Vitamin A

Vitamin A is a group of unsaturated nutritional organic compounds that includes retinol, retinal, retinoic acid, and several provitamin A carotenoids (most notably beta-carotene).[1][2] Vitamin A has multiple functions: it is important for growth and development, for the maintenance of the immune system and good vision.[3][4] Vitamin A is needed by the retina of the eye in the form of retinal, which combines with protein opsin to form rhodopsin, the light-absorbing molecule[5] necessary for both low-light (scotopic vision) and color vision.[6] Vitamin A also functions in a very different role as retinoic acid (an irreversibly oxidized form of retinol), which is an important hormone-like growth factor for epithelial and other cells.[4][7]

In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl palmitate, which is converted to retinol (chemically an alcohol) in the small intestine. The retinol form functions as a storage form of the vitamin, and can be converted to and from its visually active aldehyde form, retinal.

All forms of vitamin A have a beta-ionone ring to which an isoprenoid chain is attached, called a retinyl group.[1] Both structural features are essential for vitamin activity.[8] The orange pigment of carrots (beta-carotene) can be represented as two connected retinyl groups, which are used in the body to contribute to vitamin A levels. Alpha-carotene and gamma-carotene also have a single retinyl group, which give them some vitamin activity. None of the other carotenes have vitamin activity. The carotenoid beta-cryptoxanthin possesses an ionone group and has vitamin activity in humans.

Vitamin A can be found in two principal forms in foods:

Vitamin-A-Synthese
All-trans-Retinol
Chemical structure of retinol, one of the major forms of vitamin A

Medical use

Deficiency

Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world.[11] It is estimated to claim the lives of 670,000 children under five annually.[12] Approximately 250,000–500,000 children in developing countries become blind each year owing to vitamin A deficiency, with the highest prevalence in Southeast Asia and Africa.[13] Vitamin A deficiency is "the leading cause of preventable childhood blindness," according to UNICEF.[14][15] 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.[14]

Vitamin A deficiency can occur as either a primary or a secondary deficiency. A primary vitamin A deficiency occurs among children and adults who do not consume an adequate intake of provitamin A carotenoids from fruits and vegetables or preformed vitamin A from animal and dairy products. Early weaning from breastmilk can also increase the risk of vitamin A deficiency.

Secondary vitamin A deficiency is associated with chronic malabsorption of lipids, impaired bile production and release, and chronic exposure to oxidants, such as cigarette smoke, and chronic alcoholism. Vitamin A is a fat-soluble vitamin and depends on micellar solubilization for dispersion into the small intestine, which results in poor use of vitamin A from low-fat diets. Zinc deficiency can also impair absorption, transport, and metabolism of vitamin A because it is essential for the synthesis of the vitamin A transport proteins and as the cofactor in conversion of retinol to retinal. In malnourished populations, common low intakes of vitamin A and zinc increase the severity of vitamin A deficiency and lead physiological signs and symptoms of deficiency.[16] A study in Burkina Faso showed major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children.[17]

Due to the unique function of retinal as a visual chromophore, one of the earliest and specific manifestations of vitamin A deficiency is impaired vision, particularly in reduced light – night blindness. Persistent deficiency gives rise to a series of changes, the most devastating of which occur in the eyes. Some other ocular changes are referred to as xerophthalmia. First there is dryness of the conjunctiva (xerosis) as the normal lacrimal and mucus-secreting epithelium is replaced by a keratinized epithelium. This is followed by the build-up of keratin debris in small opaque plaques (Bitot's spots) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea (keratomalacia) and leading to total blindness.[18] Other changes include impaired immunity (increased risk of ear infections, urinary tract infections, Meningococcal disease), hyperkeratosis (white lumps at hair follicles), keratosis pilaris and squamous metaplasia of the epithelium lining the upper respiratory passages and urinary bladder to a keratinized epithelium. In relation to dentistry, a deficiency in vitamin A may lead to enamel hypoplasia.

Adequate supply, but not excess vitamin A, is especially important for pregnant and breastfeeding women for normal fetal development and in breastmilk. Deficiencies cannot be compensated by postnatal supplementation.[19][20] Excess vitamin A, which is most common with high dose vitamin supplements, can cause birth defects and therefore should not exceed recommended daily values.[21]

Vitamin A metabolic inhibition as a result of alcohol consumption during pregnancy is one proposed mechanism for fetal alcohol syndrome and is characterized by teratogenicity resembling maternal vitamin A deficiency or reduced retinoic acid synthesis during embryogenesis.[22][23][24]

Vitamin A supplementation

A 2012 systematic review found no evidence that beta-carotene or vitamin A supplements increase longevity in healthy people or in people with various diseases.[25] A meta-analysis of 43 studies showed that vitamin A supplementation of children under five who are at risk of deficiency reduced mortality by up to 24%.[26] However, a 2016 Cochrane review concluded there was not evidence to recommend blanket Vitamin A supplementation for all infants between one and six months of age, as it did not reduce infant mortality or morbidity in low- and middle-income countries.[27] The World Health Organization estimated that vitamin A supplementation averted 1.25 million deaths due to vitamin A deficiency in 40 countries since 1998.[28] In 2008, it was estimated that an annual investment of US$60 million in vitamin A and zinc supplementation combined would yield benefits of more than US$1 billion per year, with every dollar spent generating benefits of more than US$17.[29]

