- What is Vitamin A
- Vitamin A function
- Vitamin A Supplements
- How much vitamin A do you need?
- What foods provide vitamin A?
- What happens if you don’t get enough vitamin A?
- Vitamin A Deficiency
- Vitamin A Toxicity: Can Taking Too Much Vitamin A Be Harmful?
What is Vitamin A
Vitamin A is name of a group of fat-soluble vitamin (retinoids, including retinol, retinal, and retinyl esters) 1), 2), 3), that is naturally present in many foods.
Vitamin A is important for normal vision, gene expression, the immune system, embryonic development, growth, and reproduction. Vitamin A also helps the heart, lungs, kidneys, and other organs work properly 4).
Vitamin A is critical for vision as an essential component of rhodopsin, a protein that absorbs light in the retinal receptors, and because it supports the normal differentiation and functioning of the conjunctival membranes and cornea 5), 6), 7). Vitamin A also supports cell growth and differentiation, playing a critical role in the normal formation and maintenance of the heart, lungs, kidneys, and other organs 8).
There are two different types of vitamin A 9).
- The first type, preformed vitamin A (retinol and its esterified form, retinyl ester), is found in meat (especially liver), poultry, fish, and dairy products.
- The second type, provitamin A carotenoids (beta-carotene, alpha-carotene and beta-cryptoxanthin), is found in fruits, vegetables, and other plant-based products (oily fruits and red palm oil). The most common type of provitamin A carotenoids in foods and dietary supplements is beta-carotene (β-carotene). The body converts these plant pigments into vitamin A.
Both provitamin A and preformed vitamin A must be metabolized intracellularly to retinal and retinoic acid, the active forms of vitamin A, to support the vitamin’s important biological functions 10), 11). Other carotenoids found in food, such as lycopene, lutein, and zeaxanthin, are not converted into vitamin A.
Both retinyl esters and provitamin A carotenoids are converted to retinol, which is oxidized to retinal and then to retinoic acid 12). Most of the body’s vitamin A is stored in the liver in the form of retinyl esters.
Normally, the liver stores 80 to 90% of the body’s vitamin A. To use vitamin A, the body releases it into the circulation bound to prealbumin (transthyretin) and retinol-binding protein. Beta-carotene and other provitamin carotenoids, contained in green leafy and yellow vegetables and deep- or bright-colored fruits, are converted to vitamin A. Carotenoids are absorbed better from vegetables when they are cooked or homogenized and served with some fat (eg, oils).
The body can convert beta-carotene into vitamin A to help meet these requirements. Although there is no Recommended Dietary Allowance for beta-carotene, the National Institutes of Health Office of Dietary Supplements recommends eating five or more servings of fruits and vegetables per day, including dark green and leafy vegetables and deep yellow or orange fruits to get appropriate amounts of beta-carotene.
Retinol activity equivalents (RAE) were developed because provitamin A carotenoids have less vitamin A activity than preformed vitamin A; 1 µg retinol = 3.33 IU.
For dietary provitamin A carotenoids (β-carotene, α-carotene, and β-cryptoxanthin), retinol activity equivalents (RAEs) have been set at 12, 24, and 24 μg, respectively. Using μg RAE, the vitamin A activity of provitamin A carotenoids is half the vitamin A activity assumed when using μg retinol equivalents (μg RE) 13). This change in equivalency values is based on data demonstrating that the vitamin A activity of purified β-carotene in oil is half the activity of vitamin A, and based on recent data demonstrating that the vitamin A activity of dietary β-carotene is one-sixth, rather than one-third, the vitamin activity of purified β-carotene in oil. This change in bioconversion means that a larger amount of provitamin A carotenoids, and therefore darkly colored, carotene-rich fruits and vegetables, is needed to meet the vitamin A requirement.
Synthetic vitamin analogs (retinoids) are being used increasingly in dermatology. The possible protective role of beta-carotene, retinol, and retinoids against some epithelial cancers is under study. However, risk of certain cancers may be increased after beta-carotene supplementation 14).
Retinol is the form of vitamin A that causes concern. In addition to getting retinol from their diets, some people may be using synthetic retinoid preparations that are chemically similar to vitamin A to treat acne, psoriasis, and other skin conditions. These preparations have been shown to have the same negative impact on bone health as dietary retinol. Use of these medications in children and teens also has been linked to delays in growth.
Vitamin A key points
- Vitamin A is a generic term that refers to fat-soluble compounds found as preformed vitamin A (retinol) in animal products and as provitamin A carotenoids in fruit and vegetables. The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid.
- Vitamin A is involved in regulating the growth and specialization (differentiation) of virtually all cells in the human body. Vitamin A has important roles in embryonic development, organ formation during fetal development, normal immune functions, and eye development and vision.
- Vitamin A deficiency is a major cause of preventable blindness in the world. It is most prevalent among children and women of childbearing age. Vitamin A deficiency is associated with an increased susceptibility to infections, as well as to thyroid and skin disorders.
- The recommended dietary allowance (RDA) is 700 micrograms of retinol activity equivalents (μg RAE)/day for women and 900 μg RAE/day for men.
- Vitamin A prophylaxis appears to significantly reduce childhood mortality in regions at high risk of vitamin A deficiency. Further, high-dose vitamin A supplementation is widely recommended for children over six months of age when they are infected with measles while malnourished, immunodeficient, or are at risk of measles complications. (More information)
- Retinoic acid and analogs are used at pharmacological doses in the treatment of acute promyelocytic leukemia and various skin diseases.
- Animal food sources rich in preformed vitamin A include dairy products, fortified cereal, liver, and fish oils. Rich sources of provitamin A carotenoids include orange and green vegetables, such as sweet potato and spinach.
- Overconsumption of preformed vitamin A can be highly toxic and is especially contraindicated prior to and during pregnancy as it can result in severe birth defects. The tolerable upper intake level (UL) for vitamin A in adults is set at 3,000 μg RAE/day. The UL does not apply to vitamin A derived from carotenoids.
Figure 1. Vitamin A chemical structure
Vitamin A function
Vitamin A compounds are essential fat-soluble molecules predominantly stored in the liver in the form of retinyl esters (e.g., retinyl palmitate). When appropriate, retinyl esters are hydrolyzed to generate all-trans-retinol, which binds to retinol binding protein before being released in the bloodstream. The all-trans-retinol or retinol binding protein complex circulates bound to the protein, transthyretin, which delivers all-trans-retinol to peripheral tissues 15). Vitamin A as retinyl esters in chylomicrons was also found to have an appreciable role in delivering vitamin A to extrahepatic tissues, especially in early life 16).
Visual system and eyesight
Located at the back of the eye, the retina contains two main types of light-sensitive receptor cells − known as rod and cone photoreceptor cells. Photons (particles of light) that pass through the lens are sensed by the photoreceptor cells of the retina and converted to nerve impulses (electric signals) for interpretation by the brain. All-trans-retinol is transported to the retina via the circulation and accumulates in retinal pigment epithelial (RPE) cells 17). Here, all-trans-retinol is esterified to form a retinyl ester, which can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis-retinol, which can be oxidized to form 11-cis-retinal. 11-cis-retinal can be shuttled across the interphotoreceptor space to the rod photoreceptor cell that is specialized for vision in low-light conditions and for detection of motion. In rod cells, 11-cis-retinal binds to a protein called opsin to form the visual pigment rhodopsin (also known as visual purple). Absorption of a photon of light catalyzes the isomerization of 11-cis-retinal to all-trans-retinal that is released from the opsin molecule. This photoisomerization triggers a cascade of events, leading to the generation of a nerve impulse conveyed by the optic nerve to the brain’s visual cortex. All-trans-retinal is converted to all-trans-retinol and transported across the interstitial space to the retinal pigment epithelial cells, thereby completing the visual cycle.
A similar cycle occurs in cone cells that contain red, green, or blue opsin proteins required for the absorption of photons from the visible light spectrum 18). Vitamin A is also essential for mammalian eye development 19). Thus, because vitamin A is required for the normal functioning of the retina, dim-light vision, and color vision, inadequate retinol and retinal available to the retina result in impaired dark adaptation. In the severest cases of vitamin A deficiency, thinning and ulceration of the cornea leads to blindness.
Vitamin A was initially coined “the anti-infective vitamin” because of its importance in the normal functioning of the immune system 20). The skin and mucosal cells, lining the airways, digestive tract, and urinary tract function as a barrier and form the body’s first line of defense against infection. Retinoic acid (RA) is produced by antigen-presenting cells (APCs), including macrophages and dendritic cells, found in these mucosal interfaces and associated lymph nodes. Retinoic acid appears to act on dendritic cells themselves to regulate their differentiation, migration, and antigen-presenting capacity. In addition, the production of retinoic acid by antigen-presenting cells is required for the differentiation of naïve CD4 T-lymphocytes into induced regulatory T- lymphocytes (Tregs). Critical to the maintenance of mucosal integrity, the differentiation of Tregs is driven by all-trans-RA through RARα-mediated regulation of gene expression. Also, during inflammation, all-trans-RA/RARα signaling pathway promotes the conversion of naïve CD4 T-lymphocytes into effector T-lymphocytes − type 1 helper T-cells (Th1) − (rather than into Tregs) and induces the production of proinflammatory cytokines by effector T-lymphocytes in response to infection. There is also substantial evidence to suggest that retinoic acid may help prevent the development of autoimmunity 21).
Prenatal and postnatal development
Both vitamin A excess and deficiency are known to cause birth defects. Retinoid signaling begins soon after the early phase of embryonic development known as gastrulation. During fetal development, retinoic acid is critical for the development of organs, including the heart, eyes, ears, lungs, as well as other limbs and visceral organs. Vitamin A has been implicated in fetal lung maturation 22). Vitamin A status is lower in preterm newborns than in full-term infants 23). There is some evidence to suggest that vitamin A supplementation may help reduce the incidence of chronic lung disease and mortality in preterm newborns. Retinoid signaling is also involved in the expression of many proteins of the extracellular matrix (ECM; material surrounding cells), including collagen, laminin, and proteoglycans 24). Vitamin A deficiency may then result in alterations of the ECM composition, thus disrupting organ morphology and function 25).
Red blood cell production (erythropoiesis)
Red blood cells (erythrocytes), like all blood cells, are derived from pluripotent stem cells in the bone marrow. Studies involving in vitro culture systems have suggested a role for retinoids in stem cell commitment and differentiation to the red blood cell lineage. Retinoids might also regulate apoptosis (programmed cell death) of red blood cell precursors (erythropoietic progenitor cells) 26). However, whether retinoids regulate erythropoiesis in vivo has not been established. Yet, vitamin A supplementation in vitamin A deficient-individuals has been shown to increase hemoglobin concentrations. Additionally, vitamin A appears to facilitate the mobilization of iron from storage sites to the developing red blood cell for incorporation into hemoglobin, the oxygen carrier in red blood cells 27).
