Vitamin A

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Background

Vitamin A is a fat-soluble vitamin which helps maintain normal reproduction, vision and immune function. It comes in a number of forms (as retinol, retinal, retinoic acid or retinyl ester).

The term vitamin A is used in the context of dietary requirements to include provitamin A carotenoids that are dietary precursors of retinol. Of the many carotenoids in nature, several have provitamin A activity but food composition data are only readily available for a-carotene, ß-carotene and ß-cryptoxanthin. Preformed vitamin A is found only in animal-derived foods, whereas dietary carotenoids are found primarily in oils, fruits and vegetables.

Vitamin A intakes or requirements are generally expressed in terms of retinol equivalents (RE). One RE is defined as the biological activity associated with 1 µg of all-trans retinol. Although there is some ongoing discussion in the literature about the conversion rates for carotenes, 6 µg all-trans ß-carotene and 12 µg of a-carotene, ß-cryptoxanthin and other provitamin A carotenoids have been retained as the conversion figures as being equivalent to 1 RE. These traditional conversion rates align more with the sources of carotenes in the Australian and New Zealand diets. They are also in line with the most recent decision of the FAO, (FAO:WHO 2001) who concluded that the literature to date was insufficient to justify a change in conversion rates.

This table provides conversions for vitamin A measurements.
1 µg Retinol equivalent = 1 µg of all-trans retinol
  = 6 µg all-trans ß-carotene
  = 12 µg of a-carotene, ß-cryptoxanthin and other provitamin A carotenoids
1 International Unit (IU) retinol = 0.3 µg Retinol equivalents

Retinol is required for the integrity of epithelial cells throughout the body (Gudas et al 1994). Retinoic acid regulates the expression of various genes that encode structural proteins, enzymes, extracellular matrix proteins and retinol binding proteins and receptors. Retinoic acid plays an important role in embryonic development, particularly in the development of the spinal cord and vertebrae, limbs, heart, eye and ears (Morris-Kay & Sokolova 1996). It is also required to maintain differentiation of the cornea and conjunctiva, preventing xerophthalmia, as well as for photoreceptor rod and cone cells in the retina (Sommer & West 1996). The retinal form of vitamin A is also required by the eye to change light to neural signals for vision (Saari 1994). Retinol and its metabolites are necessary for maintenance of immune function (Katz et al 1987, Trechsel et al 1985, Zhao & Ross 1995).

An adequate supply of vitamin A also plays a role in preventing morbidity and mortality from infectious disease, particularly in children (Glasziou & Mackerras 1993). Infection and infestation can cause malabsorption of vitamin A (Mahalanabis et al 1979, Sivakumar & Reddy 1972, 1975). The matrix of foods eaten can affect the release of carotenoids from foods, however, processing of food (cutting up, cooking etc) greatly improves availability and thus absorption of carotenoids from foods (Micozzi et al 1992, Tang et al 2000, Torronen et al 1996). Some studies show improved absorption of carotenoids with increased fat intake (Jalal et al 1998, Reddy & Srikantia 1966, Roels et al 1963) but the data are not consistent (Borel et al 1997, Figuera et al 1969).

Positive interactions between iron or zinc status and vitamin A status have been reported in animal studies (Amine et al 1970, Rosales et al 1999) or within human population groups in developing countries (Bloem et al 1989) but the relevance to the Australia and New Zealand population is unclear. Deficiency can result in abnormal dark adaptation, followed by xerophthalmia but is uncommon in Australia and New Zealand. The New Zealand Children's Survey, 2002 (MOH 2003) did, however, state that a significant proportion of Pacific children and Maori males might be at risk of inadequate intakes. Chronically high levels of alcohol ingestion can negatively affect vitamin A status through an effect on the liver (Wang 1999).

