Vitamin A

(USAN)
Vitamin A Chemical formula
Synonyms: Retinol tamin; Axerophtholum; Oleovitamin A; Rétinol; Retinolum; Vitamin A Alcohol; Vitaminas A; Vitamine A; Vitaminum A; Witamina A. 15-Apoclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol.
Cyrillic synonym: Ретинол.

💊 Chemical information

Chemical formula: C20H30O = 286.5.
CAS — 68-26-8.
ATC — A11CA01; D10AD02; R01AX02; S01XA02.
ATC Vet — QA11C A01; QD10AD02; QR01AX02; QS01XA02.

BP 2008

). It is a liquid form (water is generally used as solvent) of synthetic retinol ester and a suitable solubiliser. It contains not less than 100 000 units of vitamin A per g. It is a yellow or yellowish liquid of variable opalescence and viscosity. Highly concentrated solutions may become cloudy at low temperatures or take the form of a gel. A mixture of 1 g with 10 mL of water previously warmed to 50° gives after cooling to 20°, a uniform, slightly opalescent and slightly yellow dispersion. Store in airtight containers. Protect from light. Once the container has been opened, its contents should be used as soon as possible and any part of the contents not used at once should be protected by an atmosphere of inert gas.

BP 2008

(Natural Vitamin A Ester Concentrate). It consists of a natural ester or a mixture of natural esters of retinol or of a solution of the ester or mixture of esters in arachis oil or other suitable vegetable oil. It contains not less than 485 000 units of vitamin A per g. It is a yellow oil or a mixture of oil and crystalline material, with a faint odour. Practically insoluble in water; soluble or partly soluble in alcohol; miscible with chloroform, with ether, and with petroleum spirit. Store in airtight containers at 8° to 15°. Protect from light.

USP 31

(Vitamin A). It may consist of retinol or its esters formed from edible fatty acids, principally acetic and palmitic acids. In liquid form, it is a light yellow to red oil that may solidify upon refrigeration. In solid form, has the appearance of any diluent that has been added. It may be practically odourless or may have a mild fishy odour but no rancid odour or taste. It is unstable in air and light. In liquid form, it is insoluble in water and in glycerol; soluble in dehydrated alcohol and in vegetable oils; very soluble in chloroform and in ether. In solid form, may be dispersible in water. Store in airtight containers, preferably under an atmosphere of inert gas. Protect from light.

💊 Units

The International Standards for vitamin A and for provitamin A were discontinued in 1954 and 1956 respectively but the International units for these substances have continued to be widely used. In 1960–1, the WHO Expert Committee on Biological Standardization stated that the International unit for vitamin A is equivalent to the activity of 0.000344 mg of pure alltrans vitamin A acetate and the International unit for provitamin A is equivalent to the activity of 0.0006 mg of pure all-trans β-carotene. The activity of one International unit is contained in 0.0003 mg of all-trans retinol, in 0.00055 mg of alltrans retinol palmitate, and in 0.000359 mg of all-trans retinol propionate. The USP 31 defines 1 USP unit as equal to the biological activity of 0.0003 mg of the all-trans isomer of retinol, and is equivalent to the International unit. Vitamin A activity in foods is currently expressed in terms of retinol equivalents: 1 retinol equivalent is defined as 1 microgram of all-trans retinol, 6 micrograms of all-trans beta carotene, or 12 micrograms of other provitamin A carotenoids.

