemistry of Retinoid Signaling II |chapter=Retinoic Acid Synthesis and Degradation |series=Subcellular Biochemistry |volume=81 |pages=127–161 |date=2016 |pmid=27830503 |pmc=5551983 |doi=10.1007/978-94-024-0945-1_5 |isbn=978-94-024-0943-7 |chapter-url=}}</ref>

==Metabolic functions==
{{further|Vitamin A deficiency}}
Other than for vision, the metabolic functions of vitamin A are mediated by [[Retinoic acid|''all-trans''-retinoic acid (RA)]]. The formation of RA from retinal is irreversible. To prevent accumulation of RA it is oxidized and eliminated fairly quickly, i.e., has a short half-life. Three cytochromes catalyze the oxidation of retinoic acid. The genes for Cyp26A1, Cyp26B1 and Cyp26C1 are induced by high levels of RA, providing a self-regulating feedback loop.<ref name="Roberts2020">{{cite journal | vauthors = Roberts C | title = Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes | journal = Journal of Developmental Biology | volume = 8 | issue = 1 | page = 6 | date = March 2020 | pmid = 32151018 | pmc = 7151129 | doi = 10.3390/jdb8010006 | doi-access = free | title-link = doi }}</ref><ref name="Isoherr2019">{{cite journal | vauthors = Isoherranen N, Zhong G | title = Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases | journal = Pharmacology & Therapeutics | volume = 204 | issue = | article-number = 107400 | date = December 2019 | pmid = 31419517 | pmc = 6881548 | doi = 10.1016/j.pharmthera.2019.107400 }}</ref>

===Vision and eye health===
Vitamin A status involves eye health via two separate functions. Retinal is an essential factor in [[rod cell]]s and [[cone cell]]s in the retina responding to light exposure by sending nerve signals to the brain. An early sign of vitamin A deficiency is night blindness.<ref name=PKIN2020VitA/> Vitamin A in the form of retinoic acid is essential to normal epithelial cell functions. Severe vitamin A deficiency, common in infants and young children in southeast Asia causes [[xerophthalmia]] characterized by dryness of the conjunctival epithelium and cornea. Untreated, xerophthalmia progresses to corneal ulceration and blindness.<ref name="Whitcher2001"/>

====Vision====
{{Main|visual cycle}}
The role of vitamin A in the visual cycle is specifically related to the retinal compound. Retinol is converted by the enzyme [[RPE65]] within the retinal pigment epithelium into 11-''cis''-retinal. Within the eye, 11-''cis''-retinal is bound to the protein [[opsin]] to form [[rhodopsin]] in rod cells and [[iodopsin]] in cone cells. As light enters the eye, the 11-''cis''-retinal is isomerized to the ''all-trans'' form. The ''all-trans''-retinal dissociates from the opsin in a series of steps called photo-bleaching. This isomerization induces a nervous signal along the optic nerve to the visual center of the brain. After separating from opsin, the ''all-trans''-retinal is recycled and converted back to the 11-''cis''-retinal form by a series of enzymatic reactions, which then completes the cycle by binding to opsin to reform rhodopsin in the retina.<ref name=PKIN2020VitA/> In addition, some of the ''all-trans''-retinal may be converted to ''all-trans''-retinol form and then transported with an interphotoreceptor retinol-binding protein to the retinal pigmented epithelial cells. Further esterification into ''all-trans''-retinyl esters allow for storage of ''all-trans''-retinol within the pigment epithelial cells to be reused when needed. It is for this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin, and will lead to one of the first symptoms, night blindness.<ref name=PKIN2020VitA/><ref name="Combs2008">{{cite book |title=The Vitamins: Fundamental Aspects in Nutrition and Health | vauthors = Combs GF |year=2008 |edition=3rd |publisher=Elsevier Academic Press |location=Burlington, MA |isbn=978-0-12-183493-7}}</ref><ref name="Miller"/>

====Night blindness====
{{Main|Nyctalopia}}
Vitamin A deficiency-caused [[Nyctalopia|night blindness]] is a reversible difficulty for the eyes to adjust to dim light. It is common in young children who have a diet inadequate in retinol and β-carotene. A process called [[Adaptation (eye)|dark adaptation]] typically causes an increase in photopigment amounts in response to low levels of illumination. This increases light sensitivity by up to 100,000 times compared to normal daylight conditions. Significant improvement in night vision takes place within ten minutes, but the process can take up to two hours to reach maximal effect.<ref name="Wolf2001"/> People expecting to work in a dark environment wore red-tinted goggles or were in a red light environment to not reverse the adaptation because red light does not deplete rhodopsin versus what occurs with yellow or green light.<ref name="Miller">{{cite journal |url=https://apps.dtic.mil/sti/citations/ADA257059 |archive-url=https://web.archive.org/web/20220104192142/https://apps.dtic.mil/sti/citations/ADA257059 |url-status=live |archive-date=4 January 2022 |title=Night Vision Manual for the Flight Surgeon|vauthors=Miller RE, Tredici TJ |date=1 August 1992 |website=US Department of Defense, Defense Technical Information Center |access-date=4 January 2022}}</ref>

====Xerophthalmia and childhood blindness====
{{Main|Xerophthalmia}}
[[File:Typical location of Bitot's spots.jpg|thumb|Typical location of Bitot's spots]]
Xerophthalmia, caused by a severe vitamin A deficiency, is described by pathologic dryness of the conjunctival epithelium and cornea. The conjunctiva becomes dry, thick, and wrinkled. Indicative is the appearance of Bitot's spots, which are clumps of keratin debris that build up inside the conjunctiva. If untreated, xerophthalmia can lead to dry eye syndrome, [[corneal ulceration]] and ultimately to blindness as a result of cornea and retina damage. Although xerophthalmia is an eye-related issue, prevention (and reversal) are functions of retinoic acid having been synthesized from retinal rather than the 11-''cis''-retinal to rhodopsin cycle.<ref name="Akhtar2013"/>

Throughout southeast Asia, estimates are that more than half of children under the age of six years have subclinical vitamin A deficiency and night blindness, with progression to xerophthalmia being the leading cause of preventable childhood blindness.<ref name="Akhtar2013">{{cite journal | vauthors = Akhtar S, Ahmed A, Randhawa MA, Atukorala S, Arlappa N, Ismail T, Ali Z | title = Prevalence of vitamin A deficiency in South Asia: causes, outcomes, and possible remedies | journal = Journal of Health, Population, and Nutrition | volume = 31 | issue = 4 | pages = 413–423 | date = December 2013 | pmid = 24592582 | pmc = 3905635 | doi = 10.3329/jhpn.v31i4.19975 }}</ref> Estimates are that each year there are 350,000 cases of childhood blindness due to vitamin A deficiency.<ref name="Whitcher2001">{{cite journal | vauthors = Whitcher JP, Srinivasan M, Upadhyay MP | title = Corneal blindness: a global perspective | journal = Bulletin of the World Health Organization | volume = 79 | issue = 3 | pages = 214–221 | date = 2001 | pmid = 11285665 | pmc = 2566379 | doi = }}</ref> The causes are vitamin A deficiency during pregnancy, followed by low transfer of vitamin A during lactation and infant/child diets low in vitamin A or β-carotene.<ref name="Akhtar2013"/><ref name="Whitcher2001"/> The [[prevalence]] of pre-school age children who are blind due to vitamin A deficiency is lower than expected from [[Incidence (epidemiology)|incidence of new cases]] only because childhood vitamin A deficiency significantly increases all-cause mortality.<ref name="Whitcher2001"/>

According to a 2017 Cochrane review, vitamin A deficiency, using serum retinol less than 0.70&nbsp;μmol/L as a criterion, is a major public health problem affecting an estimated 190 million children under five years of age in low- and middle-income countries, primarily in Sub-Saharan Africa and Southeast Asia. In lieu of or in combination with food fortification programs, many countries have implemented public health programs in which children are periodically given very large oral doses of synthetic vitamin A, usually retinyl palmitate, as a means of preventing and treating vitamin A deficiency. Doses were 50,000 to 100,000 IU ([[International unit]]s) for children aged 6 to 11 months and 100,000 to 200,000 IU for children aged 12 months to five years, the latter typically every four to six months. In addition to a 24% reduction in all-cause mortality, eye-related results were reported. Prevalence of Bitot's spots at follow-up were reduced by 58%, night blindness by 68%, xerophthalmia by 69%.<ref name="Imdad2017"/>

===Gene regulation===
RA regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs; RARα, RARβ, RARγ) which are bound to [[DNA]] as heterodimers with retinoid "X" receptors (RXRs; RXRα, RXRβ, RXRγ). RARs and RXRs must dimerize before they can bind to the DNA. Expression of more than 500 genes is responsive to retinoic acid.<ref name=PKIN2020VitA/> RAR-RXR heterodimers recognize retinoic acid response elements on DNA.<ref>{{cite journal | vauthors = Duester G | title = Retinoic acid synthesis and signaling during early organogenesis | journal = Cell | volume = 134 | issue = 6 | pages = 921–931 | date = September 2008 | pmid = 18805086 | pmc = 2632951 | doi = 10.1016/j.cell.2008.09.002 }}</ref> Upon binding retinoic acid, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery.<ref>{{cite book |title=Biochemical, Physiological and Molecular Aspects of Human Nutrition | vauthors = Stipanuk MH |year=2006 |edition=2nd |publisher=Saunders |location=Philadelphia |isbn=978-1-4160-0209-3}}</ref> This response upregulates or downregulates the expression of target genes, including the genes that encode for the receptors themselves.<ref name="Combs2008" /> To deactivate retinoic acid receptor signaling, three cytochromes (Cyp26A1, Cyp26B1 Cyp26C1) catalyze the oxidation of RA. The genes for these proteins are induced by high concentrations of RA, thus providing a regulatory feedback mechanism.<ref name=PKIN2020VitA/>

===Embryology===
In vertebrates and invertebrate chordates, RA has a pivotal role during development. Altering levels of endogenous RA signaling during early embryology, either too low or too high, leads to birth defects,<ref>{{cite journal | vauthors = Metzler MA, Sandell LL | title = Enzymatic Metabolism of Vitamin A in Developing Vertebrate Embryos | journal = Nutrients | volume = 8 | issue = 12 | page = 812 | date = December 2016 | pmid = 27983671 | pmc = 5188467 | doi = 10.3390/nu8120812 | doi-access = free | title-link = doi }}</ref><ref name=Marletaz2006>{{cite journal | vauthors = Marlétaz F, Holland LZ, Laudet V, Schubert M | title = Retinoic acid signaling and the evolution of chordates | journal = International Journal of Biological Sciences | volume = 2 | issue = 2 | pages = 38–47 | date = 2006 | pmid = 16733532 | pmc = 1458431 | doi = 10.7150/ijbs.2.38 }}</ref> including congenital vascular and cardiovascular defects.<ref>{{cite journal | vauthors = Pawlikowski B, Wragge J, Siegenthaler JA | title = Retinoic acid signaling in vascular development | journal = Genesis | volume = 57 | issue = 7–8 | article-number = e23287 | date = July 2019 | pmid = 30801891 | pmc = 6684837 | doi = 10.1002/dvg.23287 }}</ref><ref>{{cite journal | vauthors = Wang S, Moise AR | title = Recent insights on the role and regulation of retinoic acid signaling during epicardial development | journal = Genesis | volume = 57 | issue = 7–8 | article-number = e23303 | date = July 2019 | pmid = 31066193 | pmc = 6682438 | doi = 10.1002/dvg.23303 }}</ref> Of note, fetal alcohol spectrum disorder encompasses congenital anomalies, including craniofacial, auditory, and ocular defects, neurobehavioral anomalies and mental disabilities caused by maternal consumption of alcohol during pregnancy. It is proposed that in the embryo there is competition between acetaldehyde, an ethanol metabolite, and retinaldehyde (retinal) for aldehyde dehydrogenase activity, resulting in a retinoic acid deficiency, and attributing the congenital birth defects to the loss of RA activated gene activation. In support of this theory, ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol or retinal.<ref name="Shabtai2018A"/> As for the risks of too much RA during embryogenesis, the prescription drugs [[tretinoin]] (''all-trans''-retinoic acid) and [[isotretinoin]] (13-cis-retinoic acid), used orally or topically for acne treatment, are labeled with [[boxed warning]]s for pregnant women or women who may become pregnant, as they are known human teratogens.<ref name="Draghici2021">{{cite journal |vauthors=Draghici CC, Miulescu RG, Petca RC, Petca A, Dumitrașcu MC, Șandru F |date=May 2021 |title=Teratogenic effect of isotretinoin in both fertile females and males (Review) |journal=Experimental and Therapeutic Medicine |volume=21 |issue=5 |page=534 |doi=10.3892/etm.2021.9966 |pmc=8014951 |pmid=33815607}}</ref><ref name="Tretinoin">{{cite web |date=1 July 2019 |title=Tretinoin topical Use During Pregnancy |url=https://www.drugs.com/pregnancy/tretinoin-topical.html |url-status=live |archive-url=https://web.archive.org/web/20201129110248/https://www.drugs.com/pregnancy/tretinoin-topical.html |archive-date=29 November 2020 |access-date=16 January 2020 |website=Drugs.com}}</ref>

