Vitamin A

Introduction

Vitamin A is a generic term for a group of lipid soluble compounds related to retinol. Retinol is often referred to as preformed vitamin A. It is found only in animal sources, mainly as retinyl esters and in food supplements. Many cultures have used ox liver as an excellent source of vitamin A to cure night blindness. The liver was first pressed to the eye and then eaten; the Egyptians described this cure at least 3,500 years ago. Beta-carotene and other carotenoids that can be converted to vitamin A by an enzymatic process in the body are referred to as provitamin A. They are found only in plant sources.

Functions

Retinal, the oxidised metabolite of retinol, is required for the process of vision. Retinoic acid, another vitamin A metabolite, is considered to be responsible for all non-visual functions of vitamin A. Retinoic acid combines with specific nuclear receptor proteins which bind to DNA and regulate the expression of various genes, thereby influencing numerous physiological processes. Retinoic acid is therefore classified as a hormone.

Vision

Receptor cells in the retina of the eye (rod cells) contain a light-sensitive pigment called rhodopsin, which is a complex of the protein opsin and the vitamin A metabolite retinal. The light-induced disintegration of the pigment triggers a cascade of events which generate an electrical signal to the optic nerve. Rhodopsin can only be regenerated from opsin and vitamin A. Rod cells with this pigment can detect very small amounts of light, making them important for night vision.

Cellular differentiation

The many different types of cells in the body perform highly specialised functions. The process whereby cells and tissues become “programmed” to carry out their special functions is called differentiation. Through the regulation of gene expression, retinoic acid plays a major role in cellular differentiation. Vitamin A is necessary for normal differentiation of epithelial cells, the cells of all 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.

Growth and development

Retinoic acid plays an important role in reproduction and embryonic development, particularly in the development of the spinal cord and vertebrae, limbs, heart, eyes and ears.

Immune function

Vitamin A is required for the normal functioning of the immune system and therefore helps to protect against infections in a number of ways. It is essential in maintaining the integrity and function of the skin and mucosal cells, which function as a mechanical barrier and defend the body against infection. Vitamin A also plays a central role in the development and differentiation of white blood cells, such as lymphocytes, killer cells and phagocytes, which play a critical role in the defence of the body against pathogens.

Dietary sources

The richest food source of preformed vitamin A is liver, with considerable amounts also found in egg yolk, whole milk, butter and cheese. Provitamin A carotenoids are found in carrots, yellow and dark green leafy vegetables (e.g. spinach, broccoli), pumpkin, apricots and melon.

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. In order to standardise vitamin A measurement, it has now been internationally agreed to state vitamin A activity in terms of a new unit called the retinol equivalent, or RE, which accounts for the rate of conversion of carotenoids to retinol.

Absorption and body stores

Vitamin A is absorbed in the upper part of the small intestine. Provitamin A carotenoids can be cleaved into retinol via an enzymatic process. Preformed vitamin A occurs as retinyl esters of fatty acids. They are hydrolysed and retinol is absorbed into intestinal mucosal cells (i.e. enterocytes). After re-esterification it is incorporated into chylomicrons, excreted into lymphatic channels, delivered to the blood and transported to the liver.

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

Measurement

Vitamin A can be measured in the blood and other body tissues

by various modern techniques. For rapid field tests, a method has been developed recently using dried blood spots. Typical serum level is 1.1-2.3 µmol/L. According to the WHO, plasma levels of # 0,35 µmol/L indicate a vitamin A deficiency.

Stability

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 therefore contributes to the protection of vitamin A.

Interactions

Positive interactions

• Vitamin E protects vitamin A from being oxidised; hence, adequate vitamin E status protects vitamin A status.

Negative interactions

• 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.
• Vitamin A deficiency may result in impaired iron absorption and decrease its utilisation for erythropoiesis, thereby potentially exacerbating iron deficiency anaemia.
• Zinc deficiency may adversely affect mobilisation of vitamin A from hepatic stores and absorption of vitamin A from the gut.

