Continuing Education Activity

Vitamin A is a general term encompassing 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 the 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 biological processes. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of vitamin A so providers can direct patient therapy in treatment or supplementation where it is indicated as part of the interprofessional team.

Objectives:

• Identify the physiological role of vitamin A.
• Describe the potential adverse effects of vitamin A.
• Outline the signs and symptoms that accompany hypervitaminosis A toxicity.
• Summarize the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care with vitamin A to improve patient outcomes where vitamin A supplementation is indicated.

Indications

Vitamin A is a general term encompassing 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.[1]

Vitamin A is obtained through the 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 biological processes.[1]

Deprivation of vitamin A replaces normal epithelium with stratified, keratinizing epithelium in the eyes, periocular glands, respiratory tract, alimentary tract, and genitourinary tract.[2] 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.[3]

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 the 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 a vitamin deficiency to have reached 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.[4] A deficiency in vitamin A is believed to play a role in neoplastic transformation and carcinogenesis.[4]

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 has 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.[4]

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 make 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 have been shown to lower the overall incidence of death related to measles.[3]

Mechanism of Action

In the liver, retinol is esterified to retinyl esters and stored in the stellate cells. Both retinol and beta-carotene are oxidized to retinal and retinoic acid in the tissues, which are essential for vision and gene regulation, respectively. These active metabolites bind nuclear receptors of the RAR family to control gene expression.[1][5][6][7]

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.[1]

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 to 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 like yellowing, dryness, alopecia, and photosensitivity. 

Vitamin A is highly teratogenic if taken during pregnancy. Retinoids affect the expression of the homeobox gene Hoxb-1, which regulates the 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.[8]

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.[9]

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.[10]

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.[8]

Congenital disabilities caused by vitamin A are irreversible. 

Enhancing Healthcare Team Outcomes

Interprofessional healthcare team members, including clinicians, nurses, dieticians, and pharmacists, should know that empirical dispensing of vitamin A is not recommended.  Unless there is a deficiency, patients should not be encouraged to take excess amounts of this vitamin as it is known to cause toxicity. Instead, patients should be urged to eat a healthy diet rather than rely on supplements. All interprofessional team members need to share open access to patient information to prevent vitamin A toxicity and deficiency, recognize signs of both conditions, and intervene appropriately to attain the best patient outcomes. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

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;2005(4):CD001479. [PMC free article: PMC7076287] [PubMed: 16235283]

4.

Dawson MI. The importance of vitamin A in nutrition. Curr Pharm Des. 2000 Feb;6(3):311-25. [PubMed: 10637381]

5.

Kilby K, Mathias H, Boisvenue L, Heisler C, Jones JL. Micronutrient Absorption and Related Outcomes in People with Inflammatory Bowel Disease: A Review. Nutrients. 2019 Jun 20;11(6) [PMC free article: PMC6627381] [PubMed: 31226828]

6.

Meléndez-Martínez AJ. An Overview of Carotenoids, Apocarotenoids, and Vitamin A in Agro-Food, Nutrition, Health, and Disease. Mol Nutr Food Res. 2019 Aug;63(15):e1801045. [PubMed: 31189216]

7.

Elmadfa I, Meyer AL. The Role of the Status of Selected Micronutrients in Shaping the Immune Function. Endocr Metab Immune Disord Drug Targets. 2019;19(8):1100-1115. [PMC free article: PMC7360912] [PubMed: 31142256]

8.

Challem JJ. Teratogenicity of high vitamin A intake. N Engl J Med. 1996 May 02;334(18):1196-7. [PubMed: 8602194]

9.

Paulus WE. [Pharmacotherapy in pregnancy]. Ther Umsch. 1999 Oct;56(10):602-7. [PubMed: 10549233]

10.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Nov 10, 2020. Retinoids. [PMC free article: PMC547852] [PubMed: 31643883]

Disclosure: Emily McEldrew declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Lopez declares no relevant financial relationships with ineligible companies.

Disclosure: Harold Milstein declares no relevant financial relationships with ineligible companies.