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 is taken by patients to treat and prevent cancer. Vitamin A is also used for eye conditions, kidney stones, acne, and to improve immune function and growth and development in children. Vitamin A is necessary for normal differentiation of corneal, conjunctival, and retinal membranes, growth and 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 (21) and along with zinc, may reduce malaria-related morbidity (4). In developing countries, vitamin A supplementation reduced mortality in children between the ages of 6 months and 5 years (5) (22); however, its effects on infant mortality are conflicting (6) (7) (8). Maternal supplementation does not affect neonatal mortality (9). Vitamin A supplementation may also affect immune response to specific vaccines in children (11) (12); it was shown beneficial and safe in HIV-infected children (23). Studies to determine the proper dosage of vitamin A supplementation for children are still underway (10).
Vitamin A derivatives are in use and are being studied as prescription chemotherapeutic agents for cancer.
A review of 14 clinical trials showed that supplementation with antioxidants beta-carotene, vitamins A, C, and E does not seem to prevent gastrointestinal cancer and may actually increase overall mortality (13). Higher serum retinol was also associated with elevated risk of prostate cancer, with prolonged high exposure resulting in increasing the risk (14).
Adverse effects from chronic vitamin A supplementation include nausea, vomiting, headache, stomatitis, blurred vision, muscular discoordination, and hepatotoxicity. Signs and symptoms of toxicity are non-specific and may include diplopia, headache, insomnia, microcytic anemia, neutropenia, coagulation abnormalities, and bone and skin changes. Pregnant women should not consume vitamin A supplements because chronic consumption of 5,000 International units or greater may cause teratogenic effects. Supplementation with doses greater than the recommended daily allowance may result in toxicity and patients should be monitored accordingly.
Food Sources
Preformed Vitamin A: Fortified dairy products, liver, eggs, fortified margarine, fish
Pro Vitamin A (Beta-carotene): Carrots, leafy greens, cantaloupe, broccoli, squash, sweet potatoes, peas.
(15)
Purported Uses
- Acne
- Cancer prevention
- Crohns disease
- Enhancing tissue integrity
- Eye disorders
- GI disorders
- Growth and development
- Immunostimulation
- Infections
- Kidney stones
- Menorrhagia
Mechanism of Action
Vitamin A is essential for a variety of physiological processes. The retinal form of vitamin A is required for vision in the conversion of light to neuronal signals. Retinoic acid is necessary for maintaining normal differentiation of corneal, conjunctival, and retinal membranes, including the photoreceptor cone and rod cells of the retina. Other biological functions of vitamin A include significant roles in embryonic development, maintenance of epithelial cell integrity in many body tissues, and proper immune activation through cell differentiation and proliferation (15).
Pharmacokinetics
Absorption:
Absorption efficiency of preformed vitamin A is generally high, ranging from 70 to 90%. Intestinal absorption follows the breakdown of retinyl esters in the gut lumen.
Distribution:
In the presence of adequate vitamin A intake, more than 90% of total body stores are located in the liver as retinyl esters. Since vitamin A is fat-soluble, it is distributed widely to sites throughout the body including adipose tissue.
Metabolism/Excretion:
The majority of vitamin A metabolites are excreted in the urine. Retinol also is metabolized in the liver to various products, which can be conjugated prior to excretion in the bile. This additional excretion pathway is postulated to serve as a protective mechanism for decreasing the risk of excess hepatic vitamin A storage.
(15)
Contraindications
Due to possible teratogenicity, women who are pregnant should not consume vitamin A supplements.
Adverse Reactions
Reported: Nausea, vomiting, headache, stomatitis, blurred vision, muscular discoordination, elevated liver function tests.
Chronic toxicity or hypervitaminosis A: Usually associated with chronic intake of more than 30,000 IU of vitamin A. The clinical picture is complex and nonspecific and may include diplopia, headache, insomnia, microcytic anemia, neutropenia, coagulation abnormalities, hepatotoxicity, bone and skin changes, and other nonspecific adverse effects.
