This article is about the family ofvitamers. For the form usually used as a supplement, seeRetinol.
Pharmaceutical compound
Vitamin A
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.
Vitamin A occurs as two principal forms in foods: A) retinoids, found inanimal-sourced foods, either as retinol or bound to afatty acid to become a retinyl ester, and B) the carotenoidsα-carotene (alpha-carotene), β-carotene,γ-carotene (gamma-carotene), and thexanthophyllbeta-cryptoxanthin (all of which contain β-ionone rings) that function as provitamin A inherbivore andomnivore animals which possess theenzymes that cleave and convert provitamin carotenoids to retinol.[8] Somecarnivore species lack this enzyme. The other carotenoids do not have retinoid activity.[6]
Dietary retinol is absorbed from thedigestive tract viapassive diffusion. Unlike retinol, β-carotene is taken up byenterocytes by the membrane transporter proteinscavenger receptor B1 (SCARB1), which is upregulated in times ofvitamin A deficiency (VAD).[6] Retinol is stored inlipid droplets in theliver. A high capacity for long-term storage of retinol means that well-nourished humans can go months on a vitamin A-deficient diet, while maintainingblood levels in the normal range.[4] Only when the liver stores are nearly depleted will signs and symptoms of deficiency show.[4] Retinol is reversibly converted toretinal, then irreversibly toretinoic acid, which activates hundreds ofgenes.[9]
Vitamin A deficiency is common in developing countries, especially inSub-Saharan Africa andSoutheast 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 ofblindness and deaths from childhood diseases because of immune system failure.[10] Reversiblenight blindness is an early indicator of low vitamin A status. Plasma retinol is used as abiomarker 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.[6]
TheEuropean Union and various countries have set recommendations for dietary intake, and upper limits for safe intake. Vitamin A toxicity also referred to ashypervitaminosis 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.[6]
Vitamin A is afat-solublevitamin, a category that also includesvitamins D,E andK. The vitamin encompasses several chemically related naturally occurring compounds or metabolites, i.e.,vitamers, that all contain a β-ionone ring.[4] The primary dietary form isretinol, which may have afatty acid molecule attached, creating a retinylester, when stored in the liver. Retinol – the transport and storage form of vitamin A – is interconvertible withretinal, catalyzed to retinal byretinol dehydrogenases and back to retinol by retinaldehyde reductases.[11]
Retinoic acid is actively transported into thecell nucleus by CRABp2 where it regulates thousands of genes by binding directly to gene targets viaretinoic acid receptors.[6]
In addition to retinol, retinal and retinoic acid, there are plant-, fungi- or bacteria-sourcedcarotenoids which can be metabolized to retinol, and are thus vitamin A vitamers.[12]
There are also what are referred to as 2nd, 3rd and 4th generationretinoids which are not considered vitamin A vitamers because they cannot be converted to retinol, retinal orall-trans-retinoic acid. Some are prescription drugs, oral or topical, for various indications. Examples areetretinate,acitretin,adapalene,bexarotene,tazarotene andtrifarotene.[13][14]
Retinyl esters fromanimal-sourced foods (or synthesized for dietary supplements for humans and domesticated animals) are acted upon by retinyl ester hydrolases in thelumen of the small intestine to release free retinol. Retinol entersenterocytes bypassive 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.[5] Within the cell, retinol is there bound toretinol binding protein 2 (RBP2). It is then enzymatically re-esterified by the action oflecithin retinol acyltransferase and incorporated intochylomicrons that are secreted into thelymphatic system.
