Vitamin A
Overview
 
Vitamin A is a vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

 that is needed by the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

 of the eye in the form of a specific metabolite, the light-absorbing molecule retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...

, that is necessary for both low-light (scotopic vision) and color vision
Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths of the light they reflect, emit, or transmit...

. Vitamin A also functions in a very different role as an irreversibly oxidized form of retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....

 known as retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A 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 fishes to humans...

, which is an important hormone-like growth factor for epithelial and other cells.

In foods of animal origin, the major form of vitamin A is an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

, primarily retinyl palmitate
Retinyl palmitate
Retinyl palmitate, or vitamin A palmitate, is the ester of retinol and palmitic acid, with formula C36H60O2.Palmitate is the major component of palm oil...

, which is converted to the retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....

 (chemically an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

) in the small intestine.
Discussions
Encyclopedia
Vitamin A is a vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

 that is needed by the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

 of the eye in the form of a specific metabolite, the light-absorbing molecule retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...

, that is necessary for both low-light (scotopic vision) and color vision
Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths of the light they reflect, emit, or transmit...

. Vitamin A also functions in a very different role as an irreversibly oxidized form of retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....

 known as retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A 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 fishes to humans...

, which is an important hormone-like growth factor for epithelial and other cells.

In foods of animal origin, the major form of vitamin A is an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

, primarily retinyl palmitate
Retinyl palmitate
Retinyl palmitate, or vitamin A palmitate, is the ester of retinol and palmitic acid, with formula C36H60O2.Palmitate is the major component of palm oil...

, which is converted to the retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....

 (chemically an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

) 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
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

 form, retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...

. The associated acid (retinoic acid), a metabolite that can be irreversibly synthesized from vitamin A, has only partial vitamin A activity, and does not function in the retina for the visual cycle.

All forms of vitamin A have a beta-ionone
Ionone
The ionones are a series of closely related chemical substances that are part of a group of compounds known as rose ketones, which also includes damascones and damascenones. Ionones are aroma compounds found in a variety of essential oils, including rose oil...

 ring to which an isoprenoid
Isoprene
Isoprene , or 2-methyl-1,3-butadiene, is a common organic compound with the formula CH2=CCH=CH2. Under standard conditions it is a colorless liquid...

 chain is attached, called a retinyl group. Both structural features are essential for vitamin activity. The orange pigment of carrots – beta-carotene
Beta-carotene
β-Carotene is a strongly-coloured red-orange pigment abundant in plants and fruits. It is an organic compound and chemically is classified as a hydrocarbon and specifically as a terpenoid , reflecting its derivation from isoprene units...

 – can be represented as two connected retinyl groups, which are used in the body to contribute to vitamin A levels. Alpha-carotene
Alpha-carotene
α-Carotene is a form of carotene with a β-ring at one end and an ε-ring at the other. It is the second most common form of carotene.-Human physiology:...

 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
Cryptoxanthin
Cryptoxanthin is a natural carotenoid pigment. It has been isolated from a variety of sources including the petals and flowers of plants in the genus Physalis, orange rind, papaya, egg yolk, butter, apples, and bovine blood serum.-Chemistry:...

 possesses an ionone group and has vitamin activity in humans.

Vitamin A can be found in two principal forms in food
Food
Food is any substance consumed to provide nutritional support for the body. It is usually of plant or animal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals...

s:
  • Retinol
    Retinol
    Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....

    , the form of vitamin A absorbed when eating animal food sources, is a yellow, fat-soluble substance. Since the pure alcohol form is unstable, the vitamin is found in tissues in a form of retinyl ester. It is also commercially produced and administered as esters such as retinyl acetate
    Acetate
    An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

     or palmitate.