💊 Adverse Effects and Precautions

The use of excessive amounts of vitamin A substances over long periods can lead to toxicity. Rarely, acute toxicity may also occur with very high doses.
Hypervitaminosis A (chronic toxicity) is characterised by fatigue, irritability, anorexia and loss of weight, vomiting and other gastrointestinal disturbances, low-grade fever, hepatomegaly, skin changes (yellowing, dryness, sensitivity to sunlight), pruritus, alopecia, dry hair, cracking and bleeding lips, anaemia, headache, hypercalcaemia, subcutaneous swelling, nocturia, and pains in bones and joints. Symptoms of chronic toxicity may also include raised intracranial pressure and papilloedema mimicking brain tumours, and visual disturbances which may be severe. Symptoms usually clear on withdrawal of vitamin A, but in children premature closure of the epiphyses of the long bones may result in arrested bone growth.
Acute vitamin A intoxication is characterised by sedation, dizziness, confusion, diarrhoea and vomiting, sore mouth, bleeding gums, desquamation, and increased intracranial pressure (resulting in bulging fontanelle in infants or severe headache in adults). Hepatomegaly and visual disturbances may occur; irritability may be severe.
Hypervitaminosis A does not appear to be a problem with large doses of carotenoids. Enhanced susceptibility to the effects of vitamin A may be seen in children and in patients with liver disease. Excessive doses of vitamin A should be avoided in pregnancy because of potential teratogenic effects; for further details see Pregnancy, below. Gastrointestinal absorption of vitamin A may be impaired in cholestatic jaundice and fat-malabsorption conditions.

Benign intracranial hypertension.

High doses of vitamin A cause increased intracranial pressure, and, in infants, this is manifested as bulging of the fontanelle. In one study,1 11.5% of infants receiving 3 doses of 50 000 units of vitamin A at monthly intervals had bulging fontanelle, compared with 1% of infants receiving placebo. The bulging lasted between 24 and 72 hours and subsided without treatment,1 and did not appear to be associated with any physical or developmental abnormalities on long-term follow-up.2 In another study in neonates, bulging fontanelle occurred in 4.6% of recipients of vitamin A 50 000 units and 2.7% of placebo recipients 24 hours after the dose.3 In contrast, less than 1% of infants given 3 doses of 25 000 units of vitamin A at monthly intervals had bulging fontanelle in a further study.4
1. de Francisco A, et al. Acute toxicity of vitamin A given with vaccines in infancy. Lancet 1993; 342: 526–7
2. van Dillen J, et al. Long-term effect of vitamin A with vaccines. Lancet 1996; 347: 1705
3. Agoestina T, et al. Safety of one 52 micromol (50 000 IU) oral dose of vitamin A administered to neonates. Bull WHO 1994; 72: 859–68
4. WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 1998; 352: 1257–63. Correction. ibid. 1999; 353: 154.

Carcinogenicity.

For mention of the increased risk of lung cancer in high-risk individuals receiving betacarotene and vitamin A, when compared with placebo, in a study investigating vitamins in lung cancer prevention, see Prophylaxis of Malignant Neoplasms.

Effects on the blood.

Normochromic macrocytic anaemia developed in a patient who had been receiving vitamin A 150 000 units daily by mouth for several months.1 The patient’s haemoglobin returned to normal when vitamin A was stopped, and the accompanying symptoms of perioral dermatitis and glossitis also disappeared. Similarly, normochromic normocytic anaemia and thrombocytopenia in an infant given 62 000 units daily for 80 days, resolved on stopping vitamin A.2 In contrast, vitamin A has been reported to have a beneficial effect on anaemia, see under Deficiency states, below.
1. White JM. Vitamin-A-induced anaemia. Lancet 1984; ii: 573
2. Perrotta S, et al. Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. Blood 2002; 99: 2017–22.

Effects on bone.