Vitamin A status has been assessed using a variety of indicators including a dark adaptation test (Carney & Russell 1980), a pupillary response test (Stewart & Young 1989), plasma retinol concentration (Underwood 1984), total liver reserves by isotope dilution (Bausch & Rietz 1977, Furr et al 1989), relative dose response methods (Amedee-Manesme et al 1984, 1987, Loerch et al 1979, Mobarhan et al 1981) and/or immune function assessment (Butera & Krakowka 1986, Carman et al 1989, 1992, Cohen & Elin 1974, Friedman & Sklan 1989, Smith et al 1987). However, these methods have limitations in the context of setting EARs for the population. They are too specific (ie only related to visual outcomes), accurate only across a limited intake range or susceptible to confounding (FNB:IOM 2001).

The method used to set the EARs in the current document was thus based on an estimate of the amount of dietary vitamin A required to maintain a given body-pool size in well-nourished subjects (Olson 1987, FNB:IOM 2001). The modifications to this approach that were needed to determine requirements for specific age groups or for pregnancy and lactation are noted below.

Recommendations by life stage and gender

Infants

This table displays, for infants, the recommended vitamin A intake varies by age.
Age AI
0-6 months 250 µg/day of retinol (as retinyl esters)
7-12 months 430 µg/day of retinol equivalents (REs)

Rationale: The AI for 0-6 months of 250 µg retinol as retinyl esters is calculated from multiplying the average intake of breast milk (0.78 L/day) by the average concentration of retinol present as retinyl esters in human milk, 310 µg/L, (Canfield et al 2003) to give 242 µg retinol, and rounding up. It assumes no contribution from carotenes in breast milk. For 7-12 months, the equivalent calculation is average intake of breast milk (0.6 L/day) x concentration of retinol (310 µg/L) plus a contribution of 244 µg from complementary foods that includes some contribution from carotenes, giving an AI of 430 RE.

Children & adolescents

This table displays the recommended daily vitamin A intake for children and adolescents varies by age and gender.
Age EAR (as retinol equivalents) RDI (as retinol equivalents)
All    
1-3 yr 210 µg/day 300 µg/day
4-8 yr 275 µg/day 400 µg/day
Boys    
9-13 yr 445 µg/day 600 µg/day
14-18 yr 630 µg/day 900 µg/day
Girls    
9-13 yr 420 µg/day 600 µg/day
14-18 yr 485 µg/day 700 µg/day

Rationale: No data are available to estimate average requirement of children and adolescents. The computational method used by the US:Canadian DRI committee (FNB:IOM 2001) was adopted for setting the EAR. The RDI was set by using a CV for the EAR of 20% based on calculated half-life values for liver vitamin A and rounded to the nearest 100 µg.

Adults

This table displays the recommended daily vitamin A intake for adults varies by age and gender.
Age EAR (as retinol equivalents) RDI (as retinol equivalents)
Men    
19-30 yr 625 µg/day 900 µg/day
31-50 yr 625 µg/day 900 µg/day
51-70 yr 625 µg/day 900 µg/day
>70 yr 625 µg/day 900 µg/day
Women    
19-30 yr 500 µg/day 700 µg/day
31-50 yr 500 µg/day 700 µg/day
51-70 yr 500 µg/day 700 µg/day
>70 yr 500 µg/day 700 µg/day

Rationale: The computational approach of the US:Canadian DRI committee (FNB:IOM 2001) was adopted. This is based on the amount of dietary vitamin A required to maintain a given body-pool size in well-nourished subjects.

The formula used was: Average requirement = A x B x C x D x E x F where:

A = % body vitamin A stores lost per day when ingesting a vitamin A-free diet, B = minimum acceptable liver vitamin A reserve, C = liver weight:body weight ratio, D = reference weight for a specific age group and gender, E = ratio of total body:liver vitamin A reserves and F = efficiency of storage of ingested vitamin A. The RDI was set using a CV of 20% for the EAR, with rounding to the nearest 100 µg.

Pregnancy

The recommended daily intake of vitamin A during pregnancy varies depending on the age group.
Age EAR (as retinol equivalents) RDI (as retinol equivalents)
14-18 yr 530 µg/day 700 µg/day
19-30 yr 550 µg/day 800 µg/day
19-50 yr 550 µg/day 800 µg/day

Rationale: Direct studies are lacking. The model used to set the EAR is the US:Canadian DRI approach based on the accumulation of vitamin A in the liver of the foetus during gestation and an assumption that liver contains approximately 50% of the body's vitamin A when liver stores are low, as for newborns. The RDI was set on the basis of a CV of 20% for the EAR with rounding to the nearest 100 µg.