While strategies include intake of vitamin A through a combination of breast feeding and dietary intake, delivery of oral high-dose supplements remain the principal strategy for minimizing deficiency.[30] About 75% of the vitamin A required for supplementation activity by developing countries is supplied by the Micronutrient Initiative with support from the Canadian International Development Agency.[31] Food fortification approaches are feasible,[32] but cannot ensure adequate intake levels.[30] Observational studies of pregnant women in sub-Saharan Africa have shown that low serum vitamin A levels are associated with an increased risk of mother-to-child transmission of HIV. Low blood vitamin A levels have been associated with rapid HIV infection and deaths.[33][34] Reviews of clinical studies on the possible mechanisms of HIV transmission found no relationship between blood vitamin A levels in the mother and infant, with conventional intervention established by treatment with anti-HIV drugs.[35][36]

Side effects

Since vitamin A is fat-soluble, disposing of any excesses taken in through diet takes much longer than with water-soluble B vitamins and vitamin C. This allows for toxic levels of vitamin A to accumulate. These toxicities only occur with preformed (retinoid) vitamin A (such as from liver). The carotenoid forms (such as beta-carotene as found in carrots), give no such symptoms, but excessive dietary intake of beta-carotene can lead to carotenodermia, a harmless but cosmetically displeasing orange-yellow discoloration of the skin.[37][38][39]

In general, acute toxicity occurs at doses of 25,000 IU/kg of body weight, with chronic toxicity occurring at 4,000 IU/kg of body weight daily for 6–15 months.[40] However, liver toxicities can occur at levels as low as 15,000 IU (4500 micrograms) per day to 1.4 million IU per day, with an average daily toxic dose of 120,000 IU, particularly with excessive consumption of alcohol. In people with renal failure, 4000 IU can cause substantial damage. Signs of toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU per day.[1]

Excessive vitamin A consumption can lead to nausea, irritability, anorexia (reduced appetite), vomiting, blurry vision, headaches, hair loss, muscle and abdominal pain and weakness, drowsiness, and altered mental status. In chronic cases, hair loss, dry skin, drying of the mucous membranes, fever, insomnia, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity.[41] Some of these symptoms are also common to acne treatment with Isotretinoin. Chronically high doses of vitamin A, and also pharmaceutical retinoids such as 13-cis retinoic acid, can produce the syndrome of pseudotumor cerebri.[42] This syndrome includes headache, blurring of vision and confusion, associated with increased intracerebral pressure. Symptoms begin to resolve when intake of the offending substance is stopped.[43]

Chronic intake of 1500 RAE of preformed vitamin A may be associated with osteoporosis and hip fractures because it suppresses bone building while simultaneously stimulating bone breakdown,[44] although other reviews have disputed this effect, indicating further evidence is needed.[1]

A 2012 systematic review found that beta-carotene and higher doses of supplemental vitamin A increased mortality in healthy people and people with various diseases.[25] The findings of the review extend evidence that antioxidants may not have long-term benefits.

Equivalencies of retinoids and carotenoids (IU)

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. For many years, a system of equivalencies in which an international unit (IU) was equal to 0.3 μg of retinol, 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used.[45] Later, a unit called retinol equivalent (RE) was introduced. Prior to 2001, one RE corresponded to 1 μg retinol, 2 μg β-carotene dissolved in oil (it is only partly dissolved in most supplement pills, due to very poor solubility in any medium), 6 μg β-carotene in normal food (because it is not absorbed as well as when in oils), and 12 μg of either α-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" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.[46]

Substance and its chemical environment Proportion of retinol equivalent to substance (μg/μg)
Retinol 1
beta-Carotene, dissolved in oil 1/2
beta-Carotene, common dietary 1/12
alpha-Carotene, common dietary 1/24
gamma-Carotene, common dietary 1/24
beta-Cryptoxanthin, common dietary 1/24

Because the conversion of retinol from provitamin carotenoids by the human body is actively regulated by the amount of retinol available to the body, the conversions apply strictly only for vitamin A-deficient humans. The absorption of provitamins depends greatly on the amount of lipids ingested with the provitamin; lipids increase the uptake of the provitamin.[47]

A sample vegan diet for one day that provides sufficient vitamin A has been published by the Food and Nutrition Board (page 120[46]). Reference values for retinol or its equivalents, provided by the National Academy of Sciences, have decreased. The RDA (for men) established in 1968 was 5000 IU (1500 μg retinol). In 1974, the RDA was revised to 1000 RE (1000 μg retinol). As of 2001, the RDA for adult males is 900 RAE (900 μg or 3000 IU retinol). By RAE definitions, this is equivalent to 1800 μg of β-carotene supplement dissolved in oil (3000 IU) or 10800 μg of β-carotene in food (18000 IU).

