Vitamin A

Synonym(s): retinal, retinol, retinoic acid, retinyl acetate, retinyl palmitate

Nutrient group: Vitamine, Antioxidants

Sources and physiological effects

Dietary sources
Vitamin A supply is not only determined by the direct intake of vitamin A (retinol), but also by the intake of certain carotenoids which are converted into vitamin A in the body at varying levels of efficiency (vitamin A precursors / provitamin A). High concentrations are found in liver and fish liver oils. The vitamin A content of liver is sometimes so high that pregnant women are advised not to consume it. Lower vitamin A concentrations are also found in butter, cheese, eggs and fish. Vegetable foods provide vitamin A precursors, with beta-carotene being the most important provitamin. Since carotenoids are natural pigments with a yellow to reddish coloration, color-intensive yellow, orange and red vegetables and fruits – such as carrots, apricots, mangos and papayas – are rich in these plant constituents. However, dark green leafy vegetables such as spinach and kale also contain significant amounts of provitamins. The usability of vitamin A is influenced by various factors. A low-fat diet and iron and zinc deficiency reduce the bioavailability of vitamin A, while heat and light reduce the vitamin A activity of provitamins through the formation of cis-isomers. The fat-soluble vitamin is partially destroyed by prolonged cooking.
Physiological effects
Eye	Building block of the visual rods (rhodopsin) and as such essential participation in the visual process and the conversion of photoenergy into neuronal energy
Reproduction	Regulation of sperm and egg cell maturation Participation in the synthesis of androgens and estrogens
Skin	Promotes healthy cell division and repair of skin damage
Mucous membranes	Support of the mucous membranes in their function as a barrier against the intrusion of bacteria and viruses
Immune system	Participation in the production of antibodies Activation of neutrophils, macrophages, NK cells as well as T-helper cells and B cells
Blood	Supports the formation and release of new erythrocytes and the incorporation of iron into erythrocytes

EFSA Health Claims

Health Claims		EFSA Opinion
Vitamin A	Contributes to the preservation of normal mucous membranes Contributes to the maintenance of normal skin Contributes to maintaining normal vision Contributes to normal functioning of the immune system Contributes to normal iron metabolism Has a function in cell specialization

Recommended intake

D-A-CH Recommended nutrient intake (Reference values EFSA and NHI )
Age	Vitamin A
	µg-RÄ/Tag
	Men	Women
Babies
0 to under 4 months	0.5
4 to under 12 months	0.6
Children
1 to under 4 years	0.6
4 to under 7 years	0.7
7 to under 10 years	0.8
10 to under 13 years	0.9
13 to under 15 years	1.1	1
Adolescents and adults
15 to under 19 years	1.1	1
19 to under 25 years	1.1	0.9
25 to under 51 years	1	0.8
51 to under 65 years	1	0.8
65 years and older	1	0.8
Pregnancy and lactation
Pregnancy		1.1
Breast-feeding		1.5
Increased need	Growth, hyperthyroidism, chronic infections, liver diseases, vegan diet, alcohol abuse, chronic inflammatory bowel disease, zinc deficiency. Reduced availability with a very low-fat diet, bile acid deficiency and fat absorption disorders reduce the availability of vitamin A and carotenoids in the body, smoking
Special risk group for a defect	Pregnant women, children, vegans, alcoholics, chronically ill people
^a1 mg retinol equivalent = 1 mg retinol = 6 mg all-trans-β-carotene = 12 mg other provitamin A carotenoids = 1.15 mg all-trans retinyl acetate = 1.83 mg all-trans retinyl palmitate; 1 IU (International units are only given in the pharmaceutical range = 0.3 µg retinol ^bThis is an estimated value ^cca. 70 µg retinol equivalent supplement per 100 g of milk secreted

Recommended intake according to food labelling regulations
(= 100% TB marking on label)		800 µg
1 I.U. Vitamin A = 0,3 µg retinol 1 I.U. Vitamin A = 0,6 µg beta-carotene 1 µg Vitamin A = 3.3 I.U. vitamin A

Detailed information

Vitamin A – physiological functions

Vitamin A is one of the essential vitamins for the human body. This includes various compounds with vitamin A activity, which are summarized under the term “retinoids“. In addition to retinol, which is contained in animal products, vegetable carotenoids - such as β carotene - also have a provitamin A function. They can be split into 2 molecules of retinol in the body, but humans can only convert carotenoids to vitamin A to a limited extent (1). After oral intake, retinoids are absorbed into the enterocytes in the duodenum in the presence of fats and further metabolized as retinoic acid or retinol. To increase enteral absorption, vitamin A is therefore best taken with a meal.

