Health Care Professional Information

Common Name

Retinol, retinal, retinoic acid, retinoid, retinol palmitate

Clinical Summary

Derived from dietary sources and vitamin A precursors such as beta-carotene, alpha-carotene, and cryptoxanthin, vitamin A supplements are taken for eye conditions or acne, to improve immune function and growth and development in children, and to treat and prevent cancer. Vitamin A is necessary for normal differentiation of corneal, conjunctival, and retinal membranes, growth, development, and immune activation.

Clinical data suggest that vitamin A may be effective against growth retardation, acne, eczema (1), and hepatitis C (2). In children, vitamin A may also reduce recurring urinary tract infection (3), parasitic infections (4), and along with zinc, may reduce malaria-related morbidity (5). In developing countries, vitamin A supplementation reduced mortality in children (6) (7); however, its effects on infant mortality are conflicting (8) (9) (10), and maternal supplementation does not affect neonatal mortality (11). Vitamin A supplementation may also affect immune response to specific vaccines in children (12) (13), and was shown to be beneficial and safe in HIV-infected children (14). Studies to determine the proper dosage of vitamin A supplementation for children of varying demographics are still incomplete (15) (16) (17). Adults who may be malnourished, such as patients with Crohn’s disease, may also be vitamin A-deficient, and symptoms such as night vision problems should be assessed by physicians (18).

Although vitamin A derivatives are used as chemotherapeutic agents for cancer, a review of 14 clinical trials showed that supplementation with antioxidants beta-carotene, vitamin A, vitamin C, and vitamin E does not seem to prevent gastrointestinal cancer and may actually increase overall mortality (19). Higher serum retinol was also associated with elevated risk of prostate cancer, with prolonged high exposure resulting in increased risk (20) (21). Other large clinical trials have shown that vitamin A supplementation does not help to prolong survival for melanoma patients (22), prevent recurrence of head and neck cancer (23), or reduce the risk of non-small cell lung cancer (24), although a reduction in melanoma risk was associated with supplemental retinol but not carotenoid intake, particularly for women, in a large epidemiological study (25). At the same time, higher retinol intakes are associated with significant direct trends for risk of oral and pharyngeal cancers (26) and may also negatively impact high-dose vitamin D protection against colon cancer risk (27) as well as vitamin D involvement in calcium uptake in the bone (28), increasing the risk for hip fractures (29).

In assessments of nutritional status among in cancer patients, one study noted significantly lower serum retinol and beta-carotene levels in stage III versus earlier-stage breast cancer patients and also in patients after radiotherapy (30). Another study found human papillomavirus positive (HPV+) head and neck cancer patients who have diets richer in micronutrients including vitamin A may have better immune functioning and prognosis (31).

Deficiencies of vitamin A are rare in developed countries (29). Supplementation of vitamin A with doses greater than the recommended Daily Value of 5,000 IU or in conjunction with certain medications or pre-existing conditions may result in adverse effects or toxicity (32) (33). Vitamin A is therefore best obtained from a variety of dietary sources.

Food Sources

Preformed Vitamin A: Fortified and animal-based foods such as dairy products, liver, eggs, fish
Pro Vitamin A (beta-carotene): Carrots, sweet potato, cantaloupe, pumpkin, mango, papaya, dark leafy greens
(7) (28)

Purported Uses
  • Acne
  • Cancer prevention and treatment
  • Crohn's disease
  • Enhancing tissue integrity
  • Eye disorders
  • Gastrointestinal disorders
  • Growth and development
  • Immunostimulation
  • Infections
Mechanism of Action

Vitamin A is essential for many aspects of ocular metabolism, including conjunctival and corneal epithelial maintenance, retinal phototransduction, and retinal pigment epithelial cell viability (34). Nuclear receptor transcription factors are central to vitamin A activity, and most transcriptional actions require the retinoic acid receptor/retinoid x receptor (RXR/RAR) heterodimer (35). Transcriptional changes are linked to epigenetic changes in histones and DNA via recruitment of epigenetic modifying enzymes (36). All-trans retinoic acid (ATRA) has been identified as the most important active metabolite in vitamin A for tissue homeostasis in adults and segmentation control in developing organisms (37). As such, retinoids that include ATRA along with natural and synthetic derivatives exhibit anticancer properties linked to their ability to induce cellular differentiation and growth suppression (36) (37).

In animal models of melanoma, ATRA in combination with epigallocatechin-3-O-gallate (EGCG) from green tea enhanced 67-kDa laminin receptor expression and increased EGCG-induced cell growth inhibition (38). In estrogen receptor-negative breast cancer cells, ATRA halts telomerase activity and exerts antitumor effects via a rapid decrease of H3-K9 acetylation at the hTERT promoter (39). The protective effect of supplemental retinol against melanoma may be mediated by sunlight exposure (25).

Vitamin A competes with vitamin D for the same parathyroid hormone receptor (29).