=== Immune functions ===
Vitamin A deficiency has been linked to compromised resistance to infectious diseases.<ref name="Ross2012">{{cite journal | vauthors = Ross AC | title = Vitamin A and retinoic acid in T cell-related immunity | journal = The American Journal of Clinical Nutrition | volume = 96 | issue = 5 | pages = 1166S–1172S | date = November 2012 | pmid = 23053562 | pmc = 3471201 | doi = 10.3945/ajcn.112.034637 }}</ref><ref name="Pino2010">{{cite journal | vauthors = Pino-Lagos K, Guo Y, Noelle RJ | title = Retinoic acid: a key player in immunity | journal = BioFactors | volume = 36 | issue = 6 | pages = 430–436 | date = 2010 | pmid = 20803520 | pmc = 3826167 | doi = 10.1002/biof.117 }}</ref> In countries where early childhood vitamin A deficiency is common, vitamin A supplementation public health programs initiated in the 1980s were shown to reduce the incidence of diarrhea and measles, and all-cause mortality.<ref name="Imdad2017"/><ref name=Brown2015>{{cite journal | vauthors = Brown CC, Noelle RJ | title = Seeing through the dark: New insights into the immune regulatory functions of vitamin A | journal = European Journal of Immunology | volume = 45 | issue = 5 | pages = 1287–1295 | date = May 2015 | pmid = 25808452 | pmc = 4426035 | doi = 10.1002/eji.201344398 }}</ref><ref name="Guo2015">{{cite journal | vauthors = Guo Y, Brown C, Ortiz C, Noelle RJ | title = Leukocyte homing, fate, and function are controlled by retinoic acid | journal = Physiological Reviews | volume = 95 | issue = 1 | pages = 125–148 | date = January 2015 | pmid = 25540140 | pmc = 4281589 | doi = 10.1152/physrev.00032.2013 }}</ref> Vitamin A deficiency also increases the risk of immune system over-reaction, leading to chronic inflammation in the intestinal system, stronger allergic reactions and autoimmune diseases.<ref name="Ross2012"/><ref name="Pino2010"/><ref name=Bono2016/>

[[Lymphocyte]]s and [[monocyte]]s are types of [[white blood cell]]s of the [[immune system]].<ref name=Janeway>{{cite book |vauthors = Janeway C, Travers P, Walport M, Shlomchik M |author-link = Charles Janeway |title = Immunobiology |edition = 5th |publisher = Garland Science |year = 2001 |location = New York and London |url = https://www.ncbi.nlm.nih.gov/books/NBK10757/?depth=10 |isbn = 0-8153-4101-6 |access-date = 15 January 2022 |archive-date = 28 June 2009 |archive-url = https://web.archive.org/web/20090628195820/http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10 |url-status = live }}</ref> Lymphocytes include [[natural killer cell]]s, which function in [[innate immune system|innate immunity]], [[T cell]]s for [[adaptive immune system|adaptive cellular immunity]] and [[B cell]]s for [[antibody]]-driven [[adaptive immune system|adaptive humoral immunity]]. Monocytes differentiate into [[macrophage]]s and [[dendritic cell]]s. Some lymphocytes migrate to the [[thymus]] where they differentiate into several types of T cells, in some instances referred to as "killer" or "helper" T cells and further differentiate after leaving the thymus. Each subtype has functions driven by the types of [[cytokine]]s secreted and organs to which the cells preferentially migrate, also described as trafficking or homing.<ref name=Omman>{{cite book | vauthors = Omman RA, Kini AR | veditors = Keohane EM, Otto CN, Walenga JN |title=Rodak's Hematology: Clinical Principles and Applications |date=2020 |publisher=Elsevier |location=St. Louis, Missouri |isbn=978-0-323-53045-3 |pages=117–135 |edition=6th |chapter=Leukocyte development, kinetics, and functions}}</ref><ref name=Cohn>{{cite book | title=Middleton's Allergy: Principles and Practice | date=2014 | doi=10.1016/B978-0-323-08593-9.00013-9 | chapter-url=https://www.sciencedirect.com/science/article/pii/B9780323085939000139 | pages=203–14 | vauthors=Cohn L, Hawrylowicz C, Ray A | isbn=978-0-323-08593-9 | edition=8th | chapter=Biology of Lymphocytes | publisher=Saunders | location=Philadelphia | access-date=15 January 2022 | archive-date=15 January 2022 | archive-url=https://web.archive.org/web/20220115201856/https://www.sciencedirect.com/science/article/pii/B9780323085939000139 | url-status=live }}</ref>

Retinoic acid (RA) triggers receptors in bone marrow, resulting in generation of new white blood cells.<ref>{{cite journal | vauthors = Cañete A, Cano E, Muñoz-Chápuli R, Carmona R | title = Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis | journal = Nutrients | volume = 9 | issue = 2 | page = 159 | date = February 2017 | pmid = 28230720 | pmc = 5331590 | doi = 10.3390/nu9020159 | doi-access = free | title-link = doi }}</ref> RA regulates proliferation and differentiation of white blood cells, the directed movement of T cells to the [[Gastrointestinal tract|intestinal system]], and to the up- and down-regulation of lymphocyte function.<ref name="Ross2012"/><ref name="Pino2010"/><ref name=Brown2015/><ref name="Guo2015"/><ref name="Bono2016">{{cite journal | vauthors = Bono MR, Tejon G, Flores-Santibañez F, Fernandez D, Rosemblatt M, Sauma D | title = Retinoic Acid as a Modulator of T Cell Immunity | journal = Nutrients | volume = 8 | issue = 6 | page = 349 | date = June 2016 | pmid = 27304965 | pmc = 4924190 | doi = 10.3390/nu8060349 | doi-access = free | title-link = doi }}</ref><ref name="Czarn2017">{{cite journal | vauthors = Czarnewski P, Das S, Parigi SM, Villablanca EJ | title = Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity | journal = Nutrients | volume = 9 | issue = 1 | page = 68 | date = January 2017 | pmid = 28098786 | pmc = 5295112 | doi = 10.3390/nu9010068 | doi-access = free | title-link = doi }}</ref> If RA is adequate, T helper cell subtype Th1 is suppressed and subtypes Th2, Th17 and iTreg (for regulatory) are induced. Dendritic cells located in intestinal tissue have enzymes that convert retinal to ''all-trans''-retinoic acid, to be taken up by retinoic acid receptors on lymphocytes. The process triggers gene expression that leads to T cell types Th2, Th17 and iTreg moving to and taking up residence in [[mesenteric lymph node]]s and [[Peyer's patch]]es, respectively outside and on the inner wall of the small intestine.<ref name=Brown2015/><ref name="Guo2015"/> The net effect is a down-regulation of immune activity, seen as tolerance of food [[allergen]]s, and tolerance of resident bacteria and other organisms in the [[microbiome]] of the large intestine.<ref name="Ross2012"/><ref name="Pino2010"/><ref name=Bono2016/> In a vitamin A deficient state, innate immunity is compromised and pro-inflammatory Th1 cells predominate.<ref name="Ross2012"/><ref name="Czarn2017"/>

====Measles prevention====
"Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death."<ref name="Cochrane2022"/> Vitamin A deficiency is rare in the United States.<ref name=":8">{{Cite web |title=Office of Dietary Supplements - Vitamin A and Carotenoids |url=https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/ |access-date=2025-04-08 |website=ods.od.nih.gov |language=en}}</ref> A meta-analysis of clinical trials conducted in countries where VAD is prevalent concluded that when children were supplemented with vitamin A, there was a 50% reduction in incidence of contracting measles.<ref name="Cochrane2022">{{cite journal |vauthors=Imdad A, Mayo-Wilson E, Haykal MR, Regan A, Sidhu J, Smith A, Bhutta ZA |title=Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age |journal=Cochrane Database Syst Rev |volume=3 |issue=3 |article-number=CD008524 |date=March 2022 |pmid=35294044 |pmc=8925277 |doi=10.1002/14651858.CD008524.pub4 |url=}}</ref>  Vitamin A supplementation is not thought to reduce the risk of death from measles.<ref name=":8" /> Young children given high doses of vitamin A from supplements or [[cod liver oil]] can accumulate to toxic levels and this can lead to [[hypervitaminosis A]] and [[Liver disease|liver damage]].<ref name=":8" /> In the [[2025 Southwest United States measles outbreak]], centered in [[West Texas]], some families continued to refuse vaccines and instead opted for giving vitamin A supplements or vitamins A- and D-containing cod liver oil to their children after [[Robert F. Kennedy Jr.]], promoted vitamin A as prevention and treatment.<ref name="NYTimes">{{cite web | last=Rosenbluth | first=Teddy | title=For Some Measles Patients, Vitamin A Remedy Supported by RFK Jr. Leaves Them More Ill | website=The New York Times | date=2025-03-25 | url=https://www.nytimes.com/2025/03/25/health/measles-kennedy-vitamin-a.html | access-date=2025-03-26}}</ref> Multiple children hospitalized for measles at Covenant Children's Hospital in Lubbock also showed signs of [[liver damage]], a symptom of vitamin A toxicity.<ref name=":8" /><ref name="NYTimes" /><ref name="Davies2025">{{cite web | last=Davies | first=David Martin | title=West Texas children treated for vitamin A toxicity as medical disinformation spreads alongside measles outbreak | website=TPR | date=2025-03-28 | url=https://www.tpr.org/public-health/2025-03-27/west-texas-children-treated-for-vitamin-a-toxicity-as-medical-disinformation-spreads-alongside-measles-outbreak | access-date=2025-03-28}}</ref>

===Skin===
Deficiencies in vitamin A have been linked to an increased susceptibility to skin infection and inflammation.<ref name="Roche2021">{{cite journal | vauthors = Roche FC, Harris-Tryon TA | title = Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review | journal = Nutrients | volume = 13 | issue = 2 | page = 302 | date = January 2021 | pmid = 33494277 | pmc = 7909803 | doi = 10.3390/nu13020302 | doi-access = free | title-link = doi }}</ref> Vitamin A appears to modulate the [[innate immune response]] and maintains homeostasis of epithelial tissues and mucosa through its metabolite, retinoic acid (RA). As part of the innate immune system, [[toll-like receptors]] in skin cells respond to pathogens and cell damage by inducing a pro-inflammatory immune response which includes increased RA production.<ref name="Roche2021"/> The epithelium of the skin encounters bacteria, fungi and viruses. Keratinocytes of the epidermal layer of the skin produce and secrete [[antimicrobial peptides]] (AMPs). Production of AMPs [[resistin]] and [[cathelicidin]], are promoted by RA.<ref name="Roche2021"/>

==Units of measurement==
As some carotenoids can be converted into vitamin A, attempts have been made to determine how much of them in the diet is equivalent to a particular amount of retinol, so that comparisons can be made of the benefit of different foods. The situation can be confusing because the accepted equivalences have changed over time.

For many years, a system of equivalencies in which an [[international unit]] (IU) was equal to 0.3 [[microgram|μg]] of retinol (~1&nbsp;nmol), 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used.<ref>{{cite web | url = http://www.nal.usda.gov/fnic/foodcomp/Data/SR20/SR20_doc.pdf | title = Composition of Foods Raw, Processed, Prepared | work = USDA National Nutrient Database for Standard Reference, Release 20 | publisher = [[USDA]] | date = February 2008 | archive-url = https://web.archive.org/web/20081002175906/http://www.nal.usda.gov/fnic/foodcomp/Data/SR20/SR20_doc.pdf | archive-date = 2 October 2008 }}</ref> This relationship was alternatively expressed by the retinol equivalent (RE): one RE corresponded to 1 μg retinol, to 2 μg β-carotene dissolved in oil, to 6 μg β-carotene in foods, and to 12 μg of either [[Α-Carotene|α-carotene]], [[Γ-Carotene|γ-carotene]], or β-[[cryptoxanthin]] in food.

