15.1: Introduction (18a.1) (2025)

18a.1.1 Functions of vitamin A

Vitamin A has a clearly defined role in vision: when retinal tissue is deprived of vitamin A, rod and cone function is impaired. However, only the bio­chem­ical role of the 11-cis retinaldehyde form of vitamin A, in the visual process in rod cells, has been studied in detail. Vitamin A is required for the integrity of epithelial cells through­out the body. The regulatory action of retinoic acid at the level of the gene has an impor­tant role in growth, embryonic development, and maintenance of immune function. Both cell-mediated immunity and systemic and mucosal humoral immunity are affected. A review by Tanumihardjo et al. (2016) outlines the various functions and biomarkers of vitamin A.

18a.1.2 Vitamin A defi­ciency in humans

Early signs of vitamin A defi­ciency in humans include growth failure, loss of appetite, and impaired immune response with lowered resistance to infection. Xerophthalmia are the sequelae asso­ci­ated with the eye during extreme vitamin A defi­ciency. Night blindness develops when liver reserves of vitamin A are nearly exhausted. If not corrected, ocular lesions such as conjunctival xerosis, Bitot's spots, kerato­malacia, and blindness may occur. In the past, conjunc­tival impression cytology (CIC) was used to detect early physio­logical changes charac­teristic of vitamin A defi­ciency. Such changes include both the progres­sive loss of goblet cells in the conjunctiva and the appearance of enlarged, partially keratin­ized, epithelial cells (Wittepenn et al., 1986; Natadisastra et al., 1988). Filter paper is used to collect the cells and then they are stained. Results have been inconsistent and dependent in part on the severity of the vitamin A defi­ciency state (Table 18.7) and on which measures are used. Ocular infections may confound the interpretation (Carlier et al., 1992). Due to relatively low sensitivity and specificity, WHO recommends combining this test with other indicators of vitamin A status (WHO, 1996). Currently the method is not being used in human studies.

Vitamin A defi­ciency still occurs in the world, but major strides have been made in the eradication of blindness through public health interventions, such as high dose capsule distri­bution and food fortifi­cation with vitamin A. The definition for vitamin A defi­ciency includes both clinical manifest­ations-xero­phthalmia, anemia, growth retardation, increased infectious morbidity and mortality-as well as the following func­tional consequences: impaired iron mobilization, disturbed cellular differentiation, and depressed immune response (Sommer & Davidson, 2002).

Severe deficiencies of certain other nutrients may also simulate vitamin A defi­ciency. Examples include zinc (Christian and West, 1998) and protein-energy malnu­tri­tion (Russell et al., 1983); details are given in Section 18.2.1.

Vitamin A defi­ciency may occur secondary to some disease states, including cystic fibrosis, severe intestinal and liver diseases, and some severe defects in lipid absorption (e.g., cholestasis). In developed countries, the preva­lence of frank nutritional defi­ciency of vitamin A is low. In the U.S. National Health and Nutrition Exam­ination Survey (NHANES III, 1988‑1994), for example, the preva­lence of low serum retinol concen­tra­tions (<0.70µmol/L) was less than 2% in all age, sex, race or ethnic strata (Ballew et al., 2001). The World Health Organization provides guidance on the use of serum retinol concen­tra­tions to evaluate popu­la­tion vitamin A status (WHO, 2011).

18a.1.3 Food sources and dietary intakes

Pre­formed vitamin A is found only in foods of animal origin: fish-liver oils, liver, butterfat, and egg yolk are the major dietary sources. Muscle meats are poor sources of pre­formed vitamin A. Plant sources, such as nuts, grains, and vege­table oils, have no pre­formed vitamin A.

Pro­vita­min A carot­enoids are found in both plant and animal products, but in low- income countries the main food sources are yellow and orange-colored fruits (West, 2000) and dark-green leafy vege­tables. Red palm oil, and certain indigenous plants such as palm fruits (buriti) in Latin America, and the fruit termed "gac" in Vietnam, are unusually rich sources of pro­vita­min A carot­enoids (FAO/WHO, 2002).

Pro­vita­min A carot­enoids, when derived from ripe yellow- and orange-colored fruits and cooked yellow tubers (e.g., sweet potatoes), appear to be more efficiently converted to retinol than when derived from dark green leafy vege­tables (IOM, 2001; West et al., 2002). Processing methods and the food matrix also affect the bio­avail­ability of pro­vita­min A carot­enoids (Torronen et al., 1996; Rock et al., 1998; van het Hof et al., 1988).