  • The carotene
    Carotene
    The term carotene is used for several related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but cannot be made by animals. Carotene is an orange photosynthetic pigment important for photosynthesis. Carotenes are all coloured to the human eye...

    s alpha-carotene, beta-carotene, gamma-carotene; and the xanthophyll
    Xanthophyll
    Xanthophylls are yellow pigments that form one of two major divisions of the carotenoid group. The name is from Greek xanthos + phyllon , due to their formation of the yellow band seen in early chromatography of leaf pigments...

     beta-cryptoxanthin (all of which contain beta-ionone rings), but no other carotenoid
    Carotenoid
    Carotenoids are tetraterpenoid organic pigments that are naturally occurring in the chloroplasts and chromoplasts of plants and some other photosynthetic organisms like algae, some bacteria, and some types of fungus. Carotenoids can be synthesized fats and other basic organic metabolic building...

    s, function as vitamin A in herbivores and omnivore animals, which possess the enzyme required to convert these compounds to retinal
    Retinal
    Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...

    . In general, carnivores are poor converters of ionine-containing carotenoids, and pure carnivores such as cats and ferrets lack beta-carotene 15,15'-monooxygenase
    Beta-carotene 15,15'-monooxygenase
    In enzymology, a beta-carotene 15,15'-monooxygenase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are beta-carotene and O2, whereas its product is retinal....

     and cannot convert any carotenoids to retinal (resulting in none of the carotenoids being forms of vitamin A for these species).

History

The discovery of vitamin A may have stemmed from research dating back to 1906, indicating that factors other than carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...

s, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s, and fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

s were necessary to keep cattle
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...

 healthy. By 1917 one of these substances was independently discovered by Elmer McCollum
Elmer McCollum
Elmer Verner McCollum was an American biochemist known for his work on the influence of diet on health.-Life and education:McCollum was born on a farm near Fort Scott, Kansas, where he spent his first seventeen years...

 at the University of Wisconsin–Madison
University of Wisconsin–Madison
The University of Wisconsin–Madison is a public research university located in Madison, Wisconsin, United States. Founded in 1848, UW–Madison is the flagship campus of the University of Wisconsin System. It became a land-grant institution in 1866...

, and Lafayette Mendel
Lafayette Mendel
Lafayette Benedict Mendel was an American biochemist known for his work in nutrition including the study of Vitamin A, Vitamin B, lysine and tryptophan....

 and Thomas Burr Osborne
Thomas Burr Osborne (chemist)
Thomas Burr Osborne was a biochemist and co-discoverer of Vitamin A. he was the son of laywer Arthur Dimon Osborne and the grandson of US Representative Thomas Burr Osborne....

 at Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...

. Since "water-soluble factor B" (vitamin B) had recently been discovered, the researchers chose the name "fat-soluble factor A" (vitamin A). In 1919, Steenbock (University of Wisconsin) proposed a relationship between yellow plant pigments (beta-carotene) and vitamin A. Vitamin A was first synthesized in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.

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
International unit
In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...

 (IU) was equal to 0.3 μg
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...

 of retinol, 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used. 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
Alpha-carotene
α-Carotene is a form of carotene with a β-ring at one end and an ε-ring at the other. It is the second most common form of carotene.-Human physiology:...

, γ-carotene, or β-cryptoxanthin
Cryptoxanthin
Cryptoxanthin is a natural carotenoid pigment. It has been isolated from a variety of sources including the petals and flowers of plants in the genus Physalis, orange rind, papaya, egg yolk, butter, apples, and bovine blood serum.-Chemistry:...

 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
Institute of Medicine
The Institute of Medicine is a not-for-profit, non-governmental American organization founded in 1970, under the congressional charter of the National Academy of Sciences...

 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.
Substance and its chemical environment Micrograms of retinol equivalent
per microgram of the substance
retinol 1
beta-carotene
Beta-carotene
β-Carotene is a strongly-coloured red-orange pigment abundant in plants and fruits. It is an organic compound and chemically is classified as a hydrocarbon and specifically as a terpenoid , reflecting its derivation from isoprene units...

, 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.

The conclusion that can be drawn from the newer research is that fruits and vegetables are not as useful for obtaining vitamin A as was thought; in other words, the IUs that these foods were reported to contain were worth much less than the same number of IUs of fat-dissolved oils and (to some extent) supplements. This is important for vegetarians, as Night blindness is prevalent in countries where little meat or vitamin A-fortified foods are available.

