Introduction

Vitamin A is the name of a group of fat-soluble retinoids, including retinol, retinal, and retinyl esters ^[1-3]. Vitamin A is involved in immune function, vision, reproduction, and cellular communication ^[1,4,5]. 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^[2-4]. 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^[2].

Two forms of vitamin A are available in the human diet: preformed vitamin A (retinol and its esterified form, retinyl ester) and provitamin A carotenoids^[1-5]. Preformed vitamin A is found in foods from animal sources, including dairy products, fish, and meat (especially liver). By far the most important provitamin A carotenoid is beta-carotene; other provitamin A carotenoids are alpha-carotene and beta-cryptoxanthin. 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^[2,3]. Other carotenoids found in food, such as lycopene, lutein, and zeaxanthin, are not converted into vitamin A.

The various forms of vitamin A are solubilized into micelles in the intestinal lumen and absorbed by duodenal mucosal cells ^[5]. Both retinyl esters and provitamin A carotenoids are converted to retinol, which is oxidized to retinal and then to retinoic acid^[2]. Most of the body’s vitamin A is stored in the liver in the form of retinyl esters.

Retinol and carotenoid levels are typically measured in plasma, and plasma retinol levels are useful for assessing vitamin A inadequacy. However, their value for assessing marginal vitamin A status is limited because they do not decline until vitamin A levels in the liver are almost depleted^[3]. Liver vitamin A reserves can be measured indirectly through the relative dose-response test, in which plasma retinol levels are measured before and after the administration of a small amount of vitamin A^[5]. A plasma retinol level increase of at least 20% indicates an inadequate vitamin A level ^[3,5,6]. For clinical practice purposes, plasma retinol levels alone are sufficient for documenting significant deficiency.

A plasma retinol concentration lower than 0.70 micromoles/L (or 20 micrograms [mcg]/dL) reflects vitamin A inadequacy in a population, and concentrations of 0.70–1.05 micromoles/L could be marginal in some people ^[5]. In some studies, high plasma or serum concentrations of some provitamin A carotenoids have been associated with a lower risk of various health outcomes, but these studies have not definitively demonstrated that this relationship is causal.

Recommended Intakes

Intake recommendations for vitamin A and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies (formerly National Academy of Sciences) ^[5]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

· Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

· Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.

· Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.

· Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.

RDAs for vitamin A are given as retinol activity equivalents (RAE) to account for the different bioactivities of retinol and provitamin A carotenoids, all of which are converted by the body into retinol (see Table 1). One mcg RAE is equivalent to 1 mcg retinol, 2 mcg supplemental beta-carotene, 12 mcg dietary beta-carotene, or 24 mcg dietary alpha-carotene or beta-cryptoxanthin ^[5].

*Adequate Intake (AI), equivalent to the mean intake of vitamin A in healthy, breastfed infants.

International Units and mcg RAE

Vitamin A is listed on the new Nutrition Facts and Supplement Facts labels in mcg RAE^[8]. The U.S. Food and Drug Administration (FDA) required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list vitamin A in international units (IUs) until January 2021 ^[9]. To convert IU to mcg RAE, use the following ^[7]:

· 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.

Sources of Vitamin A

Food

Concentrations of preformed vitamin A are highest in liver and fish oils^[2]. Other sources of preformed vitamin A are milk and eggs, which also include some provitamin A^[2]. Most dietary provitamin A comes from leafy green vegetables, orange and yellow vegetables, tomato products, fruits, and some vegetable oils ^[2]. 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 ^[4,5].

Table 2 suggests many dietary sources of vitamin A. The foods from animal sources in Table 2 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.

*DV = Daily Value. FDA developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin A on the new Nutrition Facts and Supplement Facts labels and used for the values in Table 2 is 900 mcg RAE for adults and children age 4 years and older ^[8], where 1 mcg RAE = 1 mcg retinol, 2 mcg beta-carotene from supplements, 12 mcg beta-carotene from foods, 24 mcg alpha-carotene, or 24 mcg beta-cryptoxanthin. FDA required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list a vitamin A DV of 5,000 IU until January 2021^[9,10]. FDA does not require the new food labels to list vitamin A content unles vitamin A has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central^[11]lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin A in IUs arranged by nutrient content and by food name, and foods containing beta-carotene in mcg arranged by nutrient content and by food name.

Dietary supplements

Vitamin A is available in multivitamins and as a stand-alone supplement, often in the form of retinyl acetate or retinyl palmitate ^[2]. 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 ^[2]. Multivitamin supplements typically contain 750–3,000 mcg RAE (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 ^[12]. 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.

Vitamin A Intakes and Status

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 RAE^[13]. 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.

Data from NHANES III, conducted in 1988–1994, found that approximately 26% of the vitamin A in RAEs consumed by men and 34% of that consumed by women in the United States comes from provitamin A carotenoids, with the remainder coming from preformed vitamin A, mostly in the form of retinyl esters ^[5].

The adequacy of vitamin A intake decreases with age in children ^[4]. Furthermore, girls and African-American children have a higher risk of consuming less than two-thirds of the vitamin A RDA than other children ^[4].

Vitamin A Deficiency

Frank vitamin A deficiency is rare in the United States. However, vitamin A deficiency is common in many developing countries, often because residents have limited access to foods containing preformed vitamin A from animal-based food sources and they do not commonly consume available foods containing beta-carotene due to poverty ^[2]. According to the World Health Organization, 190 million preschool-aged children and 19.1 million pregnant women around the world have a serum retinol concentration below 0.70 micromoles/L ^[14]. In these countries, low vitamin A intake is most strongly associated with health consequences during periods of high nutritional demand, such as during infancy, childhood, pregnancy, and lactation.

In developing countries, vitamin A deficiency typically begins during infancy, when infants do not receive adequate supplies of colostrum or breast milk ^[14]. Chronic diarrhea also leads to excessive loss of vitamin A in young children, and vitamin A deficiency increases the risk of diarrhea^[5,15]. 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 ^[2,16]. Vitamin A deficiency is one of the top causes of preventable blindness in children ^[14]. 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^[3,14]. Vitamin A deficiency also increases the severity and mortality risk of infections (particularly diarrhea and measles) even before the onset of xerophthalmia ^[5,14,16].

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5. 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.
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8. U.S. Food and Drug Administration. Food Labeling: Revision of the Nutrition and Supplement Facts Labels. 2016.

9. U.S. Food and Drug Administration. Food Labeling: Revision of the Nutrition and Supplement Facts Labels and Serving Sizes of Foods That Can Reasonably Be Consumed at One Eating Occasion; Dual-Column Labeling; Updating, Modifying, and Establishing Certain Reference Amounts Customarily Consumed; Serving Size for Breath Mints; and Technical Amendments; Proposed Extension of Compliance Dates. 2017.
10. U.S. Food and Drug Administration. Guidance for Industry: A Food Labeling Guide (14. Appendix F: Calculate the Percent Daily Value for the Appropriate Nutrients). 2013.
11. U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.
12. 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.
13. U.S. Department of Agriculture, Agricultural Research Service. What We Eat in America, 2007-2008.
14. 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.
15. 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.
16. Sommer A. Vitamin A deficiency and clinical disease: An historical overview. J Nutr 2008;138:1835-9.