Dietary recommendations

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin A in 2001. For infants up to 12 months there was not sufficient information to establish a RDA, so Adequate Intake (AI) shown instead. As for safety the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs). The calculation of retinol activity equivalents (RAE) is each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.[46]

Life stage
group
U.S. RDAs or
Adequate Intakes, AI,
retinol activity equivalents (μg/day)
Upper limits,
UL* (μg/day)
Infants 0–6 months 400 (AI) 500 (AI)
7–12 months 600 600
Children 1–3 years 300 600
4–8 years 400 900
Males 9–13 years 600 1700
14–18 years 900 2800
>19 years 900 3000
Females 9–13 years 600 1700
14–18 years 700 2800
>19 years 700 3000
Pregnancy <19 years 750 2800
>19 years 770 3000
Lactation <19 years 1200 2800
>19 years 1300 3000
  • ULs are for natural and synthetic retinol ester forms of vitamin A. Beta-carotene and other provitamin A carotenoids from foods and dietary supplements are not added when calculating total vitamin A intake for safety assessments, although they are included as RAEs for RDA and AI calculations.[1][46]

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 on May 27, 2016 it was revised to 900 μg RAE.[48] A table of the pre- and post- adult Daily Values is provided at Reference Daily Intake. The deadline to be in compliance was set at January 1, 2020 for large companies and January 1, 2021 for small companies.[49]

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 defined the same as in United States. For women and men ages 15 and older the PRIs are set at 650 and 750 μg/day, respectively. PRI for pregnancy is 700 μg/day, for lactation 1300/day. For children ages 1–14 years the PRIs increase with age from 250 to 600 μg/day. These PRIs are similar to the U.S. RDAs.[50] The European Food Safety Authority reviewed the same safety question as the United States and set a UL at 3000 μg/day.[51]

Sources

Carrots
Carrots are a source of beta-carotene

Vitamin A is found in many foods, including the following list. [52] Bracketed values are retinol activity equivalences (RAEs) and percentage of the adult male RDA, per 100 grams of the foodstuff (average). Conversion of carotene to retinol varies from person to person and bioavailability of carotene in food varies. [53] [54]

Source Retinol activity
equivalences (RAEs)
(in μg)
Percentage of the
adult male RDA per
100 g of the foodstuff
cod liver oil 30000 3333%
liver turkey 8058 895%
liver beef, pork, fish 6500 722%
liver chicken 3296 366%
ghee 3069 344%
sweet potato 961 107%
carrot 835 93%
broccoli leaf 800 89%
butter 684 76%
kale 681 76%
collard greens frozen then boiled 575 64%
butternut squash 532 67%
dandelion greens 508 56%
spinach 469 52%
pumpkin 426 43%
collard greens 333 37%
cheddar cheese 265 29%
cantaloupe melon 169 19%
bell pepper/capsicum, red 157 17%
egg 140 16%
apricot 96 11%
papaya 55 6%
tomatoes 42 5%
mango 38 4%
pea 38 4%
broccoli florets 31 3%
milk 28 3%
bell pepper/capsicum, green 18 2%
spirulina 3 0.3%

Metabolic functions

Vitamin A plays a role in a variety of functions throughout the body,[3] such as:

Vision

The role of vitamin A in the visual cycle is specifically related to the retinal form. Within the eye, 11-cis-retinal is bound to the protein "opsin" to form rhodopsin in rods[5] and iodopsin (cones) at conserved lysine residues. 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. 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 (IRBP) to the pigment 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.[16] The final stage is conversion of 11-cis-retinal will rebind to opsin to reform rhodopsin (visual purple) in the retina. Rhodopsin is needed to see in low light (contrast) as well as for night vision. Kühne showed that rhodopsin in the retina is only regenerated when the retina is attached to retinal pigmented epithelium,[5] which provides retinal. It is for this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin and lead to one of the first symptoms, night blindness.[55]

Gene transcription

Vitamin A, in the retinoic acid form, plays an important role in gene transcription. Once retinol has been taken up by a cell, it can be oxidized to retinal (retinaldehyde) by retinol dehydrogenases and then retinaldehyde can be oxidized to retinoic acid by retinaldehyde dehydrogenases.[21] The conversion of retinaldehyde to retinoic acid is an irreversible step, meaning that the production of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear receptors.[16] The physiological form of retinoic acid (all-trans-retinoic acid) regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs) which are bound to DNA as heterodimers with retinoid "X" receptors (RXRs). RAR and RXR must dimerize before they can bind to the DNA. RAR will form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer (RAR-RAR). RXR, on the other hand, may form a homodimer (RXR-RXR) and will form heterodimers with many other nuclear receptors as well, including the thyroid hormone receptor (RXR-TR), the Vitamin D3 receptor (RXR-VDR), the peroxisome proliferator-activated receptor (RXR-PPAR) and the liver "X" receptor (RXR-LXR).[56]

The RAR-RXR heterodimer recognizes retinoic acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements (RXREs) on the DNA; although several RAREs near target genes have been shown to control physiological processes,[21] this has not been demonstrated for RXREs. The heterodimers of RXR with nuclear receptors other than RAR (i.e. TR, VDR, PPAR, LXR) bind to various distinct response elements on the DNA to control processes not regulated by vitamin A.[16] Upon binding of retinoic acid to the RAR component of the RAR-RXR heterodimer, 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.[56] This response can upregulate (or downregulate) the expression of target genes, including Hox genes as well as the genes that encode for the receptors themselves (i.e. RAR-beta in mammals).[16]

Immune function

Vitamin A plays a role in many areas of the immune system, particularly in T cell differentiation and proliferation.[57][58]