Vitamin A Supplements
Vitamin A is available in multivitamins and as a stand-alone supplement, often in the form of retinyl acetate or retinyl palmitate 28). A portion of the vitamin A in some supplements is in the form of beta-carotene and the remainder is preformed vitamin A; others contain only preformed vitamin A or only beta-carotene. Supplement labels usually indicate the percentage of each form of the vitamin. The amounts of vitamin A in stand-alone supplements range widely 29). Multivitamin supplements typically contain 2,500–10,000 IU vitamin A, often in the form of both retinol and beta-carotene.
About 28%–37% of the general population uses supplements containing vitamin A 30). Adults aged 71 years or older and children younger than 9 are more likely than members of other age groups to take supplements containing vitamin A.
Presently, there is little evidence that the requirement for vitamin A in older adults differs from that of younger adults. Additionally, vitamin A toxicity may occur at lower doses in older adults than in younger adults. Furthermore, data from observational studies suggested an association between intakes of preformed vitamin A in excess of 1,500 μg RAE (5,000 IU)/day and increased risk of hip fracture in older people. For this reason, experts recommend taking a multivitamin/mineral supplement that provides (750 μg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene. As for all age groups, high potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.
Chronic alcohol consumption results in depletion of liver stores of vitamin A and may contribute to alcohol-induced liver damage (cirrhosis) 31). However, the liver toxicity of preformed vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics 32). Oral contraceptives that contain estrogen and progestin increase retinol binding protein (RBP) synthesis by the liver, increasing the export of all-trans-retinol or retinol binding protein complex to the circulation. Whether this increases the dietary requirement of vitamin A is not known. Also, the use of cholesterol-lowering medications (like cholestyramine and colestipol), as well as orlistat, mineral oil, and the fat substitute, olestra, which interfere with fat absorption, may affect the absorption of fat-soluble vitamins, including vitamin A 33). Further, intake of large doses of vitamin A may decrease the absorption of vitamin K. Retinoids or retinoid analogs, including acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin, should not be used in combination with single-nutrient vitamin A supplements, because they may increase the risk of vitamin A toxicity 34).
How much vitamin A do you need?
The amount of vitamin A you need depends on your age and sex. Average daily recommended amounts are listed below in micrograms (mcg) of retinol activity equivalents (RAE).
According to an analysis of data from the 2007–2008 National Health and Nutrition Examination Survey (NHANES), the average daily dietary vitamin A intake in Americans aged 2 years and older is 607 mcg Retinol Activity Equivalents (RAE) 35). Adult men have slightly higher intakes (649 mcg RAE) than adult women (580 mcg RAE). Although these intakes are lower than the RDAs for individual men and women, these intake levels are considered to be adequate for population groups.
The adequacy of vitamin A intake decreases with age in children 36). Furthermore, girls and African-American children have a higher risk of consuming less than two-thirds of the vitamin A RDA than other children 37).
There are a variety of foods rich in vitamin A and provitamin A carotenoids that are available to Americans. Thus, current dietary patterns appear to provide sufficient vitamin A to prevent deficiency symptoms such as night blindness 38).
- The Estimated Average Requirement (EAR) is based on the assurance of adequate stores of vitamin A.
- The Recommended Dietary Allowance (RDA) (average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals) for men is 900 μg and women is 700 μg Retinol Activity Equivalents (RAE)/day.
- The Tolerable Upper Intake Level (UL) (maximum daily intake unlikely to cause adverse health effects) for adults is set at 3,000 μg/day of preformed vitamin A.
The Recommended Dietary Allowance (RDA) for vitamin A are given as mcg of retinol activity equivalents (RAE) to account for the different bioactivities of retinol and provitamin A carotenoids (see Table 1). Because the body converts all dietary sources of vitamin A into retinol, 1 mcg of physiologically available retinol is equivalent to the following amounts from dietary sources: 1 mcg of retinol, 12 mcg of beta-carotene, and 24 mcg of alpha-carotene or beta-cryptoxanthin. From dietary supplements, the body converts 2 mcg of beta-carotene to 1 mcg of retinol.
Currently, vitamin A is listed on food and supplement labels in international units (IUs) even though nutrition scientists rarely use this measure. Conversion rates between mcg RAE and IU are as follows 39):
- 1 IU retinol = 0.3 mcg RAE
- 1 IU beta-carotene from dietary supplements = 0.15 mcg RAE
- 1 IU beta-carotene from food = 0.05 mcg RAE
- 1 IU alpha-carotene or beta-cryptoxanthin = 0.025 mcg RAE
An RAE cannot be directly converted into an IU without knowing the source(s) of vitamin A. For example, the RDA of 900 mcg RAE for adolescent and adult men is equivalent to 3,000 IU if the food or supplement source is preformed vitamin A (retinol). However, this RDA is also equivalent to 6,000 IU of beta-carotene from supplements, 18,000 IU of beta-carotene from food, or 36,000 IU of alpha-carotene or beta-cryptoxanthin from food. So a mixed diet containing 900 mcg RAE provides between 3,000 and 36,000 IU of vitamin A, depending on the foods consumed.
The amount of vitamin A you need depends on your age and reproductive status. Recommended intakes for vitamin A for people aged 14 years and older range between 700 and 900 micrograms (mcg) of retinol activity equivalents (RAE) per day. Recommended intakes for women who are nursing range between 1,200 and 1,300 RAE. Lower values are recommended for infants and children younger than 14.
However, the vitamin A content of foods and dietary supplements is given on product labels in international units (IU), not mcg RAE. Converting between IU and mcg RAE is not easy. A varied diet with 900 mcg RAE of vitamin A, for example, provides between 3,000 and 36,000 IU of vitamin A depending on the foods consumed. See our Health Professional Fact Sheet on Vitamin A for more details.
For adults and children aged 4 years and older, the U.S. Food and Drug Administration has established a vitamin A Daily Value (DV) of 5,000 IU from a varied diet of both plant and animal foods. DVs are not recommended intakes; they don’t vary by age and sex, for example. But trying to reach 100% of the DV each day, on average, is useful to help you get enough vitamin A.
The Institute of Medicine developed the Recommended Dietary Allowance (RDA) for vitamin A (retinol). The recommended intakes are listed in International Units (IU) in the table, below:
Table 1: Recommended Dietary Allowances (RDAs) for Vitamin A
|Life Stage||Recommended Amount|
|Birth to 6 months||400 mcg RAE|
|Infants 7–12 months||500 mcg RAE|
|Children 1–3 years||300 mcg RAE|
|Children 4–8 years||400 mcg RAE|
|Children 9–13 years||600 mcg RAE|
|Teen boys 14–18 years||900 mcg RAE|
|Teen girls 14–18 years||700 mcg RAE|
|Adult men||900 mcg RAE|
|Adult women||700 mcg RAE|
|Pregnant teens||750 mcg RAE|
|Pregnant women||770 mcg RAE|
|Breastfeeding teens||1,200 mcg RAE|
|Breastfeeding women||1,300 mcg RAE|
Vitamin A safety in pregnancy
Although normal fetal development requires sufficient vitamin A intake, consumption of excess preformed vitamin A (such as retinol) during early pregnancy is known to cause birth defects. No increase in the risk of vitamin A-associated birth defects has been observed at doses of preformed vitamin A from supplements below 3,000 μg RAE/day (10,000 IU/day) 41). Of note, in 2011, the World Health Organization (WHO) recommended vitamin A supplementation (up to 3,000 μg RAE/day or 7,500 μg RAE/week) during pregnancy in areas with high prevalence of vitamin A deficiency for the prevention of blindness 42). In industrialized countries, pregnant or potentially pregnant women should monitor their intake of vitamin A from fortified food and food naturally high in preformed vitamin A (e.g., liver) and avoid taking daily multivitamin supplements that contain more than 1,500 μg RAE (5,000 IU) of vitamin A. There is no evidence that consumption of vitamin A from β-carotene might increase the risk of birth defects. The synthetic derivative of retinol, isotretinoin, is known to cause serious birth defects and should not be taken during pregnancy or if there is a possibility of becoming pregnant 43). Tretinoin (all-trans-retinoic acid), another retinol derivative, is prescribed as a topical preparation that is applied to the skin. Although percutaneous absorption of topical tretinoin is minimal, its use during pregnancy is not recommended 44).
Do high intakes of vitamin A increase the risk of osteoporosis?
Results from some prospective studies have suggested that long-term intakes of preformed vitamin A in excess of 1,500 μg RAE/day (equivalent to 5,000 IU/day of vitamin A as retinol) were associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fracture in older adults 45). However, other investigators failed to observe such detrimental effects on BMD and/or fracture risk 46). The recent meta-analysis of four prospective studies, including nearly 183,000 participants over 40 years of age, found that highest vs. lowest quintiles of retinol (preformed vitamin A) intake significantly increased the risk of hip fracture 47). Only excess intakes of retinol, not β-carotene, were associated with adverse effects on bone health. Besides, the pooled analysis of four observational studies also indicated that a U-shaped relationship between circulating retinol and risk of hip fracture, suggesting that both elevated and reduced retinol concentrations in the blood were associated with an increased risk of hip fracture 48).
To date, limited experimental data have suggested that vitamin A (as all-trans-retinoic acid) may affect the development of bone-remodeling cells and stimulate bone matrix degradation (resorption) 49). Vitamin A may also interfere with the ability of vitamin D to maintain calcium balance 50). In the large Women’s Health Initiative (WHI) prospective study, the highest vs. lowest quintile of retinol intake (≥1,426 μg/day vs. <474 μg/day) was found to be significantly associated with increased risk of fracture only in women with the lowest vitamin D intakes (≤440 IU/day) 51).
Until supplements and fortified food are reformulated to reflect the current RDA for vitamin A, it is advisable for older individuals to consume multivitamin supplements that contain no more than 2,500 IU (750 μg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene.
What foods provide vitamin A?
There are a variety of foods rich in vitamin A and provitamin A carotenoids that are available to Americans 52). Vitamin A is found naturally in many foods and is added to some foods, such as milk and cereal.
- The U.S. Department of Agriculture’s (USDA’s) Nutrient Database Web site 53) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin A in IUs arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitaminA-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/VitaminA-Food.pdf), and foods containing beta-carotene in mcg arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitA-betaCarotene-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/VitA-betaCarotene-Food.pdf).
Concentrations of preformed vitamin A are highest in liver and fish oils 54). Other sources of preformed vitamin A are milk and eggs, which also include some provitamin A 55). Most dietary provitamin A comes from leafy green vegetables, orange and yellow vegetables, tomato products, fruits, and some vegetable oils 56). The top food sources of vitamin A in the U.S. diet include dairy products, liver, fish, and fortified cereals; the top sources of provitamin A include carrots, broccoli, cantaloupe, and squash 57), 58).
You can get recommended amounts of vitamin A by eating a variety of foods, including the following:
- Beef liver and other organ meats (but these foods are also high in cholesterol, so limit the amount you eat).
- Some types of fish, such as salmon.
- Green leafy vegetables and other green, orange, and yellow vegetables, such as broccoli, carrots, and squash.
- Fruits, including cantaloupe, apricots, and mangos.
- Dairy products, which are among the major sources of vitamin A for Americans.
- Fortified breakfast cereals.