A sample vegan diet for one day that provides sufficient vitamin A has been published by the Food and Nutrition Board (page 120). On the other hand, reference values for retinol or its equivalents, provided by the National Academy of Sciences
United States National Academy of Sciences
The National Academy of Sciences is a corporation in the United States whose members serve pro bono as "advisers to the nation on science, engineering, and medicine." As a national academy, new members of the organization are elected annually by current members, based on their distinguished and...

, have decreased. The RDA (for men) of 1968 was 5000 IU (1500 μg retinol). In 1974, the RDA was set to 1000 RE (1000 μg retinol), whereas now the Dietary Reference Intake
Dietary Reference Intake
The Dietary Reference Intake is a system of nutrition recommendations from the Institute of Medicine of the U.S. National Academy of Sciences. The DRI system is used by both the United States and Canada and is intended for the general public and health professionals...

 is 900 RAE (900 μg or 3000 IU retinol). This is equivalent to 1800 μg of β-carotene supplement (3000 IU) or 10800 μg of β-carotene in food (18000 IU).

Recommended daily intake

Vitamin A
Dietary Reference Intake
Dietary Reference Intake
The Dietary Reference Intake is a system of nutrition recommendations from the Institute of Medicine of the U.S. National Academy of Sciences. The DRI system is used by both the United States and Canada and is intended for the general public and health professionals...

:
Life stage group RDA

Adequate intakes (AI*)

μg/day
Upper limit

μg/day
Infants
0–6 months
7–12 months

400*
500*

600
600
Children
1–3 years
4–8 years

300
400

600
900
Males
9–13 years
14–18 years
19 – >70 years

600
900
900

1700
2800
3000
Females
9–13 years
14–18 years
19 – >70 years

600
700
700

1700
2800
3000
Pregnancy
<19 years
19 – >50 years

750
770

2800
3000
Lactation
<19 years
19 – >50 years

1200
1300

2800
3000


(The limit is for synthetic and natural retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....

 ester forms of vitamin A. Carotene forms from dietary sources are not toxic.)

According to the Institute of Medicine of the National Academies, "RDAs are set to meet the needs of almost all (97 to 98%) individuals in a group. For healthy breastfed infants, the AI is the mean intake. The AI for other life stage and gender groups is believed to cover the needs of all individuals in the group, but lack of data prevents being able to specify with confidence the percentage of individuals covered by this intake."

Sources

Vitamin A is found naturally in many foods:
Note: data taken from USDA database bracketed values are retinol activity equivalences (RAEs) and percentage of the adult male RDA, per 100 gram
Gram
The gram is a metric system unit of mass....

s of the foodstuff (average).

Conversion of carotene to retinol varies from person to person and bioavailability of carotene in food varies.

Metabolic functions

Vitamin A plays a role in a variety of functions throughout the body, such as:
  • Vision
  • Gene transcription
  • Immune function
  • Embryonic development and reproduction
  • Bone metabolism
  • Haematopoiesis
    Haematopoiesis
    Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...

  • Skin and cellular health
  • Antioxidant activity

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 rhodopsin (rods) 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. The final stage is conversion of 11-cis-retinal will rebind to opsin to reform rhodopsin in the retina. Rhodopsin is needed to see in low light (contrast) as well as for night vision. 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.

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. 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. 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). 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, 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. 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. 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).

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. Exact mechanisms behind pharmacological retinoid therapy agents in the treatment of dermatological diseases are being researched. For the treatment of acne
Acne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...

, the most prescibred retinoid drug is 13-cis retinoic acid (isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...

). 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. Isotretinoin also has been shown to initiate remodeling of the sebaceous glands; triggering changes in gene expression that selectively induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. 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
Retinoic acid
Retinoic acid is a metabolite of vitamin A 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 fishes to humans...

. This reverses the growth-stunting effects of vitamin A deficiency, as well as early stages of xerophthalmia
Xerophthalmia
Xerophthalmia is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes....

. 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 intraconvertable 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.

Deficiency

Vitamin A deficiency is estimated to affect approximately 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. 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.