Deficiency

Vitamin A deficiency is rare in the Western world, but in developing countries it is one of the most widespread, yet preventable, causes of blindness. The earliest symptom of vitamin A deficiency is impaired dark adaptation, or night blindness. Severe deficiency causes a condition called xerophthalmia, characterised by changes in the cells of the cornea that ultimately result in corneal ulcers, scarring and blindness. The appearance of skin lesions (follicular hyperkeratosis) is also an early indicator of inadequate vitamin A status. Growth retardation is a common sign in children. Because vitamin A is required for the normal functioning of the immune system, even children who are only mildly deficient in vitamin A have a higher incidence of respiratory disease and diarrhoea, as well as a higher rate of mortality from infectious diseases, than children who consume sufficient vitamin A.

Some diseases may themselves induce vitamin A deficiency, most notably liver and gastrointestinal diseases, which interfere with the absorption and utilisation of vitamin A.

Vitamin A deficiency during pregnancy leads to malformations during foetal development.

Disease prevention and therapeutic use

Studies have shown that vitamin A supplementation given to children aged over 6 months reduces all-cause mortality by between 23% and 30% in low income countries. The beneficial effect is assumed to be due to the prevention of vitamin A deficiency. The World Health Organisation (WHO) recommends that supplements should be given when children are vaccinated. The currently recommended doses are 100,000 IU at age  6-11 months and 200,000 IU at age $ 12 months every 3-6 months. Xerophthalmia is treated with high doses of vitamin A (50,000-200,000 IU according to age).

In developing countries, where vitamin A deficiency is one of the most serious health problems, children under the age of 6 years and pregnant and lactating women are the main vulnerable groups. 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. In regular periodic distribution programmes for the prevention of vitamin A deficiency, infants < 6 months of age receive a dose of 50,000 IU of vitamin A, and children between six months and one year receive 100,000 IU every 4-6 months, while children > 12 months of age receive 200,000 IU every 4-6 months. 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. However, caution is necessary when considering vitamin A therapy for lactating women, otherwise a co-existing pregnancy may be endangered: during pregnancy, a daily dose of 10,000 IU vitamin A should not be exceeded.

Administration of high doses of vitamin A to children with measles complications, but no overt signs of vitamin A deficiency, decreases mortality by over 50% and significantly lowers morbidity.

Natural and synthetic vitamin A analogues have been used to treat psoriasis and severe acne.

Recommended Dietary Allowance (RDA)

The recommended daily intake of vitamin A varies according to age, sex, risk group and other criteria applied in individual countries (700–1000 µg RE/day for men, 600–800 µg RE/day for women. In the USA the RDA for adults is 900 µg (men) and 700 µg (women) per day of preformed vitamin A (retinol). During lactation, an additional 500–600 µg per day are recommended. Infants and children, due to their smaller body size, have a lower RDA than adults.

Safety

Because vitamin A (as retinyl ester) is stored in the liver, large amounts taken over a period of time can eventually exceed the liver's storage capacity, spill into the blood, and produce adverse effects (liver damage, bone abnormalities and joint pain, alopecia, headaches, vomiting, and skin desquamation). Hypervitaminosis A can occur acutely following very high doses taken over a period of several days, or as a chronic condition from high doses taken over a long period of time. Thus, there is concern about the safety of high intakes of preformed vitamin A (retinol), especially for infants, small children, and women of childbearing age.

Normal foetal development requires sufficient vitamin A intake, but consumption of excess retinol during pregnancy is known to cause malformations in the newborn.

Several recent prospective studies suggest that long-term intakes of preformed vitamin A in excess of 1,500 µg/day are associated with increased risk of osteoporotic fracture and decreased bone mineral density in older men and women. Only excess intakes of preformed vitamin A, not beta-carotene, were associated with adverse effects on bone health. Current levels of vitamin A in fortified foods are based on RDA levels, ensuring that there is no realistic possibility of vitamin A overdosage in the general 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 it is converted by the body only as needed.

The Food and Nutrition Board of the Institute of Medicine (2001) and the EC Scientific Committee on Food (2002) have set the tolerable upper intake level (UL) of vitamin A intake for adults at 3000 µg RE/day with appropriately lower levels for children.

Supplements and food fortification

Vitamin A is available in soft gelatine capsules, as chewable or effervescent tablets, or in ampoules. It is also included in most multivitamins. Retinyl acetate, retinyl palmitate and retinal are the forms of vitamin A most commonly used in supplements.

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.

Industrial production

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, multi-step process.

History

» History of Vitamin A