Plant sources of beta-carotene are not as well absorbed as the animal sources of vitamin A listed in the chart, but they are still an important source of this vitamin. Dark orange and green vegetables and fruit, including carrots, sweet potatoes, spinach, cantaloupe, and kale are excellent sources of beta-carotene. Because of concerns about the negative effects of too much retinol, some people prefer to eat more foods rich in beta-carotene to satisfy their need for vitamin A.
Although a large body of observational epidemiological evidence suggests that higher blood concentrations of β-carotenes and other carotenoids (provitamin A carotenoids) obtained from foods are associated with a lower risk of several chronic diseases, there is currently not sufficient evidence to support a recommendation that requires a certain percentage of dietary vitamin A to come from provitamin A carotenoids in meeting the vitamin A requirement. However, the existing recommendations for increased consumption of carotenoid-rich fruits and vegetables for their health-promoting benefits are strongly supported (see Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids 59)).
The chart below identifies some common food sources of retinol. Most of the reported cases of vitamin A toxicity have been blamed on the use of supplements. Healthy individuals who eat a balanced diet generally do not need a vitamin A supplement.
Table 2: Common Food Sources of Retinol
|Food Sources of Retinol||Vitamin A (IU)|
|Liver, beef, cooked 3 oz.||30,325|
|Liver, chicken, cooked, 3 oz.||13,920|
|Egg substitute, fortified, ¼ cup||1,355|
|Fat-free milk, fortified with vitamin A, 1 cup||500|
|Cheese pizza, ⅛ of a 12-inch pie||380|
|Milk, whole, 3.25% fat, 1 cup||305|
|Cheddar cheese, 1 oz||300|
|Whole egg, 1 medium||280|
Table 3 suggests many dietary sources of vitamin A. The foods from animal sources in Table 3 contain primarily preformed vitamin A, the plant-based foods have provitamin A, and the foods with a mixture of ingredients from animals and plants contain both preformed vitamin A and provitamin A.
Table 3: Selected Food Sources of Vitamin A
RAE per serving
|Beef liver, pan fried, 3 ounces||6582||731|
|Sweet potato, baked in skin, 1 whole||1403||156|
|Spinach, frozen, boiled, ½ cup||573||64|
|Pumpkin pie, commercially prepared, 1 piece||488||54|
|Carrots, raw, ½ cup||459||51|
|Ice cream, French vanilla, soft serve, 1 cup||278||31|
|Cheese, ricotta, part skim, 1 cup||263||29|
|Herring, Atlantic, pickled, 3 ounces||219||24|
|Milk, fat free or skim, with added vitamin A and vitamin D, 1 cup||149||17|
|Cantaloupe, raw, ½ cup||135||15|
|Peppers, sweet, red, raw, ½ cup||117||13|
|Mangos, raw, 1 whole||112||12|
|Breakfast cereals, fortified with 10% of the DV for vitamin A, 1 serving||90||10|
|Egg, hard boiled, 1 large||75||8|
|Black-eyed peas (cowpeas), boiled, 1 cup||66||7|
|Apricots, dried, sulfured, 10 halves||63||7|
|Broccoli, boiled, ½ cup||60||7|
|Salmon, sockeye, cooked, 3 ounces||59||7|
|Tomato juice, canned, ¾ cup||42||5|
|Yogurt, plain, low fat, 1 cup||32||4|
|Tuna, light, canned in oil, drained solids, 3 ounces||20||2|
|Baked beans, canned, plain or vegetarian, 1 cup||13||1|
|Summer squash, all varieties, boiled, ½ cup||10||1|
|Chicken, breast meat and skin, roasted, ½ breast||5||1|
|Pistachio nuts, dry roasted, 1 ounce||4||0|
Footnote: *DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin A is 5,000 IU for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.[Source 60)]
Are you getting enough vitamin A?
Most people in the United States get enough vitamin A from the foods they eat, and vitamin A deficiency is rare 61). However, certain groups of people are more likely than others to have trouble getting enough vitamin A:
- Premature infants, who often have low levels of vitamin A in their first year.
- Infants, young children, pregnant women, and breastfeeding women in developing countries.
- People with cystic fibrosis.
What happens if you don’t get enough vitamin A?
Vitamin A deficiency is rare in the United States, although it is common in many developing countries. The most common symptom of vitamin A deficiency in young children and pregnant women is an eye condition called xerophthalmia. Xerophthalmia is the inability to see in low light, and it can lead to blindness if it isn’t treated.
Benefits of Vitamin A
Vitamin A is an antioxidant. It can come from plant or animal sources. Plant sources include colorful fruits and vegetables. Animal sources include liver and whole milk. Vitamin A is also added to foods like cereals.
Vitamin A plays a role in your
- Bone growth
- Reproduction 62). The vitamin A metabolite, trans retinoic acid, is essential for reproduction in both the male and female, as well as for many events in the developing embryo.
- Cell functions
- Immune system 63)
What are some effects of vitamin A on health?
Scientists are studying vitamin A to understand how it affects health. Here are some examples of what this research has shown.
Because of the role vitamin A plays in regulating cell growth and differentiation, several studies have examined the association between vitamin A and various types of cancer. However, the relationship between serum vitamin A levels or vitamin A supplementation and cancer risk is unclear. People who eat a lot of foods containing beta-carotene might have a lower risk of certain kinds of cancer, such as lung cancer or prostate cancer. But studies to date have not shown that vitamin A or beta-carotene supplements can help prevent cancer or lower the chances of dying from this disease. In fact, studies show that smokers who take high doses of beta-carotene supplements have an increased risk of lung cancer.
Several prospective and retrospective observational studies in current and former smokers, as well as in people who have never smoked, found that higher intakes of carotenoids, fruits and vegetables, or both are associated with a lower risk of lung cancer 64), 65). However, clinical trials have not shown that supplemental beta-carotene and/or vitamin A helps prevent lung cancer. In the Carotene and Retinol Efficacy Trial (CARET), 18,314 current and former smokers (including some males who had been occupationally exposed to asbestos) took daily supplements containing 30 mg beta-carotene and 25,000 IU retinyl palmitate for 4 years, on average 66).
In the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, 29,133 male smokers took 50 mg/day alpha-tocopherol, 20 mg/day beta-carotene, 50 mg/day alpha-tocopherol and 20 mg/day beta-carotene, or placebo for 5–8 years 67). In the beta-carotene component of the Physicians’ Health Study, 22,071 male physicians took 325 mg aspirin plus 50 mg beta-carotene, 50 mg beta-carotene plus aspirin placebo, 325 mg aspirin plus beta-carotene placebo, or both placebos every other day for 12 years 68). In all three of these studies, taking very high doses of beta-carotene, with or without 25,000 IU retinyl palmitate or 325 mg aspirin, did not prevent lung cancer. In fact, both the CARET and ATBC studies showed a significant increase in lung cancer risk among study participants taking beta-carotene supplements or beta-carotene and retinyl palmitate supplements. The Physicians’ Health Study did not find an increased lung cancer risk in participants taking beta-carotene supplements, possibly because only 11% of physicians in the study were current or former smokers.
The evidence on the relationship between beta-carotene and prostate cancer is mixed. CARET study participants who took daily supplements of beta-carotene and retinyl palmitate had a 35% lower risk of nonaggressive prostate cancer than men not taking the supplements 69). However, the ATBC study found that baseline serum beta-carotene and retinol levels and supplemental beta-carotene had no effect on survival 70). Moreover, men in the highest quintile of baseline serum retinol levels were 20% more likely to develop prostate cancer than men in the lowest quintile 71).
The ATBC and CARET study results suggest that large supplemental doses of beta-carotene with or without retinyl palmitate have detrimental effects in current or former smokers and workers exposed to asbestos. The relevance of these results to people who have never smoked or to the effects of beta-carotene or retinol from food or multivitamins (which typically have modest amounts of beta-carotene) is not known. More research is needed to determine the effects of vitamin A on prostate, lung, and other types of cancer.
- Age-Related Macular Degeneration
Age-related macular degeneration (AMD), or the loss of central vision as people age, is one of the most common causes of vision loss in older people. Age-related macular degeneration’s causes is usually unknown, but the cumulative effect of oxidative stress is postulated to play a role. If so, supplements containing carotenoids with antioxidant functions, such as beta-carotene, lutein, and zeaxanthin, might be useful for preventing or treating this condition. Lutein and zeaxanthin, in particular, accumulate in the retina, the tissue in the eye that is damaged by age-related macular degeneration.
The Age-Related Eye Disease Study (AREDS), a large randomized clinical trial, found that participants at high risk of developing advanced age-related macular degeneration (i.e., those with intermediate AMD or those with advanced AMD in one eye) reduced their risk of developing advanced AMD by 25% by taking a daily supplement containing beta-carotene (15 mg), vitamin E (400 IU dl-alpha-tocopheryl acetate), vitamin C (500 mg), zinc (80 mg), and copper (2 mg) for 5 years compared to participants taking a placebo 72).
A follow-up AREDS2 study confirmed the value of this supplement in reducing the progression of age-related macular degeneration over a median follow-up period of 5 years but found that adding lutein (10 mg) and zeaxanthin (2 mg) or omega-3 fatty acids to the formulation did not confer any additional benefits 73). Importantly, the study revealed that beta-carotene was not a required ingredient; the original AREDS formulation without beta-carotene provided the same protective effect against developing advanced AMD. In a more detailed analysis of results, supplementation with lutein and zeaxanthin reduced the risk of advanced AMD by 26% in participants with the lowest dietary intakes of these two carotenoids who took a supplement containing them compared to those who did not take a supplement with these carotenoids 74). The risk of advanced AMD was also 18% lower in participants who took the modified AREDS supplement containing lutein and zeaxanthin but not beta-carotene than in participants who took the formulation with beta-carotene but not lutein or zeaxanthin.
Individuals who have or are developing AMD should talk to their health care provider about taking one of the supplement formulations used in AREDS.
When children with vitamin A deficiency (which is rare in North America) get measles, the disease tends to be more severe. In these children, taking supplements with high doses of vitamin A can shorten the fever and diarrhea caused by measles. These supplements can also lower the risk of death in children with measles who live in developing countries where vitamin A deficiency is common.
Measles is a major cause of morbidity and mortality in children in developing countries. About half of all measles deaths happen in Africa, but the disease is not limited to low-income countries. Vitamin A deficiency is a known risk factor for severe measles. The World Health Organization recommends high oral doses (200,000 IU) of vitamin A for two days for children over age 1 with measles who live in areas with a high prevalence of vitamin A deficiency 75).
A Cochrane review of eight randomized controlled trials of treatment with vitamin A for children with measles found that 200,000 IU of vitamin A on each of two consecutive days reduced mortality from measles in children younger than 2 and mortality due to pneumonia in children 76). Vitamin A also reduced the incidence of croup but not pneumonia or diarrhea, although the mean duration of fever, pneumonia, and diarrhea was shorter in children who received vitamin A supplements. A meta-analysis of six high-quality randomized controlled trials of measles treatment also found that two doses of 100,000 IU in infants and 200,000 IU in older children significantly reduced measles mortality 77). The vitamin A doses used in these studies are much higher than the UL. The effectiveness of vitamin A supplementation to treat measles in countries, such as the United States, where vitamin A intakes are usually adequate is uncertain.