Vitamin A promotes the proliferation of T cells through an indirect mechanism involving an increase in IL-2.[58] In addition to promoting proliferation, Vitamin A, specifically retinoic acid, influences the differentiation of T cells.[59][60] In the presence of retinoic acid, dendritic cells located in the gut are able to mediate the differentiation of T cells into regulatory T cells.[60] Regulatory T cells are important for prevention of an immune response against "self" and regulating the strength of the immune response in order to prevent host damage. Together with TGF-β, Vitamin A promotes the conversion of T cells to regulatory T cells.[59] Without Vitamin A, TGF-β stimulates differentiation into T cells that could create an autoimmune response.[59]

Hematopoietic stem cells are important for the production of all blood cells, including immune cells, and are able to replenish these cells throughout the life of an individual. Dormant hematopoietic stem cells are able to self-renew and are available to differentiate and produce new blood cells when they are needed. In addition to T cells, Vitamin A is important for the correct regulation of hematopoietic stem cell dormancy.[61] When cells are treated with all-trans retinoic acid, they are unable to leave the dormant state and become active, however, when vitamin A is removed from the diet, hematopoietic stem cells are no longer able to become dormant and the population of hematopoietic stem cells decreases.[61] This shows an importance in creating a balanced amount of vitamin A within the environment to allow these stem cells to transition between a dormant and activated state, in order to maintain a healthy immune system.

Vitamin A has also been shown to be important for T cell homing to the intestine, effects dendritic cells, and can play a role in increased IgA secretion which is important for the immune response in mucosal tissues.[57][62]

Dermatology

Vitamin A, and more specifically, retinoic acid, appears to maintain normal skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells.[63] Exact mechanisms behind pharmacological retinoid therapy agents in the treatment of dermatological diseases are being researched. For the treatment of acne, the most prescribed retinoid drug is 13-cis retinoic acid (isotretinoin). It reduces the size and secretion of the sebaceous glands. Although it is known that 40 mg of isotretinoin will break down to an equivalent of 10 mg of ATRA — the mechanism of action of the drug (original brand name Accutane) remains unknown and is a matter of some controversy. Isotretinoin reduces bacterial numbers in both the ducts and skin surface. This is thought to be a result of the reduction in sebum, a nutrient source for the bacteria. Isotretinoin reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils.[16] Isotretinoin also has been shown to initiate remodeling of the sebaceous glands; triggering changes in gene expression that selectively induce apoptosis.[64] Isotretinoin is a teratogen with a number of potential side-effects. Consequently, its use requires medical supervision.

Retinal/retinol versus retinoic acid

Vitamin A deprived rats can be kept in good general health with supplementation of retinoic acid. This reverses the growth-stunting effects of vitamin A deficiency, as well as early stages of xerophthalmia. However, such rats show infertility (in both male and females) and continued degeneration of the retina, showing that these functions require retinal or retinol, which are interconvertible but which cannot be recovered from the oxidized retinoic acid. The requirement of retinol to rescue reproduction in vitamin A deficient rats is now known to be due to a requirement for local synthesis of retinoic acid from retinol in testis and embryos.[65][66]

Vitamin A and derivatives in medical use

Retinyl palmitate has been used in skin creams, where it is broken down to retinol and ostensibly metabolised to retinoic acid, which has potent biological activity, as described above. The retinoids (for example, 13-cis-retinoic acid) constitute a class of chemical compounds chemically related to retinoic acid, and are used in medicine to modulate gene functions in place of this compound. Like retinoic acid, the related compounds do not have full vitamin A activity, but do have powerful effects on gene expression and epithelial cell differentiation.[67] Pharmaceutics utilizing mega doses of naturally occurring retinoic acid derivatives are currently in use for cancer, HIV, and dermatological purposes.[68] At high doses, side-effects are similar to vitamin A toxicity.

History

The discovery of vitamin A may have stemmed from research dating back to 1816, when physiologist François Magendie observed that dogs deprived of nutrition developed corneal ulcers and had a high mortality rate.[69] In 1912, Frederick Gowland Hopkins demonstrated that unknown accessory factors found in milk, other than carbohydrates, proteins, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.[69][70] 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 at Yale University who studied the role of fats in the diet. 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.[71] 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 (beta-carotene) and vitamin A. In 1931, Swiss chemist Paul Karrer described the chemical structure of vitamin A.[69] Vitamin A was first synthesized in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.

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 Airborne Intercept Radar system secret from German bombers, the British Royal Ministry told newspapers that the nighttime defensive success of Royal Air Force pilots was due to a high dietary intake of carrots rich in vitamin A, propagating the myth that carrots enable people to see better in the dark.[72]

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Further reading

External links

Alitretinoin

Alitretinoin, or 9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine as an antineoplastic (anti-cancer) agent developed by Ligand Pharmaceuticals. It is a first generation retinoid. Ligand gained Food and Drug Administration (FDA) approval for alitretinoin in February 1999.

