Ingredient review —Vitamin A
What is it?
Description
Vitamin A is a collection of fat-soluble molecules found either as preformed vitamin A (e.g., retinol, retinal, retinoic acid, or retinol esters) or as pro-formed vitamin A (e.g., mainly beta-carotene, alpha-carotene, or cryptoxanthin). Dietary preformed vitamin A mainly comes from animal sources, particularly liver, which is why cod liver oil supplements contain vitamin A. In contrast, pro-formed vitamin A is typically found in yellow and orange fruits and vegetables or in dark green leafy vegetables. (9)(18)(34)(58)
The average American two years of age or older consume 600 mcg (µg) of retinol activity equivalent (RAE) per day. (77) However, depending on age and gender, this average intake may or may not be enough. The National Institutes for Health (NIH) indicates that individuals aged 1-3, 4-8, and 9-13 should consume 300 µg RAE, 400 µg RAE, and 600 µg RAE, respectively. Males aged 14 and older should consume 900 µg RAE and females should consume 700 µg RAE, unless pregnant or lactating, during which, intakes should be as high as 770 µg RAE and 1,300 µg RAE, respectively. (58) It is estimated that vitamin A deficiency affects people living in approximately 30% of countries worldwide, as indicated by serum retinol levels lower than 20 µg/dL (0.70 mmol/L), (82) although deficiency is rare in the United States and Canada. Vitamin A deficiency can lead to xerophthalmia (dry eye), night blindness, corneal xerosis or ulceration, keratomalacia, and in some cases, blindness. (18) Vitamin A thus plays important roles particularly in vision, but also has other functions including immunity, cellular development and communication, and reproduction. (18)(34)
Topical vitamin A and its derivatives have been popularly used for skin health such as anti-aging; however, topical formulations are not covered in this review. It is also important to note that studies demonstrate beneficial effects of adequate dietary vitamin A on reducing the risk of cancers of the bladder, (75)(83) breast, (35)(64) cervix, (87) esophagus, (28) head and neck, (48) ovaries, (79) pancreas, (86) skin, (88), and stomach; (45)(84) however, this review will only focus on interventions using vitamin A supplementation. Most high-level evidence points to a lack of benefit of vitamin A or carotenoid supplementation in cancer. (25)(26)(42)(63)
Main uses
Iron status
Lung health
Skin health
Thyroid function
Vision
Formulations
Form
Absorption Rate
Vitamin A (retinol)
Retinyl palmitate
Natural (preformed) form most common in dietary supplements; esterified form of retinol and palmitic acid (55% retinol by weight) (56)
In states of deficiency, 60,000 µg RAE of retinyl palmitate and 1,200,000 µg RAE of beta-carotene supplementation (bioequivalent doses) improved vitamin A deficiency to the same extent (~50%). (12)
Retinyl acetate
Natural (preformed) form; esterified from retinol and acetate (87% retinol by weight) (57)
Dosing & administration
Acute pyelonephritis
General outcomes from A-level evidence
relative risk of renal damage (47%) after acute pyelonephritis as an adjunct therapy in children (85)
Dosing & administration
450 µg RAE/kg body weight per day (up to a max of 15,000 µg RAE) for ten days adjunct to antibiotic therapy to children with acute pyelonephritis
Outcomes
number of children with worsened kidney scarring (19-22% difference) and symptoms associated with urinary tract infection comorbidity, including fever duration (1.3 day difference), urination frequency (1.5 day difference), and inadequate eating (1.9 day difference) than children only using antibiotics (44)(72)
Class of evidence
b
Anemia
General outcomes from A-level evidence
Dosing & administration
1,500-3,000 µg RAE per day (average) to pregnant women at risk of vitamin A deficiency
Outcomes
maternal anemia (36%) (51)
Class of evidence
a
Dosing & administration
1,500 µg RAE (retinyl acetate) per day for 12 weeks to children with anemia
Outcomes
hemoglobin (3.8x; ~10g/L difference), body weight (3x; 0.4 kg difference), height (4x; 0.3 cm difference) compared to placebo
Note: Effects on iron status and growth were increased when used in conjunction with iron supplementation. (53)
Class of evidence
b
Dosing & administration
60,000 µg RAE single administration to children at risk for iron deficiency anemia
Outcomes
prevalence of anemia (~20% difference), serum ferritin (1.66x), & total iron-binding capacity (2.8x)
hemoglobin (2.4x), serum iron (3.2x), & transferrin saturation (3.2x) compared to placebo (1)
Class of evidence
b
Infant mortality and infection related to vitamin A deficiency
Dosing & administration
30,000 µg RAE (as retinol palmitate) or 60,000 µg RAE every six months to children at high risk of vitamin A deficiency aged 6-12 months or aged 1-5 years, respectively
Outcomes
risk of all-cause mortality (12-24%), mortality due to diarrhea (12%), incidence of diarrhea (15%), & measles (50%) in infants and children in low-income countries (at risk for deficiency) (40)
Note: Within total dose ranges of 40,300-660,000 µg RAE over the course of 4-60 months, increased dosing frequency, total dose, and duration did not alter the protective effect of vitamin A administration, providing indication of flexibility in dosing efficacy. (47)
Class of evidence
a
Dosing & administration
7,500-15,000 µg RAE per day for the first 2-3 days of life
Outcomes
risk of six-month mortality (13%), particularly in locations at higher risk of vitamin A deficiency (59)
Class of evidence
a
Immune/inflammatory profile
General outcomes from A-level evidence