In more affluent countries such as Canada, the United States, and the United Kingdom, the major sources of pre­formed vitamin A in the diet are liver, milk, and milk products, followed by fish in the United States and Canada (IOM, 2001) and fat spreads (e.g., fortified margarine) in the United Kingdom(Gregory et al., 1990). The major contributors of pro­vita­min A carot­enoids are generally vege­tables (Gregory et al., 1990; Chug-Ahuja et al., 1993). Of the pro­vita­min A carot­enoids, β‑carotene followed by β‑crypto­xanthin are the most impor­tant. Other carot­enoids with vitamin A activity include α‑carotene, lutein, lycopene, and zeaxanthin.

Currently two conversion factors are used for calculating the amount of vitamin A activity in foods from pro­vita­min A carot­enoids, although the values applied differ across agencies. FAO/WHO (2002) still maintain the use of 1µg retinol equals 6µg of β‑carotene and 12µg of other pro­vita­min A carot­enoids (mainly α‑carotene and β‑crypto­xanthin). These same carotenoid / equivalency ratios have also been adopted by the European Food Safety Authority (EFSA, 2017). Furthermore, these two agencies express the substances with vitamin A activity as retinol equivalents (RE), whether they are pre­formed vitamin A (mainly retinol and retinyl esters) in foods of animal origin or pro­vita­min A carot­enoids.

The U.S. Food and Nutrition Board, however, concluded that the bio­avail­ability of pro­vita­min A β‑carotene from plant sources is 12µg to 1µg retinol and 24µg to 1µg for other pro­vita­min A carot­enoids for healthy individuals. For a detailed justification of these conversion factors, see IOM (2001). The U.S has also adopted the term retinol activity equivalents (RAE) for use when calculating the total amount of vitamin A in mixed dishes or diets. If the IOM (2001) conversion factors are adopted, the vitamin A activity in a foodstuff, expressed as a retinol activity equivalency, can be calculated from the following equation:

\[\begin{aligned}
& \operatorname{RAE}(\mu \mathrm{g})=\text { retinol }(\mu \mathrm{g})+(\beta \text {-carotene }(\mu \mathrm{g}) / 12.0) \\
& \quad+(\text { other provitamin A carotenoids }(\mu \mathrm{g}) / 24.0)
\end{aligned}\nonumber\]

Such inconsistencies in the specific carot­enoids/retinol equivalency ratios applied exacerbate problems when comparing vitamin A values among food compo­sition databases and, in turn, vitamin A intakes across countries. For example, vitamin A intakes calculated from some food compo­sition data may be higher if the lower biocon­version factors for pro­vita­min A carot­enoids recommended by FAO/WHO and EFSA were used, rather than the higher biocon­version facturs adopted by the United States (IOM, 2001).

Some older food compo­sition tables continue to express vitamin A in terms of international units (IU). Use of these older units is no longer appropriate for assessing dietary adequacy of vitamin A and should be discontinued (FAO/WHO, 2002). For more discussion of the confusion that may arise when assessing dietary vitamin A intakes, see Melse-Boonstra et al. (2017).

18a.1.4 Effects of high intakes

Suggestions that vitamin A and its carotenoid precursors are cancer-preventive agents led to increased consumption of large doses of vitamin A. This is a serious health hazard, partic­ularly during pregnancy: hyper­vitamin­osis A has been asso­ci­ated with birth defects (Rothman et al., 1995; Azais-Braesco and Pascal, 2000). Clinical manifest­ations of vitamin A toxicity include a pseudo brain tumor, skeletal pain, desquamating dermatitis, and hepatic inflammation (Frame et al., 1974; Russell, 2000). Concomitant consumption of ethanol appears to enhance the toxicity of vitamin A (Leo and Lieber, 1999).

A U.S. Tolerable Upper Intake Level (UL) has not been set for β‑carotene or carot­enoids (IOM, 2000), although β‑carotene supple­ments are not advised for the general popu­la­tion. For pre­formed vitamin A, the U.S. UL varies according to life‑stage group, ranging from 600µg/d for infants to 2,800µg/d for adolescents. For nonpregnant, pregnant, and lactating women, the UL is 3000µg/d (IOM, 2001).

The U.S. UL is not applicable to vitamin A-deficient popu­la­tions who should receive vitamin A prophyl­actic­ally. Approximately 80 countries are using vitamin A sup­plement­ation (Wirth et al., 2017). The World Health Organization (2011) recom­mend routine high-dose vitamin A sup­plement­ation in developing countries for children between the ages of 6 to 59mo. For infants 6‑11mo, 100,000 IU should be given as a single dose every 4‑6mo. Children aged 12mo and older should receive 200,000 IU as a single dose every 4‑6mo. No other age groups are recommended for high dose sup­plement­ation by the World Health Organization.