Vitamin A

• How It Works

  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 of vitamin A (DV: 5,000 IU) is essential for a variety of bodily functions, including vision, embryonic development, 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. Dairy products, eggs, and fish are among the foods containing vitamin A already 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 melanoma, head and neck cancer, or non-small cell lung cancer. It may also increase risk of prostate cancer. However, overall nutritional status and diet of cancer patients is important, and a diet rich in nutrients rather than from supplements 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 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 stimulate the immune system
    Vitamin A can enhance the immune responses to certain vaccines.
• 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

  Increase in allergies: In newborn girls who received supplements.

  Case Reports
  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.
  • Multivitamins commonly include vitamin A.
  • Deficiencies of vitamin A are rare in developed countries.
• Clinical Summary

  Vitamin A is a group of nutrient compounds available from dietary sources including fruits, vegetables, eggs, dairy products, and fish. Vitamin A and its analogs such as beta-carotene, alpha-carotene, and cryptoxanthin are used as prescription drugs and as dietary supplements to improve vision, skin condition, immune function, or growth and development in children, and to treat and prevent cancer, 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⁾.

  Preliminary studies suggest Vitamin A supplementation may inhibit progression of multiple sclerosis ⁽⁶⁾ and improve fatigue and depression ⁽⁷⁾.

  Vitamin A supplementation was thought to benefit children ^{(8) (9) (10)} and affect immune response to specific vaccines ^(11) (12). However, other studies yielded conflicting results ^{(13) (14) (15) (16)}, and more recent large trials do not support neonatal supplementation ^{(17) (18) (19) (20)}. Maternal supplementation also did not affect neonatal mortality ⁽²¹⁾ or improve intelligence, memory, or motor function in children ⁽²²⁾.

  Some studies found that late-stage breast cancer patients have lower serum vitamin A levels ⁽²³⁾, and that diets richer in micronutrients including vitamin A can improve immune functioning and prognosis in head and neck cancer patients ⁽²⁴⁾, and reduce the risk of oral and pharyngeal cancers ⁽²⁵⁾. However, vitamin A supplementation does not have a protective effect against non-small cell lung cancer ⁽²⁶⁾ or prolong survival for melanoma patients ⁽²⁷⁾, and may actually elevate the risk of prostate cancer ^(28) (29).

  Vitamin A is fat-soluble and overuse may cause accumulation in the body. Supplementation 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 ^(30) (31).

• 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

  ^(9) (32)

• Purported Uses
  • Acne
  • Cancer prevention and treatment
  • Crohn’s disease
  • Eye disorders
  • Immunostimulation
• 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 ⁽³³⁾. 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 ⁽³⁴⁾. Transcriptional changes are linked to epigenetic changes in histones and DNA via recruitment of epigenetic modifying enzymes ⁽³⁵⁾.

  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 ⁽³⁶⁾. 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 ^(35) (36).

  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 ⁽³⁷⁾. 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 ⁽³⁸⁾. The protective effect of supplemental retinol against melanoma may be mediated by sunlight exposure ⁽³⁹⁾.

  In multiple sclerosis patients, vitamin A supplementation as retinyl palmitate upregulated TGF-beta and FoxP3 gene expression ⁽⁴⁰⁾ and decreased IFN-gamma and T-bet gene expression ⁽⁴¹⁾.

  Vitamin A competes with vitamin D for the same parathyroid hormone receptor ⁽⁴²⁾.

• Contraindications
  • 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 ⁽³¹⁾.
  • Women who are pregnant should not consume vitamin A supplements due to possible teratogenicity ⁽⁴²⁾.
• Adverse Reactions

  Nausea, vomiting, headache, blurred vision, muscular weakness, elevated liver function tests, hepatotoxicity ^{(9) (30) (43)}.

  Increased atopy, wheezing: In neonate girls ⁽⁴⁴⁾.

  Complex presentations may include hepatotoxicity, bone and skin changes, and other nonspecific adverse effects ⁽²⁸⁾.

  Case reports
  Chronic toxicity or hypervitaminosis A: Usually associated with chronic intake of more than 30,000 IU of vitamin A ⁽⁴⁵⁾, although there have been several cases of significant hepatotoxicity with vitamin A doses as low as 20,000 IU and in regular alcohol consumers ^(31) (46).

• Herb-Drug Interactions
  • Alcohol: Ethanol can compete with retinol for alcohol dehydrogenase, leading to reduced levels of retinol oxidation to retinaldehyde and retinoic acid ⁽⁴⁶⁾.
  • Warfarin: Large doses of vitamin A may increase the anticoagulant effects of warfarin ⁽⁴⁷⁾.
  • 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 ⁽⁴⁸⁾.
  • 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 ⁽⁴⁹⁾.
• References

  1. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol. Apr 2008;158(4):808-817.

