Vitamin A - A Current Review

Significance of Vitamin A

In the past, many unexplained episodes of illness sprouted like ants on earth. Everyone was left aghast to the immemorial acts of blasphemy while some associated it with witchcrafts. On the other hand, there were few skeptical groups of scientists, trying to prove their worth that medical sciences are the absolute key to all their answers. Many had related the phenomenal diseases to the insightful germ theory of Pasteur but there was still something invaluable hidden deep inside the everyday food we consumed, mysterious and minute, yet awaiting for another noble discovery.

In 1906, Frederick Hopkins demonstrated that foods contain a small amount of “accessory factors” in addition to proteins, carbohydrates, fats, minerals and water that are essential to life. These factors were named “vitamine” by Cashmir Funk because they are vital (vita-) to life and that the compound he had isolated was an amine (-amine). The letter “e” was shortly dropped in view of further discoveries that the factors may well exist also from the non-amine group.

The discovery of vitamin A was paved by 2 independent research groups. In 1913, Lafayette Benedict Mendel and Thomas Burr Osborne demonstrated that rats fed with lard developed a nutritional deficiency that could be corrected by the addition of butter. Elmer Verner McCollum and Marguerite Davis reported similar observation with rats fed with ether extract of egg or butter. Their findings came to a common conclusion that there was trace amount of some fat-soluble organic substance in butter or egg that was essential to life which they called fat-soluble A. However it was later shown that fat-soluble A was actually a combination of 2 separate factors, one effective against xerophthalmia was named vitamin A while the other, effective against rickets, was termed vitamin D.

Nevertheless, the prevalence of vitamin A deficiency that manifests itself in the form of night blindness, xerophthalmia and increased mortality rate occurred long before the noble discovery. Although the deficiency disease was eliminated from the developed countries in the early 1940s through a variety of dietary interventions, the main concern revolves around the plight of the developing nations where the prevalence of vitamin A deficiency diseases is a common manifestation. It is approximated that about 250 000 to 500 000 malnourished children in the developing world go blind each year from a deficiency of vitamin A.

The widespread occurrence, especially in much of South and East Asia and parts of Africa and Latin America has been recognized by the WHO. In 1995, a monograph on the Global Prevalence of Vitamin A Deficiency (WHO, 1995) was published where classification based on subclinical and clinical deficiency in all parts of the world was highlighted. Subsequently, various dietary interventions have been carried out in coherent with the global concern to reduce the symptoms of vitamin A deficiency.

Nonetheless, in the eager attempts to prevent deficiencies, there is fear of overzealous consumption of vitamin A, principally from over the counter supplements. The toxicity of vitamin A although rare, is an issue to ponder due the systemic effects of the vitamin in the body. Today, with better understanding of the molecular mechanisms of vitamin A actions, a clearer picture of health may be ascertained in association with dietary intake, deficiency, toxicity and future treatment. Thus there is an imperative need for a review for public awareness and knowledge.

What is Vitamin A?

• The term vitamin A is generically used to describe compounds that exhibit the biological properties of retinol. Retinol belongs to the family of chemical compounds known as retinoids that include naturally occurring or synthetic analogs, with or without the biological activity of vitamin A. Physiologically occurring retinoids are characterized by the presence of a β-ionone ring, a polyene chain and a functional polar group at the end of the acyclic portion. Depending on the types of functional group, retinol (an alcohol) can be converted by the body into retinal (an aldehyde), retinoic acid (a carboxylic acid) and other active forms of vitamin A. The 4 conjugated double bonds in the polyene chain allow the formation of many different geometric isomers of retinol, retinal and retinoic acid. The cis isomers are generally less stable and can readily convert to the all-trans configuration.

Sources of Vitamin A

• Vitamin A is an essential nutrient because it cannot be synthesized de novo in the human body. Hence there is a need to obtain it from the diet. Dietary sources of vitamin A come mainly in 2 forms - preformed vitamin A in animal foods and provitamin A carotenoids from plant sources. Dietary sources of vitamin A readily in the form of retinol or its derivatives are termed preformed vitamin A. Nevertheless, it is usually the ester form of retinol (mainly retinyl palmitate) that is present in abundant amount in foods or tissues since this is the primary form of storage for vitamin A. Free retinol on the other hand, is chemically unstable while retinoic acid is not stored but is metabolized rapidly; thus they do not occur to any significant extent in foods. The richest sources of preformed vitamin A come from animal products, notably the liver where excess vitamin A is stored. Kidneys and other tissues where vitamin A is known to exert its main functions, such as the eyes and epithelial tissues, are secondary. Fat based products such as milk, butter, cheese and oils are good sources in view of the fat-soluble property of vitamin A.