The body needs vitamin A to maintain the corneas and other epithelial surfaces, so the lower serum concentrations of vitamin A associated with measles, especially in people with protein-calorie malnutrition, can lead to blindness. None of the studies evaluated in a Cochrane review evaluated blindness as a primary outcome 78). However, a careful clinical investigation of 130 African children with measles revealed that half of all corneal ulcers in these children, and nearly all bilateral blindness, occurred in those with vitamin A deficiency 79).
Vitamin A Deficiency
Vitamin A deficiency can result from inadequate intake, fat malabsorption, or liver disorders. Deficiency impairs immunity and hematopoiesis and causes rashes and typical ocular effects (eg, xerophthalmia, night blindness). Vegetarians, young children, and alcoholics may need extra Vitamin A. You might also need more if you have certain conditions, such as liver diseases, cystic fibrosis, and Crohn’s disease 80). Diagnosis is based on typical ocular findings and low vitamin A levels. Treatment consists of vitamin A given orally or if symptoms are severe or malabsorption is the cause, parenterally.
Vitamin A deficiency is one of the top causes of preventable blindness in children 81). People with vitamin A deficiency (and, often, xerophthalmia with its characteristic Bitot’s spots) tend to have low iron status, which can lead to anemia 82), 83).
The most specific clinical effect of inadequate vitamin A intake is xerophthalmia 84). It is estimated that 3 to 10 million children, mostly in developing countries, become xerophthalmic, and 250,000 to 500,000 go blind annually 85), 86). The World Health Organization 87) classified various stages of xerophthalmia to include night blindness (impaired dark adaptation due to slowed regeneration of rhodopsin), conjunctival xerosis, Bitot’s spots, corneal xerosis, corneal ulceration, and scarring, all related to vitamin A deficiency. Night blindness is the first ocular symptom to be observed with vitamin A deficiency 88), and it responds rapidly to treatment with vitamin A 89). High-dose (60 mg) vitamin A supplementation reduced the incidence of night blindness by 63 percent in Nepalese children 90). Similarly, night blindness was reduced by 50 percent in women after weekly supplementation with either 7,500 μg RE of vitamin A or β-carotene 91).
In developing countries, vitamin A deficiency typically begins during infancy, when infants do not receive adequate supplies of colostrum or breast milk 92). Chronic diarrhea also leads to excessive loss of vitamin A in young children, and vitamin A deficiency increases the risk of diarrhea 93), 94). The most common symptom of vitamin A deficiency in young children and pregnant women is xerophthalmia. One of the early signs of xerophthalmia is night blindness, or the inability to see in low light or darkness 95), 96). Vitamin A deficiency also increases the severity and mortality risk of infections (particularly diarrhea and measles) even before the onset of xerophthalmia 97), 98), 99).
Because of the role of vitamin A in maintaining the structural integrity of epithelial cells, follicular hyperkeratosis has been observed with inadequate vitamin A intake 100), 101). Men who were made vitamin A deficient under controlled conditions were then supplemented with either retinol or β-carotene, which caused the hyperkeratosis to gradually clear 102).
Vitamin A deficiency has been associated with a reduction in lymphocyte numbers, natural killer cells, and antigen-specific immunoglobulin responses 103), 104). A decrease in leukocytes and lymphoid organ weights, impaired T cell function, and decreased resistance to immunogenic tumors have been observed with inadequate vitamin A intake 105), 106). A generalized dysfunction of humoral and cell-mediated immunity is common in experimental animals and is likely to exist in humans.
In addition to xerophthalmia, vitamin A deficiency has been associated with increased risk of infectious morbidity and mortality in experimental animals and humans, especially in developing countries. A higher risk of respiratory infection and diarrhea has been reported among children with mild to moderate vitamin A deficiency 107). Mortality rates were about four times greater among children with mild xerophthalmia than those without it 108). The risk of severe morbidity and mortality decreases with vitamin A repletion. In children hospitalized with measles, case fatality 109), 110) and the severity of complications on admission were reduced when they received high doses (60 to 120 mg) of vitamin A 111), 112). In some studies, vitamin A supplementation (30 to 60 mg) has been shown to reduce the severity of diarrhea 113), 114) and Plasmodium falciparum malaria 115) in young children, but vitamin A supplementation has had little effect on the risk or severity of respiratory infections, except when associated with measles 116).
In developing countries, vitamin A supplementation has been shown to reduce the risk of mortality among young children 117), 118), 119), 120), 121), infants 122), and pregnant and postpartum women 123). Meta-analyses of the results from these and other community-based trials are consistent with a 23 to 30 percent reduction in mortality of young children beyond 6 months of age after vitamin A supplementation 124), 125), 126). The World Health Organization recommends broad-based prophylaxis in vitamin A-deficient populations. It also recommends treating children who suffer from xerophthalmia, measles, prolonged diarrhea, wasting malnutrition, and other acute infections with vitamin A 127). Furthermore, the American Academy of Pediatrics 128) recommends vitamin A supplementation for children in the United States who are hospitalized with measles.
Causes of Vitamin A Deficiency
Primary vitamin Adeficiency is usually caused by:
- Prolonged dietary deprivation
It is endemic in areas such as southern and eastern Asia, where rice, devoid of beta-carotene, is the staple food. Xerophthalmia due to primary deficiency is a common cause of blindness among young children in developing countries.
Secondary vitamin A deficiencymay be due to:
- Decreased bioavailability of provitamin A carotenoids
- Interference with absorption, storage, or transport of vitamin A
Interference with absorption or storage is likely in celiac disease, cystic fibrosis, pancreatic insufficiency, duodenal bypass, chronic diarrhea, bile duct obstruction, giardiasis, and cirrhosis. Vitamin A deficiency is common in prolonged protein-energy undernutrition not only because the diet is deficient but also because vitamin A storage and transport is defective.
Groups at Risk of Vitamin A Deficiency
The following groups are among those most likely to have inadequate intakes of vitamin A.
- Premature Infants
In developed countries, clinical vitamin A deficiency is rare in infants and occurs only in those with malabsorption disorders 129). However, preterm infants do not have adequate liver stores of vitamin A at birth and their plasma concentrations of retinol often remain low throughout the first year of life 130), 131). Preterm infants with vitamin A deficiency have an increased risk of eye, chronic lung, and gastrointestinal diseases 132).
- Infants and Young Children in Developing Countries
In developed countries, the amounts of vitamin A in breast milk are sufficient to meet infants’ needs for the first 6 months of life. But in women with vitamin A deficiency, breast milk volume and vitamin A content are suboptimal and not sufficient to maintain adequate vitamin A stores in infants who are exclusively breastfed 133). The prevalence of vitamin A deficiency in developing countries begins to increase in young children just after they stop breastfeeding 134). The most common and readily recognized symptom of vitamin A deficiency in infants and children is xerophthalmia.
- Pregnant and Lactating Women in Developing Countries
Pregnant women need extra vitamin A for fetal growth and tissue maintenance and for supporting their own metabolism 135). The World Health Organization estimates that 9.8 million pregnant women around the world have xerophthalmia as a result of vitamin A deficiency 136). Other effects of vitamin A deficiency in pregnant and lactating women include increased maternal and infant morbidity and mortality, increased anemia risk, and slower infant growth and development.
- People with Cystic Fibrosis
Most people with cystic fibrosis have pancreatic insufficiency, increasing their risk of vitamin A deficiency due to difficulty absorbing fat 137), 138). Several cross-sectional studies found that 15%–40% of patients with cystic fibrosis have vitamin A deficiency 139). However, improved pancreatic replacement treatments, better nutrition, and caloric supplements have helped most patients with cystic fibrosis become vitamin A sufficient 140). Several studies have shown that oral supplementation can correct low serum beta-carotene levels in people with cystic fibrosis, but no controlled studies have examined the effects of vitamin A supplementation on clinical outcomes in patients with cystic fibrosis 141), 142), 143).
Vitamin A Deficiency prevention
The diet should include dark green leafy vegetables, deep- or bright-colored fruits (eg, papayas, oranges), carrots, and yellow vegetables (eg, squash, pumpkin). Vitamin A–fortified milk and cereals, liver, egg yolks, and fish liver oils are helpful. Carotenoids are absorbed better when consumed with some dietary fat. If milk allergy is suspected in infants, they should be given adequate vitamin A in formula feedings.
In developing countries, prophylactic supplements of vitamin A palmitate in oil 200,000 IU (60,000 RAE) orally every 6 months are advised for all children between 1 and 5 yr of age; infants < 6 months can be given a one-time dose of 50,000 IU (15,000 RAE), and those aged 6 to 12 months can be given a one-time dose of 100,000 IU (30,000 RAE).
Vitamin A Deficiency signs and symptoms
Impaired dark adaptation of the eyes, which can lead to night blindness, is an early symptom of vitamin A deficiency. Xerophthalmia (which is nearly characteristic) results from keratinization of the eyes. It involves drying (xerosis) and thickening of the conjunctivae and corneas. Superficial foamy patches composed of epithelial debris and secretions on the exposed bulbar conjunctiva (Bitot spots) develop. In advanced deficiency, the cornea becomes hazy and can develop erosions, which can lead to its destruction (keratomalacia).
Keratinization of the skin and of the mucous membranes in the respiratory, GI, and urinary tracts can occur. Drying, scaling, and follicular thickening of the skin and respiratory infections can result.
Immunity is generally impaired.
The younger the patient, the more severe are the effects of vitamin A deficiency. Growth retardation and infections are common among children. Mortality rate can exceed 50% in children with severe vitamin A deficiency.
Vitamin A Deficiency diagnosis
Serum retinol levels, clinical evaluation, and response to vitamin A help diagnose vitamin A deficiency in people with symptoms, such as night blindness, or in people with diseases that impair intestinal absorption of nutrients and who are at risk of vitamin A deficiency.
Ocular findings suggest vitamin A deficiency. Dark adaptation can be impaired in other disorders (eg, zinc deficiency, retinitis pigmentosa, severe refractive errors, cataracts, diabetic retinopathy). If dark adaptation is impaired, rod scotometry and electroretinography are done to determine whether vitamin A deficiency is the cause.
Serum levels of retinol are measured. Normal range is 28 to 86 mcg/dL (1 to 3 mcmol/L). However, levels decrease only after the deficiency is advanced because the liver contains large stores of vitamin A. Also, decreased levels may result from acute infection, which causes retinol-binding protein and transthyretin (also called prealbumin) levels to decrease transiently.
A therapeutic trial of vitamin A may help confirm the diagnosis.
Vitamin A Deficiency treatment
Vitamin A Palmitate
Dietary deficiency of vitamin A is traditionally treated with vitamin A palmitate in oil 60,000 IU po once/day for 2 days, followed by 4500 IU po once/day. If vomiting or malabsorption is present or xerophthalmia is probable, a dose of 50,000 IU for infants < 6 mo, 100,000 IU for infants 6 to 12 mo, or 200,000 IU for children > 12 mo and adults should be given for 2 days, with a third dose at least 2 wk later. The same doses are recommended for infants and children with complicated measles.