  2. Bocher WO, Wallasch C, Hohler T, et al. All-trans retinoic acid for treatment of chronic hepatitis C. Liver Int. Mar 2008;28(3):347-354.

  3. Yilmaz A, Bahat E, Yilmaz GG, et al. Adjuvant effect of vitamin A on recurrent lower urinary tract infections. Pediatr Int. Jun 2007;49(3):310-313.

  4. Lima AA, Soares AM, Lima NL, et al. Effects of vitamin A supplementation on intestinal barrier function, growth, total parasitic, and specific Giardia spp infections in Brazilian children: a prospective randomized, double-blind, placebo-controlled trial. J Pediatr Gastroenterol Nutr. Mar 2010;50(3):309-315.

  5. Zeba AN, Sorgho H, Rouamba N, et al. Major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children in Burkina Faso: a randomized double blind trial. Nutr J. Jan 31 2008;7:7.

  6. Bitarafan S, Saboor-Yaraghi A, Sahraian MA, et al. Impact of Vitamin A Supplementation on Disease Progression in Patients with Multiple Sclerosis. Arch Iran Med. Jul 2015;18(7):435-440.

  7. Bitarafan S, Saboor-Yaraghi A, Sahraian MA, et al. Effect of Vitamin A Supplementation on fatigue and depression in Multiple Sclerosis patients: A Double-Blind Placebo-Controlled Clinical Trial. Iran J Allergy Asthma Immunol. Feb 2016;15(1):13-19.

  8. Fawzi WW, Chalmers TC, Herrera MG, et al. Vitamin A supplementation and child mortality. A meta-analysis. JAMA. Feb 17 1993;269(7):898-903.

  9. Imdad A, Herzer K, Mayo-Wilson E, et al. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database Syst Rev. Dec 08 2010(12):CD008524.

  10. Irlam JH, Visser MM, Rollins NN, et al. Micronutrient supplementation in children and adults with HIV infection. Cochrane Database Syst Rev. Dec 08 2010(12):CD003650.

  11. Newton S, Owusu-Agyei S, Ampofo W, et al. Vitamin A supplementation enhances infants’ immune responses to hepatitis B vaccine but does not affect responses to Haemophilus influenzae type b vaccine. J Nutr. May 2007;137(5):1272-1277.

  12. Diness BR, Fisker AB, Roth A, et al. Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine. Am J Clin Nutr. Oct 2007;86(4):1152-1159.

  13. Fisker AB, Bale C, Rodrigues A, et al. High-dose vitamin A with vaccination after 6 months of age: a randomized trial. Pediatrics. Sep 2014;134(3):e739-748.

  14. Humphrey JH, Agoestina T, Wu L, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr. Apr 1996;128(4):489-496.

  15. Benn CS, Martins C, Rodrigues A, et al. The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea-Bissau. Int J Epidemiol. Feb 2009;38(1):304-311.

  16. Klemm RD, Labrique AB, Christian P, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics. Jul 2008;122(1):e242-250.

  17. Benn CS, Diness BR, Balde I, et al. Two different doses of supplemental vitamin A did not affect mortality of normal-birth-weight neonates in Guinea-Bissau in a randomized controlled trial. J Nutr. Sep 2014;144(9):1474-1479.

  18. Lund N, Biering-Sorensen S, Andersen A, et al. Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth. BMC Pediatr. Aug 28 2014;14:214.

  19. Edmond KM, Newton S, Shannon C, et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet. Apr 04 2015;385(9975):1315-1323.

  20. Masanja H, Smith ER, Muhihi A, et al. Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet. Apr 04 2015;385(9975):1324-1332.

  21. Christian P, Darmstadt GL, Wu L, et al. The effect of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: a randomised, controlled, community trial. Arch Dis Child. Aug 2008;93(8):660-664.

  22. Ali H, Hamadani J, Mehra S, et al. Effect of maternal antenatal and newborn supplementation with vitamin A on cognitive development of school-aged children in rural Bangladesh: a follow-up of a placebo-controlled, randomized trial. Am J Clin Nutr. Jul 2017;106(1):77-87.

  23. Matos A, Nogueira C, Franca C, et al. The relationship between serum vitamin A and breast cancer staging before and after radiotherapy. Nutr Hosp. Jan 01 2014;29(1):136-139.

  24. Arthur AE, Duffy SA, Sanchez GI, et al. Higher micronutrient intake is associated with human papillomavirus-positive head and neck cancer: a case-only analysis. Nutr Cancer. 2011;63(5):734-742.