Excessive dietary intake of vitamin A may be associated with osteoporosis. In an epidemiological study,1 a dietary intake of retinol greater than 1500 micrograms daily (5000 units) doubled the risk of hip fracture compared with an intake of less than 500 micrograms daily (about 1670 units) in women (odds ratio, 2.1; 95% confidence interval 1.1 to 4.0). These data were confirmed by the Nurses’ Health Study,2 which found that postmenopausal women with the highest vitamin A and retinol intakes were at increased risk for hip fracture, irrespective of whether the intakes were from food plus supplements, or food alone. Women with daily retinol intakes of more than 1500 micrograms had a relative risk for hip fracture of 1.64 compared with those consuming less than 500 micrograms daily. Betacarotene intake, however, did not correlate significantly with an increased risk of fracture. A large cohort study3 of men found that the overall risk of any fracture, including hip fractures, was substantially increased among men with the highest concentrations of serum retinol; there was no association between serum betacarotene levels and the risk of fracture. Subsequently, routine supplementation and the fortification of food with vitamin A in western countries has been questioned.4 A report5 from the UK Government’s Scientific Advisory Committee on Nutrition cautions against the intake of more than 1.5 mg of vitamin A daily in those at increased risk of osteoporosis, such as postmenopausal women and the elderly. However, results from a cohort study in the elderly6 suggest a U-shaped dose relationship, in that both high and low intakes of vitamin A were associated with reduced bone mineral density, and another study7 in women aged between 50 and 74 years, found both high and low serum vitamin A concentrations to be associated with an increased risk of hip fracture.
1. Melhus H, et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 1998; 129: 770–8
2. Feskanich D, et al. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002; 287: 47–54
3. Michaëlsson K, et al. Serum retinol levels and the risk of fracture. N Engl J Med 2003; 348: 287–94
4. Lips P. Hypervitaminosis A and fractures. N Engl J Med 2003; 348: 347–9
5. Scientific Advisory Committee on Nutrition. Review of dietary advice on vitamin A. London: The Stationery Office, 2005. Also available at: http://www.sacn.gov.uk/pdfs/sacn_vita_report.pdf (accessed 21/07/08
6. Promislow JHE, et al. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res 2002; 17: 1349–58
7. Opotowsky AR, Bilezikian JP. Serum vitamin A concentration and the risk of hip fracture among women 50 to 74 years old in the United States: a prospective analysis of the NHANES I Follow-up Study. Am J Med 2004; 117: 169–74.

Effects on the immune system.

Vitamin A deficiency is generally associated with impaired immunity, and treatment of deficiency results in reductions in morbidity and mortality from a number of infectious diseases (see under Deficiency States, below). However, a few studies have shown increased prevalence of diarrhoea and/or respiratory-tract infections with high doses of vitamin A. There is a possibility that high single doses of vitamin A may temporarily attenuate the immune response in non-deficient children.1 For the effect of high-dose vitamin A supplements on the response to measles vaccine in some studies.
1. Anonymous. Childhood morbidity, immunity and micronutrients. WHO Drug Inf 1996; 10: 12–16.

Effects on the liver.

Vitamin A is stored in the Dissë space of liver cells and excessive dosage can lead to fibrosis and obstruction of sinusoidal blood flow, causing non-cirrhotic portal hypertension and hepatocellular dysfunction.1 Although hepatotoxicity has typically been reported with habitual ingestion of doses of vitamin A greater than 50 000 units daily, a case of severe hepatic fibrosis, with jaundice and hepatomegaly, has been reported in a patient who had been taking 25 000 units daily for at least 6 years in a multivitamin supplement.2
1. Sherlock S. The spectrum of hepatotoxicity due to drugs. Lancet 1986; ii: 440–4
2. Kowalski TE, et al. Vitamin A hepatotoxicity: a cautionary note regarding 25,000 IU supplements. Am J Med 1994; 97: 523–8.

Effects on mortality.

Vitamin A supplementation has been reported to have beneficial effects on childhood mortality, especially in developing countries, see Deficiency States, below et seq. However, a systematic review of antoxidant supplementation in adults concluded that vitamin A either singly or with other antoxidants increased mortality.1
1. Bjelakovic G, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2008 (accessed 18/06/08).

Hypersensitivity.

Local inflammatory reactions and severe anaphylactoid reactions have occurred in patients receiving vitamin A injections, and are usually attributed to solubilisers such as polyoxyl castor oils, and, less commonly, polysorbates. A case of cutaneous hypersensitivity to retinol palmitate itself has been described.1
1. Shelley WB, et al. Hypersensitivity to retinol palmitate injection. BMJ 1995; 311: 232.

Overdosage.