Vitamin A and visual function

Vitamin A is a component of the visual rods (rhodopsin) and as such is involved in the visual process and the conversion of photo energy into neuronal energy. A vitamin A deficiency results in so-called night blindness due to the lack of rhodopsin building material, a disturbance of twilight vision and increased sensitivity to glare (1). In the case of a long-term deficiency with progressive dryness of the eye, and diseases such as xerophthalmia and keratomalacia can develop, which can ultimately lead to a complete loss of function of the eye (2).

Vitamin A and epithelial health

Vitamin A plays a central role in the structure, proliferation and differentiation of epithelial cells by promoting healthy cell division and repairing skin damage (3). The normal differentiation of the stratified squamous epithelium and the formation of keratinocytes and fibroblasts can only be guaranteed with sufficient vitamin A intake. Vitamin A deficiency leads to disorders in the differentiation of epithelial tissue and associated hyperkeratosis and atrophy (4). The changes can affect the epidermis (hyperkeratosis), but also the mucosa of the respiratory tract, urinary tract, reproductive organs and the gastrointestinal tract (5). The atrophy of the salivary glands and mucous membranes leads to dehydration and loss of function of mucous membranes. In the area of the tracheobronchial tract, gingivitis, stomatitis, bronchitis and pneumonia are more frequent. Atrophies in the intestinal mucosa are associated with increased diarrhea and resorption disorders (6), and in the urogenital tract the development of bladder and kidney stones is promoted and the function of the reproductive organs is restricted. Further vitamin A deficiency symptoms caused by epithermal differentiation disorders are dry hair, skin and nails as well as impairment of the sense of smell, taste and touch (1).

Vitamin A and the immune system

Retinoids contribute to the maintenance of an intact skin and mucous membrane barrier and thus support the body’s first defense barrier against microorganisms (5). In vitamin A deficiency the normal cellular mechanisms of the skin barrier are disturbed (4) and, as a consequence, diseases of the respiratory tract frequently occur (7). In addition to supporting the barrier function, retinoids also directly stimulate humoral and cellular defense. Infectious diseases that induce an acute phase reaction also lead to a decrease in circulating vitamin A (1). An inadequate vitamin A intake worsens the immune response by disrupting the regeneration of the mucosal barrier after infections and restricting the function of neutrophils, macrophages, NK cells, T-helper cells and B-cells (8). The immunomodulating effect on cells of the respiratory tract (9) (10) and the gastrointestinal tract (11) has been demonstrated in numerous studies.

Vitamin A – Reproduction, growth and development

Vitamin A and its derivative, all-trans-retinoic acid, are essential for healthy reproduction due to their role in the synthesis of androgens and estrogens and providing for normal oogenesis and spermatogenesis (12). In the male reproductive tract, vitamin A deficiency leads to keratinization processes of the epithelia of the epididymis, prostate and seminal vesicle and to a direct blockade of the mitosis of the spermatogonia (13). This means that normal spermatogenesis is no longer possible. In the female reproductive system, vitamin A supports placental development, implantation and embryo development (14). Retinoids play a particularly important role in the formation of the neural tube (15), but also in the development of organs such as the eyes (16), the kidneys, the diaphragm (17), the testicles (13), as well as the cardiovascular (18) and skeletal (19) systems. Retinol also plays an important role in the development of normal lung function. Studies have shown that an undersupply of vitamin A during pregnancy adversely affects the lung maturation of the child (20) and promotes later diseases such as asthma (21). There is also evidence that the vitamin A status of the pregnant woman has an influence on the later cognitive abilities of the unborn child (22). In addition, vitamin A deficits during pregnancy are discussed with the development of neuropsychiatric diseases such as schizophrenia (23).

Vitamin A and hematopoiesis

Retinol promotes the formation and release of new erythrocytes and facilitates the incorporation of iron. Vitamin A deficiency can lead to disturbed iron utilization and associated hypochromic anemia (5).

Vitamin A deficiency: only a problem in developing countries?

Vitamin A deficiency occurs very frequently in developing countries with a poor supply of vitamin A-containing foods. According to the WHO, around 140 million children and 7 million pregnant women are acutely affected. But even in countries with a good supplyof vitamin A food sources, chronic intestinal diseases, eating disorders (24) or adverse drug reactions (25) repeatedly lead to a vitamin A deficiency. In particular, chronic inflammations of the gastrointestinal tract, such as Crohn's disease and ulcerative colitis, often cause a vitamin A deficiency due to reduced intestinal absorption (26). Also, in diseases with disturbed fat absorption, such as pancreatic insufficiency, hepatopathy and gallbladder diseases, the vitamin A level is reduced due to malabsorption. In addition, regular alcohol consumption or medications such as cholesterol-lowering drugs, somatostatin analogs, and laxatives can interfere with the absorption and storage of vitamin A (27). Additionally, diabetics and people with hyperthyroidism have a hard time converting vegetable carotenoids into vitamin A.