Vitamin A deficiency is a risk factor for severe measles; treatment with vitamin A can shorten the duration of the disorder and may reduce the severity of symptoms and risk of death. The WHO recommends that all children with measles in developing countries should receive 2 doses of vitamin A, (100,000 IU for children < 12 mo and 200,000 IU for those >12 mo) given 24 h apart.
Infants born of HIV-positive mothers should receive 50,000 IU (15,000 RAE) within 48 h of birth. Prolonged daily administration of large doses, especially to infants, must be avoided because toxicity may result.
For pregnant or breastfeeding women, prophylactic or therapeutic doses should not exceed 10,000 IU (3000 RAE)/day to avoid possible damage to the fetus or infant.
Vitamin A Toxicity: Can Taking Too Much Vitamin A Be Harmful?
Yes, high intakes of some forms, usually from supplements or certain medicines, of vitamin A can be harmful. Hypervitaminosis A is having too much vitamin A in the body 144). Hypervitaminosis A is caused by overconsumption of preformed vitamin A, not carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body. Therefore, toxicity from preformed vitamin A may result acutely from high-dose exposure over a short period of time or chronically from a much lower intake 145). Acute vitamin A toxicity is relatively rare, and symptoms include nausea, headache, fatigue, loss of appetite, dizziness, dry skin, desquamation, and cerebral edema. Signs of chronic toxicity include dry itchy skin, desquamation, anorexia, weight loss, headache, cerebral edema, enlarged liver, enlarged spleen, anemia, and bone and joint pain. Also, symptoms of vitamin A toxicity in infants include bulging fontanels. Severe cases of hypervitaminosis A may result in liver damage, hemorrhage, and coma. Generally, signs of vitamin A toxicity are associated with long-term consumption of vitamin A in excess of 10 times the RDA (8,000-10,000 μg RAE/day or 25,000-33,000 IU/day). However, more research is necessary to determine if subclinical vitamin A toxicity is a concern in certain populations 146). There is evidence that some populations may be more susceptible to toxicity at lower doses, including the elderly, chronic alcohol users, and some people with a genetic predisposition to high cholesterol 147). In January 2001, the Food and Nutrition Board of the US Institute of Medicine set the tolerable upper intake level (UL) of vitamin A intake for adults at 3,000 μg RAE (10,000 IU)/day of preformed vitamin A 148).
Although carotene is converted to vitamin A in the body, excessive ingestion of carotene causes carotenemia, not vitamin A toxicity. Carotenemia is usually asymptomatic but may lead to carotenosis, in which the skin becomes yellow.
When taken as a supplement, beta-carotene has been associated with increased cancer risk; risk does not seem to increase when carotenoids are consumed in fruits and vegetables.
Although symptoms of vitamin Atoxicity may vary, headache and rash usually develop during acute or chronic toxicity.
- Acute toxicity causes increased intracranial pressure. Drowsiness, irritability, abdominal pain, nausea, and vomiting are common. Sometimes the skin subsequently peels.
- Early symptoms of chronic toxicity are sparsely distributed, coarse hair; alopecia of the eyebrows; dry, rough skin; dry eyes; and cracked lips. Later, severe headache, pseudotumor cerebri, and generalized weakness develop. Cortical hyperostosis of bone and arthralgia may occur, especially in children. Fractures may occur easily, especially in the elderly. In children, toxicity can cause pruritus, anorexia, and failure to thrive. Hepatomegaly and splenomegaly may occur.
Vitamin A Toxicity (hypervitaminosis A)
- Too much vitamin A can make you sick.
- Large doses of vitamin A during pregnancy can cause birth defects in the babies. Women who might be pregnant should not take high doses of vitamin A supplements.
- Acute vitamin A poisoning occurs quickly, most often when an adult takes several hundred thousand international units (IUs) of vitamin A.
- Chronic vitamin A poisoning may occur over time in adults who regularly take more than 25,000 IU a day.
- Babies and children are more sensitive to vitamin A. They can become sick after taking smaller doses of vitamin A or if they swallow products that contain vitamin A, such as skin cream with retinol in it.
Vitamin A Toxicity in Infants and Children
There are numerous case reports of infants, toddlers, and children who have demonstrated toxic effects due to excess vitamin A intakes for months to years. Of particular concern are intracranial (bulging fontanel) and skeletal abnormalities that can result in infants given vitamin A doses of 5,500 to 6,750 μg/day 149). The clinical presentation of vitamin A toxicity in infants and young children varies widely. The more commonly recognized signs and symptoms include skeletal abnormalities, bone tenderness and pain, increased intracranial pressure, desquamation, brittle nails, mouth fissures, alopecia, fever, headache, lethargy, irritability, weight loss, vomiting, and hepatomegaly 150). Furthermore, tolerance to excess vitamin A intake also appears to vary 151). Carpenter and coworkers 152) described two boys who developed hypervitaminosis A by age 2 years for one and by age 6 years for the other. Both were given chicken liver that supplied about 690 μg/day of vitamin A and various supplements that supplied another 135 to 750 μg/day. An older sister who had been treated similarly remained completely healthy.
How Does Vitamin A Affect Your Bones?
Vitamin A is a family of fat-soluble compounds that play an important role in vision, bone growth, reproduction, cell division, and cell differentiation. Vitamin A is important for healthy bones. However, too much vitamin A has been linked to bone loss and an increase in the risk of hip fracture. Scientists believe that excessive amounts of vitamin A trigger an increase in osteoclasts, the cells that break down bone. They also believe that too much vitamin A may interfere with vitamin D, which plays an important role in preserving bone 153).
Beta-carotene, on the other hand, is largely considered to be safe and has not been linked to adverse effects in bone or elsewhere in the body.
Causes of Vitamin A Toxicity
Vitamin A is a fat-soluble vitamin that is stored in the liver. Many foods contain vitamin A, including:
- Meat, fish, and poultry
- Dairy products
- Some fruits and vegetables
Some dietary supplements also contain Vitamin A.
Because vitamin A is fat soluble, the body stores excess amounts, primarily in the liver, and these levels can accumulate 154). Although excess preformed vitamin A can have significant toxicity also known as hypervitaminosis A, large amounts of beta-carotene and other provitamin A carotenoids are not associated with major adverse effects 155). The manifestations of hypervitaminosis A depend on the size and rapidity of the excess vitamin A intake. The symptoms of hypervitaminosis A following sudden, massive intakes of vitamin A, as with Arctic explorers who ate polar bear liver, are acute 156). The symptoms of acute hypervitaminosis A are drowsiness, sluggishness, irritability or irresistible desire to sleep and severe headache and vomiting 157). During the second 24 hours, the skin of the patients began to peel around the mouth, beginning in spots and gradually spreading over larger areas. In some cases the peeling was confined to the face, but in several it was general. Lindhard 158) also described three other cases in which the skin peeled from head to foot after eating polar bear liver. The Norwegian explorer Nansen  has mentioned that on two occasions he ate small amounts of bear liver without ill effects. It seems probable therefore that vitamin A toxicity only occur when large quantities are consumed.
Chronic intakes of excess vitamin A lead to increased intracranial pressure (pseudotumor cerebri), dizziness, nausea, headaches, skin irritation, pain in joints and bones, coma, and even death 159). Although hypervitaminosis A can be due to excessive dietary intakes, the condition is usually a result of consuming too much preformed vitamin A from supplements or therapeutic retinoids 160). When people consume too much vitamin A, their tissue levels take a long time to fall after they discontinue their intake, and the resulting liver damage is not always reversible.
Observational studies have suggested an association between high intakes of preformed vitamin A (more than 1,500 mcg daily—only slightly higher than the RDA), reduced bone mineral density, and increased fracture risk 161). However, the results of studies on this risk have been mixed, so the safe retinol intake level for this association is unknown.
Total intakes of preformed vitamin A that exceed the Upper Intake Level (UL) and some synthetic retinoids used as topical therapies (such as isotretinoin and etretinate) can cause congenital birth defects 162). These birth defects can include malformations of the eye, skull, lungs, and heart 163). Women who might be pregnant should not take high doses of vitamin A supplements 164).
Unlike preformed vitamin A, beta-carotene is not known to be teratogenic or lead to reproductive toxicity 165). And even large supplemental doses (20–30 mg/day) of beta-carotene or diets with high levels of carotenoid-rich food for long periods are not associated with toxicity. The most significant effect of long-term, excess beta-carotene is carotenodermia, a harmless condition in which the skin becomes yellow-orange 166). This condition can be reversed by discontinuing beta-carotene ingestion.
Supplementation with beta-carotene, with or without retinyl palmitate, for 5–8 years has been associated with an increased risk of lung cancer and cardiovascular disease in current and former male and female smokers and in male current and former smokers occupationally exposed to asbestos 167). In the The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study 168), beta-carotene supplements (20 mg daily) were also associated with increased mortality, mainly due to lung cancer and ischemic heart disease. The CARET study 169) ended early, after the investigators found that daily beta-carotene (30 mg) and retinyl palmitate (7,500 mcg RAE [25,000 IU]) supplements increased the risk of lung cancer and cardiovascular disease mortality.
The Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies has established Upper Intake Levels (ULs) for preformed vitamin A that apply to both food and supplement intakes 170). The FNB based these Upper Intake Levels (ULs) on the amounts associated with an increased risk of liver abnormalities in men and women, teratogenic effects, and a range of toxic effects in infants and children. The FNB also considered levels of preformed vitamin A associated with decreased bone mineral density, but did not use these data as the basis for its ULs because the evidence was conflicting. The FNB has not established Upper Intake Levels (ULs) for beta-carotene and other provitamin A carotenoids 171). The FNB advises against beta-carotene supplements for the general population, except as a provitamin A source to prevent vitamin A deficiency.
Table 4. Tolerable Upper Intake Levels (ULs) for Preformed Vitamin A
|0–12 months||600 mcg||600 mcg|
|1–3 years||600 mcg||600 mcg|
|4–8 years||900 mcg||900 mcg|
|9–13 years||1,700 mcg||1,700 mcg|
|14–18 years||2,800 mcg||2,800 mcg||2,800 mcg||2,800 mcg|
|19+ years||3,000 mcg||3,000 mcg||3,000 mcg||3,000 mcg|
Footnotes: * These Upper Intake Levels (ULs) only apply to products from animal sources and supplements whose vitamin A comes entirely from retinol or its ester forms, such as retinyl palmitate. However, many dietary supplements (such as multivitamins) do not provide all of their vitamin A as retinol or its ester forms. For example, the vitamin A in some supplements consists partly or entirely of beta-carotene or other provitamin A carotenoids. In such cases, the percentage of retinol or retinyl ester in the supplement should be used to determine whether an individual’s vitamin A intake exceeds the UL. For example, a supplement whose label indicates that the product contains 3,000 mcg RAE vitamin A and that 60% of this vitamin A comes from beta-carotene (and therefore 40% comes from retinol or retinyl ester) provides 1,200 mcg RAE of preformed vitamin A. That amount is above the UL for children from birth to 8 years but below the UL for older children and adults.[Source 172) ]
Vitamin A Toxicity prevention
How much vitamin A you need depends on your age and sex. Other factors, such as pregnancy and your overall health, are also important. Ask your provider what amount is best for you.