gene expression of pro-inflammatory cytokines IL-17, IFN-γ, & T-bet
gene expression of anti-inflammatory cytokines TGF-β & FOXP3 (33)
Dosing & administration
7,500 µg RAE (as retinyl palmitate) per day for 4-6 months to Px with multiple sclerosis or atherosclerosis
Outcomes
gene expression of pro-inflammatory cytokines IL-17, IFN-γ, & T-bet
gene expression of anti-inflammatory cytokines TGF-β & FOXP3 (33)
Class of evidence
a
Dosing & administration
7,500 µg RAE (as retinyl palmitate) per day for six months followed by 3,000 µg RAE for six months to Px with relapse-remitting multiple sclerosis adjunct to interferon beta therapy
Outcomes
Class of evidence
b
Respiratory health
General outcomes from A-level evidence
Improved clinical response rate to pneumonia therapy and reduced fever, cough, & clearance of lung infection without improving mortality; (37) however, older analyses do not support an effect in children (11)(14)(60)
odds of bronchopulmonary dysplasia (BPD) in premature infants (33%), (19) relative risk in extremely or very low-birthweight (12-13%), & mortality caused by BPD (8-10% with borderline statistical significance) (3)(17)(27)
Note: Administration of vitamin A in BPD is often done via intramuscular injections, but limited evidence supports the use of oral supplementation.
Dosing & administration
450 µg RAE per day for four weeks to extremely preterm infants
Outcomes
incidence of bronchopulmonary dysplasia (15% difference) compared to placebo (74)
Class of evidence
b
Dosing & administration
120,000 µg RAE (as retinyl palmitate) divided in two doses over two days to children with measles
Outcomes
time to recover from pneumonia (six-day difference) and incidence of croup (2x lower) (38)
Class of evidence
b
Dosing & administration
1,000 µg RAE (as retinyl palmitate) per day for 30 days to male smokers with mild chronic obstructive pulmonary disease
Outcomes
lung function (22.9%) as measured by FEV1 (62)
Class of evidence
c
Skin health
General outcomes from A-level evidence
Improves protection against sunburn with moderate to large effect (SMD = 0.63-0.8), but may require supplementation duration of at least ten weeks
Note: Sunscreen is still recommended to provide the best and most immediate protection against sunburn (46)
Dosing & administration
7,500-15,000 µg RAE (as retinyl palmitate) per day for one year to Px with sun-damaged skin
Outcomes
percent of cases with reduced skin damage dose-dependently (40-56% difference) compared to placebo (2)
Class of evidence
b
Dosing & administration
7,500 µg RAE (as retinol) per day for for up to five years in the general population
Outcomes
risk of developing a first squamous cell carcinoma by 26% (52)
Class of evidence
b
Dosing & administration
24-25 mg (total carotenoids) per day for 12 weeks to healthy volunteers
Class of evidence
c
Dosing & administration
30 mg (as beta-carotene) per day for ten weeks to healthy volunteers using sunscreen
Outcomes
UV-induced skin erythema more effectively than sunscreen alone (30)
Class of evidence
c
Thyroid health
General outcomes from A-level evidence
No data currently available.
Dosing & administration
7,500 µg RAE (as retinyl palmitate) per day for four months to healthy premenopausal women
Outcomes
TSH (30-34%)
T3 (38-61%) compared to baseline, but no change in placebo (22)
Class of evidence
b
Dosing & administration
60,000 µg RAE (as retinyl palmitate) single administration at entry and after 3-5 months to children with low vitamin A levels and iodine deficiency receiving iodized supplementation
Outcomes
TSH (35% or 71%), thyroglobulin (29% or 88%), & thyroid volume (12% or 24%) when vitamin A was used alone or when it was used alongside iodine supplementation compared to placebo, respectively, after six month follow-up (89)
TSH (54%), thyroglobulin (78%), thyroid volume (15%), & goiter rate (11% difference) compared to iodine plus placebo after ten-month follow-up (90)
Class of evidence
b
Vision
General outcomes from A-level evidence
Bitot’s spots prevalence (55%), night blindness incidence (47%) and prevalence (68%), & xerophthalmia prevalence (69%) in infants and children at risk of vitamin A deficiency (50)
relative risk of maternal night blindness (21%) in pregnant women at risk of vitamin A deficiency (51)
Dosing & administration
1,500-3,000 µg RAE per day (average) to pregnant women at risk of vitamin A deficiency
Outcomes
risk of maternal night blindness (21%) (51)
Class of evidence
a
Dosing & administration
4,500 µg RAE (as retinol palmitate) per day, ongoing, to adults with retinitis pigmentosa
Class of evidence
a
Dosing & administration
450 µg RAE per day for four weeks to extremely preterm infants
Outcomes
rate of type 1 retinopathy of prematurity (1.6% versus 6.9% in placebo) (74)
Class of evidence
b
Adverse effects
In order to avoid hypervitaminosis A, tolerable upper intake levels (ULs) have been established for preformed vitamin A but not for pro-formed vitamin A due to a lack of toxicity data available for carotenoids like beta-carotene. Upper tolerable levels are up to 3,000 µg RAE in adults. Practitioners should calculate the amount of preformed (not pro-formed) vitamin A in supplements when considering ULs. (58) Vitamin A toxicity can be classified as acute (singular large doses over a short period), chronic (moderate to high doses usually taken daily over a few months to years; for example, >10x or >3.75x the RDA for adults or infants, respectively), or teratogenic (moderate to high doses during the first trimester of pregnancy; for example >4,500 µg RAE).