Lactation

This table contains vitamin A recommendations during lactation varying by age.
Age EAR (as retinol equivalents) RDI (as retinol equivalents)
14-18 yr 780 µg/day 1,100 µg/day
19-30 yr 800 µg/day 1,100 µg/day
19-50 yr 800 µg/day 1,100 µg/day

Rationale: An average of 250 µg/day retinol (AI for infants 0-6 months) is added to the EAR for non-pregnant adolescent girls and women. The RDI was set assuming a CV of 20% for the EAR, with rounding to the nearest 100 µg.

Upper level of intake

The table provides the Upper Levels (UL) of vitamin A intake for various age groups and life stages.
Age UL
Infants  
0-12 months 600 µg/day
Children and adolescents  
1-3 yr 600 µg/day
4-8 yr 900 µg/day
9-13 yr 1,700 µg/day
14-18 yr 2,800 µg/day
Adults 19+ yr  
Men 3,000 µg/day
Women 3,000 µg/day
Pregnancy  
14-18 yr 2,800 µg/day
19-50 yr 3,000 µg/day
Lactation  
14-18 yr 2,800 µg/day
19-50 yr 3,000 µg/day

Rationale: The UL is set based on causality, quality and completeness of available data. The critical adverse event used for women of childbearing age was teratogenicity and for other adults it was liver abnormalities, notably abnormal liver pathology (FNB:IOM 2001). For infants, reports of hypervitaminosis A were used to derive the UL. There was a paucity of evidence for children and adolescents, so the UL was determined by extrapolation from adult data on the basis of relative body weight.

Those with high alcohol intake, pre-existing liver disease, hyperlipidaemia or severe protein malnutrition may be particularly susceptible to excess intake of preformed vitamin A and may not be protected by the UL for the general population.

Upper level of intake beta-carotene

The UL for ß-carotene cannot be established for supplemental use and does not need to be established for food use.

Rationale: Although ß-carotene is a precursor of vitamin A, excess intake has not been associated with vitamin A toxicity in humans as the metabolic conversion of ß-carotene is regulated by vitamin A status. Beta-carotene is of low toxicity in both animals and humans. Until recently, ß-carotene was thought to be without adverse effect other than a yellowing of the skin that occurred after sustained high intake. However, human studies in the 1990s have indicated that excess intake through supplements (20 mg/day or more) by smokers and subjects previously exposed to asbestos has been associated with an increased risk of lung cancer (ATBC trial 1994, Omenn et al 1996). However, there is insufficient scientific basis to set a precise figure for an UL for ß-carotene, as no dose-response relationship for the observed effects is available either from the intervention trials in humans or from appropriate animal models (FNB:IOM 2000, European Commission 2000).

In conclusion, there is insufficient evidence to establish a UL for ß-carotene for supplemental use, but high intakes can cause yellowing of the skin and may be harmful to smokers. A UL for ß-carotene from food does not need to be established, based on an absence of adverse effects.

References

Amedee-Manesme O, Anderson D, Olson JA. Relation of the relative dose response to liver concentrations of vitamin A in generally well nourished surgical patients. Am J Clin Nutr 1984;39:898-902.

Amedee-Manesme O, Mourey MWS, Hanck A, Therasse J. Vitamin A relative dose response test: validation by intravenous injection in children with liver disease. Am J Clin Nutr 1987;46:286-9.

Amine EK, Corey J, Hegsted DM, Hayes KC. Comparative hematology during deficiencies of iron and vitamin A in the rat. J Nutr 1970;100:1033-40.

ATBC (Alpha-tocopherol, Beta-carotene) Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-35.

Bausch J, Rietz P. Method for the assessment of vitamin A liver stores. Acta Vitaminol Enzymol 1977;31:99-112.