Unlike retinol,β-carotene is taken up by enterocytes by the membrane transporter proteinscavenger 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.[6] Also downregulated is theenzymebeta-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.[8] 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.[6][15]
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:hepatocytes andhepatic stellate cells (HSCs). Hepatocytes take up the lipid-rich chylomicrons, bind retinol toretinol-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 intoblood 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.[15]
Strictcarnivores manage vitamin A differently thanomnivores andherbivores. 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.[16] 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.[16] In general, carnivore species are poor converters of ionone-containing carotenoids, and pure carnivores such asfelidae (cats) lack the cleaving enzyme entirely. They must have retinol or retinyl esters in their diet.[16]
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 inbody fat, creating yellowfat cells. Most species havewhite fat and no β-carotene in circulation.[16]
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 ofethanol toacetaldehyde. 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 acytochrome P450 (CYP) enzyme system, specifically enzymesCYP26A1,CYP26B1 andCYP26C1. 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.[9]
Other than for vision, the metabolic functions of vitamin A are mediated byall-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.[17][18]
Vitamin A status involves eye health via two separate functions. Retinal is an essential factor inrod cells andcone cells in the retina responding to light exposure by sending nerve signals to the brain. An early sign of vitamin A deficiency is night blindness.[6] 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 causesxerophthalmia characterized by dryness of the conjunctival epithelium and cornea. Untreated, xerophthalmia progresses to corneal ulceration and blindness.[19]
The role of vitamin A in the visual cycle is specifically related to the retinal compound. Retinol is converted by the enzymeRPE65 within the retinal pigment epithelium into 11-cis-retinal. Within the eye, 11-cis-retinal is bound to the proteinopsin to formrhodopsin in rod cells andiodopsin in cone cells. As light enters the eye, the 11-cis-retinal is isomerized to theall-trans form. Theall-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, theall-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.[6] In addition, some of theall-trans-retinal may be converted toall-trans-retinol form and then transported with an interphotoreceptor retinol-binding protein to the retinal pigmented epithelial cells. Further esterification intoall-trans-retinyl esters allow for storage ofall-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.[6][20][21]
Vitamin A deficiency-causednight 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 calleddark 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.[7] 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.[21]
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.[22]
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.[22] Estimates are that each year there are 350,000 cases of childhood blindness due to vitamin A deficiency.[19] 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.[22][19] Theprevalence of pre-school age children who are blind due to vitamin A deficiency is lower than expected fromincidence of new cases only because childhood vitamin A deficiency significantly increases all-cause mortality.[19]
According to a 2017 Cochrane review, vitamin A deficiency, using serum retinol less than 0.70 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 units) 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%.[23]
RA regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs; RARα, RARβ, RARγ) which are bound toDNA 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.[6] RAR-RXR heterodimers recognize retinoic acid response elements on DNA.[24] 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.[25] This response upregulates or downregulates the expression of target genes, including the genes that encode for the receptors themselves.[20] 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.[6]
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,[26][27] including congenital vascular and cardiovascular defects.[28][29] 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.[30] As for the risks of too much RA during embryogenesis, the prescription drugstretinoin (all-trans-retinoic acid) andisotretinoin (13-cis-retinoic acid), used orally or topically for acne treatment, are labeled withboxed warnings for pregnant women or women who may become pregnant, as they are known human teratogens.[31][32]
Vitamin A deficiency has been linked to compromised resistance to infectious diseases.[33][34] 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.[23][35][36] 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.[33][34][37]
Retinoic acid (RA) triggers receptors in bone marrow, resulting in generation of new white blood cells.[41] RA regulates proliferation and differentiation of white blood cells, the directed movement of T cells to theintestinal system, and to the up- and down-regulation of lymphocyte function.[33][34][35][36][37][42] 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 toall-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 inmesenteric lymph nodes andPeyer's patches, respectively outside and on the inner wall of the small intestine.[35][36] The net effect is a down-regulation of immune activity, seen as tolerance of foodallergens, and tolerance of resident bacteria and other organisms in themicrobiome of the large intestine.[33][34][37] In a vitamin A deficient state, innate immunity is compromised and pro-inflammatory Th1 cells predominate.[33][42]
Deficiencies in vitamin A have been linked to an increased susceptibility to skin infection and inflammation.[43] Vitamin A appears to modulate theinnate 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.[43] The epithelium of the skin encounters bacteria, fungi and viruses. Keratinocytes of the epidermal layer of the skin produce and secreteantimicrobial peptides (AMPs). Production of AMPsresistin andcathelicidin, are promoted by RA.[43]
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 aninternational unit (IU) was equal to 0.3μg of retinol (~1 nmol), 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used.[44] 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 eitherα-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 USInstitute 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.[5]
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 enzymeβ-carotene-15, 15'-monooxygenase, which in humans and other mammalian species is encoded by the BCM01 gene,[8] 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.[12] Absorption suppression is not complete, as receptor 36 is not downregulated.[12]
The USNational Academy of Medicine updatedDietary Reference Intakes (DRIs) in 2001 for vitamin A, which included Recommended Dietary Allowances (RDAs).[5] 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 levels (ULs) were also established. For ULs, carotenoids are not added when calculating total vitamin A intake for safety assessments.[5]
TheEuropean 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 RE/day. PRI for pregnancy is 700 μg RE/day, for lactation 1300/day. For children of ages 1–14 years, the PRIs increase with age from 250 to 600 μg RE/day. These PRIs are similar to the US RDAs.[45] 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.[46]
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.
