Vitamin A

Vitamin A crystals

Retinol; axerophthol.

Figure 1: Chemical formula of retinol (vitamin A)

Vitamin A, a fat-soluble vitamin, occurs in two principal forms in nature: retinol, which is found only in animal sources, and certain carotenoids (provitamins), which are found only in plant sources. Carotenoids are the compounds that give many fruits and vegetables their yellow and orange colour. The most abundant and best known of the carotenoids is beta-carotene. Beta-Carotene is a precursor of vitamin A, or "provitamin A", because its vitamin A activity occurs only upon conversion to retinol within the body. One molecule of beta-carotene can be cleaved by a specific intestinal enzyme into two molecules of vitamin A (Figure 2). Foods rich in beta-carotene include carrots, yellow and dark green leafy vegetables (e.g. spinach, broccoli), pumpkin, apricots and melon. Preformed vitamin A or retinol is found in liver, egg yolk, fish, whole milk, butter and cheese.

Vitamin A is stored in the liver; stores are enough for one to two years in most adults living in industrialized countries.

Until recently, vitamin A activity in foods was expressed as international units (IU). This is still the measurement generally used on food and supplement labels. However, it is difficult to calculate the total vitamin A activity in the diet in terms of IU, because both the absorption and conversion of carotenoids, as compared with retinol, are variable. In order to standardize vitamin A measurement, it has now been internationally agreed to state vitamin A activity as a new unit called retinol equivalents or RE. By definition, one retinol equivalent is equal to:

1 RE = 1 µg retinol

1 RE = 6 µg beta-carotene

1 RE = 12 µg other provitamin A carotenoids

1 RE = 3.33 IU vitamin A activity from retinol

1 RE = 10 IU vitamin A activity from beta-carotene

Vitamin A is sensitive to oxidation by air. Loss of activity is accelerated by heat and exposure to light. Oxidation of fats and oils (e.g. butter, margarine, cooking oils) can destroy fat soluble vitamins including vitamin A. The presence of antioxidants such as vitamin E contributes to the protection of vitamin A. beta-Carotene is one of the more stable vitamins in vegetables. Cooking losses of 25% have been documented, but only after boiling for a comparatively long period.

A number of factors can influence vitamin A status, including the following:

• Disease and infection, especially measles, compromise vitamin A status and conversely, poor vitamin A status decreases resistance to diseases
• Chronic heavy alcohol intake can impair liver storage of vitamin A
• Acute protein deficiency interferes with vitamin A metabolism; similarly, too little fat in the diet interferes with the absorption of both vitamin A and carotenoids
• Alterations in iron metabolism occur in association with vitamin A deficiency, sometimes resulting in anaemia
• Vitamin E protects vitamin A from being oxidized; hence, adequate vitamin E status protects vitamin A status.

Vitamin A is essential for vision, for adequate growth and for tissue differentiation.

Vision
Light-receptor visual cells called "rods" in the retina of the eye enable us to distinguish between light and dark. These cells contain a light-sensitive pigment called visual purple (rhodopsin), which is a complex of the protein opsin and vitamin A. When a rod cell is exposed to light, the visual purple disintegrates, releasing electrical charges to the brain. These stimuli are then translated into a composite picture which we "see." At the same time, new rhodopsin is formed in the visual cells from opsin and vitamin A. Thus, vitamin A acts as a sensor of light.

Growth
Vitamin A plays an important role in normal growth and development, quite apart from its role in maintaining vision. One of the primary signs of vitamin A deficiency in animals is loss of appetite, accompanied by retardation of growth.

Tissue differentiation
The many different types of cells in the body perform highly specialized functions. The process whereby cells and tissues become "programmed" to carry out their special functions is called differentiation. Vitamin A is necessary for normal differentiation of epithelial cells, the cells of all the tissues lining the body, such as skin, mucous membranes, blood vessel walls and the cornea. In vitamin A deficiency, cells lose their ability to differentiate properly.

Glycoproteins
Retinal can be phosphorylated and the resulting retinyl phosphate will reversibly bind mannose, which is used in the synthesis of glycoproteins. Vitamin A deficient animals produce abnormal glycoproteins.

One of the earliest symptoms of vitamin A deficiency is night blindness or an impaired ability to see in dim light. Severe deficiency produces partial or total blindness, a condition called xerophthalmia.

The appearance of skin lesions (follicular hyperkeratinosis) has also been used as an early indicator of inadequate vitamin A status. Vitamin A deficiency is by far the most widespread and the most serious among young children, especially in impoverished countries. It is the leading cause of childhood blindness and, in combination with other factors such as protein-calorie malnutrition and increased incidence of infections, is associated with high rates of child mortality.

