Vitamin A deficiency is a serious public health concern globally (although not in North America). Excessive vitamin A intake can be toxic.
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Description
- Vitamin A exists in three oxidation states: the alcohol, retinol; the acid, retinoic acid; and the aldehyde, retinal. The term retinoids includes natural forms, synthetic forms, and metabolites of vitamin A. Animal products contain retinol (preformed vitamin A); plants contain provitamin A carotenoids (1). About 50 of over 600 carotenoids (including beta-carotene, alpha-carotene, gamma-carotene, and lutein) can act as precursors to vitamin A (2). Vitamin A is stored in the liver, which can hold an entire year’s supply.
Food Sources
- Retinol: liver, fish oils, egg yolk, and milk fat
- Carotenoids: Yellow-orange or red fruits (cantaloupe, peaches, mangoes, strawberries) and vegetables (carrots, sweet potatoes, tomatoes), dark green vegetables (kale, collards, spinach)
Mechanism/Pharmacokinetics
- Seventy percent to 90% of ingested vitamin A is absorbed (dietary fat is necessary for absorption). Absorption occurs through the small intestine, after which vitamin A is packaged into chylomicrons and transported to the liver, which stores 50% to 85% of total body retinol and regulates secretion of retinol (bound to retinol-binding protein).
- All-trans-retinol is the primary form found in plasma; most tissues contain esterified retinol (3).
- Main functions: vision (phototransduction and maintaining normal differentiation of cells in the cornea and conjunctiva), integrity of epithelial tissues, immunity (both cell-mediated and antibody-mediated), growth, and development (3).
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Clinical Trials
- Child health
- Vitamin A deficiency is very common in many parts of the world; it has been estimated that 3.3 million children worldwide are deficient. Most but not all community-based trials in children have found that vitamin A supplementation reduces overall mortality; pooled results from eight trials indicate that total mortality is reduced by about 34% (4).
- In hospitalized children, vitamin A supplementation reduces mortality from measles infection by about 60% (4). There is little evidence of benefit in children hospitalized for nonmeasles pneumonia; among well-nourished children, supplementation may be associated with adverse effects (4).
- Most trials of vitamin A found that supplementation reduced severity of diarrhea in children (4).
- A Cochrane meta-analysis of six randomized controlled trials of supplemental vitamin A in very low birthweight infants (<= 1,500 g) found that vitamin A reduced oxygen requirements at 36 weeks postmenstrual age [relative risk (RR) 0.85 (0.73, 0.98)].
Animal/In Vitro
- Induction of skin, lung, bladder, colon, and mammary tumors can be inhibited by high doses of vitamin A.
Other Claimed Benefits/Actions
- Cancer
- Dry skin
- Eye problems
- Lung disease
- Skin papillomas
- Vocal cord papillomas
- Wrinkles
- Wound healing
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Deficiency Signs and Symptoms
- Vitamin A deficiency is unusual in the United States and Canada, and supplementation is rarely indicated; exceptions include malnourished children, patients with cystic fibrosis, and alcoholics.
- Vision
- Globally, vitamin A is the leading cause of blindness among children. Deficiency may cause night blindness, Bitôt’s spots (small, triangular, gray deposits on the bulbar conjunctiva adjacent to the cornea, near the palpebral fissure), xerophthalmia, keratomalacia (the most severe stage of xerophthalmia, sometimes with corneal ulceration), and blindness.
- Infectious disease
- Vitamin A deficiency is associated with increased susceptibility to chicken pox, diarrhea, malaria, measles, pneumonia, respiratory syncytial virus, and HIV. Vitamin A deficiency compromises mucosal immunity, causing epithelial changes, decreased goblet cells, and decreased secretory IgA, as well as alterations in the number of CD4 cells. Acute phase response may cause abnormal urinary loss of vitamin A, thus decreasing serum levels. Acute infectious disease appears to reduce vitamin A levels. Low serum levels of serum vitamin A (whether resulting from acute phase response or insufficient hepatic stores) are associated with decreased survival in adults with HIV, measles, respiratory syncytial virus infection, and meningococcal disease. In addition, vitamin A deficiency is associated with increased maternal-fetal transmission of HIV (2).
- Other effects
- Vitamin A deficiency can cause stunting and wasting in children, decreased fertility (in males and females), chorioamnionitis, low birthweight, anemia, and increased plasma thyroxine concentrations (without symptoms of hyperthyroidism).
Risk Factors For Deficiency
- Alcoholism, poor nutrition, cystic fibrosis, pancreatic disease, and infectious disease.
Factors Decreasing Availability/Absorption
- Gastrointestinal malabsorption, gastrectomy/gastrotomy, cholestyramine, colestipol, and mineral oil
Factors Increasing Availability/Absorption
- Hepatic disease, chronic renal failure
Laboratory Tests
- Deficiency serum retinol level: < 0.35 µmol/L
- Marginal: 0.35 to 0.7µmol/L
- Adequate: 0.7 to 3.0 µmol/L
- Excessive: > 3.0 µmol/L (5)
- Other tests include dark adaptation or conjunctival impression cytology (both of which measure end-organ effects) or relative or modified relative dose response (which are indirect measures of hepatic vitamin A stores). Serum vitamin A concentrations greater than 1.4 µmol/L predicts normal dark adaptation 95% of the time (6).
