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Vitamin A

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Last Update: October 27, 2018.

Indications

Vitamin A is a general term that encompasses various fat-soluble substances such as retinol, retinyl palmitate, and beta-carotene. Its various metabolites are essential for vision, cellular differentiation, epithelial barrier function, and immune function.

Vitamin A is obtained through diet in two forms. Preformed vitamin A (retinol and retinyl ester) is derived from animal sources such as meat, dairy products, and fish. Provitamin A (beta-carotenoid) is derived from colorful fruits and vegetables. Both ingested forms of vitamin A must be converted to retinal and retinoic acid after absorption to support biologic processes.

Deprivation of vitamin A replaces normal epithelium with stratified, keratinizing epithelium in the eyes, periocular glands, respiratory tract, alimentary tract, and genitourinary tract. Excess vitamin A results in acute and chronic deleterious effects on health. Vitamin A deficiency is far more prevalent worldwide than vitamin A toxicity. The World Health Organization (WHO) estimates that 3 million children develop clinical vitamin A deficiency annually compared to an estimated 200 cases of vitamin A toxicity diagnosed annually.

Globally, vitamin A deficiency is an important public health problem. Supplementation is considered a key intervention to greatly reducing the rate of child morbidity and mortality due to preventable diseases in countries with high under-five mortality. It is recognized as one of the most cost-effective interventions to improve childhood survival rates.

Vitamin A supplementation is offered for treatment of measles, xerophthalmia, severe malnutrition, and to prevent deficiency in pregnant women living in areas endemic to vitamin A deficiency. Treatment of xerophthalmia is of special interest because it is one of the only diseases due to vitamin deficiency to reach epidemic levels. Its response to vitamin A supplementation to the eye has been well established and can prevent night blindness, a major problem in developing countries.

Vitamin A's involvement in cell morphogenesis, differentiation, and proliferation is essential to gene regulation. Additionally, its function as an antioxidant decreases free radical damage to DNA. A deficiency in vitamin A is believed to play a role in neoplastic transformation and carcinogenesis.

Studies thus far have not revealed sufficient data to indicate a strong correlation between vitamin A and cancer prevention in all populations. Supplementation in vitamin A sufficient populations have not suggested any added benefit for cancer prevention. However, supplementation in vitamin A deficient populations, such as malnourished or tobacco-dependent groups, may reduce the incidence of cancer. 

Vitamin A also modulates a broad range of immune processes. It is involved in helper T cell and B cell development, thereby important for adaptive immunity. Its contribution to mucosal epithelial regeneration and neutrophil, macrophage, and natural killer cell functioning label it important for innate immunity, as well. Vitamin A deficiency and infectious diseases that transiently suppress serum retinol concentrations impair normal immune function. In particular, vitamin A deficiency is recognized as a risk factor for the measles virus, a major cause of childhood morbidity and mortality. Megadoses (200,000 IU for two days) of vitamin A has been shown to lower the overall incidence of death related to measles.

Mechanism of Action

In the liver, retinol is esterified to retinyl esters and stored in the stellate cells. In the tissues, both retinol and beta-carotene are oxidized to retinal and retinoic acid, which are essential for vision and gene regulation, respectively. These active metabolites bind nuclear receptors of the RAR family to control gene expression.

Administration

Vitamin A supplementation may be administered orally or intramuscularly. Absorption of oral vitamin A enhanced by a fatty meal due to its lipophilic nature.

Adverse Effects

Excess natural or synthetic vitamin A levels may result in a wide array of adverse effects. Vitamin A toxicity, also known as hypervitaminosis A, is more commonly associated with abuse of vitamin A supplements than with health intervention programs. Toxic reactions may also be provoked by consuming liver products rich in vitamin A or excess administration of vitamin A preparations. The amount of vitamin A required to cause toxicity among individuals varies depending on age and hepatic function.

Acute vitamin A toxicity may occur with a single ingestion of 25,000 IU/kg or more. Signs and symptoms include nausea, vomiting, diarrhea, dizziness, lethargy, drowsiness, increased intracranial pressure, and skin changes such as erythema, pruritus, or desquamation.

Chronic vitamin A toxicity may occur with excessive ingestion of 4000 IU/kg or more daily for 6-15 months. Signs and symptoms include low-grade fever, headache, fatigue, anorexia, intestinal disturbances, hepatosplenomegaly, anemia, hypercalcemia, subcutaneous swelling, nocturia, joint and bone pain, and skin changes such as yellowing, dryness, alopecia, and photosensitivity.

Vitamin A is highly teratogenic if taken during pregnancy. Retinoids affect the expression of homeobox gene Hoxb-1, which regulates axial patterning of the embryo. Birth abnormalities include craniofacial, cardiac, and central nervous system malformations. Therefore, treatment with vitamin A should be avoided in pregnant patients except in areas where vitamin A deficiency is prevalent. In this circumstance, supplementation should not exceed 10,000 IU daily.

Of note, mild adverse effects have been observed with vitamin A given with immunization. Symptoms include loose stools, headache, irritability, fever, nausea, and vomiting. These side effects are rare and typically resolved within 24 to 48 hours.

Contraindications

Vitamin A is contraindicated in pregnancy, breastfeeding patients, and patients with hypersensitivity to this class of drugs. It should be prescribed with caution to patients with hepatic disease, renal disease, alcoholism, and acne vulgaris.

Monitoring

Isotretinoin is an oral medication derived from vitamin A that is primarily used to treat severe acne. Its package insert recommends baseline lipid and hepatic panels followed by repeat testing weekly or biweekly until the response has been established. However, a recent meta-analysis demonstrated that increases in triglycerides or cholesterol levels typically occur within the first 8 weeks of therapy with minimal to no change after that. The data was not sufficient enough to conclude an early rise in liver function tests, although it was determined that elevated liver function values were rarely high risk. Based on these findings, evidence from the meta-analysis does not support monthly laboratory testing for standard doses of oral isotretinoin.

Toxicity

Symptoms of toxicity may resolve within several weeks after discontinuing vitamin A and instituting supportive therapy. Patients with increased intracranial pressure may require lumbar punctures or medications such as mannitol and diuretics for therapy. Patients with hypercalcemia may require intravenous fluids and additional therapy such as calcitonin and corticosteroids.

Congenital disabilities caused by vitamin A are irreversible.

Questions

To access free multiple choice questions on this topic, click here.

References

1.
Moise AR, Noy N, Palczewski K, Blaner WS. Delivery of retinoid-based therapies to target tissues. Biochemistry. 2007 Apr 17;46(15):4449-58. [PMC free article: PMC2562735] [PubMed: 17378589]
2.
Wolbach SB, Howe PR. TISSUE CHANGES FOLLOWING DEPRIVATION OF FAT-SOLUBLE A VITAMIN. J. Exp. Med. 1925 Nov 30;42(6):753-77. [PMC free article: PMC2131078] [PubMed: 19869087]
3.
Huiming Y, Chaomin W, Meng M. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001479. [PubMed: 16235283]
4.
Dawson MI. The importance of vitamin A in nutrition. Curr. Pharm. Des. 2000 Feb;6(3):311-25. [PubMed: 10637381]
5.
Challem JJ. Teratogenicity of high vitamin A intake. N. Engl. J. Med. 1996 May 02;334(18):1196-7. [PubMed: 8602194]
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Bookshelf ID: NBK482362PMID: 29493984

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