Newer research has shown that the absorption of provitamin-A carotenoids is only half as much as previously thought. As a result, in 2001 the US [[Institute of Medicine]] recommended a new unit, the retinol activity equivalent (RAE). Each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" β-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.<ref name="DRI VitA">{{cite book |author=Institute of Medicine |chapter=Vitamin A |chapter-url=https://www.nap.edu/read/10026/chapter/6 |title=Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc |publisher=Food and Nutrition Board of the Institute of Medicine |pages=82–161 |year=2001 |isbn=0-309-07290-5 |access-date=23 March 2017 |archive-date=28 April 2021 |archive-url=https://web.archive.org/web/20210428110700/https://www.nap.edu/read/10026/chapter/6 |url-status=live }}</ref>

{| class="wikitable"
|-
! Substance and its chemical environment (per 1 μg)
! IU (1989)
! μg {{abbr|RE|retinol equivalent}} (1989)<ref name="DRI VitA"/>
! μg {{abbr|RAE|retinol activity equivalent}} (2001)<ref name="DRI VitA"/>
|-
| Retinol
| 3.33
| 1
| 1
|-
| [[β-Carotene]], dissolved in oil
| 1.67
| 1/2
| 1/2
|-
| β-Carotene, common dietary
| 1.67
| 1/6
| 1/12
|-
| {{plainlist|
* [[α-Carotene]], common dietary
* [[γ-Carotene]], common dietary
* [[beta-cryptoxanthin|beta-Cryptoxanthin]], common dietary
}}
| 0.83
| 1/12
| 1/24
|}

Animal models have shown that at the enterocyte cell wall, β-carotene is taken up by the membrane transporter protein scavenger receptor class B, type 1 (SCARB1). Absorbed β-carotene is converted to retinal and then retinol. The first step of the conversion process consists of one molecule of β-carotene cleaved by the enzyme
β-carotene-15, 15'-monooxygenase, which in humans and other mammalian species is encoded by the BCM01 gene,<ref name=Wu2016>{{cite journal | vauthors = Wu L, Guo X, Wang W, Medeiros DM, Clarke SL, Lucas EA, Smith BJ, Lin D | title = Molecular aspects of β, β-carotene-9', 10'-oxygenase 2 in carotenoid metabolism and diseases | journal = Experimental Biology and Medicine | volume = 241 | issue = 17 | pages = 1879–1887 | date = November 2016 | pmid = 27390265 | pmc = 5068469 | doi = 10.1177/1535370216657900 }}</ref> into two molecules of retinal. When plasma retinol is in the normal range, gene expression for SCARB1 and BC01 are suppressed, creating a feedback loop that suppresses β-carotene absorption and conversion.<ref name=PKIN2020Carotenoids/> Absorption suppression is not complete, as receptor 36 is not downregulated.<ref name=PKIN2020Carotenoids/>

==Dietary recommendations==
The US [[National Academy of Medicine]] updated [[Dietary Reference Intake]]s (DRIs) in 2001 for vitamin A, which included Recommended Dietary Allowances (RDAs).<ref name="DRI VitA"/> For infants up to 12 months, there was not sufficient information to establish an RDA, so Adequate Intake (AI) is shown instead. As for safety, [[tolerable upper intake level]]s (ULs) were also established. For ULs, carotenoids are not added when calculating total vitamin A intake for safety assessments.<ref name="DRI VitA"/>

{| class="wikitable"
|-
! colspan=2 | Life stage group
! US RDAs or AIs<br /> (μg RAE/day)<ref name="DRI VitA"/>
! US Upper limits<br /> (μg/day)<ref name="DRI VitA"/>
|-
| rowspan=2 | '''Infants'''
| 0–6 months || 400 (AI) || 600
|-
| 7–12 months || 500 (AI) || 600
|-
| rowspan=2 | '''Children'''
| 1–3 years || 300 || 600
|-
| 4–8 years || 400 || 900
|-
| rowspan=3 | '''Males'''
| 9–13 years || 600 || 1700
|-
| 14–18 years || 900 || 2800
|-
| >19<!-- – >70--> years || 900 || 3000
|-
| rowspan=3 | '''Females'''
| 9–13 years || 600 || 1700
|-
| 14–18 years || 700 || 2800
|-
| >19<!--– >70--> years || 700 || 3000
|-
| rowspan=2 | '''Pregnancy'''
| <19 years || 750 || 2800
|-
| >19<!-- – >50--> years || 770 || 3000
|-
| rowspan=2 | '''Lactation'''
| <19 years || 1200 || 2800
|-
| >19<!-- – >50--> years || 1300 || 3000
|}

The [[European Food Safety Authority]] (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For women and men of ages 15 and older, the PRIs are set respectively at 650 and 750 μg&nbsp;RE/day. PRI for pregnancy is 700 μg&nbsp;RE/day, for lactation 1300/day. For children of ages 1–14 years, the PRIs increase with age from 250 to 600 μg&nbsp;RE/day. These PRIs are similar to the US RDAs.<ref>{{cite web |title=Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies |year=2017 |url=https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf |publisher=European Food Safety Authority (EFSA) |access-date=4 September 2017 |archive-date=28 August 2017 |archive-url=https://web.archive.org/web/20170828082247/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf |url-status=live }}</ref> The EFSA reviewed the same safety question as the United States, and set ULs at 800 for ages 1–3, 1100 for ages 4–6, 1500 for ages 7–10, 2000 for ages 11–14, 2600 for ages 15–17 and 3000 μg/day for ages 18 and older for preformed vitamin A, i.e., not including dietary contributions from carotenoids.<ref name=EFSA-UL>{{cite web |title=Tolerable Upper Intake Levels For Vitamins And Minerals |publisher=European Food Safety Authority |year=2006 |url=http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf |access-date=4 September 2017 |archive-date=19 September 2017 |archive-url=https://web.archive.org/web/20170919040144/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf |url-status=live }}</ref>

===Safety===
Vitamin A toxicity ([[hypervitaminosis A]]) occurs when too much vitamin A accumulates in the body. It comes from consumption of preformed vitamin A but not of carotenoids, as conversion of the latter to retinol is suppressed by the presence of adequate retinol.

====Retinol safety====
{{Main|Hypervitaminosis A}}

There are historical reports of acute hypervitaminosis from Arctic explorers consuming bearded seal or polar bear liver, both very rich sources of stored retinol,<ref>{{cite journal | vauthors = Rodahl K, Moore T | title = The vitamin A content and toxicity of bear and seal liver | journal = The Biochemical Journal | volume = 37 | issue = 2 | pages = 166–168 | date = July 1943 | pmid = 16747610 | pmc = 1257872 | doi = 10.1042/bj0370166 }}</ref> and there are also case reports of acute hypervitaminosis from consuming fish liver,<ref>{{cite journal | vauthors = Schmitt C, Domangé B, Torrents R, de Haro L, Simon N | title = Hypervitaminosis A Following the Ingestion of Fish Liver: Report on 3 Cases from the Poison Control Center in Marseille | journal = Wilderness & Environmental Medicine | volume = 31 | issue = 4 | pages = 454–456 | date = December 2020 | pmid = 32861618 | doi = 10.1016/j.wem.2020.06.003 | s2cid = 221384282 | doi-access = free | title-link = doi }}</ref> but otherwise there is no risk from consuming too much via commonly consumed foods. Only consumption of retinol-containing dietary supplements can result in acute or chronic toxicity.<ref name=PKIN2020VitA/> Acute toxicity occurs after a single or short-term doses of greater than 150,000 μg. Symptoms include blurred vision, nausea, vomiting, dizziness and headache within 8 to 24 hours. For infants ages 0–6 months given an oral dose to prevent development of vitamin A deficiency, bulging skull fontanel was evident after 24 hours, usually resolved by 72 hours.<ref name="Imdad2016">{{cite journal | vauthors = Imdad A, Ahmed Z, Bhutta ZA | title = Vitamin A supplementation for the prevention of morbidity and mortality in infants one to six months of age | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | article-number = CD007480 | date = September 2016 | pmid = 27681486 | pmc = 6457829 | doi = 10.1002/14651858.CD007480.pub3 }}</ref> Chronic toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU/day for several months.<ref name=lpi/> Excessive consumption of alcohol can lead to chronic toxicity at lower intakes.<ref name=ods/> Symptoms may include nervous system effects, liver abnormalities, [[fatigue]], muscle weakness, bone and skin changes and others. The adverse effects of both acute and chronic toxicity are reversed after consumption is stopped.<ref name="DRI VitA"/>

In 2001, for the purpose of determining ULs for adults, the US Institute of Medicine considered three primary adverse effects and settled on two: [[teratogen]]icity, i.e., causing birth defects, and liver abnormalities. Reduced bone mineral density was considered, but dismissed because the human evidence was contradictory.<ref name="DRI VitA"/> During pregnancy, especially during the first trimester, consumption of retinol in amounts exceeding 4,500 μg/day increased the risk of birth defects, but not below that amount, thus setting a "No-Observed Adverse-Effect Level" (NOAEL).{{Medical citation needed|date=December 2024}} Given the quality of the clinical trial evidence, the NOAEL was divided by an uncertainty factor of 1.5 to set the UL for women of reproductive age at 3,000 μg/day of preformed vitamin A.{{Medical citation needed|date=December 2024}} For all other adults, liver abnormalities were detected at intakes above 14,000 μg/day.{{Medical citation needed|date=December 2024}} Given the weak quality of the clinical evidence, an uncertainty factor of 5 was used, and with rounding, the UL was set at 3,000 μg/day.{{Citation needed|date=December 2024}}

For children, ULs were extrapolated from the adult value, adjusted for relative body weight. For infants, several case studies reported adverse effects that include bulging fontanels, increased intracranial pressure, loss of appetite, hyperirritability and skin peeling after chronic ingestion of the order of 6,000 or more μg/day. Given the small database, an uncertainty factor of 10 divided into the "Lowest-Observed-Adverse-Effect Level" (LOAEL) led to a UL of 600 μg/day.<ref name="DRI VitA"/>

====β-carotene safety====
No adverse effects other than [[carotenemia]] have been reported for consumption of β-carotene rich foods. Supplementation with β-carotene does not cause hypervitaminosis A.<ref name=PKIN2020Carotenoids/> Two large clinical trials (ATBC and CARET) were conducted in tobacco smokers to see if years of β-carotene supplementation at 20 or 30&nbsp;mg/day in oil-filled capsules would reduce the risk of lung cancer.<ref name="DRItextBetaCarotene"/> These trials were implemented because observational studies had reported a lower incidence of lung cancer in tobacco smokers who had diets higher in β-carotene. Unexpectedly, high-dose β-carotene or retinol supplementation resulted in a higher incidence of lung cancer and of total mortality due to cardiac mortality.<ref>{{Cite journal |date=14 April 1994 |title=The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers |url=http://www.nejm.org/doi/abs/10.1056/NEJM199404143301501 |journal=New England Journal of Medicine |language=en |volume=330 |issue=15 |pages=1029–1035 |doi=10.1056/NEJM199404143301501 |pmid=8127329 |issn=0028-4793 | vauthors = Alpha-Tocopherol BC }}</ref><ref name=PKIN2020Carotenoids/> Taking this and other evidence into consideration, the U.S. Institute of Medicine decided not to set a Tolerable Upper Intake Level (UL) for β-carotene.<ref name=PKIN2020Carotenoids/><ref name="DRItextBetaCarotene">{{cite book |title=Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids |chapter=Beta-carotene and other Carotenoids |publisher=The National Academies Press |year=2000 |location=Washington, DC |pages=325–382 |doi=10.17226/9810 |pmid=25077263 |chapter-url=https://www.nap.edu/read/9810/chapter/10 |access-date=19 December 2021 |isbn=978-0-309-06935-9 |url-status=live |archive-url=https://web.archive.org/web/20170902180153/https://www.nap.edu/read/9810/chapter/10 |archive-date=2 September 2017|author1=Institute of Medicine (US) Panel on Dietary Antioxidants Related Compounds }}</ref> The European Food Safety Authority, acting for the European Union, also decided not to set a UL for β-carotene.<ref name=EFSA-UL/>
[[File:Carrots.JPG|thumb|upright|right|250px|[[Carrot]]s are a rich source of β-carotene.]]