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. A study in Burkina Faso
Burkina Faso
Burkina Faso – also known by its short-form name Burkina – is a landlocked country in west Africa. It is surrounded by six countries: Mali to the north, Niger to the east, Benin to the southeast, Togo and Ghana to the south, and Côte d'Ivoire to the southwest.Its size is with an estimated...

 showed major reduction of malaria morbidity with combined vitamin A and zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

 supplementation in young children.

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
Xerophthalmia
Xerophthalmia is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes....

. First there is dryness of the conjunctiva (xerosis
Xerosis
Xerosis cutis is the medical term for dry skin.It can have many different causes, including general dehydration, atopic dermatitis, Vitamin A deficiency, and maybe diabetes. Treatment is primarily symptomatic. "Xero", meaning dry or dehydrated, "osis" usually referring to a medical disease or...

) 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
Bitot's spots
Bitot's spots are the buildup of keratin debris located superficially in the conjunctiva, which are oval, triangular or irregular in shape. These spots are a sign of vitamin A deficiency and are associated with conjunctival xerosis...

) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea (keratomalacia
Keratomalacia
Keratomalacia is an eye disorder that leads to a dry cornea. One of its major causes is Vitamin A deficiency. When xerophthalmia persists for a long time, it results in keratomalacia. There is degradation of corneal epithelium which may also get vascularised. Later corneal opacities develop...

) and total blindness. Other changes include impaired immunity (increased risk of ear infections, urinary tract infections, Meningococcal disease), hyperkeratosis (white lumps at hair follicles), keratosis pilaris
Keratosis pilaris
Keratosis pilaris is a common, autosomal dominant, genetic follicular condition that is manifested by the appearance of rough bumps on the skin...

 and squamous metaplasia
Squamous metaplasia
Squamous metaplasia refers to benign changes in the epithelial linings of certain organs within the body. These cells assume a more squamous morphology. Common sites for squamous metaplasia include the bladder and cervix. Smokers often exhibit squamous metaplasia in the linings of their airways...

 of the epithelium lining the upper respiratory passages and urinary bladder to a keratinized epithelium. With relations to dentistry, a deficiency in Vitamin A leads to enamel hypoplasia.

Adequate supply, but not excess vitamin A, is especially important for pregnant and breastfeeding women for normal fetal development. Deficiencies cannot be compensated by postnatal
Postnatal
Postnatal is the period beginning immediately after the birth of a child and extending for about six weeks. Another term would be postpartum period, as it refers to the mother...

 supplementation. Excess vitamin A, which is most common with high dose vitamin supplements, can cause birth defects and therefore should not exceed recommended daily values.

Vitamin A metabolic inhibition as a result of alcohol consumption during pregnancy is the elucidated mechanism for fetal alcohol syndrome and is characterized by teratogenicity closely matching maternal vitamin A deficiency.

Vitamin A supplementation

Global efforts to support national governments in addressing vitamin A deficiency are led by the Global Alliance for Vitamin A (GAVA), which is an informal partnership between A2Z, the Canadian International Development Agency
Canadian International Development Agency
The Canadian International Development Agency was formed in 1968 by the Canadian government. CIDA administers foreign aid programs in developing countries, and operates in partnership with other Canadian organizations in the public and private sectors as well as other international organizations...

, Helen Keller International
Helen Keller International
Helen Keller International combats the causes and consequences of blindness and malnutrition by establishing programs based on evidence and research in vision, health and nutrition. Founded in 1915 by Helen Keller and George Kessler, the organization’s mission is to save the sight and lives of the...

, the Micronutrient Initiative
Micronutrient Initiative
The Micronutrient Initiative is an international not for profit agency based in Canada that works to eliminate vitamin and mineral deficiencies in developing countries...

, UNICEF, USAID, and the World Bank
World Bank
The World Bank is an international financial institution that provides loans to developing countries for capital programmes.The World Bank's official goal is the reduction of poverty...

. Joint GAVA activity is coordinated by the Micronutrient Initiative.

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. Studies have shown vitamin A supplementation of children under five who are at risk of deficiency can reduce mortality by 23%. 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. Food fortification approaches are becoming increasingly feasible but cannot yet ensure coverage levels.