There are historical reports of acute hypervitaminosis from Arctic explorers consuming bearded seal or polar bear liver, both very rich sources of stored retinol,[47] and there are also case reports of acute hypervitaminosis from consuming fish liver,[48] 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.[6] 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.[49] Chronic toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU/day for several months.[4] Excessive consumption of alcohol can lead to chronic toxicity at lower intakes.[3] 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.[5]
In 2001, for the purpose of determining ULs for adults, the US Institute of Medicine considered three primary adverse effects and settled on two:teratogenicity, i.e., causing birth defects, and liver abnormalities. Reduced bone mineral density was considered, but dismissed because the human evidence was contradictory.[5] 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] 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] For all other adults, liver abnormalities were detected at intakes above 14,000 μg/day.[medical citation needed] 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]
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.[5]
No adverse effects other thancarotenemia have been reported for consumption of β-carotene rich foods. Supplementation with β-carotene does not cause hypervitaminosis A.[12] Two large clinical trials (ATBC and CARET) were conducted in tobacco smokers to see if years of β-carotene supplementation at 20 or 30 mg/day in oil-filled capsules would reduce the risk of lung cancer.[50] 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.[51][12] 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.[12][50] The European Food Safety Authority, acting for the European Union, also decided not to set a UL for β-carotene.[46]
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 thewhite of the eye, which helps distinguish the condition fromjaundice.[52] Consumption of greater than 30 mg/day for a prolonged period has been confirmed as leading to carotenemia.[12][53]
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.[54][55] A table of the old and new adult daily values is provided atReference Daily Intake.
Vitamin A is found in many foods.[56] Vitamin A in food exists either as preformed retinol – an active form of vitamin A – 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.[4] Carotenoid pigments may be masked bychlorophylls in dark green leaf vegetables, such as spinach. The relatively lowbioavailability of plant-food carotenoids results partly from binding to proteins – chopping, homogenizing or cooking disrupts the plant proteins, increasing provitamin A carotenoid bioavailability.[4]
Vegetarian andvegan 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 mg.[57]
Some countries require or recommend fortification of foods. As of January 2022, 37 countries, mostly in Sub-Saharan Africa, require food fortification ofcooking oil, rice,wheat flour ormaize (corn) flour with vitamin A, usually as retinyl palmitate or retinyl acetate. Examples include Pakistan, oil, 11.7 mg/kg and Nigeria, oil, 6 mg/kg; wheat and maize flour, 2 mg/kg.[58] An additional 12 countries, mostly in southeast Asia, have a voluntary fortification program. For example, the government of India recommends 7.95 mg/kg in oil and 0.626 mg/kg for wheat flour and rice. However, compliance in countries with voluntary fortification is lower than countries with mandatory fortification.[58] No countries in Europe or North America fortify foods with vitamin A.[58]
Other means of fortifying foods via genetic engineering have been explored. Research on rice began in 1982.[59] The first field trials of golden rice cultivars were conducted in 2004.[60] The result was "Golden Rice", a variety ofOryza sativa rice produced through genetic engineering tobiosynthesize β-carotene, a precursor of retinol, in the edible parts of rice.[61][62] In May 2018, regulatory agencies in the United States, Canada, Australia and New Zealand had concluded that Golden Rice met food safety standards.[63] In July 2021, the Philippines became the first country to officially issue the biosafety permit for commercially propagating Golden Rice.[64][65] However, in April 2023, the Supreme Court of the Philippines issued aWrit of Kalikasan ordering the Department of Agriculture to stop the commercial distribution of genetically modified rice in the country.[66]
Vitamin A supplementation coverage rate (children ages 6–59 months), 2014[67]
Delivery of oral high-dose supplements remains the principal strategy for minimizing deficiency.[68] 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.[69] 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.[23]
Vitamin A deficiency is common indeveloping countries, especially inSub-Saharan Africa andSoutheast 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,[70] possibly leading to the deaths of 670,000 children under five annually.[71]
Between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin A deficiency.[3] Vitamin A deficiency is "the leading cause of preventable childhood blindness", according toUNICEF.[10][22] It also increases the risk of death from common childhood conditions, such asdiarrhea. UNICEF regards addressing vitamin A deficiency as critical to reducingchild mortality, the fourth of theUnited Nations'Millennium Development Goals.[10]
During diagnosis, night blindness anddry 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/grammilk fat is considered insufficient.[6] One weakness of these measures is that they are not good indicators of liver vitamin A stores as retinyl esters inhepatic stellate cells. 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.[5][72]
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.[5]Non-alcoholic fatty liver disease (NAFLD), characterized by the accumulation of fat in the liver, is the hepatic manifestation ofmetabolic syndrome. Liver damage from NAFLD reduces liver storage capacity for retinol and reduces the ability to mobilize liver stores to maintain normal circulating concentration.[73]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.