====Carotenosis====
[[Carotenosis|Carotenoderma]], also referred to as carotenemia, is a benign and reversible medical condition where an excess of dietary carotenoids results in orange discoloration of the outermost skin layer. It is associated with a high blood β-carotene value. This can occur after a month or two of consumption of β-carotene rich foods, such as carrots, carrot juice, tangerine juice, mangos, or in Africa, red palm oil. β-carotene dietary supplements can have the same effect. The discoloration extends to palms and soles of feet, but not to the [[sclera|white of the eye]], which helps distinguish the condition from [[jaundice]].<ref>{{cite journal | vauthors = Maharshak N, Shapiro J, Trau H | title = Carotenoderma – a review of the current literature | journal = International Journal of Dermatology | volume = 42 | issue = 3 | pages = 178–181 | date = March 2003 | pmid = 12653910 | doi = 10.1046/j.1365-4362.2003.01657.x | s2cid = 27934066 | doi-access = free | title-link = doi }}</ref> Consumption of greater than 30&nbsp;mg/day for a prolonged period has been confirmed as leading to carotenemia.<ref name=PKIN2020Carotenoids/><ref>{{cite book | vauthors = Al Nasser Y, Jamal Z, Albugeaey M | chapter = Carotenemia | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing | date = 2021 | pmid = 30521299 | doi = 10.1007/s00253-001-0902-7 | s2cid = 22232461 }}</ref>

===U.S. labeling===
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin A labeling purposes, 100% of the Daily Value was set at 5,000 IU, but it was revised to 900 μg RAE on 27 May 2016.<ref name="FedReg">{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels |access-date=4 September 2017 |archive-date=8 August 2016 |archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |url-status=live }}</ref><ref>{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=18 December 2021 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp }}</ref> A table of the old and new adult daily values is provided at [[Reference Daily Intake]].

==Sources==
{| class="wikitable" style="float:right; clear:left; width:18em; text-align:center;"
|-
! Food ||
μg {{abbr|RAE|retinol activity equivalent}} (2001)<ref name="DRI VitA"/>
per 100 g<ref name="USDAContent"/>
|-
| [[cod liver oil]] || 30,000
|-
| [[liver (food)|beef liver]] (cooked) || 4,970–21,145
|-
| [[liver (food)|chicken liver]] (cooked) || 4,296
|-
| [[butter]] (stick) || 684
|-
| [[cheddar cheese]] || 316
|-
| [[egg (food)|egg]] (cooked) || 140
|-
|}

Vitamin A is found in many foods.<ref name="USDAContent">{{cite web |url=https://fdc.nal.usda.gov/fdc-app.html#/?component=1106 |title=Rank order of vitamin A content in foods, retinol activity equivalent (RAE) in ug per 100 g |publisher=FoodData Central, US Department of Agriculture |date=1 October 2021 |access-date=20 December 2021 |archive-date=3 April 2019 |archive-url=https://web.archive.org/web/20190403171801/https://fdc.nal.usda.gov/fdc-app.html#/?component=1106 }}</ref> Vitamin A in food exists either as preformed retinol {{ndash}} an active form of vitamin A {{ndash}} found in animal liver, dairy and egg products, and some fortified foods, or as provitamin A carotenoids, which are plant pigments digested into vitamin A after consuming carotenoid-rich plant foods, typically in red, orange, or yellow colors.<ref name=lpi/> Carotenoid pigments may be masked by [[chlorophyll]]s in dark green leaf vegetables, such as spinach. The relatively low [[bioavailability]] of plant-food carotenoids results partly from binding to proteins {{ndash}} chopping, homogenizing or cooking disrupts the plant proteins, increasing provitamin A carotenoid bioavailability.<ref name=lpi/>

[[Vegetarianism|Vegetarian]] and [[Veganism|vegan]] diets can provide sufficient vitamin A in the form of provitamin A carotenoids if the diet contains [[carrots]], [[carrot juice]], [[sweet potatoes]], green leafy vegetables such as [[spinach]] and [[kale]], and other carotenoid-rich foods. In the U.S., the average daily intake of β-carotene is in the range 2–7&nbsp;mg.<ref>{{cite web |url=https://ods.od.nih.gov/pubs/usdandb/VitA-betaCarotene-Content.pdf#search=%22beta-carotene%22 |title=USDA National Nutrient Database for Standard Reference, Release 28 |date=28 October 2015 |access-date=5 February 2022 |archive-date=17 December 2021 |archive-url=https://web.archive.org/web/20211217094008/https://ods.od.nih.gov/pubs/usdandb/VitA-betaCarotene-Content.pdf#search=%22beta-carotene%22 |url-status=live }}</ref>

Some [[food fortification|manufactured foods]] and dietary supplements are sources of vitamin A or β-carotene.<ref name=lpi/><ref name="DRI VitA"/>

===Fortification===
Some countries require or recommend fortification of foods. As of January 2022, 37 countries, mostly in Sub-Saharan Africa, require food fortification of [[cooking oil]], rice, [[wheat]] flour or [[maize]] (corn) flour with vitamin A, usually as retinyl palmitate or retinyl acetate. Examples include Pakistan, oil, 11.7&nbsp;mg/kg and Nigeria, oil, 6&nbsp;mg/kg; wheat and maize flour, 2&nbsp;mg/kg.<ref name=FortifMap>{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Total number of nutrients in food vehicles, according to a country's fortification standard|website=Global Fortification Data Exchange|access-date=7 January 2022|archive-date=11 April 2019|archive-url=https://web.archive.org/web/20190411123853/https://fortificationdata.org/map-number-of-nutrients/|url-status=live}}</ref> An additional 12 countries, mostly in southeast Asia, have a voluntary fortification program. For example, the government of India recommends 7.95&nbsp;mg/kg in oil and 0.626&nbsp;mg/kg for wheat flour and rice. However, compliance in countries with voluntary fortification is lower than countries with mandatory fortification.<ref name=FortifMap/> No countries in Europe or North America fortify foods with vitamin A.<ref name=FortifMap/>

{| class="wikitable" style="float:right; clear:left; width:18em; text-align:center;"
|-
! Food
!
μg {{abbr|RAE|retinol activity equivalent}} (2001)<ref name="DRI VitA"/>
per 100 g<ref name="USDAContent"/>
|-
| [[Sweet potato]], baked, no added [[fat]]
| 957
|-
| [[Carrot]], frozen, cooked, no added fat
| 843
|-
| [[Pumpkin]], canned, cooked
| 767
|-
| [[Spinach]], fresh, cooked, no added fat
| 341
|-
| [[Kale]], fresh, cooked, no added fat
| 245
|-
|}
Other means of fortifying foods via genetic engineering have been explored. Research on rice began in 1982.<ref>{{cite web | url = http://www.goldenrice.org/Content3-Why/why3_FAQ.php#Inventors | title = FAQ: Who invented Golden Rice and how did the project start? | work = Goldenrice.org | access-date = 9 January 2022 | archive-date = 14 February 2022 | archive-url = https://web.archive.org/web/20220214011041/https://www.goldenrice.org/Content3-Why/why3_FAQ.php#Inventors | url-status = live }}</ref> The first field trials of golden rice cultivars were conducted in 2004.<ref>{{cite web|author=LSU AgCenter Communications|date=2004|title='Golden Rice' Could Help Reduce Malnutrition|url=http://www.lsuagcenter.com/news_archive/2004/October/Headline+News/Golden+Rice+Could+Help+Malnutrition.htm|archive-url=https://web.archive.org/web/20070928171832/http://www.lsuagcenter.com/news_archive/2004/October/Headline%2BNews/Golden%2BRice%2BCould%2BHelp%2BMalnutrition.htm|archive-date=28 September 2007}}</ref> The result was "Golden Rice", a variety of ''[[Oryza sativa]]'' rice produced through genetic engineering to [[biosynthesis|biosynthesize]] β-carotene, a precursor of retinol, in the edible parts of rice.<ref>{{cite journal | vauthors = Kettenburg AJ, Hanspach J, Abson DJ, Fischer J | title = From disagreements to dialogue: unpacking the Golden Rice debate | journal = Sustainability Science | volume = 13 | issue = 5 | pages = 1469–1482 | date = 2018 | pmid = 30220919 | pmc = 6132390 | doi = 10.1007/s11625-018-0577-y | bibcode = 2018SuSc...13.1469K }}</ref><ref>{{cite journal | vauthors = Ye X, Al-Babili S, Klöti A, Zhang J, Lucca P, Beyer P, Potrykus I | title = Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm | journal = Science | volume = 287 | issue = 5451 | pages = 303–305 | date = January 2000 | pmid = 10634784 | doi = 10.1126/science.287.5451.303 | s2cid = 40258379 | bibcode = 2000Sci...287..303Y }}</ref> In May 2018, regulatory agencies in the United States, Canada, Australia and New Zealand had concluded that Golden Rice met food safety standards.<ref>{{Cite news|url=http://irri.org/news/media-releases/golden-rice-meets-food-safety-standards-in-three-global-leading-regulatory-agencies|title=Golden Rice meets food safety standards in three global leading regulatory agencies|work=International Rice Research Institute – IRRI|access-date=30 May 2018|language=en-gb|archive-date=29 May 2018|archive-url=https://web.archive.org/web/20180529163022/http://irri.org/news/media-releases/golden-rice-meets-food-safety-standards-in-three-global-leading-regulatory-agencies|url-status=live}}</ref> In July 2021, the Philippines became the first country to officially issue the biosafety permit for commercially propagating Golden Rice.<ref>{{Cite web|vauthors=Talavera C|title=Philippines OKs GMO 'golden rice'|url=https://www.philstar.com/headlines/2021/07/24/2114742/philippines-oks-gmo-golden-rice|access-date=21 August 2021|website=Philstar.com|archive-date=24 August 2021|archive-url=https://web.archive.org/web/20210824102835/https://www.philstar.com/headlines/2021/07/24/2114742/philippines-oks-gmo-golden-rice|url-status=live}}</ref><ref>{{Cite web|date=23 July 2021|title=Filipinos soon to plant and eat Golden Rice|url=https://www.philrice.gov.ph/filipinos-soon-to-plant-and-eat-golden-rice/|access-date=21 August 2021|website=Philippine Rice Research Institute|language=en-US|archive-date=12 June 2022|archive-url=https://web.archive.org/web/20220612225828/https://www.philrice.gov.ph/filipinos-soon-to-plant-and-eat-golden-rice/|url-status=live}}</ref> However, in April 2023, the Supreme Court of the Philippines issued a [[Writ of Kalikasan]] ordering the Department of Agriculture to stop the commercial distribution of genetically modified rice in the country.<ref>{{Cite web |vauthors=Servallos NJ |date=20 April 2023 |title=SC issues writ vs GMO golden rice, eggplant |url=https://www.philstar.com/headlines/2023/04/20/2260239/sc-issues-writ-vs-gmo-golden-rice-eggplant |access-date=22 September 2023 |website=Philippine Star |archive-date=21 April 2023 |archive-url=https://web.archive.org/web/20230421061822/https://www.philstar.com/headlines/2023/04/20/2260239/sc-issues-writ-vs-gmo-golden-rice-eggplant |url-status=live }}</ref>

===Vitamin A supplementation (VAS)===
[[File:Vitamin A supplementation coverage rate (children ages 6-59 months), OWID.svg|thumb|upright=1.6|Vitamin A supplementation coverage rate (children ages 6–59 months), 2014<ref>{{cite web|title=Vitamin A supplementation coverage rate (children ages 6–59 months)|url=https://ourworldindata.org/grapher/vitamin-a-supplementation-coverage-rate-children-ages-6-59-months|website=Our World in Data|access-date=6 March 2020|archive-date=23 April 2021|archive-url=https://web.archive.org/web/20210423201341/https://ourworldindata.org/grapher/vitamin-a-supplementation-coverage-rate-children-ages-6-59-months|url-status=live}}</ref>]]

Delivery of oral high-dose supplements remains the principal strategy for minimizing deficiency.<ref name="UNICEF 2007, p.3">{{cite book | publisher = UNICEF | url = http://www.unicef.org/publications/files/Vitamin_A_Supplementation.pdf | title = Vitamin A Supplementation: A Decade of Progress | location = New York | date = 2007 | page = 3 | isbn = 978-92-806-4150-9 | access-date = 23 January 2011 | archive-date = 31 October 2020 | archive-url = https://web.archive.org/web/20201031224103/https://www.unicef.org/publications/files/Vitamin_A_Supplementation.pdf }}</ref> As of 2017, more than 80 countries worldwide are implementing universal VAS programs targeted to children 6–59 months of age through semi-annual national campaigns.<ref name="Wirth2017">{{cite journal | vauthors = Wirth JP, Petry N, Tanumihardjo SA, Rogers LM, McLean E, Greig A, Garrett GS, Klemm RD, Rohner F | title = Vitamin A Supplementation Programs and Country-Level Evidence of Vitamin A Deficiency | journal = Nutrients | volume = 9 | issue = 3 | page = 190 | date = February 2017 | pmid = 28245571 | pmc = 5372853 | doi = 10.3390/nu9030190 | doi-access = free | title-link = doi }}</ref> Doses in these programs are one dose of 50,000 or 100,000 IU for children aged 6 to 11 months and 100,000 to 200,000 IU for children aged 12 months to five years, every four to six months.<ref name="Imdad2017"/>

