What is the risk of chronic toxicity of vitamin A, especially in children?

Fråga: What is the risk of chronic toxicity of vitamin A, especially in children?

Sammanfattning: Chronic hypervitaminosis A may occur when excessive amounts of vitamin A are consumed over long periods of time. Judging from available clinical reports on vitamin A intake, there seems to be a large variability between individuals in the sensitivity to toxic effects. Important factors including dose, physical form of the vitamin, dietary factors and general health status probably account for some of this variability. The levels and duration of intake that may result in chronic hypervitaminosis are thus uncertain.

In children, symptoms of hypervitaminosis A are reported at doses from 1500 to more than 500000 IU/day depending on body size and weight.

Svar: The name vitamin A is applied to a number of substances of very similar structure (1).

Retinol, retinal (= vitamin A aldehyd) and retinoic acid (= vitamin A acid) are the biologically active forms (2). In food, vitamin A mainly occurs as esters and carotenes (= provitamins A such as beta-and alpha-carotene) which are converted into retinol (2,3). The most active substance is all-trans-retinol (1). Retinol is frequently used synonymously for vitamin A. Tretinoin is a natural metabolite of vitamin A and etretinate and isotretinoin are two new synthetic retinoids which are used mainly in dermatology (4).

Vitamin A and the carotenes are fat-soluble. Vitamin A is stored in the liver (90 per cent), and carotenes are mainly stored in fatty tissues (3). Vitamin A levels in blood are at their highest about four hours after a single oral dose (3). Retinol is bound to retinol-binding protein in plasma (alpha2-microglobulin) and the levels of vitamin A in serum must be correlated with this protein (2). Vitamin A is administered both orally and parenterally for therapeutic effect.

The requirement for vitamin A is regarded as being proportional to body weight (3). Recommended daily intake of vitamin A or its equivalent: boys and girls up to one year, 450 ug; one to six years, 300 ug; seven to eight years, 400 ug; boys and girls 9 to 17 years, 535 to 750 ug; men and women 18 years or over, 750 ug during pregnancy, 750 ug; during lactation, 1.2 mg (1). The actual requirement for most individuals, however, is lower.

The literature on vitamin A toxicity is mainly composed of several case reports. They have been analyzed and reviewed by 8, 10 and 12.

Reported incidences of vitamin A toxicity are rare and have averaged fewer than 10 cases per year from 1976 to 1987 (10). Hypervitaminosis A can be divided into two categories: acute, resulting from ingestion of a very high dose over a short period of time, and chronic, resulting from continuous ingestion of high doses for months or even years (10).

Chronic ingestion of high doses of retinol can produce toxic effects on the skin, bones, liver and the central nervous system (6). The main symptoms of chronic intoxication include malaise, gastrointestinal complaints, changes in the skin and mucous membranes, headache, tenderness and pain in bones and joints and fever (9).

In most cases, when the vitamin A intake is discontinued, most symptoms of hypervitaminosis A are relieved within a few days or a week. Irreversible effects include bone changes and liver cirrhosis (10).

Factors including dosing regimen, physical form of the vitamin, general health status, dietary factors such as ethanol and protein intake and influence of vitamins C, D, E and K (10), will all have an impact on whether intake of vitamin A will cause toxic effects.

Carotenoids in foods ingested chronically are not known to produce toxic manifestations because of their markedly reduced absorption at high doses and their relatively slow conversion rate to vitamin A in the intestine, liver and other organs (5). Therefore it might be advisable to distinguish between carotenoids, which are non- toxic, and vitamin A, which in substantial amounts, can be toxic (5). The intake of vitamin A in the United States is 624 RE (retinol equivalents, see below), which consists of 25 per cent carotenoids and 75 per cent preformed vitamin A (5).

Signs of toxicity usually appear only at chronic daily intakes from food or supplements exceeding 15 mg (50000 IU) in adults and 6 mg (20000 IU) in infants and young children according to one source (5). These doses cannot be obtained from foods except by chronic ingestion of significant amounts of liver particularly rich in vitamin A (5).

Similarly, another report (8) suggests that symptoms of chronic hypervitaminosis A can be expected after long-term (months to years) intake of 18000-60000 IU vitamin A by children and 50000-100000 IU vitamin A by adults. It was also suggested that the decisive factor in the development of clinical symptoms of hypervitaminosis A appears to be the variation in "vitamin A tolerance".

Liver damage induced by vitamin A is a special problem because it reduces the storage capacity of the organ and thus increases the risk of intoxication (8). Vitamin A toxicity in one study (10) was suggested to be uncommon at doses less than 100000 IU/day among adults. Among children chronic hypervitaminosis A appears to occur at doses in the range of 12000 to more than 500000 IU/day depending upon the size and weight of the child (10). In another report (12) adverse effects occurred with intakes as low as 1500 IU/kg/day in children. Furthermore, toxic effects have been reported (11) after daily intake of only 15 mg for a couple of years. It was therefore recommended (12) that the dose showed not exceed 7.5 mg/day.

FACTORS AND FORMULAS USED IN INTERCONVERTING UNITS OF VITAMIN A AND CAROTENOIDS: one retinol equivalent (RE) = one ug all-trans retinol; = 6 ug all-trans beta-carotene; = 12 ug other provitamin A carotenoids; = 3.33 IUa (i.e. the IU of vitamin A); = 10 IUc (i.e. the IU of provitamin A carotenoids). RE = ug retinol + ug beta- carotene/6.