Beta-Carotene

β-Carotene is an organic, strongly colored red-orange pigment abundant in plants and fruits. It is a member of the carotenes, which are terpenoids (isoprenoids), synthesized biochemically from eight isoprene units and thus having 40 carbons. Among the carotenes, β-carotene is distinguished by having beta-rings at both ends of the molecule. β-Carotene is biosynthesized from geranylgeranyl pyrophosphate.β-Carotene is the most common form of carotene in plants. When used as a food coloring, it has the E number E160a. The structure was deduced by Karrer et al. in 1930. In nature, β-carotene is a precursor (inactive form) to vitamin A via the action of beta-carotene 15,15'-monooxygenase.Isolation of β-carotene from fruits abundant in carotenoids is commonly done using column chromatography. It can also be extracted from the beta-carotene rich algae, Dunaliella salina. The separation of β-carotene from the mixture of other carotenoids is based on the polarity of a compound. β-Carotene is a non-polar compound, so it is separated with a non-polar solvent such as hexane. Being highly conjugated, it is deeply colored, and as a hydrocarbon lacking functional groups, it is very lipophilic.

Bitot's spots

Bitot's spots are the buildup of keratin located superficially in the conjunctiva of human´s eyes. They can be oval, triangular or irregular in shape. The spots are a sign of vitamin A deficiency and associated with drying of the cornea. In 1863, the French physician Pierre Bitot (1822-1888) first described these spots.

The spots may abate under replacement therapy.

In ancient Egypt, this was treated with animal liver, which is where vitamin A is stored.

Carotene

The term carotene (also carotin, from the Latin carota, "carrot") is used for many related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but in general cannot be made by animals (with the exception of some aphids and spider mites which acquired the synthesizing genes from fungi). Carotenes are photosynthetic pigments important for photosynthesis. Carotenes contain no oxygen atoms. They absorb ultraviolet, violet, and blue light and scatter orange or red light, and (in low concentrations) yellow light.

Carotenes are responsible for the orange colour of the carrot, for which this class of chemicals is named, and for the colours of many other fruits, vegetables and fungi (for example, sweet potatoes, chanterelle and orange cantaloupe melon). Carotenes are also responsible for the orange (but not all of the yellow) colours in dry foliage. They also (in lower concentrations) impart the yellow coloration to milk-fat and butter. Omnivorous animal species which are relatively poor converters of coloured dietary carotenoids to colourless retinoids have yellowed-coloured body fat, as a result of the carotenoid retention from the vegetable portion of their diet. The typical yellow-coloured fat of humans and chickens is a result of fat storage of carotenes from their diets.

Carotenes contribute to photosynthesis by transmitting the light energy they absorb to chlorophyll. They also protect plant tissues by helping to absorb the energy from singlet oxygen, an excited form of the oxygen molecule O2 which is formed during photosynthesis.

β-Carotene is composed of two retinyl groups, and is broken down in the mucosa of the human small intestine by β-carotene 15,15'-monooxygenase to retinal, a form of vitamin A. β-Carotene can be stored in the liver and body fat and converted to retinal as needed, thus making it a form of vitamin A for humans and some other mammals. The carotenes α-carotene and γ-carotene, due to their single retinyl group (β-ionone ring), also have some vitamin A activity (though less than β-carotene), as does the xanthophyll carotenoid β-cryptoxanthin. All other carotenoids, including lycopene, have no beta-ring and thus no vitamin A activity (although they may have antioxidant activity and thus biological activity in other ways).

Animal species differ greatly in their ability to convert retinyl (beta-ionone) containing carotenoids to retinals. Carnivores in general are poor converters of dietary ionone-containing carotenoids. Pure carnivores such as ferrets lack β-carotene 15,15'-monooxygenase and cannot convert any carotenoids to retinals at all (resulting in carotenes not being a form of vitamin A for this species); while cats can convert a trace of β-carotene to retinol, although the amount is totally insufficient for meeting their daily retinol needs.

Cat skin disorders

Cat skin disorders are among the most common health problems in cats.

Skin disorders in cats have many causes, and many of the common skin disorders that afflict people have a counterpart in cats. The condition of a cat's skin and coat can also be an important indicator of its general health. Skin disorders of cats vary from acute, self-limiting problems to chronic or long-lasting problems requiring life-time treatment. Cat skin disorders may be grouped into categories according to the causes.

Cod liver oil

Cod liver oil is a dietary supplement derived from liver of cod fish (Gadidae). As with most fish oils, it contains the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Cod liver oil also contains vitamin A and vitamin D. Historically, it was given to children because vitamin D had been shown to prevent rickets, a consequence of vitamin D deficiency.

Golden rice

Golden rice is a variety of rice (Oryza sativa) produced through genetic engineering to biosynthesize beta-carotene, a precursor of vitamin A, in the edible parts of rice. It is intended to produce a fortified food to be grown and consumed in areas with a shortage of dietary vitamin A, a deficiency which each year is estimated to kill 670,000 children under the age of 5 and cause an additional 500,000 cases of irreversible childhood blindness. Rice is a staple food crop for over half of the world's population, making up 30–72% of the energy intake for people in Asian countries, making it an excellent crop for targeting vitamin deficiencies.Golden rice differs from its parental strain by the addition of three beta-carotene biosynthesis genes. The parental strain can naturally produce beta-carotene in its leaves, where it is involved in photosynthesis. However, the plant does not normally produce the pigment in the endosperm, where photosynthesis does not occur. Golden rice has met significant opposition from environmental and anti-globalization activists that claim that there are sustainable, long-lasting and more efficient ways to solve vitamin A deficiency that do not compromise food, nutrition and financial security, as they claim golden rice does. A study in the Philippines is aimed to evaluate the performance of golden rice, if it can be planted, grown and harvested like other rice varieties, and whether golden rice poses risk to human health. There has been little research on how well the beta-carotene will hold up when stored for long periods between harvest seasons, or when cooked using traditional methods.In 2005, Golden Rice 2 was announced, which produces up to 23 times more beta-carotene than the original golden rice. To receive the USDA's Recommended Dietary Allowance (RDA), it is estimated that 144 g/day of the high-yielding strain would have to be eaten. Bioavailability of the carotene from golden rice has been confirmed and found to be an effective source of vitamin A for humans. Golden Rice was one of the seven winners of the 2015 Patents for Humanity Awards by the United States Patent and Trademark Office. In 2018 came the first approvals as food in Australia, New Zealand, Canada and the USA.