To avoid hypervitaminosis A, don’t take more than the recommended daily allowance of vitamin A.
Some people take vitamin A and beta carotene supplements in the belief it will help prevent cancer. This may lead to chronic hypervitaminosis A if people take more than is recommended.
Vitamin A Toxicity symptoms
Excess natural or synthetic vitamin A levels or hypervitaminosis A may result in a wide array of adverse effects. Hypervitaminosis A is more commonly associated with abuse of vitamin A supplements than with health intervention programs. Toxic reactions may also be provoked by consuming liver products rich in vitamin A or excess administration of vitamin A preparations. The amount of vitamin A required to cause toxicity among individuals varies depending on age and hepatic function.
Vitamin A toxicity symptoms may include:
- Abnormal softening of the skull bone (in infants and children)
- Blurred vision
- Bone pain or swelling
- Bulging of the soft spot in an infant’s skull (fontanelle)
- Changes in alertness or consciousness
- Decreased appetite
- Double vision (in young children)
- Hair changes, such as hair loss and oily hair
- Liver damage
- Poor weight gain (in infants and children)
- Skin changes, such as cracking at corners of the mouth, higher sensitivity to sunlight, oily skin, peeling, itching, and yellow color to the skin
- Vision changes
Acute hypervitaminosis A may occur with a single ingestion of 25,000 IU/kg or more. Signs and symptoms include nausea, vomiting, diarrhea, dizziness, lethargy, drowsiness, increased intracranial pressure, and skin changes such as erythema, pruritus, or desquamation.
Chronic hypervitaminosis A may occur with excessive ingestion of 4000 IU/kg or more daily for 6-15 months. Signs and symptoms include low-grade fever, headache, fatigue, anorexia, intestinal disturbances, hepatosplenomegaly, anemia, hypercalcemia, subcutaneous swelling, nocturia, joint and bone pain, and skin changes such as yellowing, dryness, alopecia, and photosensitivity. Neuropsychiatric changes as a consequence of chronic hypervitaminosis A have also been reported 173). It was proposed that toxic levels of unbound retinyl esters (preformed vitamin A) can elicit neuropsychiatric effects, in-cluding depression, psychosis, and impulsivity 174).
To convert International Units (IUs) to mcg RAE, use the following 175):
- 1 IU retinol = 0.3 mcg RAE
- 1 IU supplemental beta-carotene = 0.3 mcg RAE
- 1 IU dietary beta-carotene = 0.05 mcg RAE
- 1 IU dietary alpha-carotene or beta-cryptoxanthin = 0.025 mcg RAE
RAE can only be directly converted into IUs if the source or sources of vitamin A are known. For example, the RDA of 900 mcg RAE for adolescent and adult men is equivalent to 3,000 IU if the food or supplement source is preformed vitamin A (retinol) or if the supplement source is beta-carotene. This RDA is also equivalent to 18,000 IU beta-carotene from food or to 36,000 IU alpha-carotene or beta-cryptoxanthin from food. Therefore, a mixed diet containing 900 mcg RAE provides between 3,000 and 36,000 IU vitamin A, depending on the foods consumed.
Vitamin A is highly teratogenic if taken during pregnancy. Retinoids affect the expression of homeobox gene Hoxb-1, which regulates axial patterning of the embryo. Birth abnormalities include craniofacial, cardiac, and central nervous system malformations. Therefore, treatment with vitamin A should be avoided in pregnant patients except in areas where vitamin A deficiency is prevalent. In this circumstance, supplementation should not exceed 10,000 IU daily 176).
Of note, mild adverse effects have been observed with vitamin A given with immunization. Symptoms include loose stools, headache, irritability, fever, nausea, and vomiting. These side effects are rare and typically resolved within 24 to 48 hours 177).
Vitamin A Toxicity complications
Vitamin A Toxicity possible complications can include:
- Excessively high calcium level
- Failure to thrive (in infants)
- Kidney damage due to high calcium
- Liver damage
Taking too much vitamin A during pregnancy may cause abnormal development in the growing baby. Talk to your health care provider about eating a proper diet while you are pregnant.
Consuming high amounts of beta-carotene or other forms of provitamin A can turn the skin yellow-orange, but this condition is harmless. High intakes of beta-carotene do not cause birth defects or the other more serious effects caused by getting too much preformed vitamin A.
Vitamin A Toxicity diagnosis
These tests may be done if a high vitamin A level is suspected:
- Bone x-rays
- Blood calcium test
- Cholesterol test
- Liver function test
- Blood test to check vitamin A level
Diagnosis of vitamin A toxicity is clinical. Blood vitamin levels correlate poorly with toxicity. However, if clinical diagnosis is equivocal, laboratory testing may help. In vitamin A toxicity, fasting serum retinol levels may increase from normal (28 to 86 mcg/dL [1 to 3 mcmol/L]) to > 100 mcg/dL (> 3.49 mcmol/L), sometimes to > 2000 mcg/dL (> 69.8 mcmol/L). Hypercalcemia is common.
The plasma retinol concentration is not a reliable estimate of the vitamin A requirement because of its insensitive relationship between liver concentration and there is no noninvasive marker available for the assessment of vitamin A excess 178).
Differentiating vitamin A toxicity from other disorders may be difficult. Carotenosis may also occur in severe hypothyroidism and anorexia nervosa, possibly because carotene is converted to vitamin A more slowly.
Histologically, hypervitaminosis A causes hepatocyte injury, necrosis, stellate cell hyperplasia and subsequent fibrosis resulting in perisinusoidal, pericentrilobular and periportal scarring causing sinusoidal dilatation and obstruction thusimpairing hepatic venous outflow and consequently leading to noncirrhotic portal hypertension 179).
Vitamin A Toxicity treatment
Treatment involves simply stopping supplements (or rarely, foods) that contain vitamin A. Symptoms and signs of chronic toxicity usually disappear within 1 to 4 week.
However, birth defects in the fetus of a mother who has taken megadoses of vitamin A are not reversible.
Most people fully recover.
The liver injury caused by high doses of vitamin A is reversible in its early stages, but may resolve only slowly with discontinuation of vitamin A ingestion and resumption of a normal diet. Usually, portal hypertension resolves within months to years after discontinuation of the vitamin A supplement. However, in some cases, the liver injury progresses to cirrhosis, even requiring transplantation 180). Patients with increased intracranial pressure may require lumbar punctures or medications such as mannitol and diuretics for therapy. Patients with hypercalcemia may require intravenous fluids and additional therapy such as calcitonin and corticosteroids 181).
Vitamin A Toxicity prognosis
Most people fully recover from hypervitaminosis A. The liver injury caused by high doses of vitamin A is reversible in its early stages, but may resolve only slowly with discontinuation of vitamin A ingestion and resumption of a normal diet. Usually, portal hypertension resolves within months to years after discontinuation of the vitamin A supplement. However, in some cases, the liver injury progresses to cirrhosis, even requiring transplantation 182). Patients with increased intracranial pressure may require lumbar punctures or medications such as mannitol and diuretics for therapy. Patients with hypercalcemia may require intravenous fluids and additional therapy such as calcitonin and corticosteroids 183). Birth defects caused by vitamin A are irreversible.
References [ + ]
|1, 64, 165, 166.||↵||Johnson EJ, Russell RM. Beta-Carotene. In: Coates PM, Betz JM, Blackman MR, et al., eds. Encyclopedia of Dietary Supplements. 2nd ed. London and New York: Informa Healthcare; 2010:115-20.|
|2, 5, 8, 10, 12, 28, 29, 54, 55, 56, 95, 159, 162, 164.||↵||Ross CA. Vitamin A. In: Coates PM, Betz JM, Blackman MR, et al., eds. Encyclopedia of Dietary Supplements. 2nd ed. London and New York: Informa Healthcare; 2010:778-91.|
|3, 6, 11, 82, 134, 160.||↵||Ross A. Vitamin A and Carotenoids. In: Shils M, Shike M, Ross A, Caballero B, Cousins R, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:351-75.|
|4, 13, 61.||↵||Institute of Medicine, US Panel on Micronutrients. Dietary reference intakes for vitamin A, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academies Press. Washington, DC, 2001. PMID: 25057538 www.ncbi.nlm.nih.gov/pubmed/25057538.|
|7, 36, 37, 57, 163.||↵||Solomons NW. Vitamin A. In: Bowman B, Russell R, eds. Present Knowledge in Nutrition. 9th ed. Washington, DC: International Life Sciences Institute; 2006:157-83.|
|9.||↵||National Institute of Health. Vitamin A. https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional|
|14.||↵||Merck Sharp & Dohme Corp, Merck Manual. Vitamin A. https://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency,-dependency,-and-toxicity/vitamin-a#v884887|
|15, 18, 22, 145.||↵||Ross AC. Vitamin A. In: Ross A, Caballero B, Cousins R, Tucker K, Ziegler T, eds. Modern Nutrition in Health and Disease. 11th ed: Lippincott Williams & Wilkins; 2014:260-277.|
|16.||↵||Tan L, Wray AE, Green MH, Ross AC. Compartmental modeling of whole-body vitamin A kinetics in unsupplemented and vitamin A-retinoic acid-supplemented neonatal rats. J Lipid Res. 2014 Aug;55(8):1738-49. doi: 10.1194/jlr.M050518|
|17.||↵||Zhong M, Kawaguchi R, Ter-Stepanian M, Kassai M, Sun H. Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein. PLoS One. 2013 Nov 1;8(11):e73838. doi: 10.1371/journal.pone.0073838|
|19.||↵||See AW, Clagett-Dame M. The temporal requirement for vitamin A in the developing eye: mechanism of action in optic fissure closure and new roles for the vitamin in regulating cell proliferation and adhesion in the embryonic retina. Dev Biol. 2009 Jan 1;325(1):94-105. doi: 10.1016/j.ydbio.2008.09.030|
|20.||↵||Green HN, Mellanby E. VITAMIN A AS AN ANTI-INFECTIVE AGENT. Br Med J. 1928 Oct 20;2(3537):691-6. doi: 10.1136/bmj.2.3537.691|