• On the other hand, a different form of “vitamin A” exists in plants. It belongs to the family of compound known as carotenoids that usually display as orange or yellow coloration in nature. Over 600 carotenoids are found in nature but only more than 50 of them can be converted into vitamin A in the body, the latter of which, are termed provitamin A carotenoids. It should be noted that provitamin A carotenoid is not vitamin A in itself but is converted to retinol in the body to exert the properties of vitamin A. β-carotene, is the largest contributor to vitamin A activity while α-carotene, γ-carotene and cryptoxanthin contribute to a lesser extent. Lycopene, lutein and zeaxanthin on the other hand, are non-provitamin A carotenoids. Fruits and vegetables containing yellow, orange and dark green pigments are good sources of carotenoids. Dark green leafy vegetables are said to contain a higher amount of carotenoids as carotenoid content in chloroplasts is roughly proportional to the concentration of chlorophyll.

Vitamin A Deficiency

• Vitamin A deficiency (VAD) is one of the oldest recorded medical conditions since the ancient Egyptian some 3500 years ago. In the eighteenth and nineteenth centuries, the prevalence of night blindness and corneal destruction, usually in association with several systemic illnesses were recognized among children and infants in the developing countries where dietary sources of vitamin A are scarce. Poverty, the lack of nutritional varieties and improper dissemination of healthcare information are to be blamed. In fact, the tissue reserves of vitamin A are sufficiently enough and it requires only a long-term dietary deprivation (5-10 months) to induce deficiency. Hence, VAD is not an issue, unless there is an early deprivation or prolonged period of dietary deficiency especially among malnourished children in the rural areas or among adults experiencing chronic diseases.

• Children and infants are particularly at the verge of VAD because of their low immunity that renders them more susceptible to infection. Infection causes a reduced level of vitamin A whereas inadequate intake of vitamin A increases the chances of infections. Besides that, the increased demand for vitamin A among children and infants in the period of spurt growth places them more at risk of VAD. Similarly, pregnant and lactating mothers with low vitamin A intake may signify a threat to their infants. On the other hand where food supply is abundant, VAD may be prevalent especially in areas where white rice (lack of β-carotene) is the staple food.

• Apart from dietary deprivation of vitamin A, endogenous sources such as defects in the body’s physiology and transport of vitamin A are some of the contributory factors of VAD. Since vitamin A is fat soluble, any gastrointestinal diseases related to fat digestion and malabsorption such as cystic fibrosis, pancreatic insufficiency, cholestasis, sprue and inflammatory bowel disorder will greatly increase the risk of VAD. This includes also people who eat very low fat diets and those on cholesterol-lowering medications like cholestyramine and colestipol.

• Apart from that, parasitic infections by giardia lamblia, ascaris lumbricoides and ankylostoma duodenale have also been shown to reduce vitamin A absorption. Shigellosis, sepsis, pneumonia and prolonged rotavirus induced-diarrhea may cause increased urinary excretion of vitamin A. Patients with renal failure similarly, may experience urinary loss of vitamin A due to increased renal permeability and proteinuria that permit the loss of retinol-RBP-TTR. Decreased synthesis of RBP due to protein-energy malnutrition and zinc deficiency may impair retinol transport from liver to other tissues and thus deplete their supply of vitamin A. Liver cirrhosis and alcoholism may also affect the liver storage of vitamin A and its metabolism.

Hypervitaminosis A

• Although the concern of VAD strikes principally in the developing countries, at the present, there is a shift of paradigm over the fear of vitamin A toxicity to the developed nations, where food fortification and over-the-counter supplements are readily available and may be overused. Interventional programs aimed at reducing VAD on the other hand, may ironically instead, cause hypervitaminosis A with improper monitoring of the relevant dosage.

• Vitamin A toxicity occurs when the maximum limit for liver store of retinoid is exceeded. Normally, when the liver concentration of vitamin A rises above 70 µmol/kg, there is increased activity of the microsomal cytochrome P450-dependent enzyme that catalyzes the oxidation of excess retinoids to various polar metabolites for excretion in the urine and bile. The biliary excretion of retinol metabolites nevertheless, reaches a plateau at a relatively low level and successive increased intakes eventually lead to no further catabolism from the saturated microsomal pathway for excretion.

• Surplus vitamin A in due course enters the circulation as retinyl ester or retinol bound to albumin or incorporated into plasma lipoprotein rather than RBP. Uncontrolled uptake by various tissues causes systemic toxicity due to the molecular modulation activity of retinoic acid and the membrane lytic property of free retinol. Vitamin A in the form of β-carotene is only selectively converted into retinoid, and hence does not cause toxicity. Hypervitaminosis A in humans may be generally categorized as either acute or chronic. Acute toxicity is frequently due to rapid absorption with slow clearance after ingestion of a sufficiently high dose of vitamin A. Prolonged intake of substantially smaller doses on the contrary, may lead to chronic toxicity. This is further burdened by the fact that vitamin A has long biological half-life and tend to bioaccumulate.