Hypervitaminosis A

Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A. Symptoms arise as a result of altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervitaminosis A is believed to have occurred in early humans, and the problem has persisted throughout human history.

Toxicity results from ingesting too much preformed vitamin A from foods (such as fish or animal liver), supplements, or prescription medications and can be prevented by ingesting no more than the recommended daily amount.

Diagnosis can be difficult, as serum retinol is not sensitive to toxic levels of vitamin A, but there are effective tests available. Hypervitaminosis A is usually treated by stopping intake of the offending food(s), supplement(s), or medication. Most people make a full recovery.

High intake of provitamin carotenoids (such as beta-carotene) from vegetables and fruits does not cause hypervitaminosis A, as conversion from carotenoids to the active form of vitamin A is regulated by the body to maintain an optimum level of the vitamin. Carotenoids themselves cannot produce toxicity.

International unit

In pharmacology, the international unit is a unit of measurement for the amount of a substance; the mass or volume that constitutes one international unit varies based on which substance is being measured, and the variance is based on the biological activity or effect, for the purpose of easier comparison across substances. International units are used to quantify vitamins, hormones, some medications, vaccines, blood products, and similar biologically active substances.

The name international unit has often been capitalized (in English and other languages), although major English-language dictionaries treat it as a common noun and thus use lower case. The name has several accepted abbreviations. It is usually abbreviated as IU in English, and UI in Romance languages (for example Spanish unidad internacional, French unité internationale, Italian unità internazionale, Romanian unitate internațională), IE in several Germanic languages (for example German internationale Einheit, Dutch internationale eenheid) or as other forms (for example Russian МЕ, международная единица [mezhdunarodnaya yedinitsa], Hungarian NE, nemzetközi egység). In order to remove the possibility of having the letter "I" confused with the digit "1", some hospitals have it as a stated policy to omit the "I", that is, to only use U or E when talking and writing about dosages, while other hospitals require the word "units" (or words "international units") to be written out entirely. (For example, "three international units per litre" may be abbreviated "3 U/L".)

Many biological agents exist in different forms or preparations (e.g. vitamin A in the form of retinol or beta-carotene). The goal of the IU is to be able to compare these, so that different forms or preparations with the same biological effect will contain the same number of IUs. To do so, the WHO Expert Committee on Biological Standardization provides a reference preparation of the agent, arbitrarily sets the number of IUs contained in that preparation, and specifies a biological procedure to compare other preparations of the same agent to the reference preparation. Since the number of IUs contained in a new substance is arbitrarily set, there is no equivalence between IU measurements of different biological agents. For instance, one IU of vitamin E cannot be equated with one IU of vitamin A in any way, including mass or efficacy.

Despite its name, IU is not part of the International System of Units used in physics and chemistry. The IU should not be confused with the enzyme unit, also known as the international unit of enzyme activity and abbreviated as U.

Liver (food)

The liver of mammals, fowl, and fish is commonly eaten as food by humans. Domestic pig, ox, lamb, calf, chicken, goose, and cod livers are widely available from butchers and supermarkets. Animal livers are rich in iron, copper, the B vitamins and preformed vitamin A. 100 g cod liver contains 5 mg of vitamin A and 100 µg of vitamin D.Liver can be baked, boiled, broiled, fried, stir-fried, or eaten raw (asbeh nayeh or sawda naye in Lebanese cuisine, liver sashimi). In many preparations, pieces of liver are combined with pieces of meat or kidneys, like in the various forms of Middle Eastern mixed grill (e.g. meurav Yerushalmi). Spreads or pâtés made from liver have various names, including liver pâté, pâté de foie gras, chopped liver, liverwurst, and Braunschweiger. A traditional South African delicacy, namely skilpadjies, is made of minced lamb's liver wrapped in netvet (caul fat), and grilled over an open fire.

Some fish livers are valued as food, especially the stingray liver. It is used to prepare delicacies, such as poached skate liver on toast in England, as well as the beignets de foie de raie and foie de raie en croute in French cuisine. Cod liver (usually tinned in its oil and served seasoned) is a popular spread for bread or toast in several European countries. In Russia, it is served with potatoes. Cod liver oil is commonly used as a dietary supplement.

Micronutrient

Micronutrients are essential elements required by organisms in small quantities throughout life to orchestrate a range of physiological functions to maintain health. Micronutrient requirements differ between organisms; for example, humans and other animals require numerous vitamins and dietary minerals, whereas plants require specific minerals. For human nutrition, micronutrient requirements are in amounts generally less than 100 milligrams per day, whereas macronutrients are required in gram quantities daily.