In children with xerophthalmia, concurrent problems such as stunted growth, respiratory diseases, diarrhoea, parasitic and infectious diseases are common. Diseases themselves may induce vitamin A deficiency, most notably liver and gastrointestinal diseases which interfere with the absorption and utilization of vitamin A. It is currently believed that poor vitamin A status may also be involved in the development of cancer, although the precise mechanisms are not yet known.

Child with xerophthalmia in the left eye

For more information, see the Sight and Life web site.

Humans rely on their food intake to cover their vitamin A requirements. The RDA for adults in the USA is 1000 RE for men and 800 RE for women. During lactation, additional 400-500 RE per day are recommended, respectively. Infants and children, due to their smaller body size, have a lower RDA than adults.

Vitamin A is available in soft gelatine capsules, as chewable or effervescent tablets or in ampoules. It is also included in most multivitamins.

Therapeutic doses of vitamin A are distributed in targeted areas of the world to prevent xerophthalmia and to treat those in whom the early stages of blindness have already occurred.

Since vitamin A can be stored in the liver, it is possible to build up a reserve in children by administration of high-potency doses. The standard therapeutic dose currently used for children is 200 000 IU, given orally either in liquid or capsule from two to three times a year. The capsule also contains 40 IU of vitamin E, to facilitate absorption of vitamin A. Administration of 400 000 IU of vitamin A to children with measles complications, but no overt signs of vitamin A deficiency, decreased mortality by over 50% and significantly lowered morbidity.

The age range of the target population for vitamin A intervention programs is usually from birth to seven years. Xerophthalmia is characteristically a disease of children aged six months to three years. In regular periodic distribution programmes, a half dose (100 000 IU) is given to children between six months and one year. A single dose of 200 000 IU given to mothers immediately after delivery of their child has been found to increase the vitamin A content of breast milk. When considering vitamin A therapy in lactating women, caution is necessary since a co-existing pregnancy may be endangered. In pregnancy daily administration of vitamin A of 10 000 IU should not be exceeded.

Because vitamin A (as retinol) is stored in the liver, large amounts taken over a long period of time can eventually exceed the liver's storage capacity, spill into the blood and produce adverse effects. Thus, there is a concern about the safety of high intakes of preformed vitamin A (retinol), especially in infants, small children and women of childbearing age.

Field experience with nutrition intervention programmes in countries where vitamin A deficiency is prevalent indicates that single oral doses of 200 000 IU in children and 400 000-500 000 IU in adults are safe. However, it must be remembered that these are prophylactic doses, given at quite high levels in order to replenish diminished body stores for at least six months. In well-nourished people, vitamin A toxicity can occur acutely following very high doses (over 500 000 IU) taken over a period of a few days, or as a chronic condition from high doses (over 50 000 IU) taken over a long period of time. Generally, intakes of up to 10 times the RDA are considered safe.

Current levels of vitamin A in fortified foods are based on RDA levels, assuring that there is no reasonable possibility of vitamin A overdosage in the population. In the vast majority of cases, signs and symptoms of toxicity are reversible upon cessation of vitamin A intake.

Beta-carotene is considered a safe form of vitamin A because the body converts it only as needed. Beta-carotene is poorly absorbed from the gastrointestinal tract, and its conversion to retinol becomes progressively less efficient as vitamin A status improves. High intakes (over 30 mg/d) of beta-carotene, however, may result in an orange-yellow coloration of the skin, which is reversible upon cessation of beta-carotene intake.

Nowadays vitamin A is rarely extracted from fish liver oil. The modern method of industrial synthesis of nature-identical vitamin A is a highly complex, multistep process.

Margarine and milk are commonly fortified with vitamin A. beta-Carotene is added to margarine and many other foods (e.g. fruit drinks, salad dressings, cake mixes, ice cream) both for its vitamin A activity and as a natural food colourant.

Although it has been known since the time of ancient Egypt that certain foods would cure night blindness, vitamin A per se was not identified until 1913. Its chemical structure was defined by Paul Karrer in 1931. Professor Karrer received a Nobel Prize for his work, because this was the first time that a vitamin structure was determined.

1831: Wackenroder isolates the orange-yellow colourant from carrots and names it "carotene"

1876: Snell is able to demonstrate that night blindness and xerophthalmia can be cured by giving the patient cod liver oil

1880: LuAnn discovers that besides needing carbohydrates, fats and proteins, experimental animals can only survive if given small quantities of milk powder

1887: Arnaud describes the widespread presence of carotenes in plants

1909: Stepp is able to extract the vital liposoluble substance from milk

1915: McCollum differentiates between "fat soluble N' and "water soluble B"

1929: The vitamin A activity of beta-carotene is demonstrated in animal experiments

1931: Karrer isolates practically pure retinol from the liver oil of a mackerel species. Karrer and Kuhn isolate active carotenoids

1946: Isler undertakes the first large-scale industrial synthesis of vitamin A

1984: Sommer demonstrates in Indonesia that vitamin A deficiency is a major cause of infant mortality