Allvertebrate andchordate species require vitamin A,[27] 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,[74][75] also commercially raised chickens and turkeys.[76] 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.[74] 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.[16] Before the era of synthetic retinol,cod liver oil, high in vitamins A and D, was a commonly consumed dietary supplement.[77][78]Invertebrates cannot synthesize carotenoids or retinol, and thus must accrue these essential nutrients from consumption of algae, plants or animals.[79][80][81]
Recognition of its prevalence and consequences has led to governments and non-government organizations promoting vitamin A fortification of foods[58] and creating programs that administer large bolus-size oral doses of vitamin A to young children every four to six months.[69] In 2008, theWorld Health Organization estimated that vitamin A supplementation over a decade in 40 countries averted 1.25 million deaths due to vitamin A deficiency.[83] 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 ofdiarrhea by 12%.[23] 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.[49]
Retinoids:Tretinoin isall-trans-retinoic acid; initial tradename: Retin-A.Isotretinoin is 13-cis-retinoic acid; initial tradename: Accutane.Etretinate andAcitretin, its non-esterified metabolite, are used orally to treat severepsoriasis.[13]
Retinoic acidstretinoin (all-trans-retinoic acid) andisotretinoin (13-cis-retinoic acid) are prescriptiontopical medications used to treat moderate to severe cystic acne and acne not responsive to other treatments.[84][85][86][87] These are usually applied as askin cream to the face after cleansing to remove make-up and skin oils. Tretinoin and isotretinoin act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR).[88] These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation.[89] The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation.[88] Retinoic acid products also reducesebum secretion, a nutrient source for bacteria, from facial pores.[90]
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.[32] Many countries established a physician- and patient- education pregnancy prevention policy.[91]
Non-prescriptiontopical products that have health claims for reducing facial acne, combating skin dark spots and reducing wrinkles and lines associated with aging often containretinyl palmitate. The hypothesis is that this is absorbed and de-esterified to free retinol, then converted to retinaldehyde and further metabolized toall-trans-retinoic acid, whence it will have the same effects as prescription products with fewer side effects.[93] There is someex vivo evidence with human skin that esterified retinol is absorbed and then converted to retinol.[94] In addition to esterified retinol, some of these products contain hydroxypinacolone retinoate, identified as esterified 9-cis-retinoic acid.[95]
Oralisotretinoin (retinoic acidisomer) is recommended for treating treatment resistantacne, acne that can lead to scarring, and acne that is associated with psychosocial distress.[96] It is approved by the FDA for treating severe acne vulgaris that is resistant to other treatment options.[96] Isotretinoin is a known teratogen, with an estimated 20–35% risk of physical birth defects to infants that are exposed to isotretinoinin utero, including numerous congenital defects such as craniofacial defects, cardiovascular and neurological malformations or thymic disorders.[31] Neurocognitive impairments in the absence of any physical defects has been established to be 30–60%.[31] 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.[31] In the US, isotretinoin was released to the market in 1982 as a revolutionary treatment for severe and refractoryacne vulgaris. It was shown that a dose of 0.5–1.0 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.[31]
The mechanism by which orally consumed retinoic acid (RA), asall-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.[96] RA reduces the size and secretion of the sebaceous glands, and by doing so reduces bacterial numbers in both the ducts and skin surface.[96] It reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils.