The minerals for humans and other animals include 13 elements that originate from Earth's soil and are not synthesized by living organisms, such as calcium and iron. Micronutrient requirements for animals also include vitamins, which are organic compounds required in microgram or milligram amounts. Since plants are the primary origin of nutrients for humans and animals, some micronutrients may be in low levels and deficiencies can occur when dietary intake is insufficient, as occurs in malnutrition, implying the need for initiatives to deter inadequate micronutrient supply in plant foods.

Nyctalopia

Nyctalopia ( from Greek νύκτ- (nykt-), meaning 'night', ἀλαός (alaos), meaning 'blind, not seeing', and ὄψ (ops), meaning 'eye'), also called night-blindness, is a condition making it difficult or impossible to see in relatively low light. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition (for example, vitamin A deficiency). It can be described as insufficient adaptation to darkness.

The most common cause of nyctalopia is retinitis pigmentosa, a disorder in which the rod cells in the retina gradually lose their ability to respond to the light. Patients suffering from this genetic condition have progressive nyctalopia and eventually their daytime vision may also be affected. In X-linked congenital stationary night blindness, from birth the rods either do not work at all, or work very little, but the condition doesn't get worse.

Another cause of night blindness is a deficiency of retinol, or vitamin A, found in fish oils, liver and dairy products.

The opposite problem, the inability to see in bright light, is known as hemeralopia and is much rarer.

Since the outer area of the retina is made up of more rods than cones, loss of peripheral vision often results in night blindness. Individuals suffering from night blindness not only see poorly at night, but also require extra time for their eyes to adjust from brightly lit areas to dim ones. Contrast vision may also be greatly reduced.

Rods contain a receptor-protein called rhodopsin. When light falls on rhodopsin, it undergoes a series of conformational changes ultimately generating electrical signals which are carried to the brain via the optic nerve. In the absence of light, rhodopsin is regenerated. The body synthesizes rhodopsin from vitamin A, which is why a deficiency in vitamin A causes poor night vision.

Refractive "vision correction" surgery (especially PRK with the complication of "haze") may rarely cause a reduction in best night-time acuity due to the impairment of contrast sensitivity function (CSF) which is induced by intraocular light-scatter resulting from surgical intervention in the natural structural integrity of the cornea.

Retinal

Retinal is also known as retinaldehyde. It was originally called retinene, and renamed after it was discovered to be vitamin A aldehyde. Retinal is one of the many forms of vitamin A (the number of which varies from species to species). Retinal is a polyene chromophore, bound to proteins called opsins, and is the chemical basis of animal vision.

Retinal allows certain microorganisms to convert light into metabolic energy.

Vertebrate animals ingest retinal directly from meat, or they produce retinal from carotenoids, either from one of two carotenes (α-carotene, β-carotene) or from β-cryptoxanthin, a type of xanthophyll. These carotenoids must be obtained from plants or other photosynthetic organisms. No other carotenoids can be converted by animals to retinal, and some carnivores cannot convert any carotenoids at all. The other main forms of vitamin A, retinol, and a partially active form, retinoic acid, may both be produced from retinal.

Invertebrates such as insects and squid use hydroxylated forms of retinal in their visual systems, which derive from conversion from other xanthophylls.

Retinoic acid

Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.The key role of retinoic acid in embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin used for treatment of cancer and acne. Oral megadoses of pre-formed vitamin A (retinyl palmitate), and retinoic acid itself, also have teratogenic potential by this same mechanism.

Retinoid

The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth.

Retinoids have many important functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes.

Research is also being done into their ability to treat skin cancers. Currently, alitretinoin (9-cis-retinoic acid) may be used topically to help treat skin lesions from Kaposi's sarcoma.

Retinol

Retinol, also known as Vitamin A1, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. In areas where deficiency is common, a single large dose is recommended to those at high risk a couple of times a year. It is also used to prevent further issues in those who have measles. It is used by mouth or injection into a muscle.Retinol at normal doses is well tolerated. High doses may result in an enlarged liver, dry skin, or hypervitaminosis A. High doses during pregnancy may result in harm to the baby. Retinol is in the vitamin A family. It or other forms of vitamin A are needed for eyesight, maintenance of the skin, and human development. It is converted in the body to retinal and retinoic acid through which it acts. Dietary sources include fish, dairy products, and meat.Retinol was discovered in 1909, isolated in 1931, and first made in 1947. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Retinol is available as a generic medication and over the counter. The wholesale cost in the developing world is about US$0.02–0.30 per 50,000 units. In the United States it is not very expensive.

Vitamin

A vitamin is an organic molecule (or related set of molecules) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrients cannot be synthesized in the organism, either at all or not in sufficient quantities, and therefore must be obtained through the diet. Vitamin C can be synthesized by some species but not by others; it is not a vitamin in the first instance but is in the second. The term vitamin does not include the three other groups of essential nutrients: minerals, essential fatty acids, and essential amino acids. Most vitamins are not single molecules, but groups of related molecules called vitamers. For example, vitamin E consists of four tocopherols and four tocotrienols. The thirteen vitamins required by human metabolism are: vitamin A (retinols and carotenoids), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid or folate), vitamin B12 (cobalamins), vitamin C (ascorbic acid), vitamin D (calciferols), vitamin E (tocopherols and tocotrienols), and vitamin K (quinones).