Pharmacokinetics

Absorption: Dietary preformed A is absorbed via carrier-dependent proteins, while passive diffusion may occur with pharmacological compounds. Intestinal absorption follows the breakdown of retinyl esters in the duodenum. Absorption efficiency of preformed vitamin A is generally high (range 75–100%) due to an efficient and specific retinol transporter, unlike provitamin A carotenoids that are absorbed via non-specific transporters (40).

Distribution: In the presence of adequate vitamin A intake, the vast majority of total body stores are located in the liver as retinyl esters. Peripheral tissue requirements are met with the release of retinol from the liver along with retinol-binding protein carrier, complexed with another protein, transthyretin (41).

Metabolism/Excretion: Animal model estimates indicate up to 50% of plasma retinol turnover occurs in the kidney. The retinol-RBP complex is filtrated through the glomerulus and then mostly reabsorbed (99.97%) in the proximal tubule by the major scavenger receptor, megalin (42).

Contraindications
  • Women who are pregnant should not consume vitamin A supplements due to possible teratogenicity (29).
  • Pre-existing conditions such as chronic alcohol consumption, liver lesions, and concurrent medications with liver toxicity profiles may increase the risk of developing hepatotoxicity with vitamin A supplementation (33).
Adverse Reactions

Reported: Nausea, vomiting, headache, blurred vision, muscular weakness, elevated liver function tests, hepatotoxicity (7) (32) (43)

Case reports
Chronic toxicity or hypervitaminosis A: Usually associated with chronic intake of more than 30,000 IU of vitamin A (44), although there have been several cases of significant hepatotoxicity with vitamin A doses as low as 20,000 IU and in regular alcohol consumers (33) (45).

Complex presentations may include hepatotoxicity, bone and skin changes, and other nonspecific adverse effects (20).

Herb-Drug Interactions

Alcohol: Ethanol can compete with retinol for alcohol dehydrogenase, leading to reduced levels of retinol oxidation to retinaldehyde and retinoic acid (45).
Orlistat: May reduce the absorption of vitamin A. Patients taking orlistat should take a multivitamin containing vitamins D, E, K, and beta-carotene once a day at least 2 hours before or after the administration orlistat (46).
Retinoids (tretinoin, acitretin, bexarotene): May increase risks of adverse effects. Avoid vitamin A supplements in excess of minimum recommended daily allowances when on these medications (47).
Warfarin: Large doses of vitamin A may increase the anticoagulant effects of warfarin (48).

Literature Summary and Critique

Bravi F, et al. Foods, nutrients and the risk of oral and pharyngeal cancer. Br J Cancer. 2013;109:2904-2910.
In this large, long-term case control study conducted in Italy and Switzerland, dietary habits were evaluated to determine their effects on oral cavity and pharyngeal (OCP) cancer. Between 1997 and 2009, researchers evaluated 768 histologically confirmed squamous cell carcinoma patients as well as 2078 hospital controls. Relevant covariates to control for tobacco and alcohol use were included in analyses. Among a number of selected food groups and nutrients, there were significant inverse trends in risk observed for all vegetables (OR=0.19) and all fruits (OR=0.39) with significant inverse relations observed for vegetable protein (OR=0.45), vegetable fat (OR=0.54), and polyunsaturated fatty acids (OR=0.53). Among specific nutrients, there were also significant inverse trends for alpha- (OR=0.51) and beta-carotene (OR=0.28). However, there were direct associated trends observed for animal protein (OR=1.57), animal fat (OR=2.47), saturated fatty acids (OR=2.18), cholesterol (OR=2.29), and retinol (OR=1.88). In addition, the combination of low fruits and vegetable consumption and high meat, tobacco and alcohol consumption led to a 10- to >20-fold excess risk of OCP cancer. Besides lifestyle changes, this study further supports the notion of obtaining nutrients from dietary sources to receive beneficial amounts of pro-vitamin A (alpha- and beta-carotene) found in fruits and vegetables while helping to limit intake of preformed vitamin A (retinol) from animal sources.

Asgari MM, et al. Association of vitamin A and carotenoid intake with melanoma risk in a large prospective cohort. J Invest Dermatol. 2012;132:1573-1582.
In this long-term epidemiological trial known as the VITamins And Lifestyle (VITAL) study, investigators sought to determine whether there were associations between melanoma risk and vitamin A and carotenoid intake among 69,635 men and women. Average follow-up was 5.84 years, with 566 melanomas cases identified. Adjustments for other melanoma risk factors such as freckles, hair color between 10–20 years of age, sun sensitivity, sunburn history, family melanoma history, personal nonmelanoma skin cancer history, and mole removal were included in the analyses. Although there was no association with melanoma risk for dietary or total vitamin A intake or carotenoid intake, the use of individual retinol supplements indicated a significant reduction in melanoma risk (HR: 0.60; 95% CI: 0.41–0.89), as did high-dose supplemental retinol (HR: 0.74; 95% CI: 0.55–1.00), compared with non-users. Stratified by gender, the association of retinol supplements was driven by a marked risk reduction among women (HR: 0.27; 95% CI: 0.11–0.66) vs men (HR: 0.83; 95% CI: 0.54–1.27; P-interaction=0.64). Although this gender effect may have occurred by chance, investigators noted more favorable melanoma outcomes have also been previously noted with gender (49). In addition, risk reduction was found to be stronger in sun-exposed anatomic sites. Investigators determined that retinol supplementation may have a preventative role in melanoma, particularly among women.