|21.||↵||Raverdeau M, Mills KH. Modulation of T cell and innate immune responses by retinoic Acid. J Immunol. 2014 Apr 1;192(7):2953-8. doi: 10.4049/jimmunol.1303245|
|23.||↵||Spears K, Cheney C, Zerzan J. Low plasma retinol concentrations increase the risk of developing bronchopulmonary dysplasia and long-term respiratory disability in very-low-birth-weight infants. Am J Clin Nutr. 2004 Dec;80(6):1589-94. doi: 10.1093/ajcn/80.6.1589|
|24, 25.||↵||Barber T, Esteban-Pretel G, Marín MP, Timoneda J. Vitamin a deficiency and alterations in the extracellular matrix. Nutrients. 2014 Nov 10;6(11):4984-5017. doi: 10.3390/nu6114984|
|26.||↵||Semba RD, Bloem MW. The anemia of vitamin A deficiency: epidemiology and pathogenesis. Eur J Clin Nutr. 2002 Apr;56(4):271-81. doi: 10.1038/sj.ejcn.1601320|
|27.||↵||Allen LH. Iron supplements: scientific issues concerning efficacy and implications for research and programs. J Nutr. 2002 Apr;132(4 Suppl):813S-9S. doi: 10.1093/jn/132.4.813S|
|30.||↵||Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-6. https://www.ncbi.nlm.nih.gov/pubmed/21178089?dopt=Abstract|
|31, 32.||↵||Lieber CS. Relationships between nutrition, alcohol use, and liver disease. Alcohol Res Health. 2003;27(3):220-31.|
|33, 34.||↵||Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. 2nd edition ed: Thomson Reuters; 2008.|
|35.||↵||U.S. Department of Agriculture, Agricultural Research Service. What We Eat in America, 2013-2014. https://www.ars.usda.gov/northeast-area/beltsville-md/beltsville-human-nutrition-research-center/food-surveys-research-group/docs/wweia-data-tables/|
|38.||↵||Institute of Medicine, US Panel on Micronutrients. Dietary reference intakes for vitamin A, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academies Press. Washington, DC, 2001. PMID: 25057538 www.ncbi.nlm.nih.gov/pubmed/25057538|
|39.||↵||Otten JJ, Hellwig JP, Meyers LD, eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: The National Academies Press; 2006. https://www.nap.edu/catalog/11537/dietary-reference-intakes-the-essential-guide-to-nutrient-requirements|
|40, 58, 93, 97, 170, 172.||↵||Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001. https://www.nap.edu/read/10026/chapter/1|
|41, 148.||↵||Food and Nutrition Board, Institute of Medicine. Vitamin A. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, D.C.: National Academy Press; 2001:65-126.|
|42.||↵||Archived: Vitamin A supplementation in pregnant women. 2011 Guideline. https://www.who.int/nutrition/publications/micronutrients/guidelines/vas_pregnant/en|
|43.||↵||Orfanos CE, Zouboulis CC. Oral retinoids in the treatment of seborrhoea and acne. Dermatology. 1998;196(1):140-7. doi: 10.1159/000017848|
|44.||↵||Bozzo P, Chua-Gocheco A, Einarson A. Safety of skin care products during pregnancy. Can Fam Physician. 2011 Jun;57(6):665-7.|
|45.||↵||Michaëlsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003 Jan 23;348(4):287-94. doi: 10.1056/NEJMoa021171|
|46.||↵||Rejnmark L, Vestergaard P, Charles P, Hermann AP, Brot C, Eiken P, Mosekilde L. No effect of vitamin A intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int. 2004 Nov;15(11):872-80. doi: 10.1007/s00198-004-1618-1|
|47, 48.||↵||Wu AM, Huang CQ, Lin ZK, Tian NF, Ni WF, Wang XY, Xu HZ, Chi YL. The relationship between vitamin A and risk of fracture: meta-analysis of prospective studies. J Bone Miner Res. 2014 Sep;29(9):2032-9. doi: 10.1002/jbmr.2237|
|49.||↵||Conaway HH, Henning P, Lerner UH. Vitamin a metabolism, action, and role in skeletal homeostasis. Endocr Rev. 2013 Dec;34(6):766-97. doi: 10.1210/er.2012-1071|
|50.||↵||Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001 Oct;16(10):1899-905. doi: 10.1359/jbmr.2001.16.10.1899|
|51.||↵||Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women’s Health Initiative Observational Study. Am J Clin Nutr. 2009 Jan;89(1):323-30. doi: 10.3945/ajcn.2008.26451|
|52.||↵||Mason JB. Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI, eds. Goldman’s Cecil Medicine. 25th ed. Philadelphia, PA: Elsevier Saunders; 2015:chap 218.|
|53, 60.||↵||U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 24. Nutrient Data Laboratory Home Page, 2011. https://www.ars.usda.gov/northeast-area/beltsville-md/beltsville-human-nutrition-research-center/nutrient-data-laboratory/|
|59.||↵||IOM (Institute of Medicine). 2000. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids . Washington, DC: National Academy Press.|
|62.||↵||Nutrients. 2011 Apr; 3(4): 385–428. Published online 2011 Mar 29. doi: 10.3390/nu3040385. Vitamin A in Reproduction and Development. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257687/|
|63.||↵||Nat Rev Immunol. 2008 Sep; 8(9): 685–698. doi: 10.1038/nri2378. Vitamin effects on the immune system: vitamins A and D take centre stage. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906676/|
|65.||↵||Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press; 2000. https://www.nap.edu/read/10026/chapter/1|
|66.||↵||Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-5. https://www.ncbi.nlm.nih.gov/pubmed/8602180?dopt=Abstract|
|67.||↵||The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35. https://www.ncbi.nlm.nih.gov/pubmed/8127329?dopt=Abstract|
|68.||↵||Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. The New England journal of medicine 1996;334:1145-9. https://www.ncbi.nlm.nih.gov/pubmed/8602179?dopt=Abstract|
|69.||↵||Neuhouser ML, Barnett MJ, Kristal AR, Ambrosone CB, King IB, Thornquist M, et al. Dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiol Biomarkers Prev 2009;18:2202-6. https://www.ncbi.nlm.nih.gov/pubmed/19661078?dopt=Abstract|
|70.||↵||Watters JL, Gail MH, Weinstein SJ, Virtamo J, Albanes D. Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival. Cancer Res 2009;69:3833-41. https://www.ncbi.nlm.nih.gov/pubmed/19383902?dopt=Abstract|
|71.||↵||Mondul AM, Watters JL, Mannisto S, Weinstein SJ, Snyder K, Virtamo J, et al. Serum retinol and risk of prostate cancer. Am J Epidemiol 2011;173:813-21. https://www.ncbi.nlm.nih.gov/pubmed/21389041?dopt=Abstract|
|72.||↵||Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-36. www.ncbi.nlm.nih.gov/pubmed/11594942?dopt=Abstract|
|73, 74.||↵||The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013;309:2005-15. https://www.ncbi.nlm.nih.gov/pubmed/23644932?dopt=Abstract|
|75.||↵||Yang HM, Mao M, Wan C. Vitamin A for treating measles in children. Cochrane Database Syst Rev 2011;2005. http://www.cochrane.org/CD001479/ARI_vitamin-a-for-measles-in-children|
|76.||↵||Cochrane Review 19 October 2005. Vitamin A for measles in children. http://www.cochrane.org/CD001479/ARI_vitamin-a-for-measles-in-children|
|77.||↵||Sudfeld CR, Navar AM, Halsey NA. Effectiveness of measles vaccination and vitamin A treatment. Int J Epidemiol 2010;39 Suppl 1:i48-55. https://www.ncbi.nlm.nih.gov/pubmed/20348126?dopt=Abstract|
|78.||↵||Bello S, Meremikwu MM, Ejemot-Nwadiaro RI, Oduwole O. Routine vitamin A supplementation for the prevention of blindness due to measles infection in children. Cochrane Database Syst Rev 2011:CD007719. https://www.ncbi.nlm.nih.gov/pubmed/21491401?dopt=Abstract|
|79.||↵||Foster A, Sommer A. Corneal ulceration, measles, and childhood blindness in Tanzania. Br J Ophthalmol 1987;71:331-43. https://www.ncbi.nlm.nih.gov/pubmed/3580349?dopt=Abstract|
|80.||↵||U.S. National Library of Medicine, MedlinePlus. Vitamin A. https://medlineplus.gov/vitamina.html|
|81, 83, 92, 98, 136.||↵||World Health Organization. Global Prevalence of Vitamin A Deficiency in Populations at Risk 1995–2005: WHO Global Database on Vitamin A Deficiency. Geneva: World Health Organization; 2009. http://apps.who.int/iris/bitstream/10665/44110/1/9789241598019_eng.pdf|
|84.||↵||Ross AC, Tan L. Vitamin A deficiencies and excess. In: Kliegman RM, Stanton BF, St Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier; 2016:chap 48.|
|85.||↵||Sommer A, West KP Jr. 1996. Vitamin A Deficiency: Health, Survival, and Vision . New York: Oxford University Press.|
|86.||↵||WHO. 1995. Global Prevalence of Vitamin A Deficiency . Micronutrient Deficiency Information System Working Paper, No. 2. Geneva: WHO.|
|87.||↵||WHO. 1982. Control of Vitamin A Deficiency and Xerophthalmia . Technical Report Series No. 672. Geneva: WHO. https://www.ncbi.nlm.nih.gov/pubmed/6803444|
|88.||↵||Dowling JE, Gibbons IR. 1961. In: Smelser GK, ed, editor. . The Structure of the Eye . New York: Academic Press.|
|89.||↵||Sommer A. 1982. Nutritional Blindness. Xerophthalmia and Keratomalacia . New York: Oxford University Press.|
|90.||↵||Katz J, West KP Jr, Khatry SK, Thapa MD, LeClerq SC, Pradhan EK, Pokhrel RP, Sommer A. 1995. Impact of vitamin A supplementation on prevalence and incidence of xerophthalmia in Nepal. Invest Ophthalmol Vis Sci 36:2577–2583. https://www.ncbi.nlm.nih.gov/pubmed/7499080|
|91.||↵||Christian P, West KP Jr, Khatry SK, Katz J, LeClerq S, Pradhan EK, Shrestha SR. 1998. b. Vitamin A or beta-carotene supplementation reduces but does not eliminate maternal night blindness in Nepal. J Nutr 128:1458–1463. https://www.ncbi.nlm.nih.gov/pubmed/9732305|
|94.||↵||Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011;343:d5094. https://www.ncbi.nlm.nih.gov/pubmed/21868478?dopt=Abstract|
|96, 99.||↵||Sommer A. Vitamin A deficiency and clinical disease: An historical overview. J Nutr 2008;138:1835-9. https://www.ncbi.nlm.nih.gov/pubmed/18806089?dopt=Abstract|
|100.||↵||Chase HP, Kumar V, Dodds JM, Sauberlich HE, Hunter RM, Burton RS, Spalding V. 1971. Nutritional status of preschool Mexican-American migrant farm children. Am J Dis Child 122:316–324. https://www.ncbi.nlm.nih.gov/pubmed/5115528|
|101, 102.||↵||Sauberlich HE, Hodges HE, Wallace DL, Kolder H, Canham JE, Hood J, Raica N, Lowry LK. 1974. Vitamin A metabolism and requirements in the human studied with the use of labeled retinol. Vitam Horm 32:251–275. https://www.ncbi.nlm.nih.gov/pubmed/4617402|
|103.||↵||Cantorna MT, Nashold FE, Hayes CE. 1995. Vitamin A deficiency results in a priming environment conducive for TH1 cell development. Eur J Immunol 25:1673–1679. https://www.ncbi.nlm.nih.gov/pubmed/7614995|
