Ingredient review

Vitamin A

Description

What is it?

Vitamin A is a collection of fat-soluble molecules found either as preformed vitamin A (e.g., retinol, retinal, retinoic acid, or retinol esters) or as pro-formed vitamin A (e.g., mainly beta-carotene, alpha-carotene, or cryptoxanthin). Dietary preformed vitamin A mainly comes from animal sources, particularly liver, which is why cod liver oil supplements contain vitamin A. In contrast, pro-formed vitamin A is typically found in yellow and orange fruits and vegetables or in dark green leafy vegetables. (9)(18)(34)(58)

The average American two years of age or older consume 600 mcg (µg) of retinol activity equivalent (RAE) per day. (77) However, depending on age and gender, this average intake may or may not be enough. The National Institutes for Health (NIH) indicates that individuals aged 1-3, 4-8, and 9-13 should consume 300 µg RAE, 400 µg RAE, and 600 µg RAE, respectively. Males aged 14 and older should consume 900 µg RAE and females should consume 700 µg RAE, unless pregnant or lactating, during which, intakes should be as high as 770 µg RAE and 1,300 µg RAE, respectively. (58) It is estimated that vitamin A deficiency affects people living in approximately 30% of countries worldwide, as indicated by serum retinol levels lower than 20 µg/dL (0.70 mmol/L), (82) although deficiency is rare in the United States and Canada. Vitamin A deficiency can lead to xerophthalmia (dry eye), night blindness, corneal xerosis or ulceration, keratomalacia, and in some cases, blindness. (18) Vitamin A thus plays important roles particularly in vision, but also has other functions including immunity, cellular development and communication, and reproduction. (18)(34

Topical vitamin A and its derivatives have been popularly used for skin health such as anti-aging; however, topical formulations are not covered in this review. It is also important to note that studies demonstrate beneficial effects of adequate dietary vitamin A on reducing the risk of cancers of the bladder, (75)(83) breast, (35)(64) cervix, (87) esophagus, (28) head and neck, (48) ovaries, (79) pancreas, (86) skin, (88), and stomach; (45)(84) however, this review will only focus on interventions using vitamin A supplementation. Most high-level evidence points to a lack of benefit of vitamin A or carotenoid supplementation in cancer. (25)(26)(42)(63)

Main uses

Iron status
Lung health
Skin health
Thyroid function
Vision

Formulations

As a fat-soluble molecule, excess amounts of vitamin A can accumulate in the body, which can lead to toxicity. It should be noted that the delivery form of vitamin A supplements may influence the likelihood of chronic hypervitaminosis. For example, taking oil-based supplements at daily doses of 2,000 µg RAE per kilogram of body weight over several months to years may result in signs of toxicity, but the toxic threshold for water-miscible, emulsified, or solid retinol preparations is ten times lower. (54)

Form
Absorption Rate
Vitamin A (retinol)
Baseline vitamin A molecule with relatively lower stability (compared to ester forms below) when not in oil-based solutions, but is usually sold in esterified forms (55)
Esterification improves the stability of retinol (66)
1 IU of retinol = 0.3 µg RAE
1 µg of retinol = 1 µg RAE (9)(58)
Retinyl palmitate
Natural (preformed) form most common in dietary supplements; esterified form of retinol and palmitic acid (55% retinol by weight) (56)
In states of deficiency, 60,000 µg RAE of retinyl palmitate and 1,200,000 µg RAE of beta-carotene supplementation (bioequivalent doses) improved vitamin A deficiency to the same extent (~50%). (12)
Retinyl acetate
Natural (preformed) form; esterified from retinol and acetate (87% retinol by weight) (57)
Carotenoids
Includes provitamins such as beta-carotene, alpha-carotene, gamma-carotene, and cryptoxanthin
2 µg of beta-carotene in supplements = 1 µg RAE
12 µg of beta-carotene in food = 1 µg RAE(9)(58)
24 µg of alpha-carotene or beta-cryptoxanthin in food = 1 µg RAE (9)(58)

Dosing & administration

Adverse effects

In order to avoid hypervitaminosis A, tolerable upper intake levels (ULs) have been established for preformed vitamin A but not for pro-formed vitamin A due to a lack of toxicity data available for carotenoids like beta-carotene. Upper tolerable levels are up to 3,000 µg RAE in adults. Practitioners should calculate the amount of preformed (not pro-formed) vitamin A in supplements when considering ULs. (58) Vitamin A toxicity can be classified as acute (singular large doses over a short period), chronic (moderate to high doses usually taken daily over a few months to years; for example, >10x or >3.75x the RDA for adults or infants, respectively), or teratogenic (moderate to high doses during the first trimester of pregnancy; for example >4,500 µg RAE).