Reference values

transport proteins in plasma and cytosol. They bind to free vitamin A and thus facilitate the transport of lipophilic molecules in the blood and inside the cells..

Parameters	Substrate	reference value	Description
Retinol	serum/plasma	women 400 - 700 µg retinol/l	Fasted (12 h food leave), light and heat sensitive, refrigerated storage

		men 425 - 830 µg Retinol/l
Retinol-binding protein (RBP)	serum/plasma	30-60 mg RBP/l
Ratio Retinol/RBP		> 0.7	Gives important information about the presence of a vitamin A deficiency.
Interpretation
Low values		indication of vitamin A deficiency. Disorders in fat absorption caused by a liver, pancreas, gall bladder or small intestine disease. Malnutrition. Note: 90% of vitamin A is stored in the liver, therefore the determination of the plasma concentration of vitamin A alone is not sufficient.
High values		Clarification of hypervitaminosis due to increased vitamin A supply, e.g. vitamin preparation.

Nutrigenetics and cancer

Gene/miRNA	Process	Activity change	Prevention	Nutrient for cancer prevention
P16, P14, and hMLH1	Methylation	reduced	Prevention of colon cancer	Vitamin A

Deficiency symptoms

Impact on	Symptoms
General health	Increased susceptibility to infections, fatigue
Eyes	Sensitivity to glare, night blindness, dry conjunctiva
Mucous membranes	ENT: dehydration and cornification with disorders of the sense of taste and smell, gingivitis, stomatitis Respiratory tract: bronchitis, frequent respiratory infections Intestinal mucosa: diarrhea, malabsorption
Immune system	Reduced antibody production, frequent infections
Skin and hair	Dry, flaky skin, brittle nails, premature greying
Pregnancy	Increased risk of malformations of internal organs
Growth	Disorders in bone and tooth growth in children
Men	Impaired sperm formation, infertility, etc;

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For the treatment of an inadequate vitamin A status as diagnosed in the laboratory	1000 µg/d
	To increase vitamin A intake in diseases with reduced vitamin absorption from the intestine such as chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease), pancreatic insufficiency or hepatopathies	1000 µg/d
	To increase vitamin A intake in case of increased need in breastfeeding time, in growth and during regeneration	1000 µg/d
	To support of the immune system, especially in recurrent or chronic diseases of the respiratory and gastrointestinal tract	1000 µg/d
	To support fertility in men and women	1000 µg/d

Administration

General mode of administration
When	Vitamin A is fat-soluble and should be taken with or after meals. After oral intake, retinoids are taken up in the small intestine in the presence of fats in the enterocytes and further metabolized as retinoic acid or retinol. To increase enteral absorption, vitamin A is therefore best taken with a meal.
Side effects
No known side effects to date.
Contraindications
Glaucoma, increased intracranial pressure, severe hypertension, severe diabetes mellitus
Notes: Pregnancy: Vitamin A is essential for normal embryonic development. Pregnant women should consume a maximum of 3000 µg vitamin A per day in order to avoid the negative consequences of an overdose. The body's own conversion of beta-carotene into retinol is a safe method of meeting vitamin A requirements during pregnancy. Menopause: At long-term high dosage (1500 µg/d) an increase of osteoporosis risk could be observed in studies.

Interactions

Drug interactions
Retinoids (e.g. ciscutane)	The combined intake of high doses of vitamin A–analogues and vitamin A can lead to toxic reactions.
Estrogens (oral contraceptives)	Can raise vitamin A levels in the liver.
Nutrient interactions
Trace elements	Zinc deficiency can negatively influence vitamin A metabolism (absorption, transport, conversion to retinal).