|104.||↵||Nauss KM, Newberne PM. 1985. Local and regional immune function of vitamin A-deficient rats with ocular herpes simplex virus (HSV) infections. J Nutr 115:1316–1324. https://www.ncbi.nlm.nih.gov/pubmed/3876416|
|105.||↵||Dawson HD, Ross AC. 1999. Chronic marginal vitamin A status effects the distribution and function of T cells and natural T cells in aging Lewis rats. J Nutr 129:1782–1790. https://www.ncbi.nlm.nih.gov/pubmed/10498748|
|106.||↵||Wiedermann U, Hanson LA, Kahu H, Dahlgren UI. 1993. Aberrant T-cell function in vitro and impaired T-cell dependent antibody response in vivo in vitamin A-deficient rats. Immunology 80:581–586. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422259/|
|107.||↵||Sommer A, Katz J, Tarwotjo I. 1984. Increased risk of respiratory disease and diarrhea in children with pre-existing mild vitamin A deficiency. Am J Clin Nutr 40:1090–1095. https://www.ncbi.nlm.nih.gov/pubmed/6496388|
|108.||↵||Sommer A, Tarwotjo I, Hussaini G, Susanto D. 1983. Increased mortality in children with mild vitamin A deficiency. Lancet 2:585–588. https://www.ncbi.nlm.nih.gov/pubmed/6136744|
|109.||↵||Barclay AJ, Foster A, Sommer A. 1987. Vitamin A supplements and mortality related to measles: A randomised clinical trial. Br Med J 294:294–296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1245303/|
|110, 112.||↵||Hussey GD, Klein M. 1990. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 323:160–164. https://www.ncbi.nlm.nih.gov/pubmed/2194128|
|111.||↵||Coutsoudis A, Broughton M, Coovadia HM. 1991. Vitamin A supplementation reduces measles morbidity in young African children: A randomized, placebo-controlled, double-blind trial. Am J Clin Nutr 54:890–895. https://www.ncbi.nlm.nih.gov/pubmed/1951162|
|113.||↵||Barreto ML, Santos LM, Assis AM, Araujo MP, Farenzena GG, Santos PA, Fiaccone RL. 1994. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet 344:228–231. https://www.ncbi.nlm.nih.gov/pubmed/7913157|
|114.||↵||Donnen P, Dramaix M, Brasseur D, Bitwe R, Vertongen F, Hennart P. 1998. Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. Am J Clin Nutr 68:1254–1260. https://www.ncbi.nlm.nih.gov/pubmed/9846855|
|115.||↵||Shankar AH, Genton B, Semba RD, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Tielsch JM, Alpers MP, West KP Jr. 1999. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua, New Guinea: A randomised trial. Lancet 354:203–209. https://www.ncbi.nlm.nih.gov/pubmed/10421302|
|116, 122.||↵||Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP Jr, Sommer A. 1996. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 128:489–496. https://www.ncbi.nlm.nih.gov/pubmed/8618182|
|117.||↵||Ghana VAST Study Team. 1993. Vitamin A supplementation in northern Ghana: Effects on clinic attendances, hospital admissions, and child mortality. Lancet 342:7–12. https://www.ncbi.nlm.nih.gov/pubmed/8100345|
|118.||↵||Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. 1988. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: A controlled field trial. Am J Clin Nutr 48:1271–1276. https://www.ncbi.nlm.nih.gov/pubmed/3189216|
|119.||↵||Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, Babu G. 1990. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 323:929–935. https://www.ncbi.nlm.nih.gov/pubmed/2205798|
|120.||↵||Sommer A, Tarwotjo I, Djunaedi E, West KP Jr, Loeden AA, Tilden R, Mele L. 1986. Impact of vitamin A supplementation on childhood mortality: A randomized controlled community trial. Lancet 1:1169–1173. https://www.ncbi.nlm.nih.gov/pubmed/2871418|
|121.||↵||West KP Jr, Pokhrel RP, Katz J, LeClerq SC, Khatry SK, Shrestha SR, Pradhan EK, Tielsch JM, Pandey MR, Sommer A. 1991. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 338:67–71. https://www.ncbi.nlm.nih.gov/pubmed/1676467|
|123.||↵||West KP Jr, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, Conner PB, Dali SM, Christian P, Pokhrel RP, Sommer A. 1999. Double blind, cluster randomized trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. Br Med J 318:570–575. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27760/|
|124.||↵||Beaton GH, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, Harvey B. 1993. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries . Geneva: Subcommittee on Nutrition, Administrative Committee on Coordination, World Health Organization.|
|125.||↵||Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. 1993. Vitamin A supplementation and child mortality. A meta-analysis. J Am Med Assoc 269:898–903. https://www.ncbi.nlm.nih.gov/pubmed/8426449|
|126.||↵||Glasziou PP, Mackerras DE. 1993. Vitamin A supplementation and infectious disease: A meta-analysis. Br Med J 306:366–370. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1676417/|
|127.||↵||WHO. 1997. Vitamin A Supplements: A Guide to Their Use in the Treatment of Vitamin A Deficiency and Xerophthalmia . Geneva: WHO.|
|128.||↵||AAP (American Academy of Pediatrics Committee on Infectious Diseases). 1993. Vitamin A treatment of measles. Pediatrics 91:1014–1015. https://www.ncbi.nlm.nih.gov/pubmed/8474793|
|129, 130, 132.||↵||Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Arch Dis Child Fetal Neonatal Ed 2005;90:F103-8. https://www.ncbi.nlm.nih.gov/pubmed/15724031?dopt=Abstract|
|131.||↵||Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev 2007:CD000501. https://www.ncbi.nlm.nih.gov/pubmed/17943744?dopt=Abstract|
|133.||↵||Oliveira-Menegozzo JM, Bergamaschi DP, Middleton P, East CE. Vitamin A supplementation for postpartum women. Cochrane Database Syst Rev 2010:CD005944. https://www.ncbi.nlm.nih.gov/pubmed/20927743?dopt=Abstract|
|135.||↵||van den Broek N, Dou L, Othman M, Neilson JP, Gates S, Gulmezoglu AM. Vitamin A supplementation during pregnancy for maternal and newborn outcomes. Cochrane Database Syst Rev 2010:CD008666. https://www.ncbi.nlm.nih.gov/pubmed/21069707?dopt=Abstract|
|137.||↵||Graham-Maar RC, Schall JI, Stettler N, Zemel BS, Stallings VA. Elevated vitamin A intake and serum retinol in preadolescent children with cystic fibrosis. Am J Clin Nutr 2006;84:174-82. https://www.ncbi.nlm.nih.gov/pubmed/16825693?dopt=Abstract|
|138, 140, 141.||↵||O’Neil C, Shevill E, Chang AB. Vitamin A supplementation for cystic fibrosis. Cochrane Database Syst Rev 2010:CD006751.pub2. www.ncbi.nlm.nih.gov/pubmed/18254115?dopt=Abstract|
|139, 142.||↵||Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002;35:246-59.|
|143.||↵||Michel SH, Maqbool A, Hanna MD, Mascarenhas M. Nutrition management of pediatric patients who have cystic fibrosis. Pediatr Clin North Am 2009;56:1123-41. https://www.ncbi.nlm.nih.gov/pubmed/12352509?dopt=Abstract|
|144.||↵||U.S. National Library of Medicine, MedlinePlus. Hypervitaminosis A. https://medlineplus.gov/ency/article/000350.htm|
|146.||↵||Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006 Feb;83(2):191-201. doi: 10.1093/ajcn/83.2.191|
|147.||↵||Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. 2000 Apr;71(4):878-84. doi: 10.1093/ajcn/71.4.878|
|149.||↵||Persson B, Tunell R, Ekengren K. 1965. Chronic vitamin A intoxication during the first half year of life. Acta Paediatr Scand 54:49–60. https://www.ncbi.nlm.nih.gov/pubmed/14248225|
|150.||↵||Bush ME, Dahms BB. 1984. Fatal hypervitaminosis A in a neonate. Arch Pathol Lab Med 108:838–842. https://www.ncbi.nlm.nih.gov/pubmed/6548125|
|151, 152.||↵||Carpenter TO, Pettifor JM, Russell RM, Pitha J, Mobarhan S, Ossip MS, Wainer S, Anast CS. 1987. Severe hypervitaminosis A in siblings: Evidence of variable tolerance to retinol intake. J Pediatr 111:507–512. https://www.ncbi.nlm.nih.gov/pubmed/3655980|
|153.||↵||National Institute of Arthritis and Musculoskeletal and Skin Diseases. Vitamin A and Bone Health. https://www.niams.nih.gov/Health_Info/Bone/Bone_Health/Nutrition/vitamin_a.asp|
|154.||↵||Vitamin A. https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional|
|155.||↵||Grune T, Lietz G, Palou A, Ross AC, Stahl W, Tang G, Thurnham D, Yin SA, Biesalski HK. Beta-carotene is an important vitamin A source for humans. J Nutr. 2010 Dec;140(12):2268S-2285S. doi: 10.3945/jn.109.119024|
|156, 157.||↵||Rodahl K, Moore T. The vitamin A content and toxicity of bear and seal liver. Biochem J. 1943 Jul;37(2):166-8. doi: 10.1042/bj0370166 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257872/pdf/biochemj00974-0009.pdf|
|161.||↵||Ribaya-Mercado JD, Blumberg JB. Vitamin A: is it a risk factor for osteoporosis and bone fracture? Nutr Rev. 2007 Oct;65(10):425-38. doi: 10.1111/j.1753-4887.2007.tb00268.x|
|167, 169.||↵||Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL Jr, Omenn GS, Valanis B, Williams JH Jr. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004 Dec 1;96(23):1743-50. doi: 10.1093/jnci/djh320|
|168.||↵||Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994 Apr 14;330(15):1029-35. doi: 10.1056/NEJM199404143301501|
|171.||↵||Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. https://www.nap.edu/read/9810/chapter/1|
|173.||↵||O’Donnell J. Polar hysteria: An expression of hypervitaminosis A.Am JTher. 2004;11(6):507–16.|
|174.||↵||Mawson A. Mefloquine use, psychosis, and violence: A retinoid toxicityhypothesis.Med Sci Monitor. 2013;19:579–83.|
|175.||↵||Converting Units of Measure for Folate, Niacin, and Vitamins A, D, and E on the Nutrition and Supplement Facts Labels: Guidance for Industry. https://www.fda.gov/media/129863/download|
|176, 181, 183.||↵||Challem JJ. Teratogenicity of high vitamin A intake. N Engl J Med. 1996 May 2;334(18):1196-7.|
|177.||↵||Chea EP, Lopez MJ, Milstein H. Vitamin A. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482362|
|178, 180, 182.||↵||García-Muñoz P, Bernal-Bellido C, Marchal-Santiago A, et al. Liver cir-rhosis from chronic hypervitaminosis A resulting in a liver transplantation:A case report.Transpl Proc. 2019;51(1):90–1.|
|179.||↵||Sy, Alexander & Kumar, Smriti & Steinberg, Jonathan & Garcia-Buitrago, Monica & Benitez, Leopoldo. (2020). Liver Damage due to Hypervitaminosis. ACG Case Reports Journal. 7. e00431. 10.14309/crj.0000000000000431|