==Deficiency==
{{Main|Vitamin A deficiency}}

===Primary causes===
Vitamin A deficiency is common in [[Developing country|developing countries]], especially in [[Sub-Saharan Africa]] and [[Southeast Asia]]. Deficiency can occur at any age, but is most common in pre-school-age children and pregnant women, the latter due to a need to transfer retinol to the fetus. The causes are low intake of retinol-containing, animal-sourced foods and low intake of carotene-containing, plant-sourced foods. Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world,<ref>{{cite web |publisher=[[World Health Organization]] |title=Global prevalence of vitamin A deficiency in populations at risk 1995–2005 |url=http://apps.who.int/iris/bitstream/10665/44110/1/9789241598019_eng.pdf |work=WHO global database on vitamin A deficiency |year=2009 |access-date=28 June 2017 |archive-date=15 December 2017 |archive-url=https://web.archive.org/web/20171215143955/http://apps.who.int/iris/bitstream/10665/44110/1/9789241598019_eng.pdf |url-status=live }}</ref> possibly leading to the deaths of 670,000 children under five annually.<ref>{{cite journal | vauthors = Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, Mathers C, Rivera J | title = Maternal and child undernutrition: global and regional exposures and health consequences | journal = Lancet | volume = 371 | issue = 9608 | pages = 243–260 | date = January 2008 | pmid = 18207566 | doi = 10.1016/S0140-6736(07)61690-0 | url = https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=10965&content=PDF | s2cid = 3910132 | collaboration = Maternal and Child Undernutrition Study Group | archive-url = https://web.archive.org/web/20211016033636/https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=10965&content=PDF | archive-date = 16 October 2021 | url-access = subscription }}</ref>

Between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin A deficiency.<ref name="ods"/> Vitamin A deficiency is "the leading cause of preventable childhood blindness", according to [[UNICEF]].<ref name=UNICEFvitaminA>{{cite web | url = http://www.unicef.org/specialsession/about/sgreport-pdf/12_VitaminADeficiency_D7341Insert_English.pdf | title = Vitamin A Deficiency | work = UNICEF | access-date = 3 June 2015 | archive-date = 12 September 2016 | archive-url = https://web.archive.org/web/20160912193103/http://www.unicef.org/specialsession/about/sgreport-pdf/12_VitaminADeficiency_D7341Insert_English.pdf }}</ref><ref name="Akhtar2013"/> It also increases the risk of death from common childhood conditions, such as [[diarrhea]]. UNICEF regards addressing vitamin A deficiency as critical to reducing [[child mortality]], the fourth of the [[United Nations]]' [[Millennium Development Goals]].<ref name=UNICEFvitaminA/>

During diagnosis, night blindness and [[xerophthalmia|dry eyes]] are signs of vitamin A deficiency that can be recognized without requiring biochemical tests. Plasma retinol is used to confirm vitamin A status. A plasma concentration of about 2.0 μmol/L is normal; less than 0.70 μmol/L (equivalent to 20 μg/dL) indicates moderate vitamin A deficiency, and less than 0.35 μmol/L (10 μg/dL) indicates severe vitamin A deficiency. Breast milk retinol of less than 8 μg/gram [[milk fat]] is considered insufficient.<ref name=PKIN2020VitA/> One weakness of these measures is that they are not good indicators of liver vitamin A stores as retinyl esters in [[hepatic stellate cell]]s. The amount of vitamin A leaving the liver, bound to retinol binding protein (RBP), is under tight control as long as there are sufficient liver reserves. Only when liver content of vitamin A drops below approximately 20 μg/gram will concentration in the blood decline.<ref name="DRI VitA"/><ref name=Tanumihardjo>{{cite journal | vauthors = Tanumihardjo SA | title = Vitamin A: biomarkers of nutrition for development | journal = The American Journal of Clinical Nutrition | volume = 94 | issue = 2 | pages = 658S–665S | date = August 2011 | pmid = 21715511 | pmc = 3142734 | doi = 10.3945/ajcn.110.005777 }}</ref>

===Secondary causes===
There are causes for deficiency other than low dietary intake of vitamin A as retinol or carotenes. Adequate dietary protein and caloric energy are needed for a normal rate of synthesis of RBP, without which, retinol cannot be mobilized to leave the liver. Systemic infections can cause transient decreases in RBP synthesis even if protein-calorie malnutrition is absent. Chronic alcohol consumption reduces liver vitamin A storage.<ref name="DRI VitA"/> [[Non-alcoholic fatty liver disease]] (NAFLD), characterized by the accumulation of fat in the liver, is the hepatic manifestation of [[metabolic syndrome]]. Liver damage from NAFLD reduces liver storage capacity for retinol and reduces the ability to mobilize liver stores to maintain normal circulating concentration.<ref name="Saeed2017">{{cite journal | vauthors = Saeed A, Dullaart RP, Schreuder TC, Blokzijl H, Faber KN | title = Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD) | journal = Nutrients | volume = 10 | issue = 1 | page = 29 | date = December 2017 | pmid = 29286303 | pmc = 5793257 | doi = 10.3390/nu10010029 | doi-access = free | title-link = doi }}</ref>
Vitamin A appears to be involved in the pathogenesis of anemia by diverse biological mechanisms, such as the enhancement of growth and differentiation of erythrocyte progenitor cells, potentiation of immunity to infection, and mobilization of iron stores from tissues.

==Animal requirements==
All [[vertebrate]] and [[chordate]] species require vitamin A,<ref name=Marletaz2006/> either as dietary carotenoids or preformed retinol from consuming other animals. Deficiencies have been reported in laboratory-raised and pet dogs, cats, birds, reptiles and amphibians,<ref name=Hensel2010>{{cite journal | vauthors = Hensel P | title = Nutrition and skin diseases in veterinary medicine | journal = Clinics in Dermatology | volume = 28 | issue = 6 | pages = 686–693 | date = 2010 | pmid = 21034992 | doi = 10.1016/j.clindermatol.2010.03.031 }}</ref><ref>{{cite journal | vauthors = Clugston RD, Blaner WS | title = Vitamin A (retinoid) metabolism and actions: What we know and what we need to know about amphibians | journal = Zoo Biology | volume = 33 | issue = 6 | pages = 527–535 | date = 2014 | pmid = 24958673 | pmc = 4685470 | doi = 10.1002/zoo.21140 }}</ref> also commercially raised chickens and turkeys.<ref>{{cite journal | vauthors = Shojadoost B, Yitbarek A, Alizadeh M, Kulkarni RR, Astill J, Boodhoo N, Sharif S | title = Centennial Review: Effects of vitamins A, D, E, and C on the chicken immune system | journal = Poultry Science | volume = 100 | issue = 4 | page = 100930 | date = April 2021 | pmid = 33607314 | pmc = 7900602 | doi = 10.1016/j.psj.2020.12.027 }}</ref> Herbivore species such as horses, cattle and sheep can get sufficient β-carotene from green pasture to be healthy, but the content in pasture grass dry due to drought and long-stored hay can be too low, leading to vitamin A deficiency.<ref name=Hensel2010/> Omnivore and carnivore species, especially those toward the top of the food chain, can accrue large amounts of retinyl esters in their livers, or else excrete retinyl esters in urine as a means of dealing with surplus.<ref name=Green2016/> Before the era of synthetic retinol, [[cod liver oil]], high in vitamins A and D, was a commonly consumed dietary supplement.<ref>{{cite journal | vauthors = Semba RD | title = Vitamin A as "anti-infective" therapy, 1920–1940 | journal = The Journal of Nutrition | volume = 129 | issue = 4 | pages = 783–791 | date = April 1999 | pmid = 10203551 | doi = 10.1093/jn/129.4.783 | doi-access = free | title-link = doi }}</ref><ref>{{Cite web |url=https://www.iffo.com/system/files/downloads/Codex%20Standard%20for%20Fish%20Oils%20CXS_329e_Nov%202017.pdf |title=Standards for Fish Oils CODEX STAN 329-2017 |date=2017 |access-date=28 January 2022 |website=CODEX Alimentarius Commission, World Health Organization |archive-date=3 March 2022 |archive-url=https://web.archive.org/web/20220303094226/https://www.iffo.com/system/files/downloads/Codex%20Standard%20for%20Fish%20Oils%20CXS_329e_Nov%202017.pdf |url-status=live }}</ref> [[Invertebrate]]s cannot synthesize carotenoids or retinol, and thus must accrue these essential nutrients from consumption of algae, plants or animals.<ref>{{cite journal | vauthors = André A, Ruivo R, Gesto M, Castro LF, Santos MM | title = Retinoid metabolism in invertebrates: when evolution meets endocrine disruption | journal = General and Comparative Endocrinology | volume = 208 | issue = | pages = 134–145 | date = November 2014 | pmid = 25132059 | doi = 10.1016/j.ygcen.2014.08.005 | s2cid = 44685529 }}</ref><ref>{{cite book |vauthors=Gutierrez-Mazariegos J, Schubert M, Laudet V |title=The Biochemistry of Retinoic Acid Receptors I: Structure, Activation, and Function at the Molecular Level |chapter=Evolution of Retinoic Acid Receptors and Retinoic Acid Signaling |series=Subcellular Biochemistry |volume=70 |pages=55–73 |date=2014 |pmid=24962881 |doi=10.1007/978-94-017-9050-5_4 |isbn=978-94-017-9049-9 |chapter-url=}}</ref><ref>{{cite journal | vauthors = Albalat R | title = The retinoic acid machinery in invertebrates: ancestral elements and vertebrate innovations | journal = Molecular and Cellular Endocrinology | volume = 313 | issue = 1–2 | pages = 23–35 | date = December 2009 | pmid = 19737598 | doi = 10.1016/j.mce.2009.08.029 | s2cid = 41188476 }}</ref>

==Medical uses==

In 2022, vitamin A was the 346th most commonly prescribed medication in the United States, with more than 50,000 prescriptions.<ref>{{cite web | title = Vitamin A Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/VitaminA | access-date = 30 August 2024 }}</ref>

===Preventing and treating vitamin A deficiency===
{{Main|Vitamin A deficiency}}

Recognition of its prevalence and consequences has led to governments and non-government organizations promoting vitamin A fortification of foods<ref name=FortifMap/> and creating programs that administer large bolus-size oral doses of vitamin A to young children every four to six months.<ref name="Wirth2017"/> In 2008, the [[World Health Organization]] estimated that vitamin A supplementation over a decade in 40 countries averted 1.25 million deaths due to vitamin A deficiency.<ref>{{cite web |url=https://www.who.int/nutrition/topics/vad/en/index.html |title=Micronutrient Deficiencies – Vitamin A |access-date=9 April 2008 |publisher=World Health Organization |archive-url=https://web.archive.org/web/20110127030721/https://www.who.int/nutrition/topics/vad/en/index.html |archive-date=27 January 2011 }}</ref> A Cochrane review reported that vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children ages six month to five years of age. All-cause mortality was reduced by 14%, and incidence of [[diarrhea]] by 12%.<ref name="Imdad2017">{{cite journal | vauthors = Imdad A, Mayo-Wilson E, Haykal MR, Regan A, Sidhu J, Smith A, Bhutta ZA | title = Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 11 | article-number = CD008524 | date = March 2022 | pmid = 35294044 | pmc = 8925277 | doi = 10.1002/14651858.CD008524.pub4 }}</ref> However, a Cochrane review by the same group concluded there was insufficient evidence to recommend blanket vitamin A supplementation for infants one to six months of age, as it did not reduce infant mortality or morbidity.<ref name="Imdad2016"/>

=== Acne ===

==== Topical retinoic acid and retinol ====
[[File:Retinoids.svg|thumb|class=skin-invert-image|Retinoids: [[Tretinoin]] is ''all-trans''-retinoic acid; initial tradename: Retin-A. [[Isotretinoin]] is 13-''cis''-retinoic acid; initial tradename: Accutane. [[Etretinate]] and [[Acitretin]], its non-esterified metabolite, are used orally to treat severe [[psoriasis]].<ref name="Becken2015" />]]