  25. Bravi F, Bosetti C, Filomeno M, et al. Foods, nutrients and the risk of oral and pharyngeal cancer. Br J Cancer. Nov 26 2013;109(11):2904-2910.

  26. 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 01 2009;169(7):815-828.

  27. Meyskens FL, Jr., Liu PY, Tuthill RJ, et al. Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. J Clin Oncol. Oct 1994;12(10):2060-2065.

  28. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. Apr 2000;71(4):878-884.

  29. Mondul AM, Watters JL, Mannisto S, et al. Serum retinol and risk of prostate cancer. Am J Epidemiol. Apr 01 2011;173(7):813-821.

  30. Hathcock JN, Hattan DG, Jenkins MY, et al. Evaluation of vitamin A toxicity. Am J Clin Nutr. Aug 1990;52(2):183-202.

  31. Stickel F, Kessebohm K, Weimann R, et al. Review of liver injury associated with dietary supplements. Liver Int. May 2011;31(5):595-605.

  32. Cribb VL, Northstone K, Hopkins D, et al. Sources of vitamin A in the diets of pre-school children in the Avon Longitudinal Study of Parents and Children (ALSPAC). Nutrients. May 15 2013;5(5):1609-1621.

  33. Huang WB, Fan Q, Zhang XL. Cod liver oil: a potential protective supplement for human glaucoma. Int J Ophthalmol. 2011;4(6):648-651.

  34. Schmidt DR, Holmstrom SR, Fon Tacer K, et al. Regulation of bile acid synthesis by fat-soluble vitamins A and D. J Biol Chem. May 07 2010;285(19):14486-14494.

  35. Yim CY, Mao P, Spinella MJ. Headway and hurdles in the clinical development of dietary phytochemicals for cancer therapy and prevention: lessons learned from vitamin A derivatives. AAPS J. Mar 2014;16(2):281-288.

  36. Garattini E, Bolis M, Garattini SK, et al. Retinoids and breast cancer: from basic studies to the clinic and back again. Cancer Treat Rev. Jul 2014;40(6):739-749.

  37. Lee JH, Kishikawa M, Kumazoe M, et al. Vitamin A enhances antitumor effect of a green tea polyphenol on melanoma by upregulating the polyphenol sensing molecule 67-kDa laminin receptor. PLoS One. Jun 10 2010;5(6):e11051.

  38. Phipps SM, Love WK, White T, et al. Retinoid-induced histone deacetylation inhibits telomerase activity in estrogen receptor-negative breast cancer cells. Anticancer Res. Dec 2009;29(12):4959-4964.

  39. Asgari MM, Brasky TM, White E. Association of vitamin A and carotenoid intake with melanoma risk in a large prospective cohort. J Invest Dermatol. Jun 2012;132(6):1573-1582.

  40. Saboor-Yaraghi AA, Harirchian MH, Mohammadzadeh Honarvar N, et al. The Effect of Vitamin A Supplementation on FoxP3 and TGF-beta Gene Expression in Avonex-Treated Multiple Sclerosis Patients. J Mol Neurosci. Jul 2015;56(3):608-612.

  41. Mohammadzadeh Honarvar N, Harirchian MH, Abdolahi M, et al. Retinyl Palmitate Supplementation Modulates T-bet and Interferon Gamma Gene Expression in Multiple Sclerosis Patients. J Mol Neurosci. Jul 2016;59(3):360-365.

  42. Duerbeck NB, Dowling DD. Vitamin A: too much of a good thing? Obstet Gynecol Surv. Feb 2012;67(2):122-128.

  43. Sibulesky L, Hayes KC, Pronczuk A, et al. Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr. Apr 1999;69(4):656-663.

  44. Aage S, Kiraly N, Da Costa K, et al. Neonatal vitamin A supplementation associated with increased atopy in girls. Allergy. Aug 2015;70(8):985-994.

  45. Romero JB, Schreiber A, Von Hochstetter AR, et al. Hyperostotic and destructive osteoarthritis in a patient with vitamin A intoxication syndrome: a case report. Bull Hosp Jt Dis. 1996;54(3):169-174.

  46. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. Jun 1999;69(6):1071-1085.

  47. Schrogie JJ. Letter: Coagulopathy and fat-soluble vitamins. JAMA. Apr 07 1975;232(1):19.

  48. U.S. Food and Drug Administration. Safety: Xenical (orlistat) capsules. Available at: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor…. Accessed September 19, 2017.

  49. U.S. Food and Drug Administration. New Drug Application (NDA): SORIATANE® (acitretin) Capsules. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019821s024lbl…. 2014. Accessed September 19, 2017.

  50. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Available at: http://www.nap.edu/openbook.php?isbn=0309072794. 2001 Accessed September 19, 2017.