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(See Also Carotenoids)
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Recommended Dietary Allowance (in Retinol Activity Equivalents) (7)
| Infants and Children |
| 0 to 6 months | 400 µg/day (adequate intake) |
| 7 to 12 months | 500 µg/day (adequate intake) |
| 1 to 3 years | 300 µg/day |
| 4 to 8 years | 400 µg/day |
| Males |
| 9 to 13 years | 600 µg/day |
| 14 to 50 years | 900 µg/day |
| 51+ years | 900 µg/day |
| Females |
| 9 to 13 years | 600 µg/day |
| 14 to 50 years | 700 µg/day |
| 51+ years | 700 µg/day |
| Pregnant |
| <=18 years | 750 µg/day |
| 19 to 50 years | 770 µg/day |
| Lactating |
| <=18 years | 1,200 µg/day |
| 19 to 50 years | 1,300 µg/day |
Upper Limits
| Infants and Children |
| 0 to 6 months | 600 µg/day |
| 7 to 12 months | 600 µg/day |
| 1 to 3 years | 600 µg/day |
| 4 to 8 years | 900 µg/day |
| Males |
| 9 to 13 years | 1,700 µg/day |
| 14 to 18 years | 2,800 µg/day |
| 19 to 50 years | 3,000 µg/day |
| 51+ years | 3,000 µg/day |
| Females |
| 9 to 13 years | 1,700 µg/day |
| 14 to 18 years | 2,800 µg/day |
| 19 to 50 years | 3,000 µg/day |
| 51+ years | 3,000 µg/day |
| Pregnant |
| <=18 years | 2,800 µg/day |
| 19 to 50 years | 3,000 µg/day |
| Lactating |
| <=18 years | 2,800 µg/day |
| 19 to 50 years | 3,000 µg/day |
| One retinol activity equivalent (RAE) |
= 1 µg all-trans retinol |
= 12 µg all-trans- -carotene |
= 24 µg other provitamin A carotenoids |
| One IU Vitamin A activity |
= 0.3 µg all-trans retinol |
= 3.6 µg all-trans--carotene |
= 7.2 µg other provitamin A carotenoids |
- Correcting deficiency: Deficiency can generally be corrected by giving 30,000 IUs or more of retinol daily (with some dietary fat) for several days.
- In children older than 1 year, World Health Organization (WHO) recommends that vitamin A deficiency should be treated with 110 mg retinol palmitate p.o. (or 55 mg i.m.) plus two additional doses of 110 mg p.o. over the next week.
- A prophylactic regimen used for children 1 to 6 years in developing countries is a single capsule containing 200,000 IUs of vitamin A every 3 to 6 months (2).
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Q: What dose of vitamin A is teratogenic in pregnancy?
A: It is not clear. Case-control studies and cohort studies have linked high doses of vitamin A with congenital malformations. However, a large prospective study conducted by the European Network of Teratology Information Services of 423 pregnancies exposed during the first 9 weeks of gestation to vitamin A greater than 10,000 IU/day found no association of high vitamin A intake during the organogenetic period with malformations (8). Daily doses greater than 25,000 IU may be teratogenic, 5,000 IU/day is not associated with teratogenicity, and there are insufficient data available to determine whether or not doses between 5,000 IU and 25,000 IUs are teratogenic. There is no reason to supplement with more than 5,000 IU during pregnancy and that dose seems to be safe.
Q: Is it true that although vitamin A is toxic, beta-carotene is not?
A: Vitamin A is stored in the liver; although a small amount of carotenoids are stored in the liver, most are stored in fat tissue. Although it has long been thought that the body is not capable of converting enough beta-carotene (or other carotenoids) to reach toxic amounts of vitamin A, recent studies showed swollen mitochondria in the livers of animals fed alcohol in combination with beta-carotene. This may be an interaction effect.
There are other problems with beta-carotene. Two supplementation trials found that beta-carotene was associated with a higher rate of lung cancer in smokers and asbestos-exposed workers. This may be due to displacement of other carotenoids by beta-carotene. Smoke and beta-carotene may be a particularly bad combination. Experiments with ferrets found far lower levels of beta-carotene in the blood of smoke-exposed ferrets (whether or not they were beta-carotene supplemented); lower levels were correlated with increased breakdown of beta-carotene into eccentric cleavage oxidation products (6). Necropsy showed alveolar cell proliferation and squamous metaplasia in ferrets supplemented with beta-carotene and exposed to smoke.
Excess dietary or supplemental -carotene (usually more than 30 mg beta-carotene/day over an extended period) can cause hypercarotenemia and carotenodermia, a yellowish tint to the skin most easily seen on the palms and soles (-carotene is stored in adipocytes). Carotenodermia may be distinguished from jaundice because it does not involve sclerae or nails.
Q: Is it possible to overdose on vitamin A from dietary sources?
A: There is no need to worry about this in a normal diet; it is theoretically possible if someone is subsisting solely on liver. We were taught in medical school that polar bear liver contains toxic amounts of vitamin A. Although this is true (polar bear liver contains 2 million IUs vitamin A/100 g), this hardly constitutes a public health problem.
Q: Can vitamin A derivatives cause toxicity?
A: Yes. Oral forms of vitamin A derivatives such as isotretinoin (13-cis retinoic acid), tretinoin (all-trans retinoic acid), or etretinate are used to treat acne and psoriasis; isotretinoin, which is not stored, is also used to treat certain epithelial cell cancers. Although generally safer than megadoses of vitamin A, these derivatives are teratogenic and long-term oral intake can result in typical retinoid toxicity.
Topical derivatives have been used to treat acne and wrinkles; far less toxic than oral dosage forms, the main side effects with topical preparations are photosensitivity, erythema, and desquamation.