Bloem MW, Wedel M, Egger RJ, Speek AJ, Schrijver J, Saowakontha S, Scheurs WH. Iron metabolism and vitamin A deficiency in children in northeast Thailand. Am J Clin Nutr 1989;50:332-8.

Borel P, Dubois C, Mekki N, Grolier P, Partier A, Alexander-Gouabau MC, Lairon D, Azais-Braesco V. Dietary triglycerides, up to 40g/meal, do not affect preformed vitamin A bioavailability in humans. Eur J Clin Nutr 1997;51:717-72.

Butera ST, Krakowka S. Assessment of lymphocyte function during vitamin A deficiency. Am J Vet Res 1986;47:850-5.

Canfield LM, Clandinin MT, Davies DP, Fernandez MC, Jackson J, Hawkes J, Goldman WJ, Pramuk K, Reyes H, Sablan B, Sonobe T, Bo X. Multinational study of major breast milk carotenoids of healthy mothers. Eur J Nutr 2003;42:133-41.

Carman JA, Smith SM, Hayes CE. Characterisation of a helper T-lymphocyte defect in vitamin A deficient mice. J Immunol 1989;142:388-93.

Carmen JA, Pond L, Nashold F, Wassom DL, Hayes CE. Immunity to Trichinella spiralis infection in vitamin A-deficient mice. J Exp Med 1992;175:111-20.

Carney EA, Russell RM. Correlation of dark adaptation test results with serum vitamin A levels in diseased adults. J Nutr 1980;110:552-7.

Cohen BE, Elin RJ. Vitamin A-induced non-specific resistance to infection. J Infect Dis 1974;129:597-600.

European Commission Scientific Committee on Food. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Beta Carotene (expressed on
19 October 2000). Brussels: European Commission, 2000.

Figuera FF, Mendonca S, Rocha J, Azvedo M, Bunce GE, Reynolds JW. Absorption of vitamin A by infants receiving fat-free or fat-containing dried skim milk formulas. Am J Clin Nutr 1969;22:588-93.

Food and Agricultural Organization of the United Nations: World Health Organization. Human vitamin and mineral requirements. Report of a joint FAO:WHO expert consultation. Bangkok, Thailand. Rome: Food and Agricultural Organization of the United Nations, 2001.

Food and Nutrition Board: Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids, Washington, DC: National Academy Press, 2000.

Food and Nutrition Board: Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington DC: National Academy Press, 2001.

Friedman A. Sklan D. Impaired T lymphocyte immune response in vitamin A depleted rats and chicks. Br J Nutr 1989;623:439-49.

Furr HC, Amedee-Manesme O, Clifford AJ, Bergen HR, Jones AD, Anderson LD, Olson JA. Vitamin A concentrations in liver determined by isotope dilution assay with tetradeuterated vitamin A and by biopsy in generally healthy adult humans. Am J Clin Nut 1989;49:713-6.

Glasziou PP, Mackerras DE. Vitamin A supplementation in infectious diseases: a meta-analysis BMJ 1993;306:366-70.

Gudas LJ, Sporn MB, Roberts AB. Cellular biology and biochemistry of the retinoids. In: Sporn MB, Roberts AB, Goodman DS, eds. The retinoids: biology, chemistry and medicine, 2nd edition. New York: Raven Press, 1994. Pp 443-520.

Jalal F, Nesheim MC, Agus Z, Sanjur D, Habicht JP. Serum retinol concentrations in children are affected by food sources of beta-carotene, fat intake and anthelmintic drug treatment. Am J Clin Nutr 1998;68:623-9.

Katz DR, Drzymala M, Turton JA, Hicks RM, Hunt R, Palmer L, Malkovsky M. Regulation of accessory cell function by retinoids in murine immune responses. Br J Exp Pathol 1987;68:343-50.

Loerch JD, Underwood BA, Lewis KC. Response of plasma levels of vitamin A to a dose of vitamin A as an indicator of hepatic vitamin A reserves in rat. J Nutr 1979;109:
778-86.