An estimated 1.25 million deaths due to vitamin A deficiency have been averted in 40 countries since 1998. 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. These combined interventions were ranked by the Copenhagen Consensus 2008 as the world’s best development investment.

Toxicity

Since vitamin A is fat-soluble, disposing of any excesses taken in through diet is much harder than with water-soluble B vitamins and vitamin C, vitamin A toxicity is possible.

In general, acute toxicity occurs at doses of 25,000 IU
International unit
In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...

/kg
Kilogram
The kilogram or kilogramme , also known as the kilo, is the base unit of mass in the International System of Units and is defined as being equal to the mass of the International Prototype Kilogram , which is almost exactly equal to the mass of one liter of water...

 of body weight, with chronic toxicity occurring at 4,000 IU/kg of body weight daily for 6–15 months. However, liver toxicities can occur at levels as low as 15,000 IU per day to 1.4 million IU per day, with an average daily toxic dose of 120,000 IU per day, particularly with excessive consumption of alcohol. In people with renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

, 4000 IU can cause substantial damage. In addition, excessive alcohol intake can increase toxicity. Children can reach toxic levels at 1,500 IU/kg of body weight.

Excessive vitamin A consumption can lead to nausea, irritability, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

 (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
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity. Some of these symptoms are also common to acne treatment with Isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...

. Chronically high doses of vitamin A, and also pharmaceutical retinoid
Retinoid
The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth....

s such as 13-cis retinoic acid, can produce the syndrome of pseudotumor cerebri. 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.

Chronic intake of 1500 RAE of preformed vitamin A may be associated with osteoporosis and hip fractures. This may be due to the fact that an excess of vitamin A can block the expression of certain proteins dependent on vitamin K to reduce the efficacy of vitamin D, but has not yet been proven. High vitamin A intake has been associated with spontaneous bone fractures in animals. Cell culture studies have linked increased bone resorption and decreased bone formation with high intakes. This interaction may occur because vitamins A and D may compete for the same receptor and then interact with parathyroid hormone, which regulates calcium. Indeed, a study by Forsmo et al. shows a correlation between low bone mineral density and too high intake of vitamin A.

Toxic effects of vitamin A have been shown to significantly affect developing fetuses. Therapeutic doses used for acne treatment have been shown to disrupt cephalic neural cell activity. The fetus is particularly sensitive to vitamin A toxicity during the period of organogenesis. 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, except with supplements and chronoic alcoholism, but excessive dietary intake of beta-carotene can lead to carotenodermia, which causes orange-yellow discoloration of the skin.

Smokers and chronic alcohol consumers have been observed to have increased risk of mortality due to lung cancer, esophageal cancer, gastrointestinal cancer and colon cancer. Hepatic (liver) injury been found in human and animal studies where consumption of alcohol is paired with high dose vitamin A and beta-carotene supplementation.

Researchers have succeeded in creating water-soluble forms of vitamin A, which they believed could reduce the potential for toxicity. However, a 2003 study found water-soluble vitamin A was approximately 10 times as toxic as fat-soluble vitamin. A 2006 study found children given water-soluble vitamin A and D, which are typically fat-soluble, suffer from asthma twice as much as a control group supplemented with the fat-soluble vitamins.

Vitamin A and derivatives in medical use

Retinyl palmitate
Retinyl palmitate
Retinyl palmitate, or vitamin A palmitate, is the ester of retinol and palmitic acid, with formula C36H60O2.Palmitate is the major component of palm oil...

 has been used in skin creams, where it is broken down to retinoic acid, which has potent biological activity, as described above.

The retinoid
Retinoid
The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth....

s, (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.

Pharmaceutics utilizing mega doses of naturally occurring retinoic acid derivatives are currently in use for cancer, HIV, and dermatological purposes. At high doses, side-effects are similar to vitamin A toxicity. Severe side effects related to vitamin A toxicity, and a small optimal range of use are key obstacles in developing vitamin A-derived pharmaceutics for therapeutic use.

Further reading


External links

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