Khuri FR, et al. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst. 2006;98:441-450.
In this phase III randomized trial, low-dose isotretinoin was evaluated in 1190 patients with early-stage head and neck cancer to evaluate its effect on second primary tumor incidence and survival, as a previous smaller study showed encouraging results with high-dose isotretinoin. Participants were randomized to receive either isotretinoin 30 mg/day or placebo for 3 years and were monitored for up to 4 more years thereafter. No statistically significant reduction in rate of second primary tumors or increase survival was observed compared with placebo in this long-term trial. There was an observed association of reduced recurrence in the isotretinoin group, but this was seen early on and lasted only for the first 2 to 3 follow-up years, suggesting some activity against microscopic cancers. The low dose administered along with the exclusion of patients with advanced disease may have contributed to overall negative results.

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References
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  23. Khuri FR, Lee JJ, Lippman SM, et al. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst. Apr 5 2006;98(7):441-450. doi: 10.1093/jnci/djj091
  24. Satia JA, Littman A, Slatore CG, et al. Long-term use of beta-carotene, retinol, lycopene, and lutein supplements and lung cancer risk: results from the VITamins And Lifestyle (VITAL) study. Am J Epidemiol. Apr 1 2009;169(7):815-828. doi: 10.1093/aje/kwn409
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  33. Stickel F, Kessebohm K, Weimann R, et al. Review of liver injury associated with dietary supplements. Liver Int. May 2011;31(5):595-605. doi: 10.1111/j.1478-3231.2010.02439.x
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Consumer Information

How It Works

Bottom Line: Vitamin A is essential for many bodily functions. It is unclear if taking extra vitamin A can prevent cancer.

Vitamin A is best obtained from a well-balanced diet. Obtaining the recommended Daily Value (DV) of vitamin A (5,000 IU) is important because this vitamin is essential for a variety of bodily functions, including vision, embryonic development, maintenance of tissue integrity, and proper immune activation. Many fruits and vegetables are rich in vitamin A precursors, such as beta-carotene and cryptoxanthin, which are converted into the active form retinol, while dairy products, eggs, and fish are among the food sources containing vitamin A preformed as retinol. Too much retinol can cause a variety of side effects. Scientists are studying vitamin A byproducts that may be useful in cancer therapies, but these treatments are different from extra vitamin A taken in the form of supplements, the overuse of which can produce harmful effects including liver problems.

Purported Uses
  • To treat acne
    Prescription forms of vitamin A have been shown to improve acne, but there is no proof that non-prescription forms can have the same effect.
  • To prevent and treat cancer
    A few large clinical trials show that vitamin A does not help prevent recurrence or prolong survival in patients with resected melanoma, head and neck cancer, or non-small cell lung cancer. However, overall nutritional status and diet of cancer patients is important, and a diet rich in nutrients is unlikely to produce unwanted side effects. For cancer patients especially, any perceived vitamin deficiencies should be discussed with their oncology healthcare professional.
  • To treat Crohn's disease
    Although vitamin A supplementation does not treat Crohn’s disease, patients with this disorder can be malnourished. Therefore, symptoms such as night vision problems that may indicate a deficiency should be reported to and treated by your doctor.
  • To enhance tissue strength
    A diet containing adequate amounts of vitamin A is important in the maintenance of tissue strength, but human data are lacking.
  • To treat eye disorders
    Clinical trials have not definitively supported this use, although symptoms such as night vision problems that may be related to a deficiency should be reported to and treated by your doctor.
  • To treat gastrointestinal disorders
    No scientific evidence supports this use.
  • To stimulate the immune system
    This claim is not backed by clinical data.
  • To treat infections
    No scientific evidence supports this use.
Do Not Take If
  • You regularly consume alcoholic beverages: Taking supplemental vitamin A along with regular alcohol use increases the risk for liver problems.
  • You are pregnant: Doses of vitamin A 5000 IU or greater can cause birth defects.
  • You take orlistat: This drug may reduce the absorption of vitamin A. Ask your doctor to see if you need to take a vitamin A supplement.
  • You take retinoids (tretinoin, acitretin, bexarotene):  Vitamin A may increase the adverse effects.
  • You take warfarin (Coumadin®) or other blood thinners: Large doses of vitamin A may increase the risk of bleeding or bruising.
Side Effects

Nausea and vomiting, headache, blurred vision, muscular weakness, elevated liver function tests, liver toxicity

Chronic liver toxicity or vitamin A toxicity: Usually occurs with higher amounts of Vitamin A, although several cases have occurred with lower doses and among those who drink alcohol regularly.

Special Point

Supplementation with doses greater than the recommended daily allowance may result in toxicity, therefore patients should be monitored accordingly.

E-mail your questions and comments to aboutherbs@mskcc.org.