Mahalanabis D, Simpson TW, Chakraborty ML, Ganguli C, Bhattacharjee AK, Mukherjee KL. Malabsorption of water miscible vitamin A in children with giardiasis and ascariasis. Am J Clin Nutr 1979;32:313-8.

Micozzi MS, Brown ED, Edwards BK, Biewi JG, Taylor PR, Khachik F, Beecher GR, Smith JC. Plasma carotenoid response to chronic intake of selected foods and beta-carotene supplements in men. Am J Clin Nutr 1992;55:1120-5.

Ministry of Health. NZ Food: NZ Children. Key results of the 2002 national children's nutrition survey. Wellington: Ministry of Health, 2003. Pp 32.

Mobarhan S, Russell RM, Underwood BA, Wallingford J, Mathieson RD, Al-Midani H. Evaluation of the relative dose response test for vitamin A nutriture in cirrhotics. Am J Clin Nutr 1981;34:2264-70.

Morris-Kay GM, Sokolova N. Embryonic development and pattern formation. FASEB J 1996;10:961-8.

Olson JA. Recommended dietary intakes (RDI) of vitamin A in humans. Am J Clin Nutr 1987;45:704-16.

Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keough JP, Meyskens FL Jnr, Valanis B, Williams JH Jnr, Barnhart S, Cherniack, MG, Brodkin CA, Hammar S. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88:1550-9.

Reddy V, Srikantia SG. Serum vitamin A in kwashiorkor. Am J Clin Nutr 1966;18:105-9.

Roels OA, Djaeni S, Trout ME, Lauw TG, Heath A, Poey SH, Tarwotjo MS, Suhardi B. The effect of protein and fat supplements on vitamin A deficient children. Am J Clin Nutr 1963;12:380-7.

Rosales FJ, Jang JT, Pinero DJ, Erikson KM, Beard JL, Ross AC. Iron deficiencies in young rats alter the distribution of vitamin A between plasma and liver and between hepatic retinol and retinyl esters. J Nutr 1999;129:1223-8.

Saari JC. Retinoids in photosensitive systems. In; Sporn MB, Roberts AB, Goodman DS eds. The retinoids; biology, chemistry and medicine, 2nd edition. New York: Raven Press,1994. Pp 351-85.

Sivakumar B, Reddy V. Absorption of labelled vitamin A in children during infection. Br J Nutr 1972;27:299-304.

Sivakumar B, Reddy V. Absorption of vitamin A in children with ascariasis. J Trop Med Hyg 1975;78:114-5.

Smith SM, Levey NL, Hayes CE. Impaired immunity in vitamin A-deficient mice. J Nutr 1987;117:857-65.

Sommer A, West KP Jr. Vitamin A deficiency: health, survival and vision. New York: Oxford University Press, 1996.

Stewart BE, Young S. Pupillary response: an index of visual threshold. Appl Optics 1989;28:1122-7.

Tang G, Qin J, Dolnokowski GG, Russell RM. Vitamin A equivalence of beta-carotene in a woman as determined by a stable isotope reference method. Eur J Nutr 2000;39:7-11.

Torronen B, Lehmusaho M, Hakkinen S, Hanninen O, Mykkanen H. Serum beta-carotene response to supplementation with raw carrots, carrot juice or purified beta-carotene in healthy, non smoking women. Nutr Res 1996;16:565-75.

Trechsel U, Evenquoz V, Fleisch H. Stimulation of interleukin 1 and 3 production by retinoic acid in vitro. Biochem J 1985;230:339-44.

Underwood BA. Vitamin A in animal and humans and human nutrition. In: Sporn MB, Roberts AB, Goodman DS, eds. The retinoids, Vol 1.New York: Academic Press, 1984. Pp 281-392.

Wang XD. Chronic alcohol intake interferes with retinoid metabolism and signalling. Nutr Res 1999;57:51-9.

Zhao Z, Ross AC. Retinoic acid repletion restores the number of leukocytes and their subsets and stimulates natural cytotoxicity in vitamin A-deficient rats. J Nutr 1995;125:
2064-73.