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.[97]Rosacea was reported as responding favorably to doses lower than used for acne. Isotretinoin in combination with ultraviolet light was shown affective for treatingpsoriasis. Isotretinoin in combination with injectedinterferon-alpha showed some potential for treatinggenital warts. Isotretinoin in combination with topicalfluorouracil or injected interferon-alpha showed some potential for treating precancerous skin lesions and skin cancer.[97]
Vitamin A plays an important role in the body's immune function, both the adaptive response, and to help the body fight off infection.[98] The anti-inflammatory effects of vitamin A also contribute to repairing mucosal cells that can be damaged by an infection.[98] 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.[98] More research is needed to consider different doses, the ages and populations of people who may potentially benefit, and the length of treatment.[98]
Carotenoid synthesis takes place in plants, certain fungi, and bacteria. Structurally carotenes aretetraterpenes, meaning that they are synthesized biochemically from four 10-carbonterpene units, which in turn were formed from eight 5-carbonisoprene units. Intermediate steps are the creation of a 40-carbonphytoene molecule, conversion tolycopene 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.[12]
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 enzymebeta-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+. The resultant retinal is then quickly reduced to retinol by the enzyme retinol dehydrogenase.[6] Omnivore species such asdogs, wolves, coyotes and foxes in general are low producers of BCO-1. The enzyme is lacking infelids (cats), meaning that vitamin A requirements are met from the retinyl ester content of prey animals.[16]
β-carotene can be extracted from fungusBlakeslea trispora, marine algaeDunaliella salina or genetically modified yeastSaccharomyces cerevisiae, starting with xylose as a substrate.[99] Chemical synthesis uses either a method developed byBASF[100][101] or aGrignard reaction utilized byHoffman-La Roche.[102]
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.[103] 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.[103] 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 derivativesretinyl acetate orretinyl palmitate. Prior to 1999, three companies, Roche,BASF andRhone-Poulenc controlled 96% of global vitamin A sales. In 2001, the European Commission imposed total fines of 855.22 millioneuros on these and five other companies for their participation in eight distinct market-sharing and price-fixing cartels that dated back to 1989.[104] Roche sold its vitamin division toDSM in 2003. DSM and BASF have the major share of industrial production.[103] A biosynthesis alternative utilizes genetically engineered yeast speciesSaccharomyces 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.[105]
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.[106]
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.[107] High-dose β-carotene supplementation unexpectedly resulted in a higher incidence of lung cancer and of total mortality in people who were cigarette smokers.[12]
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.[121][122] The risk of FASD depends on the amount consumed, the frequency of consumption, and the points in pregnancy at which the alcohol is consumed.[123]Ethanol is a knownteratogen, i.e., causes birth defects. Ethanol is metabolized byalcohol dehydrogenase enzymes intoacetaldehyde.[124][125] The subsequent oxidation of acetaldehyde into acetate is performed byaldehyde 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 anetiological trigger in the induction of FASD.[121][122][30][126]
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.[127] 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.[127] 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.[127]
Frederick Gowland Hopkins, 1929 Nobel Prize for Physiology or Medicine
In 1912,Frederick Gowland Hopkins demonstrated that unknown accessory factors found in milk, other thancarbohydrates,proteins, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.[7][128] By 1913, one of these substances was independently discovered byElmer McCollum andMarguerite Davis at theUniversity of Wisconsin–Madison, andLafayette Mendel andThomas Burr Osborne atYale 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 theJournal of Biological Chemistry in 1913.[129] 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 chemistPaul Karrer described the chemical structure of vitamin A.[128] Retinoic acid and retinol were first synthesized in 1946 and 1947 by two Dutch chemists,David Adriaan van Dorp and Jozef Ferdinand Arens.[130][131]
George Wald, 1967 Nobel Prize for Physiology or Medicine
DuringWorld War II, German bombers would attack at night to evade British defenses. In order to keep the 1939 invention of a new on-boardAirborne Intercept Radar system secret from Germany, the British Ministry of Information told newspapers an unproven claim that the nighttime defensive success ofRoyal Air Force pilots was due to a high dietary intake of carrots rich in β-carotene, successfully convincing many people.[132]
In 1967,George Wald shared the Nobel Prize in Physiology and Medicine for his work on chemical visual processes in the eye.[133] Wald had demonstrated in 1935 thatphotoreceptor cells in the eye contain rhodopsin, achromophore composed of the proteinopsin and11-cis-retinal. When struck by light, 11-cis-retinal undergoes photoisomerization toall-trans-retinal and via signal transduction cascade send a nerve signal to the brain. Theall-trans-retinal is reduced toall-trans-retinol and travels back to the retinal pigment epithelium to be recycled to 11-cis-retinal and reconjugated to opsin.[7][134] 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 ofrod cells 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.[7] The research was taken up byWilhelm 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.[7] 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.[135]
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