Description and related substances

Description of the micronutrient

Fat-soluble vitamin

Connections

Retinyl palmitate
Beta-carotene

References

1) Biesalski, H. C. et al. Ernährungsmedizin: Nach dem Curriculum Ernährungsmedizin der Bundesärztekammer und der DGE, 4. Auflage. Stuttgart: Georg Thieme Verlag KG, 2010.
2) Leitzmann, C. et al. Ernährung in Prävention und Therapie: Ein Lehrbuch, 3. vollständig überarbeitete und erweiterte Auflage. Stuttgart: Hippokrates Verlag, 2009.
3) Blumenberg, M., Tomic-Canic, M. 1997. Human epidermal keratinocyte: keratinization processes. EXS. 78:1–29.
4) Fisher, G. J., Voorhees, J. J. 1996. Molecular mechanisms of retinoid actions in skin. FASEB J. 10(9):1002-13.
5) Biesalski, H. K., Nohr, D. 2004. New aspects in vitamin A metabolism: the role of retinyl esters as systemic and local sources for retinol in mucous epithelia. J Nutr. 134(12 Suppl):3453S-3457S.
6) Swartz-Basile, D. A. et al. 2003. Vitamin A deficiency inhibits intestinal adaptation by modulating apoptosis, proliferation and enterocyte migration. Am J Physiol Gastrointest Liver Physiol. 285(2):G424-32.
7) McGowan, S. E. et al. 2002. Vitamin A deficiency promotes bronchial hyperreactivity in rats by altering muscarinic M(2) receptor function. Am J Physiol Lung Cell Mol Physiol. 282(5):L1031-9.
8) Duriancik, D. M. et al. 2010. Vitamin A as a regulator of antigen presenting cells. J Nutr. 140(8):1395-9. doi: 10.3945/jn.110.124461.
9) Rudraraju, R. et al. 2012. Reduced frequencies and heightened CD103 expression among virus-induced CD8(+) T cells in the respiratory tract airways of vitamin A-deficient mice. Clin Vaccine Immunol. 19(5):757-65. doi: 10.1128/CVI.05576-11.
10) Kim, S. C. et al. 2012. Vitamin A deficiency induces fluid hyposecretion from the airway submucosal glands of mice. J Nutr. 142(4):739-43. doi: 10.3945/jn.111.154047.
11) Kaufman, D. R. et al. 2011. Vitamin A deficiency impairs vaccine-elicited gastrointestinal immunity. J Immunol. 187(4):1877-83. doi: 10.4049/jimmunol.1101248.
12) Dumont, L. et al. 2016. Vitamin A prevents round spermatid nuclear damage and promotes the production of motile sperm duringin vitromaturation of vitrified pre-pubertal mouse testicular tissue. Mol Hum Reprod. 22(12):819-832. doi: 10.1093/molehr/gaw063.
13) Gely-Pernot, A. et al. 2011. Spermatogonia differentiation requires retinoic acid receptor γ. Endocrinology. 153(1):438-49. doi: 10.1210/en.2011-1102.
14) Clagett-Dame, M., Knutson, D. 2001. Vitamin A in reproduction and development. Nutrients. 3(4):385–428.
15) Glover, J. C. et al. 2006. Retinoic acid and hindbrain patterning. J Neurobiol. 66(7):705–725. doi: 10.1002/neu.20272.
16) See, A. W., Clagett-Dame, M. 2009. The temporal requirement for vitamin A in the developing eye: mechanism of action in optic fissure closure and new roles for the vitamin in regulation cell proliferation and adhesion in the embryonic retina. Dev Biol. 325:94–105. doi: 10.1016/j.ydbio.2008.09.030.
17) Beurskens, L. W. et al. 2010. Retinol status of newborn infants is associated with congenital diaphragmatic hernia. Pediatrics. 126(4):712–720.
18) Hoover, L. L. et al. 2008. The expanding role for retinoid signaling in heart development. Sci World J. 8:194–211. doi: 10.1100/tsw.2008.39.
19) Quadro, L. et al. 2005. Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency. Endocrinology. 146:4479–4490.
20) Checkley, W. et al. 2010. Maternal vitamin A supplementation and lung function in offspring. N Engl J Med. 362(19):1784-94. doi: 10.1056/NEJMoa0907441.
21) Checkley, W. et al. 2011. Supplementation with vitamin A early in life and subsequent risk of asthma. Eur Respir J. 38(6):1310-9. 10.1183/09031936.00006911.
22) Jiang, W. et al. 2012. Vitamin A deficiency impairs postnatal cognitive function via inhibition of neuronal calcium excitability in hippocampus. J Neurochem. 121(6):932-43. doi: 10.1111/j.1471-4159.2012.07697.x.
23) Bao, Y. et al. 2012. Low maternal retinol as a risk factor for schizophrenia in adult offspring. Schizophr Res. 137(1–3):159-65. doi: 10.1016/j.schres.2012.02.004.
24) Velasco Cruz, A. A. et al. 2005. Adult blindness secondary to vitamin A deficiency associated with an eating disorder. Nutrition. 21(5):630-3.
25) Gröber, U. Mikronährstoffe: Metabolic Tuning – Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
26) Alkhouri, R. H. et al. 2013. Vitamin and mineral status in patients with Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 56(1):89-92. doi: 10.1097/MPG.0b013e31826a105d.
27) Fiebrich, H. B. et al. 2010. Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue. Aliment Pharmacol Ther. 32(11–12):1398-404. doi: 10.1111/j.1365-2036.2010.04479.x.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008. Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.