(16) (17)
Herb-Drug Interactions
Warfarin: Large doses of vitamin A may increase the anticoagulant effects of warfarin.
Alcohol: Ethanol can compete with retinol for alcohol dehydrogenase, leading to reduced levels of retinol oxidation to retinaldehyde and retinoic acid.
(18)
Literature Summary and Critique
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.
Participants (n=1032) with severe chronic hand eczema (CHE) refractory to corticosteroids were administered alitretinoin (9-cis retinoic acid) or placebo in this randomized, double-blind, placebo-controlled study. As measured by the Physician Global Assessment of overall CHE severity, more patients receiving either 10 or 30 mg alitretinoin daily reported complete or near disappearance of CHE as compared to the placebo group. Adverse events included headache, dry mouth nausea, low TSH, and elevated cholesterol and triglycerides. Further studies are required to determine if alitretinoin is efficacious for other forms of eczema.
Van Zandwijk N, et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. J Natl Cancer Inst 2000;92:977-86.
A prospective, open-label, randomized evaluation of vitamin A (300,000 International units (IU) daily for 1 year followed by 150,000 IU daily for 1 year), N-acetylcysteine (NAC) (600 mg once daily for 2 years), both agents, or placebo in patients with non-small cell lung cancer (NSCLC), laryngeal cancer, or cancer of the oral cavity. Primary end points were event-free survival, overall survival, and occurrence of second primary tumor. A total of 2,573 patients were randomized to vitamin A (n=647), NAC (n=642), both agents (n=643), or placebo (n=641). Demographics appear similar between treatment arms, but no statistical tests were reported. Five-year survival, event-free survival, and development of secondary tumors were not significantly different between treatment arms. Adverse events were reported by approximately 25% of patients receiving vitamin A alone or in combination with NAC. Reactions included gastric events, skin rash, transient elevations in liver function tests, and bone pain. Nearly 18% of patients receiving NAC alone reported adverse events related to gastric events and skin rash. The authors conclude that vitamin A alone or in combination with NAC or NAC alone is no better than placebo in improving survival or decreasing second tumors for patients with primary NSCLC or head and neck cancers.
References
- 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.
- Bocher WO, Wallasch C, Hohler T, Galle PR. All-trans retinoic acid for treatment of chronic hepatitis C. Liver Int. Mar 2008;28(3):347-354.
- 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.
- 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. 2008;7:7.
- Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality. A meta-analysis. JAMA. Feb 17 1993;269(7):898-903.
- 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.
- Benn CS, Diness BR, Roth A, et al. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ. Jun 21 2008;336(7658):1416-1420.
- 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.
- 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.
- Donnen P, Sylla A, Dramaix M, et al. Effect of daily low dose of vitamin A compared with single high dose on morbidity and mortality of hospitalized mainly malnourished children in senegal: a randomized controlled clinical trial. Eur J Clin Nutr. Dec 2007;61(12):1393-1399.
- 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.
- 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.
- Bjelakovic G, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364:1219-28.
- Mondul AM, Watters JL, Männistö S, et al. Serum Retinol and Risk of Prostate Cancer. Am J Epidemiol. 2011 Mar 9. [Epub ahead of print]
- Whitney EN, et al. Understanding Normal & Clinical Nutrition, 4th ed. Belmont (CA): West Publishing; 1994.
- Pronsky ZM. Power’s and Moore’s Food-Medication Interactions, 12th ed. Pottstown (PA): Food Medication Interactions; 2002.
- Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr 2000;71:878-84.
- Leo M, et al. Alcohol, vitamin A, and B-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999;69:1071-85.
- Meyskens FL, 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 1994;12:2060-5.
- Van Zandwijk N, et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. J Natl Cancer Inst 2000;92:977-86.
- 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. 2009 Dec 22. [Epub ahead of print]
- Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD008524.