A meta-analysis demonstrated that the top five most common acute adverse effects (prevalent in infants but rarely reported in individuals older than three years of age) included bulging fontanels (94%), vomiting (60%), hydrocephalus, and increased cerebrospinal fluid pressure (30% and 24%), pale skin (18%), and loss of appetite (16%). The top five adverse events associated with chronic hypervitaminosis in infants include hyperostosis (52%), loss of appetite (50%), irritability (46%), skeletal pain (42%), and bulging fontanels (38%). The top five side effects of chronic vitaminosis in children and adolescents include headaches (51%), lip fissures (41%), vomiting (41%), papillary edema (39%), and skeletal pain (39%). In adults, side effects include fatigue (45%), pigmentation (34%), headache (33%), alopecia (33%), and hepatomegaly (32%) (see reference for a full list of side effects). (54

Overall, however, adult supplementation with vitamin A at doses 50% higher than the UL (4,500 µg RAE) over the course of 12 years did not lead to signs of vitamin A toxicity. (71) Additionally, adverse effects caused by doses within the UL are rarely reported in pregnancy; (51)(76)(80) however, it should be noted that when vitamin A is consistently taken in excess of the UL, it has been estimated that one in 57 infants may be born with a secondary congenital disability. (61) In infants and children (five months to five years of age) requiring high doses (30,000-60,000 µg RAE), the risk of vomiting may double or triple within 48 hours. (40)(50) According to the World Health Organization, most additional adverse reactions in this age group (e.g., diarrhea, headache, irritability, fever, or nausea) are mild,  transient, and typically resolve within 48 hours (81) or are no more prevalent than observed in control groups. (37) One of the more prevalent adverse events to beta-carotene supplementation includes hypercarotenodermia (yellowing of the skin). One systematic review of several long-term studies showed that the proportion of patients developing hypercarotenodermia ranged between 7.4-15.8%. (49)

It should be noted that there is some evidence indicating that vitamin A supplementation led to an increased risk of cancer (16%), while beta-carotene at doses higher than 9.6 mg per day led to an increased risk of all-cause mortality by 5-6%. (7)(8)(70) Other analyses also indicated that 20-30 mg of beta-carotene per day increased the relative risk of lung cancer by 16% and stomach cancers by 34% in smokers and asbestos workers, (20) and may increase the risk of bladder cancer (44-52%). (42)(63) Finally, there is some evidence that vitamin A supplementation may increase the risk of bone decalcification and osteoporosis; however, this may be associated with the physical form of the supplement (water-miscible, emulsified, or dry retinol preparations, but not oil-based). (54

Pharmacokinetics

Absorption

  • Preformed vitamin A (retinyl esters) are hydrolyzed by pancreatic and intestinal enzymes to retinol in enterocytes before being re-esterified and transferred to mixed micelles.
  • The retinol esters then cross enterocytes via passive diffusion or facilitated transport and are subsequently incorporated into chylomicrons for blood transport to the liver. 
  • Pro-formed vitamin A (carotenoids) is directly absorbed by enterocytes, where 50% is subsequently incorporated into chylomicrons and the other 50% is oxidized to retinal, then reduced to retinol prior to chylomicron transport.
  • The presence of dietary fats improves vitamin A absorption, (9)(15) but 80-90% of vitamin A is absorbed regardless. (34)

Distribution

  • Approximately 70% of vitamin A is stored in the liver, primarily as retinyl esters.
  • Retinyl esters derived from carotenoids, such as beta-carotene, are converted to retinol and then also stored in the liver. (9)(13)(15)

Metabolism

  • To meet tissue requirements, hepatic vitamin A can be de-esterified, bound to retinol-binding protein and transthyretin, and sent to the tissue in need where it is converted to retinal by alcohol dehydrogenases and then to retinoic acid by retinal dehydrogenases to affect biological activity. (9)(13)
  • Toxicity induced by beta-carotene consumption is rare as the conversion of beta-carotene to vitamin A is highly regulated and dependent on vitamin A status. The more vitamin A replete the individual is, the less efficiently beta-carotene is converted. (31)

Excretion

  • Vitamin A is mainly excreted directly from the liver into the bile, (9) but oxidized metabolites can result in excretion in the urine. (34)

References