Vitamins have diverse biochemical functions. Some forms of vitamin A function as regulators of cell and tissue growth and differentiation. The B complex vitamins function as enzyme cofactors (coenzymes) or the precursors for them. Vitamin D has a hormone-like function as a regulator of mineral metabolism for bones and other organs. Vitamins C and E function as antioxidants. Both deficient and excess intake of a vitamin can potentially cause clinically significant illness, although excess intake of water-soluble vitamins is less likely to do so.

Before 1935, the only source of vitamins was from food. If intake of vitamins was lacking, the result was vitamin deficiency and consequent deficiency diseases. Then, commercially produced tablets of yeast-extract vitamin B complex and semi-synthetic vitamin C became available. This was followed in the 1950s by the mass production and marketing of vitamin supplements, including multivitamins, to prevent vitamin deficiencies in the general population. Governments mandated addition of vitamins to staple foods such as flour or milk, referred to as food fortification, to prevent deficiencies. Recommendations for folic acid supplementation during pregnancy reduced risk of infant neural tube defects. Although reducing incidence of vitamin deficiencies clearly has benefits, supplementation is thought to be of little value for healthy people who are consuming a vitamin-adequate diet.The term vitamin is derived from the word vitamine, coined in 1912 by Polish biochemist Casimir Funk, who isolated a complex of micronutrients essential to life, all of which he presumed to be amines. When this presumption was later determined not to be true, the "e" was dropped from the name. All vitamins were discovered (identified) between 1913 and 1948.

Vitamin A deficiency

Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues. It is common in poorer countries, but rarely is seen in more developed countries. Nyctalopia (night blindness) is one of the first signs of VAD. Xerophthalmia, keratomalacia, and complete blindness can also occur since vitamin A has a major role in phototransduction. The three forms of vitamin A include retinols, beta-carotenes, and carotenoids.Vitamin A deficiency is the leading cause of preventable childhood blindness, and is critical to achieving Millennium Development Goal 4 to reduce child mortality. About 250,000 to 500,000 malnourished children in the developing world go blind each year from a deficiency of vitamin A, around half of whom die within a year of becoming blind. The United Nations Special Session on Children in 2002 set a goal of the elimination of VAD by 2010.

The prevalence of night blindness due to VAD is also high among pregnant women in many developing countries. VAD also contributes to maternal mortality and other poor outcomes in pregnancy and lactation.VAD also diminishes the ability to fight infections. In countries where children are not immunized, infectious diseases such as measles have higher fatality rates. As elucidated by Alfred Sommer, even mild, subclinical deficiency can also be a problem, as it may increase children's risk of developing respiratory and diarrheal infections, decrease growth rate, slow bone development, and decrease likelihood of survival from serious illness.

VAD is estimated to affect about one-third of children under the age of five around the world. It is estimated to claim the lives of 670,000 children under five annually. Around 250,000–500,000 children in developing countries become blind each year owing to VAD, with the highest prevalence in Southeast Asia and Africa. According to the World Health Organization (WHO), VAD is under control in the United States, but in developing countries, VAD is a significant concern. Globally, 65% of all children aged 6 to 59 months received two doses of vitamin A in 2013, fully protecting them against VAD (80% in the least developed countries).

Xerophthalmia

Xerophthalmia (from Ancient Greek xērós (ξηρός) meaning dry and ophthalmos (οφθαλμός) meaning eye) is a medical condition in which the eye fails to produce tears. It may be caused by vitamin A deficiency, which is sometimes used to describe that condition, although there may be other causes.

Xerophthalmia caused by a severe vitamin A deficiency is described by pathologic dryness of the conjunctiva and cornea. The conjunctiva becomes dry, thick and wrinkled. If untreated, it can lead to corneal ulceration and ultimately to blindness as a result of corneal damage.

Xerophthalmia usually implies a destructive dryness of the conjunctival epithelium due to dietary vitamin A deficiency—a rare condition in developed countries, but still causing much damage in developing countries. Other forms of dry eye are associated with aging, poor lid closure, scarring from a previous injury, or autoimmune diseases such as rheumatoid arthritis and Sjögren's syndrome, and these can all cause chronic conjunctivitis. Radioiodine therapy can also induce xerophthalmia, often transiently, although in some patients late onset or persistent xerophthalmia has been observed.The damage to the cornea in vitamin A associated xerophthalmia is quite different from damage to the retina at the back of the globe, a type of damage which can also be due to lack of vitamin A, but which is caused by lack of other forms of vitamin A which work in the visual system. Xerophthalmia from hypovitaminosis A is specifically due to lack of the hormone-like vitamin A metabolite retinoic acid, since (along with certain growth-stunting effects) the condition can be reversed in vitamin A deficient rats by retinoic acid supplementation (however the retinal damage continues). Since retinoic acid cannot be reduced to retinal or retinol, these effects on the cornea must be specific to retinoic acid. This is in keeping with retinoic acid's known requirement for good health in epithelial cells, such as those in the cornea.

Fat soluble
Water soluble
Combinations
Food antioxidants
Fuel antioxidants
Measurements
RAR
RXR

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