Although no clinical manifestations of toxicity were seen in 3 boys who ingested large amounts of vitamin A, their serum retinol concentrations continued to rise over about 3 weeks, and took several months to normalise; the authors cautioned that the use of chewable vitamins resembling confectionery may increase the risk of overdose in children.1
1. Lam HS, et al. Risk of vitamin A toxicity from candy-like chewable vitamin supplements for children. Pediatrics 2006; 118: 820–4.

Pregnancy.

The fact that synthetic vitamin A derivatives such as isotretinoin are teratogenic has prompted concern about the potential teratogenicity of high doses of vitamin A. A prospective cohort study found that a total daily intake of vitamin A from all sources of greater than 15 000 units during early pregnancy was associated with a significantly increased risk of birth defects of structures arising from the cranial neural crest.1When vitamin A intake from supplements was analysed separately, an apparent vitamin A threshold dose for the development of birth defects of 10 000 units daily was suggested. However, this study has been criticised2,3 and some suggest the data allows for a higher threshold dose.3 A further study found no significant difference in birth defect rates between women consuming greater than 8000 or 10 000 units of vitamin A daily in the period around conception (as supplements and fortified cereals) and those consuming less than 5000 units daily.4 After earlier case reports in the USA suggesting that large doses of vitamin A (equivalent to about ten times the daily recommended dietary allowance of 2250 units) taken in early pregnancy may cause birth defects, the UK Chief Medical Officer cautioned women against the use of vitamin A supplements except under medical supervision.5 Additionally, advice was given that liver or liver products should not be eaten because high concentrations of vitamin A had been detected in some samples of animal liver. However, others thought that the avoidance of liver or liver products might result in inadequate nutrition in some and that a less alarmist view might have been to suggest a limitation on intake rather than total prohibition.6,7 The American College of Obstetricians and Gynecologists has recommended that women who are pregnant or planning pregnancy should ensure that any vitamin supplements they take contain a daily dose of vitamin A of no more than 5000 units.8 The Australian Adverse Drug Reactions Advisory Committee has advised women in this category to avoid vitamin A supplements and to not exceed the recommended daily allowance of 2500 units from all sources.9
1. Rothman KJ, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995; 333: 1369–73
2. Werler MM, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1996; 334: 1195–6
3. Watkins M, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1996; 334: 1196
4. Mills JL, et al. Vitamin A and birth defects. Am J Obstet Gynecol 1997; 177: 31–6
5. Department of Health. Women cautioned: watch your vitamin A intake. London: Department of Health, 1990 (18 October)
6. Nelson M. Vitamin A, liver consumption, and risk of birth defects. BMJ 1990; 301: 1176
7. Sanders TAB. Vitamin A and pregnancy. Lancet 1990; 336: 1375
8. American College of Obstetricians and Gynecologists. ACOG committee opinion: vitamin A supplementation during pregnancy. Number 196, January 1998 (replaces No. 157, September 1995). Int J Gynaecol Obstet 1998; 61: 205–6
9. Adverse Drug Reactions Advisory Committee (ADRAC). Vitamin A and birth defects. Aust Adverse Drug React Bull 1996; 15: 14–15. Also available at: http://www.tga.gov.au/adr/ aadrb/aadr9611.htm (accessed 21/07/08)

💊 Interactions

Absorption of vitamin A from the gastrointestinal tract may be reduced by the presence of neomycin, colestyramine, or liquid paraffin. There is an increased risk of hypervitaminosis A if vitamin A is given with synthetic retinoids such as acitretin, isotretinoin, and tretinoin. There is conflicting evidence regarding the effect of vitamin A on the response to measles vaccine.

💊 Pharmacokinetics

Vitamin A substances are readily absorbed from the gastrointestinal tract but absorption may be reduced in the presence of fat malabsorption, low protein intake, or impaired liver or pancreatic function. Vitamin A esters are hydrolysed by pancreatic enzymes to retinol, which is then absorbed and re-esterified. Some retinol is stored in the liver. It is released from the liver bound to a specific
Published January 31, 2019.