- Irlam JH, Visser MM, Rollins NN, Siegfried N. Micronutrient supplementation in children and adults with HIV infection. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD003650.
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 must be obtained from diet. Many vegetables and dairy products are rich in vitamin A precursors, such as beta-carotene and cryptoxanthin, which are converted into the active form retinol. Scientists are familiar with many of the normal functions that vitamin A has in the human body, but know less about what effect extra vitamin A supplementation has. Receiving the recommended daily allowance (RDA) of vitamin A 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.
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. - To treat Crohn’s disease
Clinical evidence does not support this use. - To enhance tissue strength
A diet containing adequate amounts of vitamin A is important in the maintenance of tissue strength, but there is no proof from clinical trials that high-dose vitamin A adds any benefit. - To treat eye disorders
Clinical trials have not definitively supported this use. - To treat gastrointestinal disorders
No scientific evidence supports this use. - To stimulate the immune system
No scientific evidence supports this use. - To treat infections
No scientific evidence supports this use. - To treat kidney stones
No scientific evidence supports this use. - To prevent menorrhagia (excessive bleeding at menstruation)
No scientific evidence supports this use.
Research Evidence
Melanoma:
The ability of high-dose vitamin A to prevent a recurrence of completely resected melanoma was tested in a study of 240 patients. Patients were randomly assigned to receive 100,000 International units of oral vitamin A for 18 months or no treatment for the same amount of time. After eight years of follow-up, patients taking vitamin A had the same average disease-free survival and overall survival. In addition, patients taking vitamin A reported numerous severe side effects, including headaches, nausea, blood clotting problems, dizziness, and emotional disturbances. High-dose oral vitamin A supplementation does not appear to influence recurrence or survival following complete resection of melanoma.
Preventing cancer recurrence:
The EUROSCAN clinical trial studied the effects of high-dose vitamin A and N-acetylcysteine on the recurrence rates and survival of 2573 patients with cancer of the oral cavity, laryngeal cancer, or non-small cell lung cancer (NSCLC). The patients were randomly split into four groups and given either: 1) 300,000 IU (international units) of vitamin A daily for 1 year followed by 150,000 IU daily for 1 year, 2) 600 mg of N-acetylcysteine daily for 2 years, 3) both vitamin A and N-acetylcysteine, or 3) two placebo pills. The patients were followed for an average of four years, and it was found that all four groups had similar recurrence rates and overall survival times. Many patients taking vitamin A reported having side effects. This clinical trial suggests that high-dose vitamin A and N-acetylcysteine do not prevent recurrences or extend survival in patients with head and neck cancers or NSCLC.
Gastrointestinal cancer:
A recent review of 14 clinical trials shows that supplementation with antioxidants beta-carotene, vitamins A, C, and E does not seem to prevent gastrointestinal cancer and may actually increase overall mortality.
Patient Warnings
- This product is regulated by the FDA as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.
Do Not Take If
- You are pregnant (Doses of vitamin A of 5000 IU or greater can cause birth defects).
- You take warfarin (Coumadin®) or other blood thinners (Large doses of vitamin A may increase the risk of bleeding or bruising).
- You regularly consume alcoholic beverages (Alcohol can lessen the positive effects of vitamin A on the eyes. Take with caution).
Side Effects
- Nausea and vomiting
- Headache
- Stomatitis (swelling of the mucous membranes of the mouth)
- Blurred vision
- Muscular discoordination
- Elevated liver function tests
- Chronic toxicity or hypervitaminosis A: This toxicity is usually associated with chronic intake of more than 30,000 IU of vitamin A. Symptoms may include double vision, headache, insomnia, microcytic anemia, neutropenia (abnormally low levels of white blood cells), blood clotting problems, liver damage, bone and skin changes, and other nonspecific adverse effects.
Special Point
Supplementation with doses greater than the recommended daily allowance may result in toxicity and patients should be monitored accordingly.
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