Retinoic acids [[tretinoin]] (''all-trans''-retinoic acid) and [[isotretinoin]] (13-''cis''-retinoic acid) are prescription medications used to treat moderate to severe cystic acne and acne not responsive to other treatments.<ref>{{cite web |date=22 March 2021 |title=Tretinoin |url=https://www.drugs.com/monograph/tretinoin.html |url-status=live |archive-url=https://web.archive.org/web/20161130124932/https://www.drugs.com/monograph/tretinoin.html |archive-date=30 November 2016 |access-date=23 December 2021 |publisher=The American Society of Health-System Pharmacists}}</ref><ref>{{cite journal |vauthors=Merritt B, Burkhart CN, Morrell DS |date=June 2009 |title=Use of isotretinoin for acne vulgaris |journal=Pediatric Annals |volume=38 |issue=6 |pages=311–320 |doi=10.3928/00904481-20090512-01 |pmid=19588674}}</ref><ref>{{cite journal |vauthors=Layton A |date=May 2009 |title=The use of isotretinoin in acne |journal=Dermato-Endocrinology |volume=1 |issue=3 |pages=162–169 |doi=10.4161/derm.1.3.9364 |pmc=2835909 |pmid=20436884}}</ref><ref name="Leyden2017">{{cite journal |vauthors=Leyden J, Stein-Gold L, Weiss J |date=September 2017 |title=Why Topical Retinoids Are Mainstay of Therapy for Acne |journal=Dermatology and Therapy |volume=7 |issue=3 |pages=293–304 |doi=10.1007/s13555-017-0185-2 |pmc=5574737 |pmid=28585191}}</ref> Tretinoin is usually applied as a [[cream (pharmacy)|skin cream]] to the face after cleansing to remove make-up and skin oils, while isotretinoin is taken orally. Tretinoin and isotretinoin act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR).<ref name="Kang S 2008">Kang S, Voorhees JJ. "Topical retinoids". In: ''Fitzpatrick's Dermatology in General Medicine'', 7th ed, Wolff K, Goldsmith LA, Katz SI, et al. (Eds), McGraw Hill, New York 2008. p. 2106.</ref> These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.<ref>Fernandez EM, Zaenglein A, Thiboutot D. "Acne Treatment Methodologies". In: ''Cosmetic Formulation of Skin Care Products'', Taylor and Francis Group, New York 2006. p. 273.</ref> The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.<ref name="Kang S 2008" /> Retinoic acid products also reduce [[sebum]] secretion, a nutrient source for bacteria, from facial pores.<ref>{{cite journal |vauthors=Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Kibbi AG, Nemer G, Kurban M |date=December 2017 |title=Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects |journal=The Journal of Dermatological Treatment |volume=28 |issue=8 |pages=684–696 |doi=10.1080/09546634.2017.1309349 |pmid=28318351}}</ref>

These drugs, when applied topically, are US-designated Pregnancy Category C (animal reproduction studies have shown an adverse effect on the fetus), and should not be used by pregnant women or women who are anticipating becoming pregnant.<ref name="Tretinoin" /> Many countries established a physician- and patient- education pregnancy prevention policy.<ref>{{cite journal |vauthors=Kovitwanichkanont T, Driscoll T |date=September 2018 |title=A comparative review of the isotretinoin pregnancy risk management programs across four continents |journal=International Journal of Dermatology |volume=57 |issue=9 |pages=1035–1046 |doi=10.1111/ijd.13950 |pmid=29508918 |s2cid=3726217}}</ref>

[[Trifarotene]] is a prescription retinoid for the topical treatment acne vulgaris.<ref name="Monograph" /> It functions as a [[Retinoic acid receptor gamma|retinoic acid receptor (RAR)-γ]] [[agonist]].<ref name="Scott2019">{{cite journal |vauthors=Scott LJ |date=November 2019 |title=Trifarotene: First Approval |journal=Drugs |volume=79 |issue=17 |pages=1905–1909 |doi=10.1007/s40265-019-01218-6 |pmid=31713811 |s2cid=207964653}}</ref>

Non-prescription [[cream (pharmacy)|topical products]] that have health claims for reducing facial acne, combating skin dark spots and reducing wrinkles and lines associated with aging often contain [[retinyl palmitate]]. The hypothesis is that this is absorbed and de-esterified to free retinol, then converted to retinaldehyde and further metabolized to ''all-trans''-retinoic acid, whence it will have the same effects as prescription products with fewer side effects.<ref>{{cite journal |vauthors=Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G |date=2006 |title=Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety |journal=Clinical Interventions in Aging |volume=1 |issue=4 |pages=327–348 |doi=10.2147/ciia.2006.1.4.327 |pmc=2699641 |pmid=18046911 |doi-access=free |title-link=doi}}</ref> There is some ''ex vivo'' evidence with human skin that esterified retinol is absorbed and then converted to retinol.<ref>{{cite journal |vauthors=Boehnlein J, Sakr A, Lichtin JL, Bronaugh RL |date=August 1994 |title=Characterization of esterase and alcohol dehydrogenase activity in skin. Metabolism of retinyl palmitate to retinol (vitamin A) during percutaneous absorption |journal=Pharmaceutical Research |volume=11 |issue=8 |pages=1155–1159 |doi=10.1023/A:1018941016563 |pmid=7971717 |s2cid=25458156}}</ref> In addition to esterified retinol, some of these products contain hydroxypinacolone retinoate, identified as esterified 9-''cis''-retinoic acid.<ref>{{cite journal |vauthors=Villani A, Annunziata MC, Cinelli E, Donnarumma M, Milani M, Fabbrocini G |date=October 2020 |title=Efficacy and safety of a new topical gel formulation containing retinol encapsulated in glycospheres and hydroxypinacolone retinoate, an antimicrobial peptide, salicylic acid, glycolic acid and niacinamide for the treatment of mild acne: preliminary results of a 2-month prospective study |journal=Giornale Italiano di Dermatologia e Venereologia |volume=155 |issue=5 |pages=676–679 |doi=10.23736/S0392-0488.20.06581-5 |pmid=32869963 |s2cid=221402891}}</ref>

==== Oral isotretinoin ====
Oral [[isotretinoin]] (retinoic acid [[isomer]]) is recommended for treating treatment resistant [[acne]], acne that can lead to scarring, and acne that is associated with psychosocial distress.<ref name="Reynolds_2024">{{cite journal | vauthors = Reynolds RV, Yeung H, Cheng CE, Cook-Bolden F, Desai SR, Druby KM, Freeman EE, Keri JE, Stein Gold LF, Tan JK, Tollefson MM, Weiss JS, Wu PA, Zaenglein AL, Han JM, Barbieri JS | title = Guidelines of care for the management of acne vulgaris | journal = Journal of the American Academy of Dermatology | volume = 90 | issue = 5 | pages = 1006.e1–1006.e30 | date = May 2024 | pmid = 38300170 | doi = 10.1016/j.jaad.2023.12.017 }}</ref> It is approved by the FDA for treating severe acne vulgaris that is resistant to other treatment options.<ref name="Reynolds_2024" /> Isotretinoin is a known teratogen, with an estimated 20–35% risk of physical birth defects to infants that are exposed to isotretinoin ''in utero'', including numerous congenital defects such as craniofacial defects, cardiovascular and neurological malformations or thymic disorders.<ref name="Draghici2021" /> Neurocognitive impairments in the absence of any physical defects has been established to be 30–60%.<ref name="Draghici2021" /> For these reasons, physician- and patient-education programs were initiated, recommending that for women of child-bearing age, contraception be initiated a month before starting oral (or topical) isotretinoin, and continue for a month after treatment ended.<ref name="Draghici2021"/> In the US, isotretinoin was released to the market in 1982 as a revolutionary treatment for severe and refractory [[acne vulgaris]]. It was shown that a dose of 0.5–1.0&nbsp;mg/kg body weight/day is enough to produce a reduction in sebum excretion by 90% within a month or two, but the recommended treatment duration is 4 to 6 months.<ref name="Draghici2021" />

The mechanism by which orally consumed retinoic acid (RA), as ''all-trans''-tretinoin or 13-''cis''-isotretinoin improves facial skin health is thought to be by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells.<ref name="Reynolds_2024" /> RA reduces the size and secretion of the sebaceous glands, and by doing so reduces bacterial numbers in both the ducts and skin surface.<ref name="Reynolds_2024" /> It reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils.

=== Other dermatological conditions ===
In addition to the approved use for treating acne vulgaris, researchers have investigated off-label applications for dermatological conditions, such as rosacea, psoriasis, and other conditions.<ref name="Nickle2014">{{cite journal | vauthors = Nickle SB, Peterson N, Peterson M | title = Updated Physician's Guide to the Off-label Uses of Oral Isotretinoin | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 7 | issue = 4 | pages = 22–34 | date = April 2014 | pmid = 24765227 | pmc = 3990537 | doi = }}</ref> [[Rosacea]] was reported as responding favorably to doses lower than used for acne. Isotretinoin in combination with ultraviolet light was shown affective for treating [[psoriasis]]. Isotretinoin in combination with injected [[interferon-alpha]] showed some potential for treating [[genital warts]]. Isotretinoin in combination with topical [[fluorouracil]] or injected interferon-alpha showed some potential for treating precancerous skin lesions and skin cancer.<ref name="Nickle2014"/>

=== Immune function ===
Vitamin A plays an important role in the body's immune function, both the adaptive response, and to help the body fight off infection.<ref name="Cheng_2024">{{cite journal | vauthors = Cheng X, Li D, Yang C, Chen B, Xu P, Zhang L | title = Oral vitamin A supplements to prevent acute upper respiratory tract infections in children up to seven years of age | journal = The Cochrane Database of Systematic Reviews | volume = 2024 | issue = 5 | article-number = CD015306 | date = May 2024 | pmid = 38738639 | pmc = 11089595 | doi = 10.1002/14651858.CD015306.pub2 }}</ref> The anti-inflammatory effects of vitamin A also contribute to repairing mucosal cells that can be damaged by an infection.<ref name="Cheng_2024" /> For these reasons, there have been quite a few studies looking at the potential role that Vitamin A supplementation may play in improving an immune response or to helping the body fight off an infection. The evidence supporting vitamin A supplementation for children under the age of 7 years to prevent upper respiratory tract infections is weak, and the weak evidence from low-quality clinical trials does not support vitamin A as being effective or having a benefit.<ref name="Cheng_2024" /> More research is needed to consider different doses, the ages and populations of people who may potentially benefit, and the length of treatment.<ref name="Cheng_2024" />

==Synthesis==
===Biosynthesis===
Carotenoid synthesis takes place in plants, certain fungi, and bacteria. Structurally carotenes are [[tetraterpene]]s, meaning that they are synthesized biochemically from four 10-carbon [[terpene]] units, which in turn were formed from eight 5-carbon [[isoprene]] units. Intermediate steps are the creation of a 40-carbon [[phytoene]] molecule, conversion to [[lycopene]] via desaturation, and then creation of ionone rings at both ends of the molecule. β-carotene has a β-ionone ring at both ends, meaning that the molecule can be divided symmetrically to yield two retinol molecules. α-Carotene has a β-ionone ring at one end and an Ɛ-ionone ring at the other, so it has half the retinol conversion capacity.<ref name=PKIN2020Carotenoids>{{cite book |vauthors=von Lintig J |title = Present Knowledge in Nutrition | edition = Eleventh |chapter = Carotenoids | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London |pages = 531–549 |isbn=978-0-323-66162-1}}</ref>

[[File:Chem 157 vitamin a synthesis project.png|thumb|class=skin-invert-image|Vitamin A biosynthesis from β-carotene]]
In most animal species, retinol is synthesized from the breakdown of the plant-formed provitamin, β-carotene. First, the enzyme [[beta-carotene 15,15'-dioxygenase]] (BCO-1) cleaves β-carotene at the central double bond, creating an epoxide. This epoxide is then attacked by water creating two hydroxyl groups in the center of the structure. The cleavage occurs when these alcohols are oxidized to the aldehydes using NAD<sup>+</sup>. The resultant retinal is then quickly reduced to retinol by the enzyme retinol dehydrogenase.<ref name=PKIN2020VitA/> Omnivore species such as [[Canidae|dogs, wolves, coyotes and foxes]] in general are low producers of BCO-1. The enzyme is lacking in [[felidae|felids]] (cats), meaning that vitamin A requirements are met from the retinyl ester content of prey animals.<ref name=Green2016/>

===Industrial synthesis===
[[File:Ionone beta.svg|thumb|left|class=skin-invert-image|β-ionone ring]]
β-carotene can be extracted from fungus ''Blakeslea trispora'', marine algae ''Dunaliella salina'' or genetically modified yeast ''Saccharomyces cerevisiae'', starting with xylose as a substrate.<ref name="Sun2020">{{cite journal | vauthors = Sun L, Atkinson CA, Lee YG, Jin YS | title = High-level β-carotene production from xylose by engineered Saccharomyces cerevisiae without overexpression of a truncated HMG1 (tHMG1) | journal = Biotechnology and Bioengineering | volume = 117 | issue = 11 | pages = 3522–3532 | date = November 2020 | pmid = 33616900 | doi = 10.1002/bit.27508 | osti = 1651205 | s2cid = 222411819 }}</ref> Chemical synthesis uses either a method developed by [[BASF]]<ref name="β-Carotin-1">Wittig G.; Pommer H.: ''DBP 954247'', 1956</ref><ref name="β-Carotin-2">Wittig G.; Pommer H. (1959). ''Chem. Abstr''. 53: 2279</ref> or a [[Grignard reaction]] utilized by [[Hoffman-La Roche]].<ref>{{cite patent|country = US |number = 2609396 |title = Compounds with the carbon skeleton of beta-carotene and process for the manufacture thereof |pubdate = 2 September 1952 |invent1 = Inhoffen Hans Herloff |invent2 = Pommer Horst }}</ref>

The world market for synthetic retinol is primarily for animal feed, leaving approximately 13% for a combination of food, prescription medication and dietary supplement use.<ref name="Parker2016"/> Industrial methods for the production of retinol rely on chemical synthesis. The first industrialized synthesis of retinol was achieved by the company Hoffmann-La Roche in 1947. In the following decades, eight other companies developed their own processes. β-ionone, synthesized from acetone, is the essential starting point for all industrial syntheses. Each process involves elongating the unsaturated carbon chain.<ref name="Parker2016">{{cite journal|vauthors=Parker GL, Smith LK, Baxendale IR |title=Development of the industrial synthesis of vitamin A |journal=Tetrahedron |volume=72 |issue= 13|pages=1645–1652 |date=February 2016 |doi=10.1016/j.tet.2016.02.029}}</ref> Pure retinol is extremely sensitive to oxidization and is prepared and transported at low temperatures and oxygen-free atmospheres. When prepared as a dietary supplement or food additive, retinol is stabilized as the ester derivatives [[retinyl acetate]] or [[retinyl palmitate]]. Prior to 1999, three companies, Roche, [[BASF]] and [[Rhone-Poulenc]] controlled 96% of global vitamin A sales. In 2001, the European Commission imposed total fines of 855.22 million [[euro]]s on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989.<ref>{{cite news |url=https://www.nytimes.com/2001/11/21/business/vitamin-makers-fined-record-7551-million-in-pricefixing-case.html#:~:text=BRUSSELS%20%2D%2D%20The%20European%20Commission,Holding%20AG's%20(RHHBY)%20F |author=<!--not stated--> |collaboration=Dow Jones Business News |title=Vitamin Makers Fined Record $755.1 Million in Price-Fixing Case |newspaper=The New York Times |date=21 November 2001 |access-date=24 March 2022 |archive-date=24 March 2022 |archive-url=https://web.archive.org/web/20220324195813/https://www.nytimes.com/2001/11/21/business/vitamin-makers-fined-record-7551-million-in-pricefixing-case.html#:~:text=BRUSSELS%20%2D%2D%20The%20European%20Commission,Holding%20AG's%20(RHHBY)%20F |url-status=live }}</ref> Roche sold its vitamin division to [[DSM (company)|DSM]] in 2003. DSM and BASF have the major share of industrial production.<ref name="Parker2016"/> A biosynthesis alternative utilizes genetically engineered yeast species ''Saccharomyces cerevisiae'' to synthesize retinal and retinol, using xylose as a starting substrate. This was accomplished by having the yeast first synthesize β-carotene and then the cleaving enzyme β-carotene 15,15'-dioxygenase to yield retinal.<ref name="Sun2019">{{cite journal | vauthors = Sun L, Kwak S, Jin YS | title = Vitamin A Production by Engineered ''Saccharomyces cerevisiae'' from Xylose ''via'' Two-Phase ''in Situ'' Extraction | journal = ACS Synthetic Biology | volume = 8 | issue = 9 | pages = 2131–2140 | date = September 2019 | pmid = 31374167 | doi = 10.1021/acssynbio.9b00217 | osti = 1547320 | s2cid = 199389319 }}</ref>

==Research==
===Brain===
Animal research (on mice), which is pre-clinical, also found Retinoid acid, the bioactive metabolite of vitamin A, to have an effect on brain areas responsible for memory and learning.<ref>{{cite journal | vauthors = Olson CR, Mello CV | title = Significance of vitamin A to brain function, behavior and learning | journal = Molecular Nutrition & Food Research | volume = 54 | issue = 4 | pages = 489–495 | date = April 2010 | pmid = 20077419 | pmc = 3169332 | doi = 10.1002/mnfr.200900246 }}</ref>

===Cancer===
Meta-analyses of intervention and observational trials for various types of cancer report mixed results. Supplementation with β-carotene did not appear to decrease the risk of cancer overall, nor specific cancers including: pancreatic, colorectal, prostate, breast, melanoma, or skin cancer generally.<ref name=Druesne2010>{{cite journal | vauthors = Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S | title = Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials | journal = International Journal of Cancer | volume = 127 | issue = 1 | pages = 172–84 | date = July 2010 | pmid = 19876916 | doi = 10.1002/ijc.25008 | s2cid = 24850769 | doi-access = free | title-link = doi }}</ref> High-dose β-carotene supplementation unexpectedly resulted in a higher incidence of lung cancer and of total mortality in people who were cigarette smokers.<ref name=PKIN2020Carotenoids/>

For dietary retinol, no effects were observed for high dietary intake and [[breast cancer]] survival,<ref>{{cite journal | vauthors = He J, Gu Y, Zhang S | title = Vitamin A and Breast Cancer Survival: A Systematic Review and Meta-analysis | journal = Clinical Breast Cancer | volume = 18 | issue = 6 | pages = e1389–e400 | date = December 2018 | pmid = 30190194 | doi = 10.1016/j.clbc.2018.07.025 | s2cid = 52169953 }}</ref> risk of [[liver cancer]],<ref>{{cite journal | vauthors = Leelakanok N, D'Cunha RR, Sutamtewagul G, Schweizer ML | title = A systematic review and meta-analysis of the association between vitamin A intake, serum vitamin A, and risk of liver cancer | journal = Nutrition and Health | volume = 24 | issue = 2 | pages = 121–31 | date = June 2018 | pmid = 29792083 | doi = 10.1177/0260106018777170 | s2cid = 43944154 }}</ref> risk of [[bladder cancer]]<ref>{{cite journal | vauthors = Tang JE, Wang RJ, Zhong H, Yu B, Chen Y | title = Vitamin A and risk of bladder cancer: a meta-analysis of epidemiological studies | journal = World Journal of Surgical Oncology | volume = 12 | issue = | page = 130 | date = April 2014 | pmid = 24773914 | pmc = 4030017 | doi = 10.1186/1477-7819-12-130 | doi-access = free | title-link = doi }}</ref> or risk of [[colorectal cancer]],<ref>{{cite journal | vauthors = Liu Y, Yu Q, Zhu Z, Zhang J, Chen M, Tang P, Li K | title = Vitamin and multiple-vitamin supplement intake and incidence of colorectal cancer: a meta-analysis of cohort studies | journal = Medical Oncology | volume = 32 | issue = 1 | page = 434 | date = January 2015 | pmid = 25491145 | doi = 10.1007/s12032-014-0434-5 | s2cid = 25904916 }}</ref><ref name="Xu2013">{{cite journal | vauthors = Xu X, Yu E, Liu L, Zhang W, Wei X, Gao X, Song N, Fu C | title = Dietary intake of vitamins A, C, and E and the risk of colorectal adenoma: a meta-analysis of observational studies | journal = European Journal of Cancer Prevention | volume = 22 | issue = 6 | pages = 529–39 | date = November 2013 | pmid = 24064545 | doi = 10.1097/CEJ.0b013e328364f1eb | s2cid = 36958552 }}</ref> although the last review did report lower risk for higher β-carotene consumption.<ref name="Xu2013"/> In contrast, an inverse association was reported between retinol intake and relative risk of [[esophageal cancer]],<ref>{{cite journal | vauthors = Li K, Zhang B | title = The association of dietary β-carotene and vitamin A intake on the risk of esophageal cancer: a meta-analysis | journal = Revista Española de Enfermedades Digestivas | volume = 112 | issue = 8 | pages = 620–26 | date = August 2020 | pmid = 32543872 | doi = 10.17235/reed.2020.6699/2019 | s2cid = 219724574 | doi-access = free | title-link = doi }}</ref> [[gastric cancer]],<ref>{{cite journal | vauthors = Wu Y, Ye Y, Shi Y, Li P, Xu J, Chen K, Xu E, Yang J | title = Association between vitamin A, retinol intake and blood retinol level and gastric cancer risk: A meta-analysis | journal = Clinical Nutrition | volume = 34 | issue = 4 | pages = 620–26 | date = August 2015 | pmid = 25008141 | doi = 10.1016/j.clnu.2014.06.007 }}</ref> [[ovarian cancer]],<ref>{{cite journal | vauthors = Wang Q, He C | title = Dietary vitamin A intake and the risk of ovarian cancer: a meta-analysis | journal = Bioscience Reports | volume = 40 | issue = 4 | date = April 2020 | pmid = 32149329 | pmc = 7138903 | doi = 10.1042/BSR20193979 }}</ref> [[pancreatic cancer]],<ref>{{cite journal | vauthors = Zhang T, Chen H, Qin S, Wang M, Wang X, Zhang X, Liu F, Zhang S | title = The association between dietary vitamin A intake and pancreatic cancer risk: a meta-analysis of 11 studies | journal = Bioscience Reports | volume = 36 | issue = 6 | date = December 2016 | pmid = 27756825 | pmc = 5293573 | doi = 10.1042/BSR20160341 }}</ref> [[lung cancer]],<ref name="Yu2015">{{cite journal | vauthors = Yu N, Su X, Wang Z, Dai B, Kang J | title = Association of Dietary Vitamin A and β-Carotene Intake with the Risk of Lung Cancer: A Meta-Analysis of 19 Publications | journal = Nutrients | volume = 7 | issue = 11 | pages = 9309–24 | date = November 2015 | pmid = 26569298 | pmc = 4663591 | doi = 10.3390/nu7115463 | doi-access = free | title-link = doi }}</ref> [[melanoma]],<ref>{{cite journal | vauthors = Zhang YP, Chu RX, Liu H | title = Vitamin A intake and risk of melanoma: a meta-analysis | journal = PLOS ONE | volume = 9 | issue = 7 | article-number = e102527 | date = 2014 | pmid = 25048246 | pmc = 4105469 | doi = 10.1371/journal.pone.0102527 | doi-access = free | title-link = doi | bibcode = 2014PLoSO...9j2527Z }}</ref> and [[cervical cancer]].<ref>{{cite journal | vauthors = Zhang X, Dai B, Zhang B, Wang Z | title = Vitamin A and risk of cervical cancer: a meta-analysis | journal = Gynecologic Oncology | volume = 124 | issue = 2 | pages = 366–73 | date = February 2012 | pmid = 22005522 | doi = 10.1016/j.ygyno.2011.10.012 }}</ref> For lung cancer, an inverse association was also seen for β-carotene intake, separate from the retinol results.<ref name="Yu2015"/> When high dietary intake was compared to low dietary intake, the decreases in relative risk were in the range of 15 to 20%. For gastric cancer, a meta-analysis of prevention trials reported a 29% decrease in relative risk from retinol supplementation at 1500 μg/day<ref name="Kong2014">{{cite journal | vauthors = Kong P, Cai Q, Geng Q, Wang J, Lan Y, Zhan Y, Xu D | title = Vitamin intake reduce the risk of gastric cancer: meta-analysis and systematic review of randomized and observational studies | journal = PLOS ONE | volume = 9 | issue = 12 | article-number = e116060 | date = 2014 | pmid = 25549091 | pmc = 4280145 | doi = 10.1371/journal.pone.0116060 | doi-access = free | title-link = doi | bibcode = 2014PLoSO...9k6060K }}</ref>