A meta-analysis demonstrated that the top five most common acute adverse effects (prevalent in infants but rarely reported in individuals older than three years of age) included bulging fontanels (94%), vomiting (60%), hydrocephalus, and increased cerebrospinal fluid pressure (30% and 24%), pale skin (18%), and loss of appetite (16%). The top five adverse events associated with chronic hypervitaminosis in infants include hyperostosis (52%), loss of appetite (50%), irritability (46%), skeletal pain (42%), and bulging fontanels (38%). The top five side effects of chronic vitaminosis in children and adolescents include headaches (51%), lip fissures (41%), vomiting (41%), papillary edema (39%), and skeletal pain (39%). In adults, side effects include fatigue (45%), pigmentation (34%), headache (33%), alopecia (33%), and hepatomegaly (32%) (see reference for a full list of side effects). (54)
Overall, however, adult supplementation with vitamin A at doses 50% higher than the UL (4,500 µg RAE) over the course of 12 years did not lead to signs of vitamin A toxicity. (71) Additionally, adverse effects caused by doses within the UL are rarely reported in pregnancy; (51)(76)(80) however, it should be noted that when vitamin A is consistently taken in excess of the UL, it has been estimated that one in 57 infants may be born with a secondary congenital disability. (61) In infants and children (five months to five years of age) requiring high doses (30,000-60,000 µg RAE), the risk of vomiting may double or triple within 48 hours. (40)(50) According to the World Health Organization, most additional adverse reactions in this age group (e.g., diarrhea, headache, irritability, fever, or nausea) are mild, transient, and typically resolve within 48 hours (81) or are no more prevalent than observed in control groups. (37) One of the more prevalent adverse events to beta-carotene supplementation includes hypercarotenodermia (yellowing of the skin). One systematic review of several long-term studies showed that the proportion of patients developing hypercarotenodermia ranged between 7.4-15.8%. (49)
It should be noted that there is some evidence indicating that vitamin A supplementation led to an increased risk of cancer (16%), while beta-carotene at doses higher than 9.6 mg per day led to an increased risk of all-cause mortality by 5-6%. (7)(8)(70) Other analyses also indicated that 20-30 mg of beta-carotene per day increased the relative risk of lung cancer by 16% and stomach cancers by 34% in smokers and asbestos workers, (20) and may increase the risk of bladder cancer (44-52%). (42)(63) Finally, there is some evidence that vitamin A supplementation may increase the risk of bone decalcification and osteoporosis; however, this may be associated with the physical form of the supplement (water-miscible, emulsified, or dry retinol preparations, but not oil-based). (54)
Pharmacokinetics
Absorption
- Preformed vitamin A (retinyl esters) are hydrolyzed by pancreatic and intestinal enzymes to retinol in enterocytes before being re-esterified and transferred to mixed micelles.
- The retinol esters then cross enterocytes via passive diffusion or facilitated transport and are subsequently incorporated into chylomicrons for blood transport to the liver.
- Pro-formed vitamin A (carotenoids) is directly absorbed by enterocytes, where 50% is subsequently incorporated into chylomicrons and the other 50% is oxidized to retinal, then reduced to retinol prior to chylomicron transport.
- The presence of dietary fats improves vitamin A absorption, (9)(15) but 80-90% of vitamin A is absorbed regardless. (34)
Distribution
Metabolism
- To meet tissue requirements, hepatic vitamin A can be de-esterified, bound to retinol-binding protein and transthyretin, and sent to the tissue in need where it is converted to retinal by alcohol dehydrogenases and then to retinoic acid by retinal dehydrogenases to affect biological activity. (9)(13)
- Toxicity induced by beta-carotene consumption is rare as the conversion of beta-carotene to vitamin A is highly regulated and dependent on vitamin A status. The more vitamin A replete the individual is, the less efficiently beta-carotene is converted. (31)
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