Editing Vitamin A (section)

==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 = | pages = 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=9781416002093}}</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 | pages = 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 | pages = 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 |pages=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/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&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=9780323085939 | 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 |pages=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"/>