===Fetal alcohol spectrum disorder===
[[Fetal alcohol spectrum disorder]] (FASD), formerly referred to as fetal alcohol syndrome, presents as craniofacial malformations, neurobehavioral disorders and mental disabilities, all attributed to exposing human embryos to alcohol during fetal development.<ref name="Fainsod2020"/><ref name="Petrelli2019"/> The risk of FASD depends on the amount consumed, the frequency of consumption, and the points in pregnancy at which the alcohol is consumed.<ref>{{cite web|title=Fetal Alcohol Exposure |url=https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/understanding-fetal-alcohol-spectrum-disorders|access-date=16 December 2021|date=April 2015|url-status=live|archive-url=https://web.archive.org/web/20150610050738/http://pubs.niaaa.nih.gov/publications/FASDFactsheet/FASDfact.htm|archive-date=10 June 2015}}</ref> [[Ethanol]] is a known [[teratogen]], i.e., causes birth defects. Ethanol is metabolized by [[alcohol dehydrogenase]] enzymes into [[acetaldehyde]].<ref name="Farrés">{{cite journal | vauthors = Farrés J, Moreno A, Crosas B, Peralba JM, Allali-Hassani A, Hjelmqvist L, Jörnvall H, Parés X | title = Alcohol dehydrogenase of class IV (sigma sigma-ADH) from human stomach. cDNA sequence and structure/function relationships | journal = European Journal of Biochemistry | volume = 224 | issue = 2 | pages = 549–57 | date = September 1994 | pmid = 7925371 | doi = 10.1111/j.1432-1033.1994.00549.x | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Edenberg HJ, McClintick JN | title = Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review | journal = Alcoholism: Clinical and Experimental Research | volume = 42 | issue = 12 | pages = 2281–97 | date = December 2018 | pmid = 30320893 | pmc = 6286250 | doi = 10.1111/acer.13904 }}</ref> The subsequent oxidation of acetaldehyde into acetate is performed by [[aldehyde dehydrogenase]] enzymes. Given that retinoic acid (RA) regulates numerous embryonic and differentiation processes, one of the proposed mechanisms for the teratogenic effects of ethanol is a competition for the enzymes required for the biosynthesis of RA from vitamin A. Animal research demonstrates that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for aldehyde dehydrogenase activity. In this model, acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Thus, animal research supports the reduction of retinoic acid activity as an [[etiological]] trigger in the induction of FASD.<ref name="Fainsod2020">{{cite book |vauthors=Fainsod A, Bendelac-Kapon L, Shabtai Y |title=The Biochemistry of Retinoid Signaling III |chapter=Fetal Alcohol Spectrum Disorder: Embryogenesis Under Reduced Retinoic Acid Signaling Conditions |series=Subcellular Biochemistry |volume=95 |pages=197–225 |date=2020 |pmid=32297301 |doi=10.1007/978-3-030-42282-0_8|isbn=978-3-030-42280-6 |s2cid=215793789 }}</ref><ref name="Petrelli2019">{{cite journal | vauthors = Petrelli B, Bendelac L, Hicks GG, Fainsod A | title = Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder | journal = Genesis | volume = 57 | issue = 1 | article-number = e23278 | date = January 2019 | pmid = 30614633 | doi = 10.1002/dvg.23278 | s2cid = 58603210 }}</ref><ref name="Shabtai2018A">{{cite journal | vauthors = Shabtai Y, Fainsod A | title = Competition between ethanol clearance and retinoic acid biosynthesis in the induction of fetal alcohol syndrome | journal = Biochemistry and Cell Biology | volume = 96 | issue = 2 | pages = 148–60 | date = April 2018 | pmid = 28982012 | doi = 10.1139/bcb-2017-0132 }}</ref><ref name="Shabtai2018B">{{cite journal | vauthors = Shabtai Y, Bendelac L, Jubran H, Hirschberg J, Fainsod A | title = Acetaldehyde inhibits retinoic acid biosynthesis to mediate alcohol teratogenicity | journal = Scientific Reports | volume = 8 | issue = 1 | page = 347 | date = January 2018 | pmid = 29321611 | pmc = 5762763 | doi = 10.1038/s41598-017-18719-7 | bibcode = 2018NatSR...8..347S }}</ref>

===Malaria===
Malaria and vitamin A deficiency are both common among young children in sub-Saharan Africa. Vitamin A supplementation to children in regions where vitamin A deficiency is common has repeatedly been shown to reduce overall mortality rates, especially from measles and diarrhea.<ref name="Sanj2009"/> For malaria, clinical trial results are mixed, either showing that vitamin A treatment did not reduce the incidence of probable malarial fever, or else did not affect incidence, but did reduce slide-confirmed parasite density and reduced the number of fever episodes.<ref name="Sanj2009">{{cite journal | vauthors = Sanjoaquin MA, Molyneux ME | title = Malaria and vitamin A deficiency in African children: a vicious circle? | journal = Malaria Journal | volume = 8 | page = 134 | date = June 2009 | pmid = 19534807 | pmc = 2702350 | doi = 10.1186/1475-2875-8-134 | doi-access = free | title-link = doi }}</ref> The question was raised as to whether malaria causes vitamin A deficiency, or vitamin A deficiency contributes to the severity of malaria, or both. Researchers proposed several mechanisms by which malaria (and other infections) could contribute to vitamin A deficiency, including a fever-induced reduction in synthesis of retinal-binding protein (RBP) responsible for transporting retinol from liver to plasma and tissues, but reported finding no evidence for a transient depression or restoration of plasma RBP or retinol after a malarial infection was eliminated.<ref name="Sanj2009"/>

==History==
[[File:Frederick Gowland Hopkins nobel.jpg|thumb|Frederick Gowland Hopkins, 1929 Nobel Prize for Physiology or Medicine]]
In 1912, [[Frederick Gowland Hopkins]] demonstrated that unknown accessory factors found in milk, other than [[carbohydrate]]s, [[protein]]s, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.<ref name="Wolf2001"/><ref name=Semba>{{cite journal | vauthors = Semba RD | title = On the 'discovery' of vitamin A | journal = Annals of Nutrition & Metabolism | volume = 61 | issue = 3 | pages = 192–198 | year = 2012 | pmid = 23183288 | doi = 10.1159/000343124 | s2cid = 27542506 }}</ref> By 1913, one of these substances was independently discovered by [[Elmer McCollum]] and [[Marguerite Davis]] at the [[University of Wisconsin–Madison]], and [[Lafayette Mendel]] and [[Thomas Burr Osborne (chemist)|Thomas Burr Osborne]] at [[Yale University]]. McCollum and Davis ultimately received credit because they submitted their paper three weeks before Mendel and Osborne. Both papers appeared in the same issue of the ''[[Journal of Biological Chemistry]]'' in 1913.<ref>{{cite journal | vauthors = Rosenfeld L | title = Vitamine – vitamin. The early years of discovery | journal = Clinical Chemistry | volume = 43 | issue = 4 | pages = 680–685 | date = April 1997 | pmid = 9105273 | doi = 10.1093/clinchem/43.4.680 | doi-access = free | title-link = doi }}</ref> The "accessory factors" were termed "fat soluble" in 1918, and later "vitamin A" in 1920. In 1919, [[Harry Steenbock]] (University of Wisconsin–Madison) proposed a relationship between yellow plant pigments (β-carotene) and vitamin A. In 1931, Swiss chemist [[Paul Karrer]] described the chemical structure of vitamin A.<ref name=Semba/> Retinoic acid and retinol were first synthesized in 1946 and 1947 by two Dutch chemists, [[David Adriaan van Dorp]] and Jozef Ferdinand Arens.<ref>{{cite journal | vauthors = Arens JF, Van Dorp DA | title = Synthesis of some compounds possessing vitamin A activity | journal = Nature | volume = 157 | issue = 3981 | pages = 190–191 | date = February 1946 | pmid = 21015124 | doi = 10.1038/157190a0 | s2cid = 27157783 | bibcode = 1946Natur.157..190A }}</ref><ref>{{cite journal | vauthors = Van Dorp DA, Arens JF | title = Synthesis of vitamin A aldehyde | journal = Nature | volume = 159 | issue = 4058 | page = 189 | date = August 1947 | pmid = 20256189 | doi = 10.1038/160189a0 | s2cid = 4137483 | bibcode = 1947Natur.160..189V | doi-access = free | title-link = doi }}</ref>

[[File:George Wald nobel.jpg|thumb|left|George Wald, 1967 Nobel Prize for Physiology or Medicine]]
During [[World War II]], German bombers would attack at night to evade British defenses. In order to keep the 1939 invention of a new on-board [[Radar in World War II#Aircraft Intercept|Airborne Intercept Radar]] system secret from Germany, the British Ministry of Information told newspapers an unproven claim that the nighttime defensive success of [[Royal Air Force]] pilots was due to a high dietary intake of carrots rich in β-carotene, successfully convincing many people.<ref>{{cite web |url=https://www.sciencefocus.com/the-human-body/do-carrots-really-help-you-see-in-the-dark/ |title=Do carrots really help you see in the dark? |vauthors=Villazon L |date= 24 October 2013|publisher=sciencefocus.com |archive-date=31 August 2022 |archive-url=https://web.archive.org/web/20220831000514/https://www.sciencefocus.com/the-human-body/do-carrots-really-help-you-see-in-the-dark/ |url-status=live }}</ref>

In 1967, [[George Wald]] shared the Nobel Prize in Physiology and Medicine for his work on chemical visual processes in the eye.<ref name="nobel-1967">{{cite web|title=The Nobel Prize in Physiology or Medicine 1967|url=http://www.nobelprize.org/nobel_prizes/medicine/laureates/1967/index.html|publisher=Nobel Foundation|access-date=28 July 2007|archive-url=https://web.archive.org/web/20131204095703/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1967/index.html|archive-date=4 December 2013|url-status=live}}</ref> Wald had demonstrated in 1935 that [[photoreceptor cell]]s in the eye contain rhodopsin, a [[chromophore]] composed of the protein [[opsin]] and [[11-cis retinal|11-''cis''-retinal]]. When struck by light, 11-''cis''-retinal undergoes photoisomerization to ''all-trans''-retinal and via signal transduction cascade send a nerve signal to the brain. The ''all-trans''-retinal is reduced to ''all-trans''-retinol and travels back to the retinal pigment epithelium to be recycled to 11-''cis''-retinal and reconjugated to opsin.<ref name="Wolf2001"/><ref>{{cite journal | vauthors = Ebrey T, Koutalos Y | title = Vertebrate photoreceptors | journal = Progress in Retinal and Eye Research | volume = 20 | issue = 1 | pages = 49–94 | date = January 2001 | pmid = 11070368 | doi = 10.1016/S1350-9462(00)00014-8 | s2cid = 2789591 }}</ref> Wald's work was the culmination of nearly 60 years of research. In 1877, [[Franz Christian Boll]] identified a light-sensitive pigment in the outer segments of [[rod cell]]s of the retina that faded/bleached when exposed to light, but was restored after light exposure ceased. He suggested that this substance, by a photochemical process, conveyed the impression of light to the brain.<ref name="Wolf2001"/> The research was taken up by [[Wilhelm Kühne]], who named the pigment rhodopsin, also known as "visual purple." Kühne confirmed that rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions, and that it was this chemical decomposition that stimulated nerve impulses to the brain.<ref name="Wolf2001"/> Research stalled until after identification of "fat-soluble vitamin A" as a dietary substance found in milkfat but not lard, would reverse night blindness and xerophthalmia. In 1925, Fridericia and Holm demonstrated that vitamin A deficient rats were unable to regenerate rhodopsin after being moved from a light to a dark room.<ref>{{cite journal| vauthors = Fridericia LS, Holm E |title=Experimental contribution to the study of the relation between night blindness and malnutrition |journal=American Journal of Physiology |volume=73 |issue= |pages=63–78 |date= June 1925 |doi=10.1152/ajplegacy.1925.73.1.63}}</ref>

== References ==
{{reflist}}

== External links ==
* {{MeSH name|Vitamin A}}
* [https://web.archive.org/web/20061215060250/http://www.who.int/nutrition/publications/vitamin_a_pub/en/index.html WHO publications on Vitamin A Deficiency]

{{Vitamins}}
{{Antioxidants}}
{{Dietary supplement}}
{{Retinoid receptor modulators}}
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[[Category:Vitamin A| ]]
[[Category:Biomolecules